Accumulating evidence has established a firm role for synaptic plasticity in the pathogenesis of neuropathic pain. Recent advances have highlighted the importance of dendritic spine remodeling in ...driving synaptic plasticity within the CNS. Identifying the molecular players underlying neuropathic pain induced structural and functional maladaptation is therefore critical to understanding its pathophysiology. This process of dynamic reorganization happens in unique phases that have diverse pathologic underpinnings in the initiation and maintenance of neuropathic pain. Recent evidence suggests that pharmacological targeting of specific proteins during distinct phases of neuropathic pain development produces enhanced antinociception. These findings outline a potential new paradigm for targeted treatment and the development of novel therapies for neuropathic pain. We present a concise review of the role of dendritic spines in neuropathic pain and outline the potential for modulation of spine dynamics by targeting two proteins, srGAP3 and Rac1, critically involved in the regulation of the actin cytoskeleton.
Background
The incidence of surgery for degenerative cervical spine disease (DCSD) has risen by almost 150% in the USA in the last three decades and stabilized at slightly over 70 operations/100,000 ...people. There has been significant regional variation in the operation incidences. We aim to assess the diagnosis-based, age-adjusted trends in the operation incidences and the regional variation in Finland between 1999 and 2015.
Methods
Data from the Finnish Hospital Discharge Register (FHDR), the Cause of Death Register, and the registers of the Social Insurance Institution were combined to analyze all the primary operations for DCSD or rheumatoid atlanto-axial subluxation (rAAS). Combinations of the operative and the diagnosis codes were used to classify the patients into five diagnostic groups.
Results
A total of 19,701 primary operations were included. The age-adjusted operation incidence rose from 21.0 to 36.5/100,000 people between 1999 and 2013 and plateaued thereafter. The incidence of surgery for radiculopathy increased from 13.1 to 23.3 operations/100,000 people, and the incidence of surgery for DCM increased from 5.8 to 7.0 operations/100,000 people. The rise was especially pronounced in surgery for foraminal stenosis, which increased from 5.3 to 12.4 operations/100,000 people. Of the five diagnostic groups, only operations for rAAS declined. Operations increased especially in the 40- to 65-year-old age group. The overall operation incidences varied from 18.3 to 43.1 operations/100,000 people between the university hospitals.
Conclusions
The age-adjusted incidence of surgery for DCSD has risen in Finland by 76%, but the rise has plateaued. Surgery for radiculopathy, especially for foraminal stenosis, increased more steeply than surgery for degenerative medullopathy, with vast regional differences in the operation incidences.
Dendritic spine dynamics Bhatt, D Harshad; Zhang, Shengxiang; Gan, Wen-Biao
Annual review of physiology,
01/2009, Letnik:
71
Journal Article
Recenzirano
Dendritic spines are the postsynaptic components of most excitatory synapses in the mammalian brain. Spines accumulate rapidly during early postnatal development and undergo a substantial loss as ...animals mature into adulthood. In past decades, studies have revealed that the number and size of dendritic spines are regulated by a variety of gene products and environmental factors, underscoring the dynamic nature of spines and their importance to brain plasticity. Recently, in vivo time-lapse imaging of dendritic spines in the cerebral cortex suggests that, although spines are highly plastic during development, they are remarkably stable in adulthood, and most of them last throughout life. Therefore, dendritic spines may provide a structural basis for lifelong information storage, in addition to their well-established role in brain plasticity. Because dendritic spines are the key elements for information acquisition and retention, understanding how spines are formed and maintained, particularly in the intact brain, will likely provide fundamental insights into how the brain possesses the extraordinary capacity to learn and to remember.
Obesity affects >600 million people worldwide, a staggering number that appears to be on the rise. One of the lesser known consequences of obesity is its deleterious effects on cognition, which have ...been well documented across many cognitive domains and age groups. To investigate the cellular mechanisms that underlie obesity-associated cognitive decline, we used diet-induced obesity in male mice and found memory impairments along with reductions in dendritic spines, sites of excitatory synapses, increases in the activation of microglia, the brain's resident immune cells, and increases in synaptic profiles within microglia, in the hippocampus, a brain region linked to cognition. We found that partial knockdown of the receptor for fractalkine, a chemokine that can serve as a "find me" cue for microglia, prevented microglial activation and cognitive decline induced by obesity. Furthermore, we found that pharmacological inhibition of microglial activation in obese mice was associated with prevention of both dendritic spine loss and cognitive degradation. Finally, we observed that pharmacological blockade of microglial phagocytosis lessened obesity-associated cognitive decline. These findings suggest that microglia play an active role in obesity-associated cognitive decline by phagocytosis of synapses that are important for optimal function.
Obesity in humans correlates with reduced cognitive function. To investigate the cellular mechanisms underlying this, we used diet-induced obesity in mice and found impaired performance on cognitive tests of hippocampal function. These deficits were accompanied by reduced numbers of dendritic spines, increased microglial activation, and increased synaptic profiles within microglia. Inhibition of microglial activation by transgenic and pharmacological methods prevented cognitive decline and dendritic spine loss in obese mice. Moreover, pharmacological inhibition of the phagocytic activity of microglia was also sufficient to prevent cognitive degradation. This work suggests that microglia may be responsible for obesity-associated cognitive decline and dendritic spine loss.
Diffuse idiopathic skeletal hyperostosis (DISH) is an incompletely defined disease process with no known unifying pathophysiological mechanism.
To our knowledge, no genetic studies have been ...performed in a North American population. To summarize genetic findings from previous studies and to comprehensively test for these associations in a novel and diverse, multi-institutional population.
Cross-sectional, single nucleotide polymorphism (SNP) analysis was performed in 55 of 121 enrolled patients with DISH. Baseline demographic data were available on 100 patients. Based on allele selection from previous studies and related disease conditions, sequencing was performed on COL11A2, COL6A6, fibroblast growth factor 2 gene, LEMD3, TGFB1, and TLR1 genes and compared with global haplotype rates.
Consistent with previous studies, older age (mean 71 years), male sex predominance (80%), a high frequency of type 2 diabetes (54%), and renal disease (17%) were observed. Unique findings included high rates of tobacco use (11% currently smoking, 55% former smoker), a higher predominance of cervical DISH (70%) relative to other locations (30%), and an especially high rate of type 2 diabetes in patients with DISH and ossification of the posterior longitudinal ligament (100%) relative to DISH alone (100% vs 47%, P < .001). Compared with global allele rates, we found higher rates of SNPs in 5 of 9 tested genes ( P < .05).
We identified 5 SNPs in patients with DISH that occurred more frequently than a global reference. We also identified novel environmental associations. We hypothesize that DISH represents a heterogeneous condition with both multiple genetic and environmental influences.
Background
The judicialization of medicine can lead to professional disenchantment and defensive attitudes among surgeons. Some quantitative studies have investigated this topic in spine surgery, but ...none has provided direct thematic feedback from physicians. This qualitative study aimed to identify the impact of this phenomenon in the practice of spine neurosurgeons.
Methods
We proposed a qualitative study using grounded theory approach. Twenty-three purposively selected private neurosurgeons participated. Inclusion took place until data saturation was reached. Data were collected through individual interviews and analyzed thematically and independently by three researchers (an anthropologist, a psychiatrist, and a neurosurgeon).
Results
Data analysis identified five superordinate themes that were based on items that recurred in interviews: (1) private practice of spinal surgery (high-risk surgery based on frequent functional symptoms, in an unfavorable medicolegal context); (2) societal transformation of the doctor-patient relationship (new societal demands, impact of the internet and social network); (3) judicialization of spine surgery (surgeons’ feelings about the frequency and motivation of the complaints they receive, and their own management of them); (4) coping strategies (identification and solutions for “at risk” situations and patients); and (5) professional disenchantment (impact of these events on surgeons’ daily practice and career planning). Selected quotes of interviews were reported to support these findings.
Conclusions
Our study highlights several elements that can alter the quality of care in a context of societal change and the judicialization of medicine. The alteration of the doctor-patient relationship and the permanent pressure of a possible complaint encourage surgeons to adopt defensive attitudes in order to minimize the risks of litigation and increased insurance premiums. These phenomena can affect the quality of care and the privacy of physicians to the extent that they may consider changing or interrupting their careers earlier.
Multidisciplinary spine conferences (MSCs) are a strategy for discussing diagnostic and treatment aspects of patient care. Although they are becoming more common in hospitals, literature ...investigating how they impact patient care and outcomes is scarce. The aim of this study is to examine the impact of MSCs on surgical management and outcomes in elective spine surgical care.
A systematic review of the literature was conducted to evaluate the impact of MSCs on patient management and outcomes. PubMed and Cochrane databases were searched using combinations and variations of search terms "Spine Conferences," "Multidisciplinary," and "Spine Team."
The literature search yielded 435 articles, of which 120 were selected for full-text review. Four articles (N = 529 patients) were included. Surgical plans were discussed in 211 patients. The decision was altered to conservative treatment in 70 patients (33.17%) and a different surgical strategy in 34 patients (16.11%). The differences were significant in 2 studies (P < 0.05). A 51% reduction in 30-day complications rates was observed when MSC was implemented in patients with adult complex scoliosis. Other spinal disorders showed a 30-day complication rate between 0% and 14% after MSC.
To our knowledge, this is the first systematic review of outcomes of MSCs in elective spine surgery and it confirms that MSCs impact management plan and outcomes. Consistent MSCs that include surgeons and nonsurgeons have the potential to enhance communication between specialists, standardize treatments, improve patient care, and encourage teamwork. More analysis is warranted to determine if patient outcomes are improved with these measures.
DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline ...loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP-like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules.
Purpose
Chondroblastoma (CB) in the spine is extremely rare and there is little published information regarding this subject. We attempt to explore the clinical features of spinal CB and address the ...importance of total resection, especially total en bloc spondylectomy (TES) for the treatment of spinal CB.
Methods
Clinical data of 13 consecutive CB patients who received surgical treatment in our center between January 2006 and December 2016 were reviewed retrospectively. Recurrence-free survival (RFS) was estimated by Kaplan–Meier method and Log-rank test.
Results
The 13 CB patients included 9 men and 4 women with a mean age of 32 years. The lesions were located in the cervical spine in 2 cases, thoracic spine in 5 cases, and lumbar spine in 6 cases. All the patients were treated surgically using either curettage, piecemeal total resection, or TES. Postoperative radiotherapy was administered in 2 cases. The mean follow-up period was 41.6 months. Relapse occurred in 3 (23.1%) cases, resulting in one death in 60 months. The mean RFS duration was 28.7 months.
Conclusions
CB predominantly affects males and various age groups. Spinal CB more commonly involves the thoracic and lumbar segments. Spinal CB usually appears as an aggressive and destructive bony lesion with a soft tissue mass on imaging, forming compression on the spinal cord in some cases. Recurrence is not uncommon for spinal CB. Total resection, especially TES, has been confirmed as a powerful method to control the disease, while curettage is more likely to associate with local recurrence. Radiotherapy does not seem to reduce local recurrence.
Dopamine D2 receptors (D2Rs) are densely expressed in the striatum and have been linked to neuropsychiatric disorders such as schizophrenia
. High-affinity binding of dopamine suggests that D2Rs ...detect transient reductions in dopamine concentration (the dopamine dip) during punishment learning
. However, the nature and cellular basis of D2R-dependent behaviour are unclear. Here we show that tone reward conditioning induces marked stimulus generalization in a manner that depends on dopamine D1 receptors (D1Rs) in the nucleus accumbens (NAc) of mice, and that discrimination learning refines the conditioning using a dopamine dip. In NAc slices, a narrow dopamine dip (as short as 0.4 s) was detected by D2Rs to disinhibit adenosine A
receptor (A
R)-mediated enlargement of dendritic spines in D2R-expressing spiny projection neurons (D2-SPNs). Plasticity-related signalling by Ca
/calmodulin-dependent protein kinase II and A
Rs in the NAc was required for discrimination learning. By contrast, extinction learning did not involve dopamine dips or D2-SPNs. Treatment with methamphetamine, which dysregulates dopamine signalling, impaired discrimination learning and spine enlargement, and these impairments were reversed by a D2R antagonist. Our data show that D2Rs refine the generalized reward learning mediated by D1Rs.
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