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Knee osteoarthritis (OA) is a leading cause of late life pain and disability, and non-Hispanic black (NHB) adults experience greater OA-related pain and disability than non-Hispanic whites (NHWs). Recent evidence implicates psychosocial stress, cognitive-attentional processes, and altered central pain processing as contributors to greater OA-related pain and disability among NHBs. To address these ethnic/race disparities, this clinical trial will test whether a mindfulness intervention (Breathing and Attention Training, BAT) combined with transcranial direct current stimulation (tDCS) will enhance pain modulatory balance and pain-related brain function, reduce clinical pain, and attenuate ethnic differences therein, among NHBs and NHWs with knee OA. Participants will complete assessments of clinical pain, function, psychosocial measures, and quantitative sensory testing (QST), including mechanical temporal summation and conditioned pain modulation. Neuroimaging will be performed to examine pain-related brain structure and function. Then, participants will be randomized to one of four groups created by crossing two BAT conditions (Real vs. Sham) with two tDCS conditions (Real vs. Sham). Participants will then undergo five treatment sessions during which the assigned BAT and tDCS interventions will be delivered concurrently for 20 min over one week. After the fifth intervention session, participants will undergo assessments of clinical pain and function, QST and neuroimaging identical to the pretreatment measures, and monthly follow-up assessments of pain will be conducted for three months. This will be the first study to determine whether mindfulness and tDCS treatments will show additive or synergistic effects when combined, and whether treatment effects differ across ethnic/race groups.

INTRODUCTION: Sepsis is a life-threatening, dysregulated response to infection. Both high-density lipoprotein and low-density lipoprotein cholesterol should protect against sepsis by several mechanisms; however, for partially unknown reasons, cholesterol levels become critically low in patients with early sepsis who experience poor outcomes. An anti-inflammatory lipid injectable emulsion containing fish oil is approved by the Food and Drug Administration as parenteral nutrition for critically ill patients and may prevent this decrease in serum cholesterol levels by providing substrate for cholesterol synthesis and may favourably modulate inflammation. This LIPid Intensive Drug therapy for Sepsis Pilot clinical trial is the first study to attempt to stabilise early cholesterol levels using lipid emulsion as a treatment modality for sepsis. METHODS AND ANALYSIS: This is a two-centre, phase I/II clinical trial. Phase I is a non-randomised dose-escalation study using a Bayesian optimal interval design in which up to 16 patients will be enrolled to evaluate the safest and most efficacious dose for stabilising cholesterol levels. Based on phase I results, the two best doses will be used to randomise 48 patients to either lipid injectable emulsion or active control (no treatment). Twenty-four patients will be randomised to one of two doses of the study drug, while 24 control group patients will receive no drug and will be followed during their hospitalisation. The control group will receive all standard treatments mandated by the institutional sepsis alert protocol. The phase II study will employ a permuted blocked randomisation technique, and the primary endpoint will be change in serum total cholesterol level (48 hours - enrolment). Secondary endpoints include change in cholesterol level from enrolment to 7 days, change in Sequential Organ Failure Assessment score over the first 48 hours and 7 days, in-hospital and 28-day mortality, lipid oxidation status, inflammatory biomarkers, and high-density lipoprotein function. ETHICS AND DISSEMINATION: Investigators are trained and follow good clinical practices, and each phase of the study was reviewed and approved by the institutional review boards of each institution. Results of each phase will be disseminated through presentations at national meetings and publication in peer-reviewed journals. If promising, data from the pilot study will be used for a larger, multicentre, phase II clinical trial. TRIAL REGISTRATION NUMBER: NCT03405870.

Mycobacteriophages Deby, LaterM, LilPharaoh, Paola, SgtBeansprout, and Sulley were isolated from soil using Mycobacterium smegmatis mc2155. Genomic analysis indicated that they belong to subclusters K1 and K5. Their genomic architectures are typical of cluster K mycobacteriophages, with most variability occurring on the right end of the genome sequence.

BackgroundEvidence-based guidelines are needed to inform rehabilitation practice, including the effect of number of exercise training sessions on recovery of walking ability after stroke.ObjectiveThe objective of this study was to determine the response to increasing number of training sessions of 2 interventions-locomotor training and strength and balance exercises-on poststroke walking recovery.DesignThis is a secondary analysis of the Locomotor Experience Applied Post-Stroke (LEAPS) randomized controlled trial.SettingSix rehabilitation sites in California and Florida and participants' homes were used.ParticipantsParticipants were adults who dwelled in the community (N=347), had had a stroke, were able to walk at least 3 m (10 ft) with assistance, and had completed the required number of intervention sessions.InterventionParticipants received 36 sessions (3 times per week for 12 weeks), 90 minutes in duration, of locomotor training (gait training on a treadmill with body-weight support and overground training) or strength and balance training.MeasurementsTalking speed, as measured by the 10-Meter Walk Test, and 6-minute walking distance were assessed before training and following 12, 24, and 36 intervention sessions.ResultsParticipants at 2 and 6 months after stroke gained in gait speed and walking endurance after up to 36 sessions of treatment, but the rate of gain diminished steadily and, on average, was very low during the 25- to 36-session epoch, regardless of treatment type or severity of impairment.LimitationsResults may not generalize to people who are unable to initiate a step at 2 months after stroke or people with severe cardiac disease.ConclusionsIn general, people who dwelled in the community showed improvements in gait speed and walking distance with up to 36 sessions of locomotor training or strength and balance exercises at both 2 and 6 months after stroke. However, gains beyond 24 sessions tended to be very modest. The tracking of individual response trajectories is imperative in planning treatment.

Intraocular pressure (IOP) is a critical risk factor in glaucoma, and the available evidence derived from experimental studies in primates and rodents strongly indicates that the site of IOP-induced axonal damage in glaucoma is at the optic nerve head (ONH). However, the mechanisms that cause IOP-induced damage at the ONH are far from understood. A possible sequence of events could originate with IOP-induced stress in the ONH connective tissue elements (peripapillary sclera, scleral canal and lamina cribrosa) that leads to an increase in biomechanical strain. In consequence, molecular signaling cascades might be activated that result in extracellular matrix turnover of the peripapillary sclera, changing its biomechanical properties. Peripapillary sclera strain might induce reactive changes in ONH astrocytes and cause astrogliosis. The biological changes that are associated with ONH astrocyte reactivity could lead to withdrawal of trophic or metabolic support for optic nerve axons and cause their degeneration. Alternatively, the expression of neurotoxic molecules might be induced. Unfortunately, direct experimental in vivo evidence for these or other scenarios is currently lacking. The pathogenic processes that cause axonal degeneration at the ONH in glaucoma need to be identified before any regenerative therapy is likely to succeed. Several topics and emerging techniques should be pursued to enhance our understanding of the mechanisms that are behind axonal degeneration. Among them are: Advanced imaging techniques, the development of in vivo markers to identify axonal injury, the generation of molecular approaches for in vivo detection of mechanosensitivity and for molecular manipulation of the ONH, a more complete characterization of retinal ganglion cells, the use of organ cultures, 3D-bioprinting, and the engineering of microdevices that can measure pressure. Questions that need to be answered relate to the specific roles of astrogliosis, neuroinflammation, blood flow and intracranial pressure in axonal degeneration at the ONH.

Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases.

Introduction: Mechanical sensitive channels expressed in mammalian retinas are effectors of elevated pressure stresses, but it is unclear how their activation affects visual function in pressure-related retinal disorders. Methods: This study investigated the role of the transient potential channel vanilloid TRPV4 in photoreceptors and rod bipolar cells (RBCs) with immunohistochemistry, confocal microscopy, electroretinography (ERG), and patch-clamp techniques. Results: TRPV4 immunoreactivity (IR) was found in the outer segments of photoreceptors, dendrites and somas of PKCa-positive RBCs and other BCs, plexiform layers, and retinal ganglion cells (RGCs) in wild-type mice. TRPV4-IR was largely diminished in the retinas of homozygous TRPV4 transgenic mice. Genetically suppressing TRPV4 expression moderately but significantly enhanced the amplitude of ERG a- and b-waves evoked by scotopic and mesopic lights (0.55 to 200 Rh*rod-1 s-1) and photopic lights (105-106 Rh*rod-1 s-1) compared to wildtype mice in fully dark-adapted conditions. The implicit time evoked by dim lights (0.55 to 200 Rh*rod-1 s-1) was significantly decreased for b-waves and elongated for a-waves in the transgenic mice. ERG b-wave evoked by dim lights is primarily mediated by RBCs, and under voltage-clamp conditions, the latency of the lightevoked cation current in RBCs of the transgenic mice was significantly shorter compared to wild-type mice. About 10% of the transgenic mice had one eye undeveloped, and the percentage was significantly higher than in wild-type mice. Conclusions: The data indicates that TRPV4 involves ocular development and is expressed and active in outer retinal neurons, and interventions of TRPV4 can variably affect visual signals in rods, cones, RBCs, and cone ON BCs. [ABSTRACT FROM AUTHOR]

Photoreceptors are electrically coupled to one another, and the spatiotemporal properties of electrical synapses in a two-dimensional retinal network are still not well studied, because of the limitation of the single electrode or pair recording techniques which do not allow simultaneously measuring responses of multiple photoreceptors at various locations in the retina. A multiple electrode recording system is needed. In this study, we investigate the network properties of the two-dimensional rod coupled array of the salamander retina (both sexes were used) by using the newly available multiple patch electrode system that allows simultaneous recordings from up to eight cells and to determine the electrical connectivity among multiple rods. We found direct evidence that voltage signal spread in the rod-rod coupling network in the absence of Ih (mediated by HCN channels) is passive and follows the linear cable equation. Under physiological conditions, Ih shapes the network signal by progressively shortening the response time-to-peak of distant rods, compensating the time loss of signal traveling from distant rods to bipolar cell somas and facilitating synchronization of rod output signals. Under voltage-clamp conditions, current flow within the coupled rods follows Ohm's law, supporting the idea that nonlinear behaviors of the rod network are dependent on membrane voltage. Rod-rod coupling is largely symmetrical in the 2D array, and voltage-clamp blocking the next neighboring rod largely suppresses rod signal spread into the second neighboring rod, suggesting that indirect coupling pathways play a minor role in rod-rod coupling. [ABSTRACT FROM AUTHOR]

Background Paresis in stroke is largely a result of damage to descending corticospinal and corticobulbar pathways. Recovery of paresis predominantly reflects the impact on the neural consequences of this white matter lesion by reactive neuroplasticity (mechanisms involved in spontaneous recovery) and experience-dependent neuroplasticity, driven by therapy and daily experience. However, both theoretical considerations and empirical data suggest that type of stroke (large vessel distribution/lacunar infarction, hemorrhage), locus and extent of infarction (basal ganglia, right-hemisphere cerebral cortex), and the presence of leukoaraiosis or prior stroke might influence long-term recovery of walking ability. In this secondary analysis based on the 408 participants in the Locomotor Experience Applied Post-Stroke (LEAPS) study database, we seek to address these possibilities. Methods Lesion type, locus, and extent were characterized by the 2 neurologists in the LEAPS trial on the basis of clinical computed tomography and magnetic resonance imaging scans. A series of regression models was used to test our hypotheses regarding the effects of lesion type, locus, extent, and laterality on 2- to 12-month change in gait speed, controlling for baseline gait speed, age, and Berg Balance Scale score. Results Gait speed change at 1 year was significantly reduced in participants with basal ganglia involvement and prior stroke. There was a trend toward reduction of gait speed change in participants with lacunar infarctions. The presence of right-hemisphere cortical involvement had no significant impact on outcome. Conclusions Type, locus, and extent of lesion, and the loss of substrate for neuroplastic effect as a result of prior stroke may affect long-term outcome of rehabilitation of hemiparetic gait.