End binding-3 inhibitor activates regenerative program in age-related macular degeneration.

Wet age-related macular degeneration (AMD), characterized by leaky neovessels emanating from the choroid, is a main cause of blindness. As current treatments for wet AMD require regular intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, there is a need for the development of less invasive treatments. Here, we designed an allosteric inhibitor of end binding-3 (EB3) protein, termed EBIN, which reduces the effects of environmental stresses on endothelial cells by limiting pathological calcium signaling. Delivery of EBIN via eye drops in mouse and non-human primate (NHP) models of wet AMD prevents both neovascular leakage and choroidal neovascularization. EBIN reverses the epigenetic changes induced by environmental stresses, allowing an activation of a regenerative program within metabolic-active endothelial cells comprising choroidal neovascularization (CNV) lesions. These results suggest the therapeutic potential of EBIN in preventing the degenerative processes underlying wet AMD.

Can Commercially Available Pedometers Be Used For Physical Activity Monitoring In Patients With COPD Following Exacerbations?

BACKGROUND: Commercially available pedometers have been used as tools to measure endpoints in studies evaluating physical activity promotion programs. However, their accuracy in patients recovering from COPD exacerbations is unknown. The objectives of this study were to 1) assess the relative accuracy of different commercially available pedometers in healthy volunteers and 2) evaluate the accuracy of the top-performing commercially available pedometer in patients recovering from COPD exacerbations following hospital discharge. METHODS: Twelve healthy volunteers wore 2 pedometers, 2 smartphones with pedometer apps and an accelerometer for 15 minutes of indoor activity. The top-performing device in healthy volunteers was evaluated in 4 patients recovering from COPD exacerbations following hospital discharge during 6 minutes of walking performed at home. Bland-Altman plots were employed to evaluate accuracy of each device compared with direct observation (the reference standard). RESULTS: In healthy volunteers, the mean percent error compared to direct observation of the various devices ranged from -49% to +1%. The mean percent error [95% confidence interval (CI)] of the top-performing device in healthy volunteers, the Fitbit Zip®, was +1% [-33 to +35%], significantly lower than that of the accelerometer (-13% [-56 to +29%], p=0.01). The mean percent error [95% CI] for the Fitbit Zip® in patients recovering from COPD exacerbations was -3% [-7 to +12%]. CONCLUSIONS: The accuracy of commercially available pedometers in healthy volunteers is highly variable. The top-performing pedometer in our study, the Fitbit Zip,® accurately measures step counts in both healthy volunteers and patients recovering from COPD exacerbations.

Role of adult hippocampal neurogenesis in persistent pain.

The full role of adult hippocampal neurogenesis (AHN) remains to be determined, yet it is implicated in learning and emotional functions, and is disrupted in negative mood disorders. Recent evidence indicates that AHN is decreased in persistent pain consistent with the idea that chronic pain is a major stressor, associated with negative moods and abnormal memories. Yet, the role of AHN in development of persistent pain has remained unexplored. In this study, we test the influence of AHN in postinjury inflammatory and neuropathic persistent pain-like behaviors by manipulating neurogenesis: pharmacologically through intracerebroventricular infusion of the antimitotic AraC; ablation of AHN by x-irradiation; and using transgenic mice with increased or decreased AHN. Downregulating neurogenesis reversibly diminished or blocked persistent pain; oppositely, upregulating neurogenesis led to prolonged persistent pain. Moreover, we could dissociate negative mood from persistent pain. These results suggest that AHN-mediated hippocampal learning mechanisms are involved in the emergence of persistent pain.

Opioid signaling in mast cells regulates injury responses associated with heterotopic ossification.

INTRODUCTION: Previous studies found that neuron specific enolase promoter (Nse-BMP4) transgenic mice have increased expression of the nociceptive mediator, substance P and exaggerated local injury responses associated with heterotopic ossification (HO). It is of interest great to know the pain responses in these mice and how the opioid signaling is involved in the downstream events such as mast cell (MC) activation. MATERIALS AND METHODS: This study utilized a transgenic mouse model of HO in which BMP4 is expressed under the control of the Nse-BMP4. The tactile sensitivity and the cold sensitivity of the mice were measured in a classic inflammatory pain model (carrageenan solution injected into the plantar surface of the left hind paw). The MC activation and the expression profiles of different components in the opioid signaling were demonstrated through routine histology and immunohistochemistry and Western blotting, in the superficial and deep muscle injury models. RESULTS: We found that the pain responses in these mice were paradoxically attenuated or unchanged, and we also found increased expression of both Methionine Enkephalin (Met-Enk), and the µ-opioid receptor (MOR). Met-Enk and MOR both co-localized within activated MCs in limb tissues. Further, Nse-BMP4;MOR(-/-) double mutant mice showed attenuated MC activation and had a significant reduction in HO formation in response to injuries. CONCLUSIONS: These observations suggest that opioid signaling may play a key role in MC activation and the downstream inflammatory responses associated with HO. In addition to providing insight into the role of MC activation and associated injury responses in HO, these findings suggest opioid signaling as a potential therapeutic target in HO and possibly others disorders involving MC activation.

Reorganization of hippocampal functional connectivity with transition to chronic back pain.

The hippocampus has been shown to undergo significant changes in rodent models of neuropathic pain; however, the role of the hippocampus in human chronic pain and its contribution to pain chronification have remained unexplored. Here we examine hippocampal processing during a simple visual attention task. We used functional MRI to identify intrinsic and extrinsic hippocampal functional connectivity (synchronous neural activity), comparing subacute back pain (SBP, back pain 1-4 mo) and chronic back pain (CBP, back pain >10 yr) patients to control (CON) subjects. Both groups showed more extensive hippocampal connectivity than CON subjects. We then examined the evolution of hippocampal connectivity longitudinally in SBP patients who recovered (SBPr, back pain decreased >20% in 1 yr) and those with persistent pain (SBPp). We found that SBPp and SBPr subjects have distinct changes in hippocampal-cortical connectivity over 1 yr; specifically, SBPp subjects showed large decreases in hippocampal connectivity with medial prefrontal cortex (HG-mPFC). Furthermore, in SBP patients the strength of HG-mPFC reflected variations in back pain over the year. These relationships were replicated when examined in a different task performed by SBP patients (rating fluctuations of back pain), indicating that functional connectivity of the hippocampus changes robustly in subacute pain and the nature of these changes depends on whether or not patients recover from SBP. The observed reorganization of processing within the hippocampus and between the hippocampus and the cortex seems to contribute to the transition from subacute to chronic pain and may also underlie learning and emotional abnormalities associated with chronic pain.

Abnormalities in hippocampal functioning with persistent pain.

Chronic pain patients exhibit increased anxiety, depression, and deficits in learning and memory. Yet how persistent pain affects the key brain area regulating these behaviors, the hippocampus, has remained minimally explored. In this study we investigated the impact of spared nerve injury (SNI) neuropathic pain in mice on hippocampal-dependent behavior and underlying cellular and molecular changes. In parallel, we measured the hippocampal volume of three groups of chronic pain patients. We found that SNI animals were unable to extinguish contextual fear and showed increased anxiety-like behavior. Additionally, SNI mice compared with Sham animals exhibited hippocampal (1) reduced extracellular signal-regulated kinase expression and phosphorylation, (2) decreased neurogenesis, and (3) altered short-term synaptic plasticity. To relate the observed hippocampal abnormalities with human chronic pain, we measured the volume of human hippocampus in chronic back pain (CBP), complex regional pain syndrome (CRPS), and osteoarthritis patients (OA). Compared with controls, CBP and CRPS, but not OA, had significantly less bilateral hippocampal volume. These results indicate that hippocampus-mediated behavior, synaptic plasticity, and neurogenesis are abnormal in neuropathic rodents. The changes may be related to the reduction in hippocampal volume we see in chronic pain patients, and these abnormalities may underlie learning and emotional deficits commonly observed in such patients.