Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

CCR6 Expression on B Cells Is Not Required for Clinical or Pathological Presentation of MOG Protein-Induced Experimental Autoimmune Encephalomyelitis despite an Altered Germinal Center Response.

B cells have been implicated in the pathogenesis of multiple sclerosis, but the mechanisms that guide B cell activation in the periphery and subsequent migration to the CNS remain incompletely understood. We previously showed that systemic inflammation induces an accumulation of B cells in the spleen in a CCR6/CCL20-dependent manner. In this study, we evaluated the role of CCR6/CCL20 in the context of myelin oligodendrocyte glycoprotein (MOG) protein-induced (B cell-dependent) experimental autoimmune encephalomyelitis (EAE). We found that CCR6 is upregulated on murine B cells that migrate into the CNS during neuroinflammation. In addition, human B cells that migrate across CNS endothelium in vitro were found to be CCR6+, and we detected CCL20 production by activated CNS-derived human endothelial cells as well as a systemic increase in CCL20 protein during EAE. Although mice that lack CCR6 expression specifically on B cells exhibited an altered germinal center reaction in response to MOG protein immunization, CCR6-deficient B cells did not exhibit any competitive disadvantage in their migration to the CNS during EAE, and the clinical and pathological presentation of EAE induced by MOG protein was unaffected. These data, to our knowledge, provide new information on the role of B cell-intrinsic CCR6 expression in a B cell-dependent model of neuroinflammation.

Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory.

The complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer and co-localized with inhibitory synapses engulfed by microglia/macrophages. In agreement with the loss of inhibitory perisomatic synapses, we found that Schaffer collateral feedforward inhibition but not excitation was impaired in CA2 pyramidal neurons and accompanied by intrinsic changes and a reduced spike output. Finally, consistent with excitability deficits, we show that cuprizone-treated mice exhibit impaired encoding of social memories. Together, our findings identify CA2 as a critical circuit in demyelinated intrahippocampal lesions and memory dysfunctions in MS.

Isotype-Switched Autoantibodies Are Necessary To Facilitate Central Nervous System Autoimmune Disease in Aicda-/- and Ung-/- Mice.

B cell-depleting therapies have been shown to ameliorate symptoms in multiple sclerosis (MS) patients; however, the mechanism of action remains unclear. Following priming with Ag, B cells undergo secondary diversification of their BCR, including BCR class-switch recombination (CSR) and somatic hypermutation (SHM), with both processes requiring the enzyme activation-induced (cytidine) deaminase. We previously reported that activation-induced (cytidine) deaminase is required for full clinical manifestation of disease in an animal model of MS (experimental autoimmune encephalomyelitis; EAE) provoked by immunization with the extracellular domain of recombinant human myelin oligodendrocyte glycoprotein (hMOG). In this study, we investigated the role of CSR versus SHM in the pathogenesis of EAE. We found that passive transfer of class-switched anti-MOG IgG1 Abs into hMOG-primed Aicda-/- mice is sufficient to fully rescue EAE disease. In addition, we found that the nature of the Ag is an important determinant of EAE severity in Aicda-/- mice because the lack of a diversified BCR does not affect the induction of EAE when immunized with the extracellular domain of rat MOG. To discriminate the effect of either CSR or SHM, we induced EAE in uracil DNA glycosylase-deficient mice (Ung-/-) that exhibit a defect primarily in CSR. We observed that Ung-/- mice exhibit milder clinical disease compared with control mice, concomitant with a reduced amount of anti-MOG IgG1 class-switched Abs that preserved normal affinity. Collectively, these results indicate that CSR plays an important role in governing the incidence and severity of EAE induced with hMOG but not rat MOG.

Anatomy of the Posterior Antebrachial Cutaneous Nerve, Revisited.

PURPOSE: To describe the branching pattern of the posterior antebrachial cutaneous nerve (PABCN) and to corroborate measurements and observations reported by previous authors. METHODS: Using 28 fresh-frozen cadaver specimens, we dissected the PABCN from its origin from the radial nerve to its terminal arborization in the distal forearm. Measurements relative to the lateral humeral epicondyle were recorded. The course of the nerve over the muscles of the mobile wad and its branching pattern in the proximal forearm were noted. RESULTS: The PABCN originated from the radial nerve at a mean of 14.2 cm proximal to the lateral epicondyle. The fascial hiatus through which the PABCN emerged to become superficial was a mean of 8.2 cm proximal to the lateral epicondyle. All specimens had at least 1 longitudinal branch that passed a mean of 2.8 cm anterior to the lateral epicondyle. Thirty-two percent of specimens had a lesser proximal branch in the distal third of the lateral arm; 86% had an epicondylar branch to the lateral epicondyle; and 21% had a second longitudinal branch. Ninety-three percent had a longitudinal branch coursing over the interval between the brachioradialis and the extensor carpi radialis longus in the proximal forearm. CONCLUSIONS: After becoming superficial in the distal brachium, the PABCN typically gives off a discrete epicondylar branch and then continues distally in the forearm as 1 or 2 longitudinal branches. In addition, in the proximal third of the forearm, a consistent longitudinal branch of the PABCN courses over the interval between the brachioradialis and the extensor carpi radialis longus. This review confirms previous observations of the PABCN. CLINICAL RELEVANCE: Knowledge of the course of the PABCN will assist surgeons in identifying and avoiding injury in clinical situations such as plating the proximal radius or releasing the radial tunnel.

Three-Dimensional Imaging of Transparent Tissues via Metal Nanoparticle Labeling.

Chemical probes are key components of the bioimaging toolbox, as they label biomolecules in cells and tissues. The new challenge in bioimaging is to design chemical probes for three-dimensional (3D) tissue imaging. In this work, we discovered that light scattering of metal nanoparticles can provide 3D imaging contrast in intact and transparent tissues. The nanoparticles can act as a template for the chemical growth of a metal layer to further enhance the scattering signal. The use of chemically grown nanoparticles in whole tissues can amplify the scattering to produce a 1.4 million-fold greater photon yield than obtained using common fluorophores. These probes are non-photobleaching and can be used alongside fluorophores without interference. We demonstrated three distinct biomedical applications: (a) molecular imaging of blood vessels, (b) tracking of nanodrug carriers in tumors, and (c) mapping of lesions and immune cells in a multiple sclerosis mouse model. Our strategy establishes a distinct yet complementary set of imaging probes for understanding disease mechanisms in three dimensions.

The effect of smoking on biliary complications following liver transplantation.

We sought to estimate the effect of smoking on the biliary complication rate following orthotopic liver transplantation. We retrospectively evaluated the records of liver transplant recipients at our center from July 1, 1999 to October 26, 2007. Using Cox proportional hazards models, we estimated the time to the earliest biliary complication (leak or stricture) based on smoking exposure, as active, former, or lifetime nonsmoker, adjusting for other clinical factors. Overall, 409 liver transplant recipients were evaluated. The overall biliary complication rate was 37.7% (n = 154). Biliary complications included 66 anastomotic leaks, 60 anastomotic strictures, and 28 nonanastomotic lesions. ERCP was the primary diagnostic modality (n = 112). 18.1% of liver transplant recipients were active smokers (n = 74) and 42.8% were former smokers (n = 175). Active smokers were at greatest risk for biliary complications on unadjusted analysis (P = 0.022). After multivariable adjustment, active smokers had a 92% higher rate of biliary complication rates compared with lifetime nonsmokers (HR 1.92, 95% CI 1.07-3.43), but no difference was noted in the rate of complication resolution. Smoking clearly portends a significant risk of biliary complications following liver transplantation. Smoking status should be clearly defined when evaluating transplant candidacy and in counseling patients with cirrhosis.

B cell depletion therapies in autoimmune disease: advances and mechanistic insights.

In the past 15 years, B cells have been rediscovered to be not merely bystanders but rather active participants in autoimmune aetiology. This has been fuelled in part by the clinical success of B cell depletion therapies (BCDTs). Originally conceived as a method of eliminating cancerous B cells, BCDTs such as those targeting CD20, CD19 and BAFF are now used to treat autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis. The use of BCDTs in autoimmune disease has led to some surprises. For example, although antibody-secreting plasma cells are thought to have a negative pathogenic role in autoimmune disease, BCDT, even when it controls the disease, has limited impact on these cells and on antibody levels. In this Review, we update our understanding of B cell biology, review the results of clinical trials using BCDT in autoimmune indications, discuss hypotheses for the mechanism of action of BCDT and speculate on evolving strategies for targeting B cells beyond depletion.

The Impact of IgA and the Microbiota on CNS Disease.

Although anatomically distant from the central nervous system (CNS), gut-derived signals can dynamically regulate both peripheral immune cells and CNS-resident glial cells to modulate disease. Recent discoveries of specific microbial taxa and microbial derived metabolites that modulate neuroinflammation and neurodegeneration have provided mechanistic insight into how the gut may modulate the CNS. Furthermore, the participation of the gut in regulation of peripheral and CNS immune activity introduces a potential therapeutic target. This review addresses emerging literature on how the microbiome can affect glia and circulating lymphocytes in preclinical models of human CNS disease. Critically, this review also discusses how the host may in turn influence the microbiome, and how this may impact CNS homeostasis and disease, potentially through the production of IgA.

Eugène Apert and his contributions to plastic surgery.

French pediatrician Eugène Apert is best known for his 1906 description of the eponymous Apert Syndrome: the widely recognized congenital condition that is known as acrocephalosyndactyly, which is characterized by distinct craniofacial deformities and bilateral syndactyly of the hands and feet. Subsequent efforts to study and treat this condition have led to contributions from numerous medical and surgical specialties under the guidance of plastic surgery. Apert's influence on medicine, however, extends far beyond what can be appreciated by the impact of his eponymous syndrome. Considered one of France's eminent pediatricians, Apert additionally made important contributions to the study of adult diseases. He was also a founding member of the French Eugenics Society, serving as its secretary general and president in a tenure that lasted for most of his career. Apert's medical contributions within the context of this scientific ideology make him an important and potentially controversial figure in medicine.

Drill and Fill Technique for the Treatment of Scaphoid Delayed Unions and Nonunions.

Background This article reviews the results of a surgical technique using three iterations of drilling , autologous cancellous bone grafting ( filling ), and use of an intraosseous compression screw for the treatment of nondisplaced or minimally displaced scaphoid delayed unions or nonunions. Methods Part 1-Cadaveric study: Three cadaveric scaphoids underwent stained cancellous bone graft packing and headless cannulated compression screw placement using a single iteration of drilling and graft packing. Three additional scaphoids were allocated to the triple "drill and fill" group, and underwent three iterations of drilling and graft packing before screw insertion. Graft particle distribution on mid-sagittal sections was assessed under fluorescence microscopy. Comparison of normalized areas between the single and triple "drill and fill" groups was performed using repeated measures ANOVA and Tukey's post hoc test. Part 2-Clinical study: Twelve patients with minimally displaced scaphoid delayed unions and nonunions treated between April 2007 and December 2013 with the triple "drill and fill" technique were included. The average follow-up was 60.4 weeks. Two fellowship-trained musculoskeletal radiologists independently reviewed images for fracture healing. Results By the histomorphometric analysis, there was improved autograft distribution along the screw tract, particularly within the proximal pole, with three iterations of drilling and filling. Clinically, 11 of 12 delayed unions and nonunions had healed. Conclusion Our results support the use of the "drill and fill" technique as an option for the treatment of select nondisplaced or minimally displaced scaphoid nonunions and delayed unions at the waist without avascular necrosis of the proximal pole. Level of Evidence This is a Level IV study.

Obesity, surgical site infection, and outcome following renal transplantation.

OBJECTIVE: We sought to understand whether obesity imparts detriment in outcome beyond risk of developing surgical site infection (SSI). SUMMARY BACKGROUND DATA: Obesity is a risk factor for SSI following renal transplantation, and has been implicated in inferior patient and graft survival postoperatively. METHODS: We conducted a retrospective review of all adult kidney-only transplants performed at the University of Michigan between September 2003 and April 2008. The primary exposure variable was recipient body mass index (BMI). Cox multivariable regression and Kaplan-Meier analysis were used to identify factors associated with SSI, graft loss, and patient death. RESULTS: In total, 869 recipients were studied, including 351 with BMI >30. Multivariate analysis revealed recipient age, delayed graft function, and BMI >30 to be independent risk factors for SSI. SSI was a significant risk factor for graft loss (HR: 2.194, 95% CI: 1.357-3.546) and approached significance as a risk factor for patient death (HR: 1.689, 95% CI: 0.941-3.028). Obesity had no independent effect on graft or patient outcome. CONCLUSIONS: SSI is associated with detriment to patient and graft survival following renal transplantation. The prevalence of SSI is higher among obese recipients, but those who avoid SSI have comparable outcomes to nonobese recipients. These findings redemonstrate the importance of SSI prevention following renal transplantation.

Complications of Distal Radius Fixation.

Complications following any form of distal radius fixation remain prevalent. With an armamentarium of fixation options available to practicing surgeons, familiarity with the risks of newer plate technology as it compares with other conventional methods is crucial to optimizing surgical outcome and managing patient expectations. This article presents an updated review on complications following various forms of distal radius fixation.

Increased Preoperative Narcotic Use and Its Association With Postoperative Complications and Length of Hospital Stay in Patients Undergoing Spine Surgery.

STUDY DESIGN: Prospective cohort analysis. OBJECTIVE: To assess the effect of preoperative narcotic use on the incidence of 30- and 90-day postoperative complications, as well as length of hospital stay (LOS) in patients undergoing spine surgery. SUMMARY OF BACKGROUND DATA: Previous work has associated an increased incidence of complications and length of stay following surgery in patients with increased preoperative narcotic use. Despite this and recent national attention highlighting the negative effects of narcotics, they remain commonly used for the management of pain in patients undergoing spine surgery. MATERIALS AND METHODS: A total of 583 patients undergoing spine surgery for a structural lesion were evaluated. Self-reported preoperative narcotic consumption was obtained and converted to morphine equivalents at the initial preoperative visit. LOS was recorded upon discharge and presence/type of a postoperative complication within 30/90 days was obtained. A multivariable logistic and linear regression analysis was performed for the incidence of complications and length of stay controlling for clinically important covariates. RESULTS: Narcotic use was not associated with 30- or 90-day complications; however, smoking status was significantly associated with 30-day complications. Increased preoperative narcotic use was significantly associated with increased LOS, as was age, type of surgery, and depression. CONCLUSIONS: Increased preoperative narcotic use and depression are associated with increased LOS in patients undergoing spine surgery. We calculated that for every 100 morphine equivalents a patient is taking preoperatively; their stay is extended 1.1 days. Narcotic use was not associated with 30- or 90-day postoperative complications. As reimbursement is bundled before surgery, providing interventions for patients with treatable causes for increased length of stay can save cost overall.

Global systems of health care and trauma.

Health care policy continues to occupy the center of national debate in the United States. Exploration of international health care and trauma systems allows for better comprehension of our own policies. Four basic models of health care exist across the globe: Bismarck, Beveridge, National Health Insurance, and Out-of-Pocket. Expectantly, disparities in trauma care necessarily follow inequities in overall health care and infrastructure. In this article, we aim to review several countries' health care models and their respective trauma systems. Critical analysis of international solutions to deficiencies in overall health and trauma care may serve as a guide for issues in the United States.

Preoperative opioid use and its association with perioperative opioid demand and postoperative opioid independence in patients undergoing spine surgery.

STUDY DESIGN: Prospective cohort. OBJECTIVE: To assess whether preoperative opioid use is associated with increased perioperative opioid demand and postoperative opioid independence in patients undergoing spine surgery. SUMMARY OF BACKGROUND DATA: Previous work has demonstrated increased opioid requirements during the intraoperative and immediate postoperative period in patients with high levels of preoperative opioid use. Despite this, they remain a common agent class used for the management of pain in patients prior to spine surgery. METHODS: A total of 583 patients were included. Self-reported daily opioid consumption was obtained preoperatively and converted into morphine equivalent amounts and opioid use was recorded at the 12-month postoperative time. Intraoperative and immediate postoperative opioid demand was calculated. Linear regression analyses for intraoperative and immediate postoperative opioid demand while logistic regression analyses for opioid independence at 12 months including relevant covariates such as depression and anxiety were performed. RESULTS: The median preoperative morphine equivalent amount for the cohort was 8.75 mg, with 55% of patients reporting some degree of opioid use. Younger age, more invasive surgery, anxiety, and primary surgery were significantly associated with increased intraoperative opioid demand (P < 0.05). Younger age, anxiety, and greater preoperative opioid use were significantly associated with increased immediate postoperative opioid demand (P < 0.05). More invasive surgery, anxiety, revision surgery, and greater preoperative opioid use were significantly associated with a decreased incidence of opioid independence at 12 months postoperatively (P < 0.01). CONCLUSION: Greater preoperative opioid use prior to undergoing spine surgery predicts increased immediate postoperative opioid demand and decreased incidence of postoperative opioid independence. Psychiatric diagnoses in those using preoperative opioids were predictors of continued opioid use at 12 months. Patients may benefit from preoperative counseling that emphasizes minimizing opioid use prior to undergoing spine surgery. LEVEL OF EVIDENCE: 2.

Approach to pain management in chronic opioid users undergoing orthopaedic surgery.

Opioids are commonly used for the management of pain in patients with musculoskeletal disorders; however, national attention has highlighted the potential adverse effects of the use of opioid analgesia in this and other nonmalignant pain settings. Chronic opioid users undergoing orthopaedic surgery represent a particularly challenging patient population in regard to their perioperative pain control and outcomes. Preoperative evaluation provides an opportunity to estimate a patient's preoperative opioid intake, discuss pain-related fears, and identify potential psychiatric comorbidities. Patients using high levels of opioids may also require referral to an addiction specialist. Various regional blockade and pharmaceutical options are available to help control perioperative pain, and a multimodal pain management approach may be of particular benefit in chronic opioid users undergoing orthopaedic surgery.

Preoperative narcotic use and its relation to depression and anxiety in patients undergoing spine surgery.

STUDY DESIGN: Prospective review of registry data at a single institution from October 2010 to June 2012. OBJECTIVE: To assess whether the amount of preoperative narcotic use is associated with preoperative depression and anxiety in patients undergoing spine surgery for a structural lesion. SUMMARY OF BACKGROUND DATA: Previous work suggests that narcotic use and psychiatric comorbidities are significantly related. Among other psychological considerations, depression and anxiety may be associated with the amount of preoperative narcotic use in patients undergoing spine surgery. METHODS: Five hundred eighty-three patients undergoing lumbar (60%), thoracolumbar (11%), or cervical spine (29%) were included. Self-reported preoperative narcotic consumption was obtained at the initial preoperative visit and converted to daily morphine equivalent amounts. Preoperative Zung Depression Scale (ZDS) and Modified Somatic Perception Questionnaire (MSPQ) scores were also obtained at the initial preoperative visit and recorded as measures of depression and anxiety, respectively. Resistant and robust bootstrapped multivariable linear regression analysis was performed to determine the association between ZDS and MSPQ scores and preoperative narcotics, controlling for clinically important covariates. Mann-Whitney U tests examined preoperative narcotic use in patients who were categorized as depressed (ZDS ≥ 33) or anxious (MSPQ ≥ 12). RESULTS: Multivariable analysis controlling for age, sex, smoking status, preoperative employment status, and prior spinal surgery demonstrated that preoperative ZDS (P = 0.006), prior spine surgery (P = 0.007), and preoperative pain (0.014) were independent risk factors for preoperative narcotic use. Preoperative MSPQ (P = 0.083) was nearly a statistically significant risk factor. Patients who were categorized as depressed or anxious on the basis of ZDS and MSPQ scores also showed higher preoperative narcotic use than those who were not (P < 0.0001). CONCLUSION: Depression and anxiety as assessed by ZDS and MSPQ scores were significantly associated with increased preoperative narcotic use, underscoring the importance of thorough psychological and substance use evaluation in patients being evaluated for spine surgery.

Effects of smoking on survival for patients with end-stage liver disease.

BACKGROUND: Smokers with chronic liver disease can become eligible for transplantation, but some insurers refuse reimbursement pending smoking cessation. STUDY DESIGN: Our hypothesis is that liver transplantation candidates and recipients who smoke have inferior survival compared with nonsmokers. Using a retrospective cohort study design, three Cox proportional hazards models were constructed to determine covariate-adjusted mortality from transplantation evaluation and transplantation based on smoking status at evaluation, transplantation, and posttransplantation followup. RESULTS: From 1999 to 2007, 2,260 patients were evaluated. Seven hundred sixty were active smokers, and 1,500 were nonsmokers. Smokers at evaluation were younger (49.3 versus 51.7 years), were more likely to be men (65.9% versus 58.7%), have hepatitis C (54.2% versus 30.1%), have a lower Model for End-Stage Liver Disease score (10.5 versus 12.3), and less likely to receive transplant (12.2% versus 18.6%) (all p < 0.05). The postevaluation multivariate model indicated that substance use, higher Model for End-Stage Liver Disease score, hepatitis C, and older age increased mortality risk (all p < 0.05), and liver transplantation (hazards ratio = 0.986; 95% CI, 0.977 to 0.994) was associated with lower mortality. Smoking was not associated with increased mortality risk at any time point in those evaluated or receiving transplants. CONCLUSIONS: Providers should continue encouraging potential liver transplantation candidates to stop smoking, but insurer-driven mandated smoking cessation might not improve survival.