Do pedometers increase activity and improve health outcomes?

Q: Do pedometers increase activity and improve health outcomes? Evidence-based answer: yes. In overweight and obese patients, exercise interventions using a pedometer increase steps by about a mile per day over the same interventions without access to pedometer information (strength of recommendation [SOR]: A, meta-analysis of randomized controlled trials [RCTs]) and are associated with a modest 4 mm Hg reduction in systolic blood pressure (BP) over baseline (SOR: B, meta-analysis of RCTs and cohort studies). In overweight patients with diabetes, pedometer use with nutritional counseling is associated with 0.86 kg greater weight loss than nutritional counseling alone (SOR: B, meta-analysis of lower quality RCTs). Pedometers increase activity in patients with various musculoskeletal conditions and may help reduce pain (SOR: B, meta-analysis of RCTs with heterogeneous outcomes). In low-activity elderly patients, pedometers do not appear to increase total activity when added to an exercise program, but they do appear to increase walking (SOR: B, RCT). There is no evidence concerning the impact of pedometers on cardiovascular outcomes

Separating the Wheat from the Chaff: The Use of Upstream Regulator Analysis to Identify True Differential Expression of Single Genes within Transcriptomic Datasets

The development of DNA microarray and RNA-sequencing technology has led to an explosion in the generation of transcriptomic differential expression data under a wide range of biologic systems including those recapitulating the monogenic muscular dystrophies. Data generation has increased exponentially due in large part to new platforms, improved cost-effectiveness, and processing speed. However, reproducibility and thus reliability of data remain a central issue, particularly when resource constraints limit experiments to single replicates. This was observed firsthand in a recent rare disease drug repurposing project involving RNA-seq-based transcriptomic profiling of primary cerebrocortical cultures incubated with clinic-ready blood–brain penetrant drugs. Given the low validation rates obtained for single differential expression genes, alternative approaches to identify with greater confidence genes that were truly differentially expressed in our dataset were explored. Here we outline a method for differential expression data analysis in the context of drug repurposing for rare diseases that incorporates the statistical rigour of the multigene analysis to bring greater predictive power in assessing individual gene modulation. Ingenuity Pathway Analysis upstream regulator analysis was applied to the differentially expressed genes from the Care4Rare Neuron Drug Screen transcriptomic database to identify three distinct signaling networks each perturbed by a different drug and involving a central upstream modulating protein: levothyroxine (DIO3), hydroxyurea (FOXM1), dexamethasone (PPARD). Differential expression of upstream regulator network related genes was next assessed in in vitro and in vivo systems by qPCR, revealing 5× and 10× increases in validation rates, respectively, when compared with our previous experience with individual genes in the dataset not associated with a network. The Ingenuity Pathway Analysis based gene prioritization may increase the predictive value of drug–gene interactions, especially in the context of assessing single-gene modulation in single-replicate experiments.Care4Rare Canada Consortium funded by Genome CanadaCanadian Institutes of Health ResearchOntario Genomics Institute (OGI-049)Ontario Research FundGenome QuebecGenome British ColumbiaCHEO Foundation (3 July 2014

The Corticostriatal System in Dissociated Cell Culture

The sparse connectivity within the striatum in vivo makes the investigation of individual corticostriatal synapses very difficult. Most studies of the corticostriatal input have been done using electrical stimulation under conditions where it is hard to identify the precise origin of the cortical input. We have employed an in vitro dissociated cell culture system that allows the identification of individual corticostriatal pairs and have been developing methods to study individual neuron inputs to striatal neurons. In mixed corticostriatal cultures, neurons had resting activity similar to the system in vivo. Up/down states were obvious and seemed to encompass the entire culture. Mixed cultures of cortical neurons from transgenic mice expressing green fluorescent protein with striatal neurons from wild-type mice of the same developmental stage allowed visual identification of individual candidate corticostriatal pairs. Recordings were performed between 12 and 37 days in vitro (DIV). To investigate synaptic connections we recorded from 69 corticostriatal pairs of which 44 were connected in one direction and 25 reciprocally. Of these connections 41 were corticostriatal (nine inhibitory) and 53 striatocortical (all inhibitory). The observed excitatory responses were of variable amplitude (−10 to −370 pA, n = 32). We found the connections very secure – with negligible failures on repeated stimulation (approximately 1 Hz) of the cortical neuron. Inhibitory corticostriatal responses were also observed (−13 to −314 pA, n = 9). Possibly due to the mixed type of culture we found an inhibitory striatocortical response (−14 to −598 pA, n = 53). We are now recording from neurons in separate compartments to more closely emulate neuroanatomical conditions but still with the possibility of the easier identification of the connectivity

Dewatering Well Assessment for the Highway Drainage System at Four Sites in the East St. Louis Area, Illinois (Phase 3)

published or submitted for publicationis peer reviewedOpe

The Physiological and Molecular Links Between Physical Activity and Brain Health: A Review

There is currently an epidemic of sedentary behavior throughout the world, leading to negative impacts on physical health and contributing to both mortality and burden of disease. The consequences of this also impact the brain, where increased levels of cognitive decline are observed in individuals who are more sedentary. This review explores the physiological and molecular responses to our sedentary propensity, its contribution to several medical conditions and cognitive deficits, and the benefits of moderate levels of physical activity and exercise. Also presented is the recommended level of activity for overall physical health improvement

Compounded topographical and physicochemical cueing by micro-engineered chitosan substrates on rat dorsal root ganglion neurons and human mesenchymal stem cells

Given the intertwined physicochemical effects exerted in vivo by both natural and synthetic (e.g., biomaterial) interfaces on adhering cells, the evaluation of structure-function relationships governing cellular response to micro-engineered surfaces for applications in neuronal tissue engineering requires the use of in vitro testing platforms which consist of a clinically translatable material with tunable physiochemical properties. In this work, we micro-engineered chitosan substrates with arrays of parallel channels with variable width (20 and 60 mu m). A citric acid (CA)-based crosslinking approach was used to provide an additional level of synergistic cueing on adhering cells by regulating the chitosan substrate's stiffness. Morphological and physicochemical characterization was conducted to unveil the structure-function relationships which govern the activity of rat dorsal root ganglion neurons (DRGs) and human mesenchymal stem cells (hMSCs), ultimately singling out the key role of microtopography, roughness and substrate's stiffness. While substrate's stiffness predominantly affected hMSC spreading, the modulation of the channels' design affected the neuronal architecture's complexity and guided the morphological transition of hMSCs. Finally, the combined analysis of tubulin expression and cell morphology allowed us to cast new light on the predominant role of the microtopography over substrate's stiffness in the process of hMSCs neurogenic differentiation

Achievement of insulin independence in three consecutive type-1 diabetic patients via pancreatic islet transplantation using islets isolated at a remote islet isolation center

As a result of advances in both immunosuppressive protocols and pancreatic islet isolation techniques, insulin independence has recently been achieved in several patients with type 1 diabetes mellitus via pancreatic islet transplantation (PIT). Although the dissemination of immunosuppressive protocols is quite easy, transferring the knowledge and expertise required to isolate a large number of quality human islets for transplantation is a far greater challenge. Therefore, in an attempt to centralize the critical islet processing needed for islet transplantation and to avoid the development of another islet processing center, we have established a collaborative islet transplant program between two geographically distant transplant centers. Three consecutive patients with type 1 diabetes mellitus with a history of severe hypoglycemia and metabolic instability underwent PIT at the Methodist Hospital (TMH), Houston, Texas, using pancreatic islets. All pancreatic islets were isolated from pancreata procured in Houston and subsequently transported for isolation to the Human Islet Cell Processing Facility of the Diabetes Research Institute (DRI) at the University of Miami, Miami, Florida. Pancreatic islets were isolated at DRI after enzymatic ductal perfusion (Liberase-HI) by the automated method (Ricordi Chamber) using endotoxin-free and xenoprotein-free media. After purification, the islets were immediately transported back to TMH and transplanted via percutaneous transhepatic portal embolization. Immunosuppression consisted of sirolimus, tacrolimus, and daclizumab. After donor cross-clamp in Houston, donor pancreata arrived at DRI and the isolation process began within 6.5 hr in all cases (median, 5.4 hr; range, 4.8-6.5 hr). At the completion of the isolation process, the islets were immediately transported back to TMH and transplanted. All three patients attained sustained insulin independence after transplantation of 395,567, 394,381, and 563,206 pancreatic islet equivalents (IEQ), respectively. Despite insulin independence, the first two patients received less than 10,000 IEQ/kg; therefore, to increase their functional pancreatic islet reserve, they underwent a second islet transplant with 326,720 and 768,132 IEQ, respectively. Posttransplantation follow-up for these three patients is 4, 3, and 0.5 months, respectively. The mean glycosylated hemoglobin values have been dramatically reduced in the first two patients. In addition, the mean amplitude of glycemic excursions have also been reduced in all three recipients (patient 1: before transplantation 197 mg/dL vs. after transplantation 61 mg/dL; patient 2: before transplantation 202 mg/dL vs. after transplantation 52 mg/dL; patient 3: before transplantation 245 mg/dL vs. after transplantation 58 mg/dL) after PIT. All pancreatic islet allografts demonstrated the ability to respond to an in vitro glucose stimulus at the DRI before shipment and at TMH after shipment and final processing with a median stimulation index of 2.1 and 2.2, respectively. None of the transplant recipients have had a hyper- or hypoglycemic episode since PIT and no complications have occurred. These early data demonstrate that (1) pancreatic islets remain viable after shipment to remote transplant sites; (2) pancreatic islet isolation techniques and experience can be concentrated at a small number of regional facilities that could supply islets to remote transplant centers; and (3) insulin independence via PIT can be achieved using a remote pancreatic islet isolation center