Effect of CHRFAM7A Δ2bp gene variant on secondary inflammation after spinal cord injury.

The α7 neuronal nicotinic acetylcholine receptors (α7nAChRs) are essential for anti-inflammatory responses. The human-specific CHRFAM7A gene and its 2bp deletion polymorphism (Δ2bp variant) encodes a structurally-deficient α7nAChRs that may impact the anti-inflammatory function. We studied 45 spinal cord injury (SCI) patients for up to six weeks post SCI to investigate the role of the Δ2bp variant on multiple circulating inflammatory mediators and two outcome measures (neuropathic pain and risk of pressure ulcers). The patient's SCI were classified as either severe or mild. Missing values were imputed. Overall genetic effect was conducted with independent sample t-test and corrected with false discovery rate (FDR). Univariate analysis and regression analysis were applied to evaluate the Δ2bp effects on temporal variation of inflammatory mediators post SCI and their interaction with outcome measures. In severe SCI, the Δ2bp carriers showed higher levels of circulating inflammatory mediators than the Δ2bp non-carriers in TNF-α (FDR = 9.6x10-4), IFN-γ (FDR = 1.3x10-3), IL-13 (FDR = 1.6x10-3), CCL11 (FDR = 2.1x10-3), IL-12p70 (FDR = 2.2x10-3), IL-8 (FDR = 2.2x10-3), CXCL10 (FDR = 3.1x10-3), CCL4 (FDR = 5.7x10-3), IL-12p40 (FDR = 7.1x10-3), IL-1b (FDR = 0.014), IL-15 (FDR = 0.024), and IL-2 (FDR = 0.037). IL-8 and CCL2 were negatively associated with days post injury (DPI) for the Δ2bp carriers (P = 2x10-7 and P = 2x10-8, respectively) and IL-5 was positively associated with DPI for the Δ2bp non-carriers (P = 0.015). Neuropathic pain was marginally positively associated with IL-13 for the Δ2bp carriers (P = 0.056). In mild SCI, the Δ2bp carriers had lower circulating levels of IL-15 (FDR = 0.04) than the Δ2bp non-carriers. Temporal variation of inflammatory mediators post SCI was not associated with the Δ2bp variant. For the mild SCI Δ2bp carriers, risk of pressure ulcers was positively associated with circulating levels of IFN-γ, CXCL10, and CCL4 and negatively associated with circulating levels of IL-12p70. These findings support an important role for the human-specific CHRFAM7A Δ2bp gene variant in modifying anti-inflammatory function of α7nAChRs following SCI.

Association of a Functional Polymorphism in the CHRFAM7A Gene with Inflammatory Response Mediators and Neuropathic Pain after Spinal Cord Injury.

The alpha 7 nicotinic acetylcholine receptor, α7 nAChR, plays a central role in regulating inflammatory responses. Previous studies showed that pharmacological inhibitors of α7nAChR have a pro-inflammatory effect, increasing the circulating levels of cytokines such as tumor necrosis factor alpha (TNFα). This study focused on how genetic polymorphisms of the partially duplicated α7nAChR gene (CHRFAM7A), which is highly expressed in peripheral blood cells, contribute to functional outcome after spinal cord injury (SCI). In a cohort of 27 SCI patients and 25 emergency room consented controls (% F/M: 15/85, 24/76; mean ± SE age: 35 ± 1.38 and 35 ± 2.0 respectively), a panel of circulating cytokines, noradrenergic metabolite (normetanephrine [NMN]) levels, and clinical data were available within the first 7 days post-injury (DPI) up to 90 DPI, and were investigated in the acute/subacute (DPI 1-21) and intermediate (DPI 22-90) temporal periods. Cytokine and NMN plasma levels on different DPI were analyzed as a function of CHRFAM7A genotype. TNFα levels, as a representative of some elevated inflammatory mediators, were nearly threefold higher in individuals carrying the del-2bp variant of the CHRFAM7A gene compared with that in the no-deletion genotype (p = 0.001 analysis of variance [ANOVA]) 3 weeks DPI, and twofold higher than genotype-matched acute/subacute non-SCI injury controls within 7 days DPI. In contrast, NMN levels were initially unchanged, although after 3 weeks, NMN levels were significantly decreased in SCI individuals carrying the del-2bp variant compared with non-carriers (p = 0.011 ANOVA). Numerical pain scores over this same period post-injury were significantly elevated in SCI patients carrying the del-2bp variant relative to non-carriers (p = 0.001 ANOVA). Taken together, these data reveal that pro-inflammatory responses associated with CHRFAM7A gene variation may also be associated with differences in pain experience in patients following SCI, at least during the intermediate phase.

Acute management of military-related injury.

Since the dawn of armed conflict head trauma has remained one of the most challenging afflictions for surgeons and medical personnel to treat. Interventions for head trauma from antiquity through the American Civil War were met with dismal outcomes. In the 20th century, despite greater lethality of weapons, progressive advances in management led to improved outcomes for head injured patients. A triage system consisting of appropriate levels of care from the front lines, through combat support hospitals to reconstructive and rehabilitative hospitals, has also contributed to the improved outcomes of head injured patients. This chapter examines the progressive improvement in management strategies during major conflicts, the mechanisms causing head trauma during conflict, and the current medical and surgical therapies recommended in the care of head-injured patients during armed conflict.

Establishment of the Military Neurosurgeons Committee within the World Federation of Neurosurgical Societies.

In 2009, during the World Congress of Neurological Surgery in Boston, Massachusetts, the World Federation of Neurosurgical Societies (WFNS) Executive Committee decided to establish a Military Neurosurgeons Committee. A separate scientific session on military neurosurgery was held at the next WFNS Interim Meeting in September 2011 in Brazil. A further separate session on military neurosurgery will take place at the next WFNS Meeting in Seoul, South Korea.

Traumatic brain injury in modern war.

PURPOSE OF REVIEW: To review the emerging literature on traumatic brain injury (TBI) caused by explosive blast. RECENT FINDINGS: Efforts are underway to understand how explosive blast injures brain, what is the clinical presentation and how best to manage it. A major way blast injures brain is from detonation pressure waves coupling to a victim's head leading to brain deformation. The effect of other explosion-related elements is unknown. Because scientific insights take time to develop but injuries are occurring now, the military adopts existing civilian standard of care practices developed for similar diseases, such as the Guidelines for the Management of Severe Traumatic Brain Injury developed mainly for closed head TBI. When these do not exist, the military creates them, such as the Veterans Administration and Department of Defense Clinical Practice Guidelines for Concussion/Mild TBI. Another treatment advance is the creation of the first large system-wide approach to diagnosis and clinical management of TBI, which begins at the site of injury and extends through both the military and the Veterans' Administration medical care systems. SUMMARY: Explosive blast TBI is being addressed at all levels - basic research through clinical care. New clinical practice guidelines are being used in a standardized system-wide approach.

Surgical innovations arising from the Iraq and Afghanistan wars.

The delivery of combat casualty care poses numerous challenges including austere conditions, limited supplies and medical personnel, and multiple simultaneous patients. However, the exigent circumstances of the battlefield compel the development of research and the advancement of adaptive, practical medical technologies to support and sustain military health. In Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), modern changes in medical management, coupled with improved protective gear and evacuation capabilities, have facilitated the highest survival rate in combat history.

From the battlefront: peripheral nerve surgery in modern day warfare.

Warfare historically causes a large number of peripheral nerve injuries. During the current global war on terror, an increased use of advanced regional anesthesia techniques appears to have significantly reduced pain syndromes that have been previously reported with missile-induced nerve injuries. Additionally, a new program has been established to develop advanced prosthetic devises that can interface with neural tissue to obtain direct neural control. As this technology matures, the functional restoration gained from these new generation prosthetic devices may exceed that which can be obtained by standard nerve repair techniques.

Effect of penetrating brain injury on aquaporin-4 expression using a rat model.

Cerebral edema (CE) is a frequent and potentially lethal consequence of various neurotraumas, including penetrating brain injury (PBI). Aquaporin-4 (AQP4) water channel is predominantly expressed by astrocytes and plays an important role in regulating water balance in the normal and injured brain. Using a rat model of PBI, we show that AQP4 immunoreactivity was substantially increased in the peri-injury area at both 24 and 72 h after PBI. The increase in AQP4 expression was paralleled by increased GFAP expression. The two proteins were co-expressed by peri-vascular astrocytes, whereas reactive astroglia identified by their stellar morphology did not express AQP4 at either time points after injury. Western analysis confirmed the increase in AQP4 immunoreactivity observed in the injured tissue. The apparent increase in AQP4 immunoreactivity was likely due to de novo AQP4 protein synthesis, as most of the increased AQP4 immunoreactivity was found in the soluble (cytosolic) fraction. Our results demonstrate dynamic spatial and temporal changes in AQP4 expression that contribute to the molecular pathophysiology of PBI.

Cranial burr holes and emergency craniotomy: review of indications and technique.

Burr hole craniotomy for posttraumatic intracranial hematoma is rarely performed since the advent of computerized tomography revolutionized the treatment of these patients. It is still necessary in unique circumstances although, and the clinical urgency may require surgery by a non-neurosurgeon. This occurs rarely in rural or overseas locations in peacetime, but more commonly in combat health support operations where computed tomography and neurosurgeons are not widely available. Recent experiences in the Global War on Terrorism have prompted a detailed review of this procedure. The nonoperative care, localization of intracranial hematoma, and surgical technique are outlined here in detail, and results from the literature are reviewed. This review emphasizes that burr holes should not be performed at random on head-injured patients and should be performed only by general surgeons or other physicians who have undergone formal instruction by experienced neurosurgeons, and every reasonable attempt to contact a neurosurgeon should be made first.

Physician knowledge of the Glasgow Coma Scale.

Appropriate triage is critical to optimizing outcome from battle related injuries. The Glasgow Coma Scale (GCS) is the primary means by which combat casualties, who have suffered head injury, are triaged. For the GCS to be reliable in this critical role, it must be applied accurately. To determine the level of knowledge of the GCS among military physicians with exposure and/or training in the scale we administered a prospective, voluntary, and anonymous survey to physicians of all levels of training at military medical centers with significant patient referral base. The main outcome measures were correct identification of title and categories of the GCS along with appropriate scoring of each category. Overall performance on the survey was marginal. Many were able to identify what "GCS" stands for, but far fewer were able to identify the titles of the specific categories, let alone identify the specific scoring of each category. When evaluated based on medical specialties, those in surgical specialties outperformed those in the medical specialties. When comparing the different levels of training, residents and fellows performed better than attending staff or interns. Finally, those with Advanced Trauma Life Support (ATLS) certification performed significantly better than those without the training. Physician knowledge of the GCS, as demonstrated in this study, is poor, even in a population of individuals with specific training in the use of the scale. It is concluded that, to optimize outcome from combat related head injury, methods for improving accurate quantitation of neurologic state need to be explored.

Erdheim-Chester disease mimicking a primary brain tumor. Case report.

Erdheim-Chester disease (ECD) is a rare systemic histiocytic disease. The authors present a case report detailing the presentation and treatment of a 26-year-old man diagnosed with seizures and a well-circumscribed temporoparietal mass that had been demonstrated on imaging studies. Both preoperative and intraoperative diagnoses were consistent with a low-grade astrocytic neoplasm. Subsequent pathological examination indicated a histiocytic proliferation positive for CD68 and factor VIII, and negative for CD1a and S100, with Touton giant cells characteristic of ECD. This case represents the first isolated occurrence of intracranial ECD and its potential to mimic glial neoplasms.

Socioeconomic issues of United States military neurosurgery.

Although the practice of neurosurgery in the United States (US) Armed Forces is in many ways similar to the civilian practice of neurosurgery, there are many differences as well. The unique challenges, duties, and opportunities US military neurosurgeons are given, both in peacetime and in times of conflict, are discussed, as are pathways for entering into service. The advantages of military service for neurosurgeons include sponsored training, decreased direct exposure to tort actions, little involvement with third-party payers, significant opportunities for travel, and military specific experiences. The most appealing aspect of military practice is serving fellow members of the US Armed Forces. Disadvantages include the extreme gap between the military and civilian pay scales, lack of support personnel, and in some areas low surgery-related case volume. The greatest concern faced by the military neurosurgical community is the failure to retain experienced neurosurgeons after their obligated service time has been completed, for which several possible solutions are described. It is hoped that future changes will make the practice of military neurosurgery attractive enough so that it will be seen as a career in itself and not an obligation to endure before starting practice in the "real world."