Ishan Ghai

Effect of rhythmic auditory cueing on parkinsonian gait: A systematic review and meta-analysis

The use of rhythmic auditory cueing to enhance gait performance in parkinsonian patients’ is an emerging area of interest. Different theories and underlying neurophysiological mechanisms have been suggested for ascertaining the enhancement in motor performance. However, a consensus as to its effects based on characteristics of effective stimuli, and training dosage is still not reached. A systematic review and meta-analysis was carried out to analyze the effects of different auditory feedbacks on gait and postural performance in patients affected by Parkinson’s disease. Systematic identification of published literature was performed adhering to PRISMA guidelines, from inception until May 2017, on online databases; Web of science, PEDro, EBSCO, MEDLINE, Cochrane, EMBASE and PROQUEST. Of 4204 records, 50 studies, involving 1892 participants met our inclusion criteria. The analysis revealed an overall positive effect on gait velocity, stride length, and a negative effect on cadence with application of auditory cueing. Neurophysiological mechanisms, training dosage, effects of higher information processing constraints, and use of cueing as an adjunct with medications are thoroughly discussed. This present review bridges the gaps in literature by suggesting application of rhythmic auditory cueing in conventional rehabilitation approaches to enhance motor performance and quality of life in the parkinsonian community.

Effects of dual tasks and dual-task training on postural stability: a systematic review and meta-analysis

The use of dual-task training paradigm to enhance postural stability in patients with balance impairments is an emerging area of interest. The differential effects of dual tasks and dual-task training on postural stability still remain unclear. A systematic review and meta-analysis were conducted to analyze the effects of dual task and training application on static and dynamic postural stability among various population groups. Systematic identification of published literature was performed adhering to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, from inception until June 2016, on the online databases Scopus, PEDro, MEDLINE, EMBASE, and SportDiscus. Experimental studies analyzing the effects of dual task and dual-task training on postural stability were extracted, critically appraised using PEDro scale, and then summarized according to modified PEDro level of evidence. Of 1,284 records, 42 studies involving 1,480 participants met the review’s inclusion criteria. Of the studies evaluating the effects of dual-task training on postural stability, 87.5% of the studies reported significant enhancements, whereas 30% of the studies evaluating acute effects of dual tasks on posture reported significant enhancements, 50% reported significant decrements, and 20% reported no effects. Meta-analysis of the pooled studies revealed moderate but significant enhancements of dual-task training in elderly participants (95% CI: 1.16–2.10) and in patients suffering from chronic stroke (−0.22 to 0.86). The adverse effects of complexity of dual tasks on postural stability were also revealed among patients with multiple sclerosis (−0.74 to 0.05). The review also discusses the significance of verbalization in a dual-task setting for increasing cognitive–motor interference. Clinical implications are discussed with respect to practical applications in rehabilitation settings.

Effect of rhythmic auditory cueing on gait in cerebral palsy: a systematic review and meta-analysis

Auditory entrainment can influence gait performance in movement disorders. The entrainment can incite neurophysiological and musculoskeletal changes to enhance motor execution. However, a consensus as to its effects based on gait in people with cerebral palsy is still warranted. A systematic review and meta-analysis were carried out to analyze the effects of rhythmic auditory cueing on spatiotemporal and kinematic parameters of gait in people with cerebral palsy. Systematic identification of published literature was performed adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses and American Academy for Cerebral Palsy and Developmental Medicine guidelines, from inception until July 2017, on online databases: Web of Science, PEDro, EBSCO, Medline, Cochrane, Embase and ProQuest. Kinematic and spatiotemporal gait parameters were evaluated in a meta-analysis across studies. Of 547 records, nine studies involving 227 participants (108 children/119 adults) met our inclusion criteria. The qualitative review suggested beneficial effects of rhythmic auditory cueing on gait performance among all included studies. The meta-analysis revealed beneficial effects of rhythmic auditory cueing on gait dynamic index (Hedge’s g=0.9), gait velocity (1.1), cadence (0.3), and stride length (0.5). This review for the first time suggests a converging evidence toward application of rhythmic auditory cueing to enhance gait performance and stability in people with cerebral palsy. This article details underlying neurophysiological mechanisms and use of cueing as an efficient home-based intervention. It bridges gaps in the literature, and suggests translational approaches on how rhythmic auditory cueing can be incorporated in rehabilitation approaches to enhance gait performance in people with cerebral palsy.

General Method to Determine the Flux of Charged Molecules through Nanopores Applied to β-Lactamase Inhibitors and OmpF

A major challenge in the discovery of the new antibiotics against Gram-negative bacteria is to achieve sufficiently fast permeation in order to avoid high doses causing toxic side effects. So far, suitable assays for quantifying the uptake of charged antibiotics into bacteria are lacking. We apply an electrophysiological zero-current assay using concentration gradients of β-lactamase inhibitors combined with single-channel conductance to quantify their flux rates through OmpF. Molecular dynamic simulations provide in addition details on the interactions between the nanopore wall and the charged solutes. In particular, the interaction barrier for three β-lactamase inhibitors is surprisingly as low as 3-5 kcal/mol and only slightly above the diffusion barrier of ions such as chloride. Within our macroscopic constant field model, we determine that at a zero-membrane potential a concentration gradient of 10 μM of avibactam, sulbactam, or tazobactam can create flux rates of roughly 620 molecules/s per OmpF trimer.

“Low road” to rehabilitation: a perspective on subliminal sensory neuroprosthetics

Fear can propagate parallelly through both cortical and subcortical pathways. It can instigate memory consolidation habitually and might allow internal simulation of movements independent of the cortical structures. This perspective suggests delivery of subliminal, aversive and kinematic audiovisual stimuli via neuroprosthetics in patients with neocortical dysfunctions. We suggest possible scenarios by which these stimuli might bypass damaged neocortical structures and possibly assisting in motor relearning. Anticipated neurophysiological mechanisms and methodological scenarios have been discussed in this perspective. This approach introduces novel perspectives into neuropsychology as to how subcortical pathways might be used to induce motor relearning.

Engineering enhanced pore sizes using FhuA Δ1-160 from E. coli outer membrane as template

Biological membranes are the perfect example of a molecular filter using membrane channels to control the permeability of small water-soluble molecules. To allow filtering of larger hydrophilic molecules we started from the known mutant channel FhuA Δ1-160 in which the cork domain closing the channel had been removed. Here we further expand the pore diameter by copying the amino acid sequence of two β-strands in a stepwise manner increasing the total number of β-strands from 22 to 34. The pore size of the respective expanded channel protein was characterized by single-channel conductance. Insertion of additional β-strands increased the pore conductance but also induced more ion current flickering on the millisecond scale. Further, polymer exclusion measurements were performed by analyzing single-channel conductance in the presence of differently sized polyethylene glycol of known polymer random coil radii. The conclusion from channel conductance of small channel penetrating polymers versus larger excluded ones suggested an increase in pore radii from 1.6 nm for FhuA Δ1-160 up to a maximum of about 2.7 nm for +8 β insertion. Integration of more β-strand caused instability of the channel and exclusion of smaller sized polymer. FhuA Δ1-160 + 10 β and FhuA Δ1-160 + 12 β effective radius decreased to 1.4 and 1.3 nm, respectively, showing the limitations of this approach.

Ampicillin permeation across OmpF, the major outer-membrane channel in Escherichia coli

The outer cell wall of the Gram-negative bacteria is a crucial barrier for antibiotics to reach their target. Here, we show that the chemical stability of the widely used antibiotic ampicillin is a major factor in the permeation across OmpF to reach the target in the periplasm. Using planar lipid bilayers we investigated the interactions and permeation of OmpF with ampicillin, its basic pH–induced primary degradation product (penicilloic acid), and the chemically more stable benzylpenicillin. We found that the solute-induced ion current fluctuation is 10 times higher with penicilloic acid than with ampicillin. Furthermore, we also found that ampicillin can easily permeate through OmpF, at an ampicillin gradient of 10 μm and a conductance of Gamp ≅ 3.8 fS, with a flux rate of roughly 237 molecules/s of ampicillin at Vm = 10 mV. The structurally related benzylpenicillin yields a lower conductance of Gamp ≅ 2 fS, corresponding to a flux rate of ≈120 molecules/s. In contrast, the similar sized penicilloic acid was nearly unable to permeate through OmpF. MD calculations show that, besides their charge difference, the main differences between ampicillin and penicilloic acid are the shape of the molecules, and the strength and direction of the dipole vector. Our results show that OmpF can impose selective permeation on similar sized molecules based on their structure and their dipolar properties.

Understanding antibiotic resistance via outer membrane permeability

Collective antibiotic drug resistance is a global threat, especially with respect to Gram-negative bacteria. The low permeability of the bacterial outer cell wall has been identified as a challenging barrier that prevents a sufficient antibiotic effect to be attained at low doses of the antibiotic. The Gram-negative bacterial cell envelope comprises an outer membrane that delimits the periplasm from the exterior milieu. The crucial mechanisms of antibiotic entry via outer membrane includes general diffusion porins (Omps) responsible for hydrophilic antibiotics and lipid-mediated pathway for hydrophobic antibiotics. The protein and lipid arrangements of the outer membrane have had a strong impact on the understanding of bacteria and their resistance to many types of antibiotics. Thus, one of the current challenges is effective interpretation at the molecular basis of the outer membrane permeability. This review attempts to develop a state of knowledge pertinent to Omps and their effective role in solute influx. Moreover, it aims toward further understanding and exploration of prospects to improve our knowledge of physicochemical limitations that direct the translocation of antibiotics via bacterial outer membrane.

Probing transport of fosfomycin through substrate specific OprO and OprP from Pseudomonas aeruginosa

Increasing antimicrobial drug resistance is a global threat especially with respect to Gram-negative bacteria. The low permeability of the bacterial outer cell wall has been identified as an important bottleneck that prevents a sufficient antibacterial effect to be achieved at low doses of the antibiotics. In particular, the outer membrane permeability for negatively charged molecules of the clinical important ESKAPE bacterium Pseudomonas aeruginosa is determined by the low conductance porins OprO and OprP Here we show that the alternative phosphonic-acid antibiotic fosfomycin is highly permeable through the OprO and OprP channels. For this, we applied an electrophysiological zero-current assay using concentration gradients of fosfomycin under tri-ionic conditions to quantify flux of fosfomycin through OprO and OprP. Our analyzes show that OprO, and to a lesser degree OprP, have unexpected very high permeability to fosfomycin, so the antibiotic should be a potentially excellent alternative choice for the control of Pseudomonas aeruginosa infections.

Getting drugs through small pores: exploiting the porins pathway in Pseudomonas aeruginosa

Understanding molecular properties of outer membrane channels of Gram-negative bacteria is of fundamental significance as they are the entry point of polar antibiotics into bacteria. Outer membrane proteomics revealed OccK8 (OprE) to be among the five most expressed substrate specific channels of the clinically important Pseudomonas aeruginosa. The high-resolution X-ray structure and electrophysiology highlighted a very narrow pore. However, experimental in vitro methods showed the transport of natural amino acids and antibiotics, among them ceftazidime. We used molecular dynamics simulations to reveal the importance of the physicochemical properties of ceftazidime in modulating the translocation through OccK8, proposing a structure-function relationship. As in general porins, the internal electric field favors the translocation of polar molecules by gainful energy compensation in the central constriction region. Importantly, the comparatively narrow OccK8 pore can undergo a substrate-induced expansion to accommodate relatively large-sized substrates.