Endogenous analgesic action of the pontospinal noradrenergic system spatially restricts and temporally delays the progression of neuropathic pain following tibial nerve injury

Pontospinal noradrenergic neurons form part of an endogenous analgesic system that suppresses acute pain, but there is conflicting evidence about its role in neuropathic pain. We investigated the chronology of descending noradrenergic control during the development of a neuropathic pain phenotype in rats following tibial nerve transection (TNT). A lumbar intrathecal cannula was implanted at the time of nerve injury allowing administration of selective α-adrenoceptor (α-AR) antagonists to sequentially assay their effects upon the expression of allodynia and hyperalgesia. Following TNT animals progressively developed mechanical and cold allodynia (by day 10) and subsequently heat hypersensitivity (day 17). Blockade of α₂-AR with intrathecal yohimbine (30 μg) revealed earlier ipsilateral sensitization of all modalities while prazosin (30 μg, α₁-AR) was without effect. Established allodynia (by day 21) was partly reversed by the re-uptake inhibitor reboxetine (5 μg, i.t.) but yohimbine no longer had any sensitising effect. This loss of effect coincided with a reduction in the descending noradrenergic innervation of the ipsilateral lumbar dorsal horn. Yohimbine reversibly unmasked contralateral hindlimb allodynia and hyperalgesia of all modalities and increased dorsal horn c-fos expression to an innocuous brush stimulus. Contralateral thermal hyperalgesia was also reversibly uncovered by yohimbine administration in a contact heat ramp paradigm in anaesthetised TNT rats. Following TNT there is an engagement of inhibitory α₂-AR-mediated noradrenergic tone which completely masks contralateral and transiently suppresses the development of ipsilateral sensitization. This endogenous analgesic system plays a key role in shaping the spatial and temporal expression of the neuropathic pain phenotype after nerve injury.     

Blood Pressure Regulation during Exercise

This brief review examines five problems concerning arterial blood pressure regulation during exercise. These are:

1. A history and summary of evidence that baroreflexes are, or are not, active during exercise.

2. What might be other “regulators” of blood pressure during exercise? The characteristics of a blood pressure-raising reflex from ischemic and active skeletal muscle (muscle chemoreflex) is reviewed along with a putative role for centrally generated motor command signals (central command).

3. How blood pressure is maintained during exercise. The importance of regional vasoconstriction, particularly in active skeletal muscle, is reviewed.

4. How well matched are cardiac output and total vascular conductance? Does demand for muscle blood flow outstrip cardiac pumping capacity?

5. Reflex control of blood pressure by both baroreflexes and muscle chemoreflexes. The importance of baroreflexes and evidence for resetting is reviewed. A new hypothesis is stated.     

Overview of stem cell therapy for Crohn's disease

Background: Crohn's disease (CD) therapy is rapidly evolving. Recent and ongoing clinical trials using immunologically active stem cells (SC) for the treatment of CD demonstrate the potential for this novel therapy to induce complete and long-lasting remission of symptoms in settings where ‘standard’ therapies have been unsuccessful. Objective/methods: This review of SC, including mesenchymal stem cell (MSC) therapy for CD discusses how the immunological effects of MSC may correct some of the pathophysiological defects underpinning CD, and examines the latest clinical trial data providing evidence of their efficacy in the treatment of Crohn's disease. Results/conclusions: Given the beneficial effects on mucosal healing seen in animal models of inflammation and results from early clinical trials, MSC may serve as a candidate therapy for patients who have failed to respond to biological therapy.     

locStra: Fast analysis of regional/global stratification in whole‐genome sequencing studies

locStra is an ‐package for the analysis of regional and global population stratification in whole‐genome sequencing (WGS) studies, where regional stratification refers to the substructure defined by the loci in a particular region on the genome. Population substructure can be assessed based on the genetic covariance matrix, the genomic relationship matrix, and the unweighted/weighted genetic Jaccard similarity matrix. Using a sliding window approach, the regional similarity matrices are compared with the global ones, based on user‐defined window sizes and metrics, for example, the correlation between regional and global eigenvectors. An algorithm for the specification of the window size is provided. As the implementation fully exploits sparse matrix algebra and is written in C++, the analysis is highly efficient. Even on single cores, for realistic study sizes (several thousand subjects, several million rare variants per subject), the runtime for the genome‐wide computation of all regional similarity matrices does typically not exceed one hour, enabling an unprecedented investigation of regional stratification across the entire genome. The package is applied to three WGS studies, illustrating the varying patterns of regional substructure across the genome and its beneficial effects on association testing.     

以馆藏资源助力地域文化符号搭建文旅融合底蕴平台

地域文化符号是地方历史文化发展的载体,也是地域文明的象征。图书馆作为地域信息及文献资源的收藏地,在地域文化发展中起着至关重要的作用,在当前经济社会发展的背景下,也是文旅融合发展的重要组成部分。本文以图书馆助力地域文化符号搭建文旅融合底蕴平台为出发点,通过分析找准地域文化符号的意义和方法,探究图书馆在充分利用馆藏资源的基础上,找准文旅融合的契合点,厚积地域文化底蕴的方式和路径,通过进一步融合现代发展元素,打造文化旅游特色品牌项目,使文旅产业成为带动地域经济发展的"动力产业"。     

Pharmacotherapeutic options for complex regional pain syndrome

Introduction: Complex regional pain syndromes (CRPS) are rare painful conditions characterized by considerable variability in possible triggering factors, usually traumatic, and in the clinical scenario. The limited knowledge of the pathophysiological mechanisms has led to countless treatment attempts with multiple conservative and surgical options that act by different mechanisms of action.

Areas covered: In this narrative review, the authors discuss key points about CRPS definitions, diagnostic criteria and pitfalls, pathophysiological hypotheses, and treatment strategies with particular reference to pharmacotherapy. The article was based on a literature search using PubMed while the available guidelines for the management of CRPS were also examined.

Expert opinion: According to the quality of evidence, pharmacological interventions for CRPS seem to be more effective all the more so when they act on peripheral mechanisms, particularly on nociceptive pain, and when applied early in the disease, while reliable evidence about central mechanisms of chronic pain in CRPS is lacking. In our opinion, drug therapy should be preferred as early as possible, particularly in warm forms of CRPS to prevent significant functional limitation, psychological distress, and social and economic fallout.     

Reduction of exercise-induced regional contractile dysfunction in dogs using a novel calcium channel blocker (Ro 40-5967)

Summary Ro 40-5967 is a calcium channel blocker with a novel chemical structure. The purpose of this study was to evaluate the effects of Ro 40-5967 on systemic hemodynamics and regional contractile function in a canine model of chronic coronary artery stenosis in which no contractile dysfunction is observed at rest, but dynamic exercise elicits regional myocardial ischemia and contractile dysfunction. Thirteen dogs were chronically instrumented with sonomicrometers for the measurement of wall thickness in the anterior and posterior left ventricular walls, a micromanometer for measuring left ventricular pressure (LVP) and its first derivative (dP/dt), and a catheter in the aorta for measuring systemic arterial pressure. An ameroid constrictor on the left circumflex coronary artery produced gradual constriction of the vessel such that treadmill exercise elicited regional contractile dysfunction. Runs were repeated 3 hours later after the administration of Ro 40-5967 (0.3 mg/kg, IV). During the control run, regional systolic wall thickening in the posterior wall fell from 25.5 ± 6.3% (SD) to 15.9 ± 5.1% (p<0.05). Ro 40-5967 did not change resting function in the poststenotic myocardium (26.9 ± 8.4%) but improved regional function during the run to 18.2 ± 6.2% (p<0.05). This improvement was associated with a slight decrease in the exercise heart rate (213 ± 18 vs. 200 ± 16 bpm, NS), no change in peak ventricular pressure (156 ± 22 vs. 157 ± 20 mmHg), mean aortic pressure (123 ± 19 vs. 118 ± 20 mmHg), dP/dt (5129 ± 1143 vs. 5288 ± 1120 mm Hg/sec), or systolic wall thickening in a distant control region. Thus, in the exercising dog with fixed coronary stenosis, Ro 40-5967 had an antiischemic effect with no detectable negative inotropic effect.Studies were performed at the Seaweed Canyon Laboratory, Division of Cardiology, Department of Medicine, University of California, San Diego     

The Rodent Tibia Fracture Model: A Critical Review and Comparison With the Complex Regional Pain Syndrome Literature

Distal limb fracture is the most common cause of complex regional pain syndrome (CRPS), thus the rodent tibia fracture model (TFM) was developed to study CRPS pathogenesis. This comprehensive review summarizes the published TFM research and compares these experimental results with the CRPS literature. The TFM generated spontaneous and evoked pain behaviors, inflammatory symptoms (edema, warmth), and trophic changes (skin thickening, osteoporosis) resembling symptoms in early CRPS. Neuropeptides, inflammatory cytokines, and nerve growth factor (NGF) have been linked to pain behaviors, inflammation, and trophic changes in the TFM model and proliferating keratinocytes were identified as the primary source of cutaneous cytokines and NGF. Tibia fracture also activated spinal glia and upregulated spinal neuropeptide, cytokine, and NGF expression, and in the brain it changed dendritic architecture. B cell-expressed immunoglobulin M antibodies also contributed to pain behavior, indicating a role for adaptive immunity. These results modeled many findings in early CRPS, but significant differences were also noted.