Examining the association between balance self-efficacy and virtual balance performance in individuals with stroke: a cross-sectional study.

BACKGROUND: Balance self-efficacy is a strong predictor of fall risk after stroke and is related to performance on balance and walking tests. The use of telerehabilitation for delivering stroke rehabilitation has increased in recent years and there is a need to adapt common clinical assessments to be administered in virtual formats, but the association between balance self-efficacy and virtually administered clinical tests of balance performance has yet to be established. This study examined the association between the Activities-specific Balance Confidence (ABC) Scale and virtually administered Timed Up and Go (TUG), Tandem Stand, and Functional Reach tests (FRT) in individuals with stroke. METHODS: This was a secondary analysis of baseline data from two telerehabilitation trials with individuals with stroke. All assessments were administered by trained physical therapists through videoconferencing software. Multivariate regression analyses were used to examine the associations between the ABC scale and TUG test, Tandem Stand test, and FRT, adjusted for age and number of comorbidities. RESULTS: Data from 51 participants (n = 11 female, median age = 64 [IQR: 18] years, 9.3 ± 4.6 months poststroke) were analyzed. The ABC scores were associated with TUG (R2 = 0.56, F(3,47) = 20.26, p < 0.01), but not Tandem Stand (R2 = 0.18, F(5,45) = 1.93, p = 0.11) or FRT (R2 = 0.14, F(3,47) = 2.55, p = 0.07) tests. CONCLUSION: We observed associations between the ABC scores and virtual TUG, but not with Tandem Stand or FRT, which may be attributed to the context-specificity of balance self-efficacy. As virtual administration of outcomes assessments becomes part of common practice in stroke rehabilitation, our study supports the use of virtually administered TUG in stroke.

Optimal resistance exercise training parameters for stroke recovery: A protocol for a systematic review.

BACKGROUND: Stroke impacts nearly 14 million people annually. Muscle strength and physical function are often affected by stroke and important determinants of stroke recovery. Resistance exercise training (RT) has been shown to improve muscle strength, but RT prescriptions may be suboptimal for other aspects of stroke recovery. Parameters such as frequency, intensity, type, and duration may influence the effectiveness of RT interventions but have not been systematically evaluated. OBJECTIVES: 1) To determine the effects of RT on stroke recovery, and 2) to examine the influence of RT parameters on intervention effects. ELIGIBILITY CRITERIA: Randomized controlled trials examining the effects of RT will be eligible for this systematic review if they: 1) included only adults with stroke or transient ischemic attack, 2) compared RT to no exercise or usual care, and 3) did not apply a co-intervention. STUDY SELECTION: Eight databases (MEDLINE, EMBASE, EMCARE, AMED, PsychINFO, CINAHL, SPORTDiscus, and Web of Science) and 2 clinical trials registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform) will be searched from inception. Two independent pairs of authors will compare titles, abstracts, and full-text reports against the eligibility criteria. Conflicts will be resolved by consensus or third author. MAIN OUTCOME MEASURES: The construct of interest is stroke recovery. An advisory group of clinicians, researchers, and partners with lived experience of stroke will be consulted to determine specific outcome measures of interest, and to rank their relative importance. We expect to include measures of physical function, strength, cognition, and quality of life. Random-effects meta-analyses will be used to pool results for each outcome across studies, and RT parameters (frequency, intensity, type, and duration) will be used as covariates in meta-regression analyses. CONCLUSION: The results of this review will inform the optimal RT prescription parameters for promoting stroke recovery.

Potassium channel modulators and schizophrenia: an overview of investigational drugs.

INTRODUCTION: Schizophrenia is a severe mental illness comprising positive, negative, and cognitive symptoms. Existing pharmacologic options exert their actions on the dopamine receptor but are largely ineffective at treating negative and cognitive symptoms. Alternative pharmacologic options that do not act directly on the dopamine receptor are being investigated, including potassium channel modulators. It has been hypothesized that dysfunctional fast-spiking parvalbumin-positive GABA interneurons, regulated by Kv3.1 and Kv3.2 potassium channels, contribute to the symptoms of schizophrenia, making potassium channels an area of clinical interest. AREAS COVERED: This review will highlight potassium channel modulators for the treatment of schizophrenia, with a focus on AUT00206. Background on Kv3.1 and Kv3.2 potassium channels will be explored. Our search strategy included a literature review utilizing PubMed, Clinicaltrials.gov, and sources available on the manufacturer's website. EXPERT OPINION: Initial data on potassium channel modulators is promising; however, further study is needed, and existing evidence is limited. Early data suggests that dysfunctional GABA interneurons can be ameliorated through modulators of Kv3.1 and Kv3.2 channels. AUT00206 has been shown to improve dopaminergic dysfunction induced by ketamine and PCP, improve resting gamma power in patients with schizophrenia, impact dopamine synthesis capacity in a subgroup of individuals with schizophrenia, and affect reward anticipation-related neural activation.

SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer's Disease.

Alzheimer's disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 - a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses - in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins - including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aß and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD.

Calcium phosphate nanoparticles as intrinsic inorganic antimicrobials: mechanism of action.

This is the final report of the study aimed at assessing the antimicrobial activity of calcium phosphate (CP) nanoparticles delivered in the form of hydroxyapatite (HAp) or amorphous CP (ACP) and understanding the fundamental principles behind their mechanisms of action. Not responding to propidium iodide and causing no gross morphological changes except moderate stress-induced filamentation in Escherichia coli (E. coli), CP nanoparticles were shown to be bacteriostatic, not bactericidal. Also, the lack of expression of genes involved in DNA repair indicated no genotoxic activity. In contrast, the softening of amide infrared bands and the partial dissociation of lipopolysaccharide structures comprising the membrane of Gram-negative Pseudomonas aeruginosa (P. aeruginosa) was detected in a vibrational spectroscopic analysis of the nanoparticle/bacterium interaction. Similarly, the inhibition of the growth of Staphylococcus aureus (S. aureus) was paralleled by a reduced integrated intensity and the softening of the C = O ester carbonyl stretch in lipoteichoic acid, a major component of the Gram-positive cell membrane. Electron microscopy analyses confirmed that changes to the cell membrane are a major mode of action of CP nanoparticles. While HAp got internalized by E. coli significantly more than ACP, the membrane damage was more pronounced in ACP-treated bacteria, which was explained by the higher surface reactivity of ACP. HAp nanoparticles decreased the activity of overexpressed efflux pumps in methicillin-resistant S. aureus, suggesting that they may hijack these pumps and use them to enter the cell without producing any visible damage to the membrane, thus acting on the cell from the inside out, as opposed to ACP, whose action is mostly external in mechanism. This may explain why HAp, unlike ACP, suppresses the mechanisms of resistance in methicillin- and multidrug-resistant S. aureus and P. aeruginosa, respectively. The findings of this study will be essential in the optimization of these nanoparticles for becoming an alternative to less biocompatible inorganics and small molecule antibiotics in the global effort to curb the rising resistance of bacterial pathogens to the existing therapies.

Colloids or powders: Which nanoparticle formulations do cells like more?

Understanding the difference in physicochemical properties and biological response between colloidal and powder formulations of identical materials is important before the given materials are used in a medical milieu. In this study we compared a set of biological effects of colloidal and powder formulations of composite nanoparticles comprising superparamagnetic iron oxide cores and silicate/carbon shells. Magnetic dipole interaction between adjacent nanoparticles was more pronounced in their powders than in their colloidal formulations. Nanoparticles delivered as powders were thus more responsive to the magnetic field, but exhibited reduced uptake in bone and brain cancer cells, including K7M2 osteosarcoma line and U87 and E297 glioblastoma lines. Specifically, while the alternate magnetic field elicited a more rapid heat generation in cell culture media supplemented with the magnetic powders, the nanoparticles dispersed in the same media were uptaken by the cancer cells more copiously. The cellular uptake proved to be more crucial in defining the effect on cell survival, given that suspended formulations elicited a greater degree of cancer cell death in the magnetic field compared to the powder-containing formulations. Because of this effect, colloidal formulations were able to target cancer cells more effectively than the powders: they reduced the viability of all three tested cancer cell lines to a significantly greater degree that the viability of the normal, MDCK-MDR1 cell line. It is concluded that better uptake profile can make up for the lower heating rate in the AC field and lead to a more effective magnetic hyperthermia therapy. These results also demonstrate that the direct delivery of ferrofluids is more optimal than the administration of their constitutive particles as powders.

Promoting Shared Decision-Making Behaviors During Inpatient Rounds: A Multimodal Educational Intervention.

PURPOSE: To estimate the effectiveness of a multimodal educational intervention to increase use of shared decision-making (SDM) behaviors by inpatient pediatric and internal medicine hospitalists and trainees at teaching hospitals at Stanford University and the University of California, San Francisco. METHOD: The 8-week Patient Engagement Project Study intervention, delivered at four services between November 2014 and January 2015, included workshops, campaign messaging, report cards, and coaching. For 12-week pre- and postintervention periods, clinician peers used the nine-point Rochester Participatory Decision-Making Scale (RPAD) to evaluate rounding teams' SDM behaviors with patients during ward rounds. Eligible teams included a hospitalist and at least one trainee (resident, intern, medical student), in addition to nonphysicians. Random-effects models were used to estimate intervention effects based on RPAD scores that sum points on nine SDM behaviors per patient encounter. RESULTS: In total, 527 patient encounters were scored during 175 rounds led by 49 hospitalists. Patient and team characteristics were similar across pre- and postintervention periods. Improvement was observed on all nine SDM behaviors. Adjusted for the hierarchical study design and covariates, the mean RPAD score improvement was 1.68 points (95% CI, 1.33-2.03; P < .001; Cohen d = 0.82), with intervention effects ranging from 0.7 to 2.5 points per service. Improvements were associated with longer patient encounters and a higher percentage of trainees per team. CONCLUSIONS: The intervention increased behaviors supporting SDM during ward rounds on four independent services. The findings recommend use of clinician-focused interventions to promote SDM adoption in the inpatient setting.

Brain and bone cancer targeting by a ferrofluid composed of superparamagnetic iron-oxide/silica/carbon nanoparticles (earthicles).

Despite the advances in molecularly targeted therapies, delivery across the blood-brain barrier (BBB) and the targeting of brain tumors remains a challenge. Like brain, bone is a common site of metastasis and requires therapies capable of discerning the tumor from its healthy cellular milieu. To tackle these challenges, we made a variation on the previously proposed concept of the earthicle and fabricated an aqueous, surfactant-free ferrofluid containing superparamagnetic iron oxide nanoparticles (SPIONs) coated with silicate mesolayers and carbon shells, having 13 nm in size on average. Nanoparticles were synthesized hydrothermally and characterized using a range of spectroscopic, diffractometric, hydrodynamic and electron microscopy techniques. The double coating on SPIONs affected a number of physicochemical and biological properties, including colloidal stability and cancer targeting efficacy. Nanoparticles decreased the viability of glioblastoma and osteosarcoma cells and tumors more than that of their primary and non-transformed analogues. They showed a greater preference for cancer cells because of a higher rate of uptake by these cells and a pronounced adherence to cancer cell membrane. Even in an ultralow alternate magnetic field, nanoparticles generated sufficient heat to cause tumor death. Nanoparticles in MDCK-MDR1 BBB model caused mislocalization of claudin-1 at the tight junctions, underexpression of ZO-1 and no effect on occludin-1 and transepithelial resistance. Nanoparticles were detected in the basolateral compartments and examination of LAMP1 demonstrated that nanoparticles escaped the lysosome, traversed the BBB transcellularly and localized to the optic lobes of the third instar larval brains of Drosophila melanogaster. The passage was noninvasive and caused no adverse systemic effects to the animals. In conclusion, these nanoparticulate ferrofluids preferentially bind to cancer cells and, hence, exhibit a greater toxicity in these cells compared to the primary cells. They are also effective against solid tumors in vitro, can cross the BBB in Drosophila, and are nontoxic based on the developmental studies of flies raised in ferrofluid-infused media. STATEMENT OF SIGNIFICANCE: We demonstrate that a novel, hydrothermally synthesized composite nanoparticle-based ferrofluid is effective in reducing the viability of osteosarcoma and glioblastoma cells in vitro, while having minimal effects on primary cell lines. In 3D tumor spheroids, nanoparticles greatly reduced the metastatic migration of cancer cells, while the tumor viability was reduced compared to the control group by applying magnetic hyperthermia to nanoparticle-treated spheroids. Both in vitro and in vivo models of the blood-brain barrier evidence the ability of nanoparticles to cross the barrier and localize to the brain tissue. These composite nanoparticles show great promise as an anticancer biomaterial for the treatment of different types of cancer and may serve as an alternative or addendum to traditional chemotherapies.

New findings on SNP variants of human protein L-isoaspartyl methyltransferase that affect catalytic activity, thermal stability, and aggregation.

Protein L-isoaspartyl methyltransferase (PIMT/PCMT1), a product of the pcmt1 gene, catalyzes repair of abnormal L-isoaspartyl linkages in age-damaged proteins. Pcmt1 knockout mice exhibit a profound neuropathology and die 30-60 days postnatal from an epileptic seizure. Here we characterize four new SNP variants of human PIMT with respect to enzymatic activity, thermal stability, and propensity to aggregation. Under standard assay conditions, L191S, A150V, P174H and A65V showed activity losses of 72%, 64%, 61%, and 11% respectively. By differential scanning fluorimetry, melting temperature deviations were -5.2, -4.5, +0.5, and -3.4°C. SDS-PAGE of purified protein reveal significant aggregation of L191S, A150V, and P174H, but not A65V. We also report new data on three unusual PIMT variants among the 13 recently characterized by our laboratory. A7P and I58V were previously found to have 1.8-2.0 times the activity of WT PIMT in the standard assay; however, upon kinetic analysis, we find both variants exhibit reduced catalytic efficiency (Vmax/Km) due to weak isoaspartyl substrate binding. The near complete loss of activity (<1%) seen in R36C was investigated by comparing activity of two artificial variants. R36K shows 4.6X the activity of R36C, while R36A shows no improvement, suggesting the guanidino nitrogens of the R36 play a key role in binding the methyl donor S-adenosyl-L-methionine (AdoMet). The new findings reported here extend the list of human PIMT variants that may contribute to neurological diseases in the young and the decline of CNS function in the aged.

Shared Decision-Making During Inpatient Rounds: Opportunities for Improvement in Patient Engagement and Communication.

BACKGROUND: Shared decision-making (SDM) improves patient engagement and may improve outpatient health outcomes. Little is known about inpatient SDM. OBJECTIVE: To assess overall quality, provider behaviors, and contextual predictors of SDM during inpatient rounds on medicine and pediatrics hospitalist services. DESIGN: A 12-week, cross-sectional, single-blinded observational study of team SDM behaviors during rounds, followed by semistructured patient interviews. SETTING: Two large quaternary care academic medical centers. PARTICIPANTS: Thirty-five inpatient teams (18 medicine, 17 pediatrics) and 254 unique patient encounters (117 medicine, 137 pediatrics). INTERVENTION: Observational study. MEASUREMENTS: We used a 9-item Rochester Participatory Decision-Making Scale (RPAD) measured team-level SDM behaviors. Same-day interviews using a modified RPAD assessed patient perceptions of SDM. RESULTS: Characteristics associated with increased SDM in the multivariate analysis included the following: service, patient gender, timing of rounds during patient's hospital stay, and amount of time rounding per patient (P < .05). The most frequently observed behaviors across all services included explaining the clinical issue and matching medical language to the patient's level of understanding. The least frequently observed behaviors included checking understanding of the patient's point of view, examining barriers to follow-through, and asking if the patient has any questions. Patients and guardians had substantially higher ratings for SDM quality compared to peer observers (7.2 vs 4.4 out of 9). CONCLUSIONS: Important opportunities exist to improve inpatient SDM. Team size, number of learners, patient census, and type of decision being made did not affect SDM, suggesting that even large, busy services can perform SDM if properly trained.

Polymorphic Variants of Human Protein l-Isoaspartyl Methyltransferase Affect Catalytic Activity, Aggregation, and Thermal Stability: IMPLICATIONS FOR THE ETIOLOGY OF NEUROLOGICAL DISORDERS AND COGNITIVE AGING.

Protein l-isoaspartyl methyltransferase (PIMT/PCMT1), a product of the human pcmt1 gene, catalyzes repair of abnormal l-isoaspartyl linkages in age-damaged proteins. Pcmt1 knock-out mice exhibit a profound neuropathology and die 30-60 days postnatal from an epileptic seizure. Here we express 15 reported variants of human PIMT and characterize them with regard to their enzymatic activity, thermal stability, and propensity to aggregation. One mutation, R36C, renders PIMT completely inactive, whereas two others, A7P and I58V, exhibit activity that is 80-100% higher than wild type. G175R is highly prone to aggregation and has greatly reduced activity. R17S and R17H show markedly enhanced sensitivity to thermal denaturation. Based on previous studies of moderate PIMT variation in humans and mice, we predict that heterozygosity for R36C, G175R, R17S, and R17H will prove detrimental to cognitive function and successful aging, whereas homozygosity (if it ever occurs) will lead to severe neurological problems in the young.

Organoselenium Polymer Inhibits Biofilm Formation in Polypropylene Contact Lens Case Material.

OBJECTIVES: Contact lens-acquired bacterial infections are a serious problem. Of the reported cases, inadequate cleaning of the lens case was the most common cause of lens contamination. Organoselenium has been shown to inhibit bacterial attachment to different polymer materials. This study evaluates the ability of an organoselenium monomer, incorporated into the polymer of a polypropylene contact lens case coupon, to block the formation of biofilms in a lens case. METHODS: The bacteria tested were Pseudomonas aeruginosa, Staphylococcus aureus, Stenotrophomonas maltophilia, and Serratia marcescens. For this study, the bacteria were allowed to grow overnight, in trypticase soy broth media, in the presence of the selenium-containing polymer or the same polymer without organoselenium. The material was studied by both colony-forming unit determination and by confocal laser scanning microscopy. RESULTS: The results showed that the organoselenium polymer versus the control polymer resulted in the following effect on biofilm formation: (1) a reduction in P. aeruginosa of 7.3 logs (100%); (2) a reduction in S. aureus of 7.3 logs (100%); (3) a reduction in S. maltophilia of 7.5 logs (100%); and (4) a reduction in S. marcescens reduction of 3.3 logs (99.9%). To test the stability of the organoselenium polypropylene contact lens coupon, the coupon was soaked in PBS for eight weeks at room temperature. It was found that when these soaked coupons were tested against S. aureus, complete inhibition (8.1 logs) was obtained. Because organoselenium cannot leach from the polymer, this would imply that the organoselenium polypropylene contact lens case coupon would be inhibitory toward bacterial biofilm for the life of the case. CONCLUSION: The organoselenium polypropylene contact lens case coupon shows the ability to inhibit biofilm formation. The use of organoselenium copolymer should play an important role in protecting against contact lens case-acquired infection.

The ability of quaternary ammonium groups attached to a urethane bandage to inhibit bacterial attachment and biofilm formation in a mouse wound model.

For proper wound healing, control of bacteria or bacterial infections is of major importance. While caring for a wound, dressing material plays a key role as bacteria can live in the bandage and keep re-infecting the wound. They do this by forming biofilms in the bandage, which slough off planktonic bacteria and overwhelm the host defense. It is thus necessary to develop a wound dressing that will inhibit bacterial growth. This study examines the effectiveness of a polyurethane foam wound dressing bound with polydiallyl-dimethylammonium chloride (pDADMAC) to inhibit the growth of bacteria in a wound on the back of a mouse. This technology does not allow pDADMAC to leach away from the dressing into the wound, thereby preventing cytotoxic effects. Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii were chosen for the study to infect the wounds. S. aureus and P. aeruginosa are important pathogens in wound infections, while A. baumannii was selected because of its ability to acquire or upregulate antibiotic drug resistance determinants. In addition, two different isolates of methicillin-resistant S. aureus (MRSA) were tested. All the bacteria were measured in the wound dressing and in the wound tissue under the dressing. Using colony-forming unit (CFU) assays, over six logs of inhibition (100%) were found for all the bacterial strains using pDADMAC-treated wound dressing when compared with control-untreated dressing. The CFU assay results obtained with the tissues were significant as there were 4-5 logs of reduction (100%) of the test organism in the tissue of the pDADMAC-covered wound versus that of the control dressing-covered wound. As the pDADMAC cannot leave the dressing (like other antimicrobials), this would imply that the dressing acts as a reservoir for free bacteria from a biofilm and plays a significant role in the development of a wound infection.