Comparison of military and civilian surgeon outcomes with emergent trauma laparotomy in a mature military-civilian partnership.

Introduction: Medical readiness is of paramount concern for active-duty military providers. Low volumes of complex trauma in military treatment facilities has driven the armed forces to embed surgeons in high-volume civilian centers to maintain clinical readiness. It is unclear what impact this strategy may have on patient outcomes in these centers. We sought to compare emergent trauma laparotomy (ETL) outcomes between active-duty Air Force Special Operations Surgical Team (SOST) general surgeons and civilian faculty at an American College of Surgeons verified level 1 trauma center with a well-established military-civilian partnership. Methods: Retrospective review of a prospectively maintained, single-center database of ETL from 2019 to 2022 was performed. ETL was defined as laparotomy from trauma bay within 90 min of patient arrival. The primary outcome was to assess for all-cause mortality differences at multiple time points. Results: 514 ETL were performed during the study period. 22% (113 of 514) of patients were hypotensive (systolic blood pressure ≤90 mm Hg) on arrival. Six SOST surgeons performed 43 ETL compared with 471 ETL by civilian faculty. There were no differences in median ED length of stay (27 min vs 22 min; p=0.21), but operative duration was significantly longer for SOST surgeons (129 min vs 110 min; p=0.01). There were no differences in intraoperative (5% vs 2%; p=0.30), 6-hour (3% vs 5%; p=0.64), 24-hour (5% vs 5%; p=1.0), or in-hospital mortality rates (5% vs 8%; p=0.56) between SOST and civilian surgeons. SOST surgeons did not significantly impact the odds of 24-hour mortality on multivariable analysis (OR 0.78; 95% CI 0.10, 6.09). Conclusion: Trauma-related mortality for patients undergoing ETL was not impacted by SOST surgeons when compared with their civilian counterparts. Military surgeons may benefit from the valuable clinical experience and mentorship of experienced civilian trauma surgeons at high volume trauma centers without creating a deficit in the quality of care provided. Level of evidence: Level IV, therapeutic/care management.

The 16-year evolution of a military-civilian partnership: The University of Alabama at Birmingham experience.

BACKGROUND: At the University of Alabama at Birmingham (UAB), a multi-tiered military-civilian partnership (MCP) has evolved since 2006. We aimed to outline this model to facilitate potential replication nationally. METHODS: We performed a comprehensive review of the partnership between UAB, the United States Air Force Special Operations Command, and the Department of Defense (DoD) reviewing key documents and conducting interviews with providers. As a purely descriptive study, this project did not involve any patient data acquisition or analysis and therefore was exempt from institutional review board approval per institutional policy. RESULTS: At the time of this review, six core programs existed targeting training, clinical proficiency, and research. Training: (1) The Special Operations Center for Medical Integration and Development trains up to 144 combat medics yearly. (2) UAB trains one integrated military Surgery resident yearly with two additional civilian-sponsored military residents in Emergency Medicine. (3) UAB's Surgical Critical Care Fellowship had one National Guard member with two incoming Active-Duty, one Reservist and one prior service member in August 2022. Clinical Proficiency: (4) UAB hosts four permanently assigned United States Air Force Special Operations Command Special Operations Surgical Teams composed of general surgeons, anesthesiologists, certified registered nurse anesthetists, surgical technologists, emergency physicians, critical care registered nurses, and respiratory therapists totaling 24 permanently assigned active-duty health care professionals. (5) In addition, two fellowship-trained Air Force Trauma Critical Care Surgeons, one Active-Duty and one Reservist, are permanently assigned to UAB. These clinicians participate fully and independently in the routine care of patients alongside their civilian counterparts. Research: (6) UAB's Division of Trauma and Acute Care Surgery is currently conducting nine DoD-funded research projects totaling $6,482,790, and four research projects with military relevance funded by other agencies totaling $15,357,191. CONCLUSION: The collaboration between UAB and various elements within the DoD illustrates a comprehensive approach to MCP. Replicating appropriate components of this model nationally may aid in the development of a truly integrated trauma system best prepared for the challenges of the future. LEVEL OF EVIDENCE: Economic and Value-based Evaluations; Level IV.

Decoding the molecular crosstalk between grafted stem cells and the stroke-injured brain.

Stem cell therapy shows promise for multiple disorders; however, the molecular crosstalk between grafted cells and host tissue is largely unknown. Here, we take a step toward addressing this question. Using translating ribosome affinity purification (TRAP) with sequencing tools, we simultaneously decode the transcriptomes of graft and host for human neural stem cells (hNSCs) transplanted into the stroke-injured rat brain. Employing pathway analysis tools, we investigate the interactions between the two transcriptomes to predict molecular pathways linking host and graft genes; as proof of concept, we predict host-secreted factors that signal to the graft and the downstream molecular cascades they trigger in the graft. We identify a potential host-graft crosstalk pathway where BMP6 from the stroke-injured brain induces graft secretion of noggin, a known brain repair factor. Decoding the molecular interplay between graft and host is a critical step toward deciphering the molecular mechanisms of stem cell action.

The sustained effect of a temporary measure: Urban firearm mortality following expiration of the Federal Assault Weapons Ban.

BACKGROUND: The Federal Assault Weapons Ban (FAWB) was in effect from 1994 to 2004. We sought to examine its impact on firearm-related homicides. METHODS: All firearm-related homicides occurring in three metropolitan United States cities were analyzed during the decade preceding (PRE), during (BAN), and after (POST) the FAWB. Files were obtained from the Federal Bureau of Investigation. Rates of firearm-related homicides were stratified by year and compared using simple linear regression. RESULTS: 21,327 firearm-related homicides were analyzed. The median number of firearm-related homicides per year decreased from 333 (PRE) to 199 (BAN) (p = 0.008). This effect persisted following expiration of the ban (BAN 199 vs POST 206, p = 0.429). The rate of firearm-related homicides per 1 M population also decreased from 119.4 in 1985 to 49.2 in 2014 (ß = -2.73, p < 0.0001). CONCLUSIONS: During the FAWB, there was a significant decrease in firearm-related homicides in three of the most dangerous cities, underscoring the need for better directed prevention efforts.

Re-Sighting the Gun Debate: Defining Patterns of Firearm-Related Death to Help Focus Prevention Efforts.

BACKGROUND: Gun violence remains a significant public health problem. Although gun violence prevention efforts mostly target homicides, nationally, two-thirds of all firearm deaths are suicides. The purpose of this study was to define patterns of firearm-related deaths and examine the effect of population size. STUDY DESIGN: All firearm-related deaths in the US between 1999 and 2016 were analyzed. Homicides and suicides were obtained from the Federal Bureau of Investigation and the Centers for Disease Control and Prevention, respectively, comprising the database. For each state, the largest metropolitan city by population and a corresponding small urban city were selected. Firearm-related deaths were stratified by type and city size and compared. Rates of firearm-related homicides and suicides per 1 million population were stratified by year and compared over time using simple linear regression. RESULTS: 544,749 firearm-related deaths occurred across the US over the study period (38% homicides, 62% suicides). The median rate of firearm-related suicides was significantly greater than firearm-related homicides regardless of city size and across the US. Linear regression analysis failed to identify a significant change in the rate of firearm-related homicides over the study period. However, the rate of firearm-related suicides increased significantly regardless of city size between 1999 and 2016. CONCLUSION: Although homicides account for the majority of firearm-related deaths in metropolitan areas, suicides constitute a disproportionate number in smaller urban areas. Although the rate of homicides has stabilized, the rate of firearm-related suicides continues to increase significantly, underscoring the need for better direct prevention efforts and public health policy.

Caught in the crossfire: 37 Years of firearm violence afflicting America's youth.

INTRODUCTION: Publicly available firearm data are difficult to access. Trauma registry data are excellent at documenting patterns of firearm-related injury. Law enforcement data excel at capturing national violence trends to include both circumstances and firearm involvement. The goal of this study was to use publicly available law enforcement data from all 50 states to better define patterns of firearm-related homicides in the young. METHODS: All homicides in individuals 25 years or younger in the United States over a 37-year period ending in 2016 were analyzed: infant, 1 year or younger; child, 1 to 9 years old; adolescent, 10 to 19 years old; and young adult, 20 to 25 years old. Primary data files were obtained from the Federal Bureau of Investigation and comprised the database. Data analyzed included homicide type, situation, circumstance, month, firearm type, and demographics. Rates of all homicides and firearm-related homicides per 1 million population and the proportion of firearm-related homicides (out of all homicides) were stratified by year and compared over time using simple linear regression. RESULTS: A total of 171,113 incidents of firearm-related homicide were analyzed (69% of 246,437 total homicides): 5,313 infants, 2,332 children, 59,777 adolescents, and 103,691 young adults. Most (88%) were male and Black (59%) with a median age of 20 years. Firearm-related homicides peaked during the summer months of June, July, and August (median, 1,156 per year; p = 0.0032). Rates of all homicides (89 to 53 per 1 million population) and firearm-related homicides (56 to 41 per 1 million population) decreased significantly from 1980 to 2016 (ß = -1.12, p < 0.0001 and ß = -0.57, p = 0.0039, respectively). However, linear regression analysis identified a significant increase in the proportion of firearm-related homicides (out of all homicides) from 63% in 1980 to 76% in 2016 (ß = 0.33, p < 0.0001). CONCLUSION: For those 25 years or younger, the proportion of firearm-related homicides has steadily and significantly increased over the past 37 years, with 3 of 4 homicides firearm related in the modern era. Despite focused efforts, reductions in the rate of firearm-related homicides still lag behind those for all other methods of homicide by nearly 50%. That is, while the young are less likely to die from homicide, for those unfortunate victims, it is more likely to be due to a firearm. This increasing role of firearms in youth homicides underscores the desperate need to better direct prevention efforts and firearm policy if we hope to further reduce firearm-related deaths in the young. LEVEL OF EVIDENCE: Epidemiological study, level III.

Separating Truth from Alternative Facts: 37 Years of Guns, Murder, and Violence Across the US.

BACKGROUND: Gun violence remains a significant public health problem that is both understudied and underfunded, and plagued by inadequate or inaccessible data sources. Over the years, numerous trauma centers have attempted to use local registries to study single-institutional trends, however, this approach limits generalizability to our national epidemic. In fact, even easily accessible, health-centered data from the CDC lack national relevance because they are limited to those enrolled states only. We sought to examine how publicly available law enforcement data from all 50 states might complement our understanding of circumstances and demographics surrounding national firearm death and help forge the first step in partnering law enforcement with trauma centers. METHODS: All homicide that occurred in the US during a 37-year period ending in 2016 was analyzed. Primary data files were obtained from the Federal Bureau of Investigation and comprised the database. Data analyzed included homicide type, situation, circumstance, firearm type, and demographic characteristics of victims and offenders. The proportion of firearm-related homicide was stratified by year and compared over time using simple linear regression. RESULTS: There were 485,288 incidents of firearm homicide analyzed (64% of 752,935 total homicides). Most victims were male (85%), black (53%), and a mean age of 33 years; offenders were predominantly male (67%), black (39%), and a mean age of 30 years. Fifty-four percent of all homicide involved a single victim and single offender, followed by a single victim and unknown offender(s) (31%); 4% of firearm homicide had multiple victims. Overall, handguns, shotguns, and rifles accounted for 76%, 7%, and 5% of all firearm homicide, respectively; 11% had no firearm type listed and <1% were other gun or unknown. Linear regression analysis identified a significant increase in the proportion of firearm-related homicide from 61% in 1980 to 71% in 2016 (ß = 0.25; p < 0.0001). CONCLUSIONS: Gun violence represents an ongoing public health concern, with the proportion of firearm homicide steadily and significantly increasing from 1980 to 2016. Homicide data from the Federal Bureau of Investigation can serve to supplement trauma registry data by helping to define gun violence patterns. However, stronger partnerships between local law enforcement agencies and trauma centers are necessary to better characterize firearm type and resultant injury patterns, direct prevention efforts and firearm policy, and reduce gun-related deaths.

Major venous injury and large volume crystalloid resuscitation: A limb threatening combination.

INTRODUCTION: Major venous injury (MVI) affecting the lower extremity can result in subsequent amputation. The contribution of intraoperative resuscitation efforts on the need for amputation is not well defined. We hypothesized that intraoperative large volume crystalloid resuscitation (LVCR) increases the risk of amputation after MVI, while massive transfusion (MT) does not. METHODS: We performed a retrospective review of patients with infrarenal MVI from 2005 to 2015 at seven urban level I trauma centers. The outcome of interest was the need for secondary amputation. RESULTS: 478 patients were included. 31 (6.5%) patients with MVI required amputation. LVCR(p < 0.001), combined arterial/venous injury (p = 0.001), and associated fracture (p = 0.001) were significant risk factors for amputation. MT did not significantly increase amputation risk (p = 0.44). Multivariable logistic regression model demonstrated that patients receiving ≥5L LVCR(aOR (95% CI): 9.7 (2.9, 33.0); p < 0.001), with combined arterial/venous injury (aOR (95% CI):3.6 (1.5, 8.5); p = 0.004), and with an associated fracture (aOR (95% CI):3.2 (1.5, 7.1); p = 0.004) were more likely to require amputation. CONCLUSION: Patients with MVI who receive LVCR, have combined arterial/venous injuries and have associated fractures are more likely to require amputation. MT was not associated with delayed amputation.

Evolution of Firearm Violence over 20 Years: Integrating Law Enforcement and Clinical Data.

BACKGROUND: Data linking ballistics to injury are lacking. To address this data chasm, a partnership with law enforcement was developed to describe clinical outcomes from specific firearms. STUDY DESIGN: A random sample of patients with gunshot wounds over a 20-year period ending in 2015, was identified. Circumstances of incident, firearm type, and/or caliber were extracted from police reports. Data on demographics, mortality, injury severity, and clinical outcomes were collected from the trauma registry, and these datasets were linked. Firearms were stratified by velocity (high > 2,500 ft/sec; low < 1,200 ft/sec) and caliber (large = .40 and .45; small = .20 and .25) and compared over time. RESULTS: Police reports were obtained on 366 patients who had a gun type or caliber documented. The majority were male (82%) with a median age of 28 years. Twenty-one percent of patients had an Injury Severity Score > 25, 60% required immediate operative intervention, and overall mortality was 13%. The use of large caliber firearms increased from 4% (1996 to 2000) to 33% (2011 to 2015); small caliber guns decreased from 33% to 7% over the same time period (p < 0.0001). High velocity firearm usage significantly increased (p = 0.0320). Recovered shell casings doubled from the first decade to the second (2 vs 4; p = 0.0006). Both median New Injury Severity Score (p = 0.0488) and hospital days (p = 0.0321) increased from 1996 to 2015. CONCLUSIONS: Larger caliber and higher velocity firearms have significantly increased over the past 20 years in conjunction with injury severity, hospital days, and mean number of gun-related homicides per year (112 in 1996 to 2000 vs 143 in 2011 to 2015). Robust data sharing partnerships can be built between police and trauma centers to address the dearth of data on firearm crime and resulting injury.

Analysis of over 2 decades of colon injuries identifies optimal method of diversion: Does an end justify the means?

INTRODUCTION: Conflicting evidence exists regarding the definitive management of destructive colon injuries. Although diversion with an end ostomy can theoretically decrease initial complications, it mandates a more extensive reversal procedure. Conversely, anastomosis with proximal loop ostomy diversion, while simplifying the reversal, increases the number of suture lines and potential initial morbidity. Thus, the purpose of this study was to evaluate the impact of diversion technique on morbidity and mortality in patients with destructive colon injuries. METHODS: Consecutive patients with destructive colon injuries managed with diversion from 1996 to 2016 were stratified by demographics, severity of shock and injury, operative management, and timing of reversal. Outcomes, including ostomy complications (obstruction, ischemia, readmission) and reversal complications (obstruction, abscess, suture line failure, fascial dehiscence), were compared between patients managed with a loop versus end colostomy. Patients with rectal injuries and who died within 24 hours were excluded. RESULTS: A total of 115 patients were identified: 80 with end colostomy and 35 with loop ostomy. Ostomy complications occurred in 22 patients (19%), and 11 patients (10%) suffered reversal complications. There was no difference in ostomy-related (2.9% vs. 3.8%, p = 0.99) mortality. For patients without a planned ventral hernia (PVH), there was no difference in ostomy complications between patients managed with a loop versus end colostomy (12% vs. 18%, p = 0.72). However, patients managed with a loop ostomy had a shorter reversal operative time (95 vs. 245 minutes, p = 0.002) and reversal length of stay (6 vs. 10, p = 0.03) with fewer reversal complications (0% vs. 36%, p = 0.02). For patients with a PVH, there was no difference in outcomes between patients managed with a loop versus end colostomy. CONCLUSION: For patients without PVH, anastomosis with proximal loop ostomy reduced reversal-related complications, operative time, LOS, and hospital charges without compromising initial morbidity. Therefore, loop ostomy should be the preferred method of diversion, if required, following destructive colon injury. LEVEL OF EVIDENCE: Therapeutic, level IV.

Factors Contributing to Morbidity after Combined Arterial and Venous Lower Extremity Trauma.

The purpose of this study was to evaluate the impact of management of venous injury on clinical outcomes in patients with combined lower extremity arterial and venous trauma. Patients with common and external iliac, common and superficial femoral, and popliteal artery injuries were identified. Patients who underwent vein repair and those who received vein ligation were compared. The analysis was repeated for those patients who required secondary intervention for their arterial injury and those who did not require secondary intervention. Seventy patients were identified with both arterial and venous injuries: 40 underwent vein ligation and 30 received vein repair. There was no difference in ischemic time between patients undergoing vein repair compared with ligation. Vein ligation did not produce a higher incidence of muscle debridement (10% vs 15%, P = 0.72), necessity for secondary intervention (10% vs 7.5%, P = 0.99), or amputation (3.3% vs 7.5%, P = 0.63). Patients who required secondary intervention had a greater degree of shock on presentation (packed red blood cells (PRBC), 13 units vs 6 units, P = 0.02) and were more likely to require muscle debridement (50% vs 9%, P = 0.02) and amputation (33% vs 3%, P = 0.03). Vein ligation did not impact muscle ischemia or success of arterial repair in patients with combined venous and arterial trauma in the lower extremities. Patient morbidity after extremity vascular trauma is most related to degree of shock.

Impact of venorrhaphy and vein ligation in isolated lower-extremity venous injuries on venous thromboembolism and edema.

BACKGROUND: Following venous injury, venorrhaphy can restore outflow, although it risks thrombosis and venous thromboembolism (VTE). Vein ligation is a faster option, although it potentially risks extremity edema. The purpose of this study was to evaluate the management of venous injury on VTE and extremity edema in patients with isolated lower-extremity venous injuries. METHODS: Patients with common iliac, external iliac, and femoral venous injuries over a 10-year period were stratified by age, shock, management of venous injury, injury severity, and timing and type of anticoagulation. Outcomes included development of extremity edema and VTE (pulmonary embolism, deep venous thrombosis). Outcomes were then evaluated to determine risk factors for symptomatic lower-extremity edema and VTE by the management of venous injuries. RESULTS: Eighty-four patients were identified: 20 common iliac, 27 external iliac, 37 femoral. Forty-nine underwent vein repair and 35 underwent vein ligation. Ninety-three percent were male with a mean Injury Severity Score and Glasgow Coma Scale score of 17 and 14, respectively. Venous thromboembolism occurred in 18 (21%), 15 (18%) deep venous thrombosis, and 4 (5%) pulmonary embolisms. Thirty-two (38%) patients developed lower-extremity edema. Those who underwent vein ligation had a greater degree of shock on presentation (RBC transfusions, 14 vs. 8 units; p = 0.03) and were more likely to receive prophylactic fasciotomies (60% vs. 33%, p = 0.01). There was no difference in time to or type of chemoprophylaxis between patients who underwent vein repair and those who received vein ligation. However, patients with vein ligation had fewer episodes of VTE (9% vs. 31%, p = 0.02) with no difference in symptomatic lower-extremity edema (37% vs. 39%, p = 0.88) or amputation rates (0% vs. 2%, p = 0.99). CONCLUSION: Vein repair had a higher incidence of VTE while providing no additional benefit in reducing symptomatic extremity edema compared to ligation in patients suffering venous injury. Ligation of most extremity venous injuries can be performed without increasing patient morbidity. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Good news, bad news: An analysis of 11,294 gunshot wounds (GSWs) over two decades in a single center.

INTRODUCTION: Gun violence is a substantial public health problem accounting for significant physical, psychological, and financial costs. Although aggregate data sources demonstrate decreasing rates of firearm violence, analyses from individual trauma centers have shown that mortality and injury severity from gunshot wounds (GSWs) are increasing. To evaluate the evolving characteristics of gun violence in our region, we studied all GSWs admitted to our trauma center over a 20-year period. METHODS: A retrospective analysis of all newly admitted patients with GSWs was performed from 1996 to 2016. Our trauma registry was used to collect data on demographics, mortality, injury severity, body regions injured, and geographic location of injury. Homicide data were obtained from local law enforcement. RESULTS: A total of 11,294 patients with GSWs were reviewed. The number of GSWs treated per biennium increased from 1,349 in 1996-1997 to 1,484 in 2014-2015, with a 59% increase occurring from 2010-2011 to 2014-2015. Overall mortality was 14.6% and decreased from 15.8% in 1996-1997 to 10.2% in 2014-2015 (p < 0.0001). Mean Injury Severity Score was 12.6 and the percentage of patients who suffered GSWs to ≥3 Abbreviated Injury Scale body regions increased from 2.5% in 1996-1997 to 7.7% in 2014-2015 (p < 0.0001). Local firearm homicide data show a 118% increase from 2010 to 2016. CONCLUSIONS: In contrast to other recent studies, we found that mortality decreased whereas the number of patients treated for GSWs and those with multicompartmental injuries increased. The decrease in mortality suggests improved trauma systems as well as an increase in nonfatal GSWs that dilutes overall mortality. Wounding in multiple body regions suggests more effective weaponry, including increased magazine size. The recent increase in local homicides parallels trends in registry data and illustrates worsening gun violence in our region. Further research is needed to understand local and regional determinants of increased gun violence to better guide prevention strategies. LEVEL OF EVIDENCE: Epidemiological study, level III.

Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cells: Preclinical Efficacy and Safety in Cervical Spinal Cord Injury.

Cervical spinal cord injury (SCI) remains an important research focus for regenerative medicine given the potential for severe functional deficits and the current lack of treatment options to augment neurological recovery. We recently reported the preclinical safety data of a human embryonic cell-derived oligodendrocyte progenitor cell (OPC) therapy that supported initiation of a phase I clinical trial for patients with sensorimotor complete thoracic SCI. To support the clinical use of this OPC therapy for cervical injuries, we conducted preclinical efficacy and safety testing of the OPCs in a nude rat model of cervical SCI. Using the automated TreadScan system to track motor behavioral recovery, we found that OPCs significantly improved locomotor performance when administered directly into the cervical spinal cord 1 week after injury, and that this functional improvement was associated with reduced parenchymal cavitation and increased sparing of myelinated axons within the injury site. Based on large scale biodistribution and toxicology studies, we show that OPC migration is limited to the spinal cord and brainstem and did not cause any adverse clinical observations, toxicities, allodynia, or tumors. In combination with previously published efficacy and safety data, the results presented here supported initiation of a phase I/IIa clinical trial in the U.S. for patients with sensorimotor complete cervical SCI. Stem Cells Translational Medicine 2017;6:1917-1929.

Preclinical safety of human embryonic stem cell-derived oligodendrocyte progenitors supporting clinical trials in spinal cord injury.

AIM: To characterize the preclinical safety profile of a human embryonic stem cell-derived oligodendrocyte progenitor cell therapy product (AST-OPC1) in support of its use as a treatment for spinal cord injury (SCI). MATERIALS & METHODS: The phenotype and functional capacity of AST-OPC1 was characterized in vitro and in vivo. Safety and toxicology of AST-OPC1 administration was assessed in rodent models of thoracic SCI. RESULTS: These results identify AST-OPC1 as an early-stage oligodendrocyte progenitor population capable of promoting neurite outgrowth in vitro and myelination in vivo. AST-OPC1 administration did not cause any adverse clinical observations, toxicities, allodynia or tumors. CONCLUSION: These results supported initiation of a Phase I clinical trial in patients with sensorimotor complete thoracic SCI.

Toxoplasma gondii is dependent on glutamine and alters migratory profile of infected host bone marrow derived immune cells through SNAT2 and CXCR4 pathways.

The obligate intracellular parasite, Toxoplasma gondii, disseminates through its host inside infected immune cells. We hypothesize that parasite nutrient requirements lead to manipulation of migratory properties of the immune cell. We demonstrate that 1) T. gondii relies on glutamine for optimal infection, replication and viability, and 2) T. gondii-infected bone marrow-derived dendritic cells (DCs) display both "hypermotility" and "enhanced migration" to an elevated glutamine gradient in vitro. We show that glutamine uptake by the sodium-dependent neutral amino acid transporter 2 (SNAT2) is required for this enhanced migration. SNAT2 transport of glutamine is also a significant factor in the induction of migration by the small cytokine stromal cell-derived factor-1 (SDF-1) in uninfected DCs. Blocking both SNAT2 and C-X-C chemokine receptor 4 (CXCR4; the unique receptor for SDF-1) blocks hypermotility and the enhanced migration in T. gondii-infected DCs. Changes in host cell protein expression following T. gondii infection may explain the altered migratory phenotype; we observed an increase of CD80 and unchanged protein level of CXCR4 in both T. gondii-infected and lipopolysaccharide (LPS)-stimulated DCs. However, unlike activated DCs, SNAT2 expression in the cytosol of infected cells was also unchanged. Thus, our results suggest an important role of glutamine transport via SNAT2 in immune cell migration and a possible interaction between SNAT2 and CXCR4, by which T. gondii manipulates host cell motility.

Glucocorticoids increase excitotoxic injury and inflammation in the hippocampus of adult male rats.

BACKGROUND/AIMS: Stress exacerbates neuron loss in many CNS injuries via the actions of adrenal glucocorticoid (GC) hormones. For some injuries, this GC endangerment of neurons is accompanied by greater immune cell activation in the CNS, a surprising outcome given the potent immunosuppressive properties of GCs. METHODS: To determine whether the effects of GCs on inflammation contribute to neuron death or result from it, we tested whether nonsteroidal anti-inflammatory drugs could protect neurons from GCs during kainic acid excitotoxicity in adrenalectomized male rats. We next measured GC effects on (1) chemokine production (CCL2 and CINC-1), (2) signals that suppress immune activation (CX3CL1, CD22, CD200, and TGF-ß), and (3) NF-κB activity. RESULTS: Concurrent treatment with minocycline, but not indomethacin, prevented GC endangerment. GCs did not substantially affect CCL2, CINC-1, or baseline NF-κB activity, but they did suppress CX3CL1, CX3CR1, and CD22 expression in the hippocampus - factors that normally restrain inflammatory responses. CONCLUSIONS: These findings demonstrate that cellular inflammation is not necessarily suppressed by GCs in the injured hippocampus; instead, GCs may worsen hippocampal neuron death, at least in part by increasing the neurotoxicity of CNS inflammation.

Intraarterial transplantation of human umbilical cord blood mononuclear cells is more efficacious and safer compared with umbilical cord mesenchymal stromal cells in a rodent stroke model.

INTRODUCTION: Stroke is the second leading cause of death worldwide, claims six lives every 60 seconds, and is a leading cause of adult disability across the globe. Tissue plasminogen activator, the only United States Food and Drug Administration (FDA)-approved drug currently available, has a narrow therapeutic time window of less than 5 hours. In the past decade, cells derived from the human umbilical cord (HUC) have emerged as a potential therapeutic alternative for stroke; however, the most effective HUC-derived cell population remains unknown. METHODS: We compared three cell populations derived from the human umbilical cord: cord blood mononuclear cells (cbMNCs); cord blood mesenchymal stromal cells (cbMSCs), a subpopulation of cbMNCs; and cord matrix MSCs (cmMSCs). We characterized these cells in vitro with flow cytometry and assessed the cells' in vivo efficacy in a 2-hour transient middle cerebral artery occlusion (MCAo) rat model of stroke. cbMNCs, cbMSCs, and cmMSCs were each transplanted intraarterially at 24 hours after stroke. RESULTS: A reduction in neurologic deficit and infarct area was observed in all three cell groups; however, this reduction was significantly enhanced in the cbMNC group compared with the cmMSC group. At 2 weeks after stroke, human nuclei-positive cells were present in the ischemic hemispheres of immunocompetent stroke rats in all three cell groups. Significantly decreased expression of rat brain-derived neurotrophic factor mRNA was observed in the ischemic hemispheres of all three cell-treated and phosphate-buffered saline (PBS) group animals compared with sham animals, although the decrease was least in cbMNC-treated animals. Significantly decreased expression of rat interleukin (IL)-2 mRNA and IL-6 mRNA was seen only in the cbMSC group. Notably, more severe complications (death, eye inflammation) were observed in the cmMSC group compared with the cbMNC and cbMSC groups. CONCLUSIONS: All three tested cell types promoted recovery after stroke, but cbMNCs showed enhanced recovery and fewer complications compared with cmMSCs.