Delayed-release rapamycin halts progression of left ventricular hypertrophy in subclinical feline hypertrophic cardiomyopathy: results of the RAPACAT trial.

OBJECTIVE: Feline hypertrophic cardiomyopathy (HCM) remains a disease with little therapeutic advancement. Rapamycin modulates the mTOR pathway, preventing and reversing cardiac hypertrophy in rodent disease models. Its use in human renal allograft patients is associated with reduced cardiac wall thickness. We sought to evaluate the effects of once-weekly delayed-release (DR) rapamycin over 6 months on echocardiographic, biochemical, and biomarker responses in cats with subclinical, nonobstructive HCM. ANIMALS: 43 client-owned cats with subclinical HCM. METHODS: Cats enrolled in this double-blinded, multicentered, randomized, and placebo-controlled clinical trial were allocated to low- or high-dose DR rapamycin or placebo. Cats underwent physical examination, quality-of-life assessment, blood pressure, hematology, biochemistry, total T4, urinalysis, N-terminal pro-B-type natriuretic peptide, and cardiac troponin I at baseline and days 60, 120, and 180. Fructosamine was analyzed at screening and day 180. Echocardiograms were performed at all time points excluding day 120. Outcome variables were compared using a repeated measures ANCOVA. RESULTS: No demographic, echocardiographic, or clinicopathologic values were significantly different between study groups at baseline, confirming successful randomization. At day 180, the primary study outcome variable, maximum LV myocardial wall thickness at any location, was significantly lower in the low-dose DR rapamycin group compared to placebo (P = .01). Oral DR rapamycin was well tolerated with no significant differences in adverse events between groups. CLINICAL RELEVANCE: Results demonstrate that DR rapamycin was well tolerated and may prevent or delay progressive LV hypertrophy in cats with subclinical HCM. Additional studies are warranted to confirm and further characterize these results.

Case Report: Successful Reperfusion of Pulmonary Thromboembolism Using tPA in a Cat.

Pulmonary thromboembolism is a potentially life threatening condition that is uncommonly recognized in cats. Thrombolytic agents have been described as a treatment for this condition in human and canine patients, particularly in cases where hemodynamic instability is persistent despite supportive care. This report describes the clinical course, echocardiographic diagnosis, and successful thrombolysis of a cat with pulmonary thromboembolism. Despite confirmed reperfusion, the cat succumbed to thromboembolic disease highlighting the dearth of knowledge about optimal treatment of this disease process in small animals, particularly in cats.

Setting an agenda to catalyze research in the social and organizational dimensions of Great Lakes remediation, restoration, and revitalization.

The Great Lakes region was once a hub of industry and innovation that provided wealth and identity to the region. Economic upheavals have left the region trying to recreate economies and cleanup degraded environments. There have been multiple, overlapping efforts to change these conditions and create a new narrative for the region through environmental remediation, habitat restoration, and community revitalization on the path towards resilience. The elements that contribute to success are organized differently in different places, and are not always identified or characterized in the environmental literature. Trying to fill this conceptual gap is critical because landscape-scale environmental cleanup has been delivered at the local scale through various partnerships and arrangements. Thus, this special collection of articles in the Journal of Great Lakes Research explores how individuals, organizations, and communities are engaging in the complex process of environmental cleanup and revitalization throughout the region. This collection of articles represents a range of approaches to unpack how people are navigating and contributing to this regenerative process from quantitative studies at the regional scale that characterize global patterns to in-depth qualitative studies that identify and characterize the processes that unfold in specific places to change our environments both ecologically and socially. These articles represent the broad experience unfolding in the region to understand these activities through research and navigate them through practice. This collection will add new dimensions to Great Lakes research by including the individuals, organizations, and agencies as components of the ecosystem.

Identification and characterisation of peptides from a boarfish (Capros aper) protein hydrolysate displaying in vitro dipeptidyl peptidase-IV (DPP-IV) inhibitory and insulinotropic activity.

Twenty-two novel dipeptidyl peptidase-IV (DPP-IV) inhibitory peptides (with IC50 values <200 µM) and fifteen novel insulinotropic peptides were identified in a boarfish protein hydrolysate generated at semi-pilot scale using Alcalase 2.4L and Flavourzyme 500L. This was achieved by bioassay-driven semi-preparative reverse phase-high performance liquid chromatography fractionation, liquid chromatography-mass spectrometry and confirmatory studies with synthetic peptides. The most potent DPP-IV inhibitory peptide (IPVDM) had a DPP-IV half maximal inhibitory concentration (IC50) value of 21.72 ±â€¯1.08 µM in a conventional in vitro and 44.26 ±â€¯0.65 µM in an in situ cell-based (Caco-2) DPP-IV inhibition assay. Furthermore, this peptide stimulated potent insulin secretory activity (1.6-fold increase compared to control) from pancreatic BRIN-BD11 cells grown in culture. The tripeptide IPV exhibited potent DPP-IV inhibitory activity (IC50: 5.61 ±â€¯0.20 µM) comparable to that reported for the known DPP-IV inhibitor IPI (IC50: 3.20 µM). Boarfish proteins contain peptide sequences with potential to play a role in glycaemic management in vivo.

Effects of Liraglutide and Fenretinide treatments on the diabetic phenotype of neuronal human BACE1 knock-in mice.

We recently reported that brain-specific human ß-secretase 1 (BACE1) knock-in (PLB4), a mouse model of sporadic Alzheimer's disease (AD), also develops a severe diabetic phenotype characterised by impaired glucose homeostasis, decreased insulin sensitivity and a fatty liver phenotype. Hence, we here aimed to assess if targeted anti-diabetic therapies (Liraglutide and Fenretinide) would attenuate the diabetic and behavioural phenotype of these mice. PLB4 mice and wild-type (WT) controls were administered Liraglutide or Fenretinide for ten consecutive weeks alongside vehicle-treated mice. Physiological (body weight and mass composition, glucose tolerance, serum hormone concentration), behavioural (locomotor activity) and molecular assessments were performed in mice pre- and post-treatment. Liraglutide and Fenretinide treatments inhibited adiposity gain and decreased circulating serum triglyceride (with Liraglutide) and leptin (with Fenretinide) levels in PLB4 mice. We also found that PLB4 mice exhibited increased levels of serum dipeptidyl peptidase 4 (DPP4), together with up-regulated hepatic expression of Dpp4, retinol binding protein 4 (Rbp4) and sterol regulatory element-binding 1c (Srebp1c), which was normalised by both treatments. Interestingly, Liraglutide treatment slowed down habituation to a novel environment and increased secondary night activity peak in WT mice, suggesting an impact on circadian activity regulation. However, neither treatment improved glucose homeostasis in PLB4 mice, implying that impaired glucose metabolism in this genotype may not be associated with glucagon like peptide 1 (GLP-1) and/or RBP4-mediated pathways. In summary, this study provides new insights into molecular mechanisms underlying neuronal BACE1-mediated metabolic regulation and implicates BACE1 as a putative regulator of systemic DPP4 levels.

Zeolites ameliorate asbestos toxicity in a transgenic model of malignant mesothelioma.

Malignant mesothelioma (MM) is an almost invariably fatal cancer caused by asbestos exposure. The toxicity of asbestos fibers is related to their physicochemical properties and the generation of free radicals. We set up a pilot study to investigate the potential of the zeolite clinoptilolite to counteract the asbestos carcinogenesis by preventing the generation of reactive nitrogen and oxygen radicals. In cell culture experiments, clinoptilolite prevented asbestos-induced cell death, reactive oxygen species production, DNA degradation, and overexpression of genes known to be up-regulated by asbestos. In an asbestos-induced transgenic mouse model of MM, mice were injected intraperitoneal injections with blue asbestos, with or without clinoptilolite, and monitored for 30 weeks. By the end of the trial all 13 mice injected with asbestos alone had reached humane end points, whereas only 7 of 29 mice receiving crocidolite and clinoptilolite reached a similar stage of disease. Post-mortem examination revealed pinpoint mesothelioma-like tumors in affected mice, and the absence of tumor formation in surviving mice. Interestingly, the macrophage clearance system, which was largely suppressed in asbestos-treated mice, exhibited evidence of increased phagocytosis in mice treated with asbestos and clinoptilolite. Our study suggests that inhibiting the asbestos-induced generation of reactive oxygen species and stimulating the macrophage system may represent a pathway to amelioration of asbestos-induced toxicity. Additional studies are warranted to explore the underlying mechanisms responsible for our observations.

Zeolite protects mice from iron-induced damage in a mouse model trial.

For centuries, zeolites have been used for their utility in binding metals, and they feature in a multitude of agricultural and industrial applications in which the honeycombed zeolite structures form ideal ion exchangers, catalysts and binding agents. Zeolites are currently in a transition period, moving towards implementation in human ailments and diseases. Here, we postulated that zeolites may be able to counter the effects of excess iron and conducted a mouse model trial to gauge the utility of this notion. We used the transgenic mouse strain MexTAg299 for a thirty-week pilot trial in which iron polymaltose and/or the zeolite clinoptilolite was injected into the peritoneum twice weekly. Mice were sacrificed at the end of the trial period and examined by postmortem and histology for significant physiological differences between mouse subgroups. In this study, we demonstrated that a common zeolite, clinoptilolite, is able to maintain the general health and well-being of mice and prevent iron-induced deleterious effects following iron overload. When zeolites are given with iron biweekly as intraperitoneal injections, mice showed far less macroscopic visual organ discoloration, along with near normal histology, under iron overload conditions when compared to mice injected with iron only. The purpose of the present pilot study was to examine potential alternatives to current iron chelation treatments, and the results indicate an advantage to using zeolites in conditions of iron excess. Zeolites may have translational potential for use in cases of human iron overload.

Atlantic salmon (Salmo salar) co-product-derived protein hydrolysates: A source of antidiabetic peptides.

Large quantities of low-value protein rich co-products, such as salmon skin and trimmings, are generated annually. These co-products can be upgraded to high-value functional ingredients. The aim of this study was to assess the antidiabetic potential of salmon skin gelatin and trimmings-derived protein hydrolysates in vitro. The gelatin hydrolysate generated with Alcalase 2.4L and Flavourzyme 500L exhibited significantly higher (p < 0.001) insulin and GLP-1 secretory activity from pancreatic BRIN-BD11 and enteroendocrine GLUTag cells, respectively, when tested at 2.5 mg/mL compared to hydrolysates generated with Alcalase 2.4L or Promod 144MG. The gelatin hydrolysate generated with Alcalase 2.4L and Flavourzyme 500L showed significantly more potent (p < 0.01) DPP-IV inhibitory activity than those generated with Alcalase 2.4L or Promod 144MG. No significant difference was observed in the insulinotropic activity mediated by any of the trimmings-derived hydrolysates when tested at 2.5 mg/mL. However, the trimmings hydrolysate generated with Alcalase 2.4L and Flavourzyme 500L exhibited significantly higher DPP-IV inhibitory (p < 0.05:Alcalase 2.4L and p < 0.01:Promod 144MG) and GLP-1 (p < 0.001, 2.5 mg/mL) secretory activity than those generated with Alcalase 2.4L or Promod 144MG. The salmon trimmings hydrolysate generated with Alcalase 2.4L and Flavourzyme 500L when subjected to simulated gastrointestinal digestion (SGID) was shown to retain its GLP-1 secretory and DPP-IV inhibitory activities, in addition to improving its insulin secretory activity. However, the gelatin hydrolysate generated with Alcalase 2.4L and Flavourzyme 500L was shown to lose GLP-1 secretory activity following SGID. A significant increase in membrane potential (p < 0.001) and intracellular calcium (p < 0.001) by both co-product hydrolysates generated with Alcalase 2.4L and Flavourzyme 500L suggest that both hydrolysates mediate their insulinotropic activity through the KATP channel-dependent pathway. Additionally, by stimulating a significant increase in intracellular cAMP release (p < 0.05) it is likely that the trimmings-derived hydrolysate may also mediate insulin secretion through the protein kinase A pathway. The results presented herein demonstrate that salmon co-product hydrolysates exhibit promising in vitro antidiabetic activity.

SFRP Tumour Suppressor Genes Are Potential Plasma-Based Epigenetic Biomarkers for Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is associated with asbestos exposure. Asbestos can induce chronic inflammation which in turn can lead to silencing of tumour suppressor genes. Wnt signaling pathway can be affected by chronic inflammation and is aberrantly activated in many cancers including colon and MPM. SFRP genes are antagonists of Wnt pathway, and SFRPs are potential tumour suppressors in colon, gastric, breast, ovarian, and lung cancers and mesothelioma. This study investigated the expression and DNA methylation of SFRP genes in MPM cells lines with and without demethylation treatment. Sixty-six patient FFPE samples were analysed and have showed methylation of SFRP2 (56%) and SFRP5 (70%) in MPM. SFRP2 and SFRP5 tumour-suppressive activity in eleven MPM lines was confirmed, and long-term asbestos exposure led to reduced expression of the SFRP1 and SFRP2 genes in the mesothelium (MeT-5A) via epigenetic alterations. Finally, DNA methylation of SFRPs is detectable in MPM patient plasma samples, with methylated SFRP2 and SFRP5 showing a tendency towards greater abundance in patients. These data suggested that SFRP genes have tumour-suppresive activity in MPM and that methylated DNA from SFRP gene promoters has the potential to serve as a biomarker for MPM patient plasma.

An appraisal of management pathologies in the Great Lakes.

Recent research has produced broad application of the health concept to regional ecosystems, including the Great Lakes. The attention is warranted, as new and recurring stresses on the health of the Great Lakes undermine our understanding and hinder our ability to manage and restore critical ecological functions. There is widespread agreement that the Great Lakes are presently exhibiting symptoms of extreme stress and potentially irreversible and catastrophic damage. Historical command and control management has resulted simultaneously in environmental benefits to people and a loss of resilience in Great Lakes ecosystems. Surprising system responses often prompt further control, and the continued decline in resilience has been called the pathology of natural resource management. The pathology is also suggested to affect human systems of organization such as management authorities. We use published criteria of institutional pathologies and illustrate their occurrence in the Great Lakes with evidence of non-existent program evaluation, program incompatibility, lack of coordination among programs, authorities that establish and then abandon public participatory initiatives, and inappropriate choice of policy mechanisms or inadequate level of support for an appropriate mechanism (either of which creates disincentives for stakeholders). Learning is an element of resilience, as managed systems are inherently dynamic and our understanding is therefore always incomplete. Policy mechanisms that mimic learning techniques to improve understanding are therefore central to avoiding pathologies in management. But learning (individually or institutionally) can be threatening and very difficult, and its proper conduct necessarily involves a continuous process of feedback, interpretation, and reformulation. Double-loop learning processes that institutionalize learning in policy are recommended, as these will be required to overcome pathologies in management and maintain resilience of the Great Lakes system.

The distribution of outcomes research papers across clinical journals.

This study examines the distribution of health outcomes research (HOR) studies in the clinical literature by clinical areas and journal impact factor. The authors reviewed 535 journals and divided the sample into higher and lower impact journals across four clinical area. Mann-Whitney and Kruskal-Wallis tests were used to examine differences across four categories of outcomes research articles published, specifically the incidence of articles in higher versus lower impact journals and differences across clinical areas. All high-impact journals published more safety and quality articles than process assessment, quality of life, or cost analysis studies. The number of each type of outcomes research study published was highly variable across all clinical areas. Only arthritis and outcomes research journals showed statistically significant differences between higher versus lower impact journals. Authors may benefit from considering these differences in their clinical specialty area when deciding where to submit HOR studies.

Age-related changes in attentional tracking of multiple moving objects.

In a multiple-object tracking (MOT) task, young and older adults attentively tracked a subset of 10 identical, randomly moving disks for several seconds, and then tried to identify those disks that had comprised the subset. Young adults who habitually played video games performed significantly better than those who did not. Compared to young subjects (mean age = 20.6 years) with whom they were matched for video game experience, older subjects (mean age = 75.3 years) showed much reduced ability to track multiple moving objects, particularly with faster movement or longer tracking times. Control measurements with stationary disks show that the age-related decline in MOT was not caused by a general change in memory per se. To generate an item-wise performance measure, we examined older subjects' proportion correct according to the serial order in which individual disks were identified. Correct identification of target disks declined with the order in which targets were reported, suggesting that attentional tracking produced graded, rather than all-or-none, outcomes.

Recognition and position information in working memory for visual textures.

In three experiments, we examined connections between item-recognition memory and memory for item-position information. With sequences of compound gratings as study and probe items, subjects made either item-position judgments (Experiments 1 and 2), by identifying the serial position of the study item that matched the probe, or recognition judgments (Experiment 3), by judging whether the probe had or had not been presented in the study series. Integrating a summed-similarity account of recognition into a signal detection framework shows that the variance of summed similarities on lure trials (probe not present in the study series) exceeds the variance on target trials (probe present in the study series). This prediction is borne out by the empirical zROC functions, all of which had slopes that were greater than 1. Additionally, about 25% of correct recognitions were accompanied by incorrect item position identification. Misidentifications of item position arose from two sources--structural similarity and positional similarity-which combined in an approximately additive fashion.

Fifteen years of aligning faculty development with primary care clinician-educator roles and academic advancement at the Medical College of Wisconsin.

Starting in 1991, the Medical College of Wisconsin's (MCW) primary care-focused faculty development programs have continuously evolved in order to sustain tight alignment among faculty members' needs, institutional priorities, and academic reward structures. Informed by literature on the essential competencies associated with academic success and using educational methods demonstrated to achieve targeted objectives, MCW's initial 1.5-day per month comprehensive faculty development programs prepared faculty as clinician-researchers, leaders, and educators. As institutional priorities and faculty roles shifted, a half-day per month advanced education program was added, and the comprehensive faculty development program transitioned to its current half-day per month program. Using a modular approach, this program focuses exclusively on clinician-educator competencies in curriculum, teaching, leadership, evaluation, and learner assessment. Instructional methods combine interactive, face-to-face sessions modeling a range of instructional strategies with between-session assignments now supported through an e-learning platform. All participants complete a required project, which addresses a divisional or departmental need, meets standards associated with scholarship, and is submitted to a peer-reviewed forum. To date, over 115 faculty members have enrolled in MCW's faculty development programs. Program evaluation over the 15-year span has served to guide program revision and to provide clear evidence of program impact. A longitudinal evaluation of comprehensive program graduates from 1993 to 1999 showed that 88% of graduates' educational projects were implemented and sustained more than one year after program completion. Since 2001, each participant, on average, attributes more than two peer-reviewed presentations and one peer-reviewed publication to program participation. Based on 15 years of evaluation data, five tenets associated with program success are outlined.

Short-term visual recognition and temporal order memory are both well-preserved in aging.

Increased difficulty with memory for recent events is a well-documented consequence of normal aging, but not all aspects of memory are equally affected. To compare the impact of aging on short-term recognition and temporal order memory, young and older adults were asked to identify the serial position that a probe item had occupied in a study set, or to judge that the probe was novel (had not been in the study set). Stimuli were compound sinusoidal gratings, which resist verbal description and rehearsal. With retention intervals of 1 or 4 seconds, young and older adults produced highly similar overall performance, serial position curves, and proportions of trials on which a correct recognition response was accompanied by an incorrect temporal order judgment. Temporal order errors, which occurred on about one quarter of trials, were traced to two factors: perceptual similarity between the wrongly identified study item and the correct item, and temporal similarity between the wrongly identified item and the correct one. Our results show that short-term visual temporal order memory is well-preserved in normal aging, and when temporal order errors do occur, they arise from similar causes for young and older people.

Preservation of episodic visual recognition memory in aging.

Visual episodic recognition memory was assessed in young (mean age 22.5 years) and older (mean age 74.1 years) adults. To isolate purely visual memory, recognition was tested with sets of briefly-presented compound sinusoidal gratings, which minimized age-related differences in visual processing, and resisted verbal encoding. Recognition was measured after delays of 1, 2 or 4 seconds. Overall, neither accuracy of recognition nor speed of response differed significantly between groups, or with probe delay, which strengthens recent claims that visual memory tends to be spared during the course of normal aging.