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Find video protocols related to scientific articles indexed in Pubmed.
Acute care clinical indicators associated with discharge outcomes in children with severe traumatic brain injury*.
Crit. Care Med.
PUBLISHED: 08-02-2014
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The effect of the 2003 severe pediatric traumatic brain injury (TBI) guidelines on outcomes has not been examined. We aimed to develop a set of acute care guideline-influenced clinical indicators of adherence and tested the relationship between these indicators during the first 72 hours after hospital admission and discharge outcomes.
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A CD8 T-cell epitope variant enhances immune targeting to a recombinant picornavirus vaccine antigen.
Viral Immunol.
PUBLISHED: 07-15-2014
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Recombinant virus vaccines are often less effective due to immunodominant responses against endogenous vector antigens. However, the use of small RNA virus vectors provides an opportunity to limit host exposure to endogenous virus antigens and focus immune responses on the desired vaccine antigen. Using the Daniel's strain of Theiler's murine encephalomyelitis virus, we have identified strategies to modulate responses to endogenous viral proteins by manipulating the host CD8+ T-cell repertoire prior to infection or through the use of mutations introduced into the virus genome. Both of these approaches enhance responses to vaccine antigens introduced into the picornavirus. However, the use of mutant immunodominant epitopes provides an opportunity for enhancing vaccine responses without further manipulation of the host. Using this strategy, we demonstrate that modification of the consensus MHC class I anchor residue within the virus genome can promote enhanced immunity to foreign antigens and self-antigens embedded in the virus genome.
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Development of a high-throughput assay for aldosterone synthase inhibitors using high-performance liquid chromatography-tandem mass spectrometry.
Anal. Biochem.
PUBLISHED: 06-13-2014
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Aldosterone plays a key role in the pathogenesis of hypertension, congestive heart failure, and chronic kidney disease. Aldosterone biosynthesis involves three membrane-bound enzymes: aldosterone synthase, adrenodoxin, and adrenodoxin reductase. Here, we report the development of a mass spectrometry-based high-throughput whole cell-based assay for aldosterone synthesis. A human adrenal carcinoma cell line (H295R) overexpressing human aldosterone synthase cDNA was established. The production of aldosterone in these cells was initiated with the addition of 11-deoxycorticosterone, the immediate substrate of aldosterone synthase. An automatic liquid handler was used to gently distribute cells uniformly to well plates. The adaption of a second automated liquid handling system to extract aldosterone from the cell culture medium into organic solvent enabled the development of 96- and 384-well plate formats for this cellular assay. A high-performance liquid chromatography-tandem mass spectrometry method was established for the detection of aldosterone. Production of aldosterone was linear with time and saturable with increasing substrate concentration. The assay was highly reproducible with an overall average Z' value=0.49. This high-throughput assay would enable high-throughput screening for inhibitors of aldosterone biosynthesis.
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Factors associated with hemispheric hypodensity after subdural hematoma following abusive head trauma in children.
J. Neurotrauma
PUBLISHED: 06-12-2014
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Abusive head trauma (AHT) is a unique form of pediatric TBI with increased mortality and neurologic sequelae. Hemispheric hypodensity (HH) in association with subdural blood after AHT has been described. Though risk factors for HH are not understood, we hypothesized that risk factors could be identified. We retrospectively enrolled children under 5 years with TBI secondary to AHT (child advocacy diagnosis) who had undergone initial and interval brain imaging. Records were interrogated for prearrival and in-hospital physiologic and radiographic findings. HH was determined by a blinded observer. Twenty-four children were enrolled and 13 developed HH. HH was not significantly associated with age, initial Glascow Coma Scale, or mortality. Pediatric Intensity Level of Therapy (PILOT) scores (p=0.01) and daily maximal intracranial pressure (ICPmax; p=0.037) were higher in HH. Hypoxia, hypotension, cardiopulmonary arrest, need for blood transfusion, and daily blood glucoses tended to be greater in HH. Whereas all children with HH had acute subdural hematoma (SBH), many children without HH also had subdural blood; the presence of skull fracture was more likely in the children who did not develop HH (p=0.04), but no other intracranial radiographic pattern of injury was associated with HH. Surgical intervention did not appear to protect against development of HH. A variety of insults associated with ischemia, including intracranial hypertension, ICP-directed therapies, hypoxia, hypotension, and cardiac arrest, occurred in the children who developed HH. Given the morbidity and mortality of this condition, larger studies to identify mechanisms leading to the development of HH and mitigating clinical approaches are warranted.
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Simulated climate change impact on summer dissolved organic carbon release from peat and surface vegetation: Implications for drinking water treatment.
Water Res.
PUBLISHED: 05-30-2014
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Uncertainty regarding changes in dissolved organic carbon (DOC) quantity and quality has created interest in managing peatlands for their ecosystem services such as drinking water provision. The evidence base for such interventions is, however, sometimes contradictory. We performed a laboratory climate manipulation using a factorial design on two dominant peatland vegetation types (Calluna vulgaris and Sphagnum Spp.) and a peat soil collected from a drinking water catchment in Exmoor National Park, UK. Temperature and rainfall were set to represent baseline and future conditions under the UKCP09 2080s high emissions scenario for July and August. DOC leachate then underwent standard water treatment of coagulation/flocculation before chlorination. C. vulgaris leached more DOC than Sphagnum Spp. (7.17 versus 3.00 mg g(-1)) with higher specific ultraviolet (SUVA) values and a greater sensitivity to climate, leaching more DOC under simulated future conditions. The peat soil leached less DOC (0.37 mg g(-1)) than the vegetation and was less sensitive to climate. Differences in coagulation removal efficiency between the DOC sources appears to be driven by relative solubilisation of protein-like DOC, observed through the fluorescence peak C/T. Post-coagulation only differences between vegetation types were detected for the regulated disinfection by-products (DBPs), suggesting climate change influence at this scale can be removed via coagulation. Our results suggest current biodiversity restoration programmes to encourage Sphagnum Spp. will result in lower DOC concentrations and SUVA values, particularly with warmer and drier summers.
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Cerebrospinal fluid mitochondrial DNA: a novel DAMP in pediatric traumatic brain injury.
Shock
PUBLISHED: 03-27-2014
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Danger-associated molecular patterns (DAMPs) are nuclear or cytoplasmic proteins that are released from the injured tissues and activate the innate immune system. Mitochondrial DNA (mtDNA) is a novel DAMP that is released into the extracellular milieu subsequent to cell death and injury. We hypothesized that cell death within the central nervous system in children with traumatic brain injury (TBI) would lead to the release of mtDNA into the cerebrospinal fluid (CSF) and has the potential to predict the outcome after trauma. Cerebrospinal fluid was collected from children with severe TBI who required intracranial pressure monitoring with Glasgow Coma Scale (GCS) scores of 8 or less via an externalized ventricular drain. Control CSF was obtained in children without TBI or meningoencephalitis who demonstrated no leukocytes in the diagnostic lumbar puncture. The median age for patients with TBI was 6.3 years, and 62% were male. The common mechanisms of injury included motor vehicle collision (35.8%), followed by falls (21.5%) and inflicted TBI (19%); six children (14.2%) died during their intensive care unit course. The mean CSF mtDNA concentration was 1.10E+05 ± 2.07E+05 and 1.63E+03 ± 1.80E+03 copies/?L in the pediatric TBI and control populations, respectively. Furthermore, the mean CSF mtDNA concentration in pediatric patients who later died or had severe disability was significantly higher than that of the survivors (1.63E+05 ± 2.77E+05 vs. 5.05E+04 ± 6.21E+04 copies/?L) (P < 0.0001). We found a significant correlation between CSF mtDNA and high mobility group box 1, another prototypical DAMP, concentrations (? = 0.574, P < 0.05), supporting the notion that both DAMPs are increased in the CSF after TBI. Our data suggest that CSF mtDNA is a novel DAMP in TBI and appears to be a useful biomarker that correlates with neurological outcome after TBI. Further inquiry into the components of mtDNA that modulate the innate immune response will be helpful in understanding the mechanism of local and systemic inflammation after TBI.
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Energy expenditure in children after severe traumatic brain injury.
Pediatr Crit Care Med
PUBLISHED: 01-08-2014
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To evaluate energy expenditure in a cohort of children with severe traumatic brain injury.
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An elite controller of picornavirus infection targets an epitope that is resistant to immune escape.
PLoS ONE
PUBLISHED: 01-01-2014
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The emergence of novel viral pathogens can lead to devastating consequences in the infected population. However, on occasion, rare hyper-responsive elite controllers are able to mount a protective primary response to infection and clear the new pathogen. Factors distinguishing elite controllers from other members of the population are not completely understood. We have been using Theiler's murine encephalomyelitis as a model of primary infection in mice and clearance of the virus is limited to one MHC genotype capable of generating a protective response to a single viral peptide VP2121-130. The genetics of host susceptibility to TMEV, a natural mouse pathogen, has been studied extensively and non-protective CD8 responses to other peptides have been documented, however, little is known why the protective response to infection focuses on the VP2121-130 peptide. To study this question, we have generated TMEV mutants that encode for mutations within the VP2121-130 peptide. We find that very few of mutants are able to assemble and infect in vitro. These mutations are not related to virus RNA structure since non-coding mutations do not interfere with assembly. In the rare event when functional VP2121-130 mutant viruses did emerge, they were attenuated to some level or retained the ability to develop an immune response to the wild-type VP2121-130 sequence, demonstrating that the virus is incapable of escaping the protective response. These findings advance our understanding of how characteristics of the host immune response and an infectious agent can interact to lead to the appearance of rare super controllers in a population. Furthermore, the immutable nature of the viral antigen highlights the importance of choosing appropriate vaccine antigens and has implications for the development of agents that are able to generate protective CD8 T-cell responses.
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Correcting for background nitrate contamination in KCl-extracted samples during isotopic analysis of oxygen and nitrogen by the denitrifier method.
Rapid Commun. Mass Spectrom.
PUBLISHED: 01-01-2014
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Previous research has shown that the denitrifying bacteria Pseudomonas chlororaphis ssp. aureofaciens (P. aureofaciens) can be used to measure the ?(15)N and ?(18)O values of extracted soil nitrate (NO3(-)) by isotope ratio mass spectrometry. We discovered that N2O production from reference blanks made in 1 M KCl increased relative to blanks made of deionized water (DIW). Further investigation showed that isotopic standards made in KCl yielded ?(15)N and ?(18)O values different from the standards prepared in DIW.
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Effect of a Single Dose of Propofol and Lack of Dextrose Administration in a Child With Mitochondrial Disease: A Case Report.
J. Child Neurol.
PUBLISHED: 09-11-2013
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Propofol infusion syndrome is a recognized complication of prolonged propofol use in the pediatric population, but little is reported on other metabolic effects of propofol, especially in children with mitochondrial disorders. We report on a child with metabolic encephalopathy, lactic acidosis, and stroke-like syndrome who received a single dose of propofol for procedural sedation. The patients initial presentation was consistent with a mild exacerbation of her underlying disease. She received a single dose of propofol and non-dextrose-containing fluids during a magnetic resonance imaging (MRI) study to rule out stroke and progressed to develop severe acidosis, neurologic deterioration, and cardiorespiratory compromise. This is the first case report of severe metabolic disturbances after a single dose of propofol administered for procedural sedation in a patient with metabolic encephalopathy, lactic acidosis, and stroke-like syndrome and it questions the safety of propofol and absence of dextrose infusions during an acute illness in patients with mitochondrial disorders.
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Risk factors associated with suicide in current and former US military personnel.
JAMA
PUBLISHED: 08-09-2013
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Beginning in 2005, the incidence of suicide deaths in the US military began to sharply increase. Unique stressors, such as combat deployments, have been assumed to underlie the increasing incidence. Previous military suicide studies, however, have relied on case series and cross-sectional investigations and have not linked data during service with postservice periods.
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Delivery of ibuprofen to the skin.
Int J Pharm
PUBLISHED: 08-06-2013
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Ibuprofen (IBU) has been available as a topical skin preparation for more than two decades. Its primary indication is for the relief of pain and inflammation in rheumatic disease and other musculoskeletal conditions. This article reviews the various formulation strategies which have been investigated for percutaneous IBU delivery to date. The focus is on studies which have been conducted with IBU in the free base form on human or porcine skin as data from other species are known to overestimate likely permeation in man. Emerging technologies for enhanced dermal delivery of IBU are considered including methods which require physical disruption of the membrane. The role of biophysical techniques such as Confocal Raman Spectroscopy in the rational development of IBU formulations is also discussed.
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Therapeutic hypothermia decreases phenytoin elimination in children with traumatic brain injury.
Crit. Care Med.
PUBLISHED: 07-31-2013
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Preclinical and clinical studies have suggested that therapeutic hypothermia, while decreasing neurologic injury, may also lead to drug toxicity that may limit its benefit. Cooling decreases cytochrome P450 (CYP)-mediated drug metabolism, and limited clinical data suggest that drug levels are elevated. Fosphenytoin is metabolized by cytochrome P450 2C, has a narrow therapeutic range, and is a commonly used antiepileptic medication. The objective of this study was to evaluate the impact of therapeutic hypothermia on phenytoin levels and pharmacokinetics in children with severe traumatic brain injury.
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Influence of ATP-binding cassette polymorphisms on neurological outcome after traumatic brain injury.
Neurocrit Care
PUBLISHED: 07-31-2013
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As important mediators of solute transport at the blood-brain and blood-cerebrospinal fluid barriers, ATP-binding cassette (ABC) transporters (including ABCB1, ABCC1, and ABCC2), impact the bioavailability of drugs and endogenous substrates in the brain. While several ABCB1, ABCC1, and ABCC2 single nucleotide polymorphisms (SNPs) have been identified, their impact on outcome after traumatic brain injury (TBI) is unknown.
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GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: in vitro profile and in vivo analgesic efficacy.
Bioorg. Med. Chem. Lett.
PUBLISHED: 07-19-2013
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We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
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Differences in medical therapy goals for children with severe traumatic brain injury-an international study.
Pediatr Crit Care Med
PUBLISHED: 07-19-2013
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To describe the differences in goals for their usual practice for various medical therapies from a number of international centers for children with severe traumatic brain injury.
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National variability in intracranial pressure monitoring and craniotomy for children with moderate to severe traumatic brain injury.
Neurosurgery
PUBLISHED: 07-19-2013
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Traumatic brain injury (TBI) is a significant cause of mortality and disability in children. Intracranial pressure monitoring (ICPM) and craniotomy/craniectomy (CRANI) may affect outcomes. Sources of variability in the use of these interventions remain incompletely understood.
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Hospitalizations of children with neurologic disorders in the United States.
Pediatr Crit Care Med
PUBLISHED: 07-12-2013
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Although neurologic disorders are among the most serious acute pediatric illnesses, epidemiologic data are scarce. We sought to determine the scope and outcomes of children with these disorders in the United States.
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GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models.
Bioorg. Med. Chem. Lett.
PUBLISHED: 07-05-2013
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The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
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The association between combat exposure and negative behavioral and psychiatric conditions.
J. Nerv. Ment. Dis.
PUBLISHED: 07-03-2013
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This study evaluated the association between cumulative combat exposures and negative behavioral and psychiatric conditions. A total of 6128 active-duty soldiers completed a survey approximately 6 months after their units most recent combat deployment. The soldiers self-reported combat exposures and behavioral and psychiatric conditions. Multivariable logistic regression was used to assess the association between cumulative combat exposures and behavioral and psychiatric outcomes. In comparison with the referent group of soldiers not previously deployed, the soldiers categorized as having the highest cumulative combat exposures were significantly associated with self-reporting a history of behavioral and psychiatric diagnoses, problematic alcohol misuse, aggression, criminal behavior, and physical altercations with a significant other. The magnitude and the consistency of the association among the soldiers with the highest number of combat exposures suggest that the number of cumulative combat deployment exposures is an important consideration for identifying and treating high-risk soldiers and units returning from combat.
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Triage of children with moderate and severe traumatic brain injury to trauma centers.
J. Neurotrauma
PUBLISHED: 06-25-2013
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Outcomes after pediatric traumatic brain injury (TBI) are related to pre-treatment factors including age, injury severity, and mechanism of injury, and may be positively affected by treatment at trauma centers relative to non-trauma centers. This study estimated the proportion of children with moderate to severe TBI who receive care at trauma centers, and examined factors associated with receipt of care at adult (ATC), pediatric (PTC), and adult/pediatric trauma centers (APTC), compared with care at non-trauma centers (NTC) using a nationally representative database. The Kids Inpatient Database was used to identify hospitalizations for moderate to severe pediatric TBI. Pediatric inpatients ages 0 to 17 years with at least one diagnosis of TBI and a maximum head Abbreviated Injury Scale score of ?3 were studied. Multinomial logistic regression was performed to examine factors predictive of the level and type of facility where care was received. A total of 16.7% of patients were hospitalized at NTC, 44.2% at Level I or II ATC, 17.9% at Level I or II PTC, and 21.2% at Level I or II APTC. Multiple regression analyses showed receipt of care at a trauma center was associated with age and polytrauma. We concluded that almost 84% of children with moderate to severe TBI currently receive care at a Level I or Level II trauma center. Children with trauma to multiple body regions in addition to more severe TBI are more likely to receive care a trauma center relative to a NTC.
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Assessing professionalism and ethics knowledge and skills: preferences of psychiatry residents.
Acad Psychiatry
PUBLISHED: 06-18-2013
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Professionalism is one of the fundamental expectations and a core competency in residency education. Although programs use a variety of evaluative methods, little is known about residents views of and preferences regarding various methods of assessment.
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An ecological perspective on medical care: environmental, occupational, and public health impacts of medical supply and pharmaceutical chains.
Ecohealth
PUBLISHED: 06-13-2013
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Healthcare organizations are increasingly examining the impacts of their facilities and operations on the natural environment, their workers, and the broader community, but the ecological impacts of specific healthcare services provided within these institutions have not been assessed. This paper provides a qualitative assessment of healthcare practices that takes into account the life-cycle impacts of a variety of materials used in typical medical care. We conducted an ethnographic study of three medical inpatient units: a conventional cancer ward, palliative care unit, and a hospice center. Participant observations (73 participants) of healthcare and support staff including physicians, nurses, housekeepers, and administrators were made to inventory materials and document practices used in patient care. Semi-structured interviews provided insight into common practices. We identified three major domains that highlight the cumulative environmental, occupational health, and public health impacts of medical supplies and pharmaceuticals used at our research sites: (1) medical supply procurement; (2) generation, handling, and disposal of medical waste; and (3) pharmaceutical handling and disposal. Impacts discovered through ethnographic inquiry included occupational exposures to chemotherapy and infectious waste, and public health exposures to pharmaceutical waste. This study provides new insight into the environmental, occupational, and public health impacts resulting from medical practices. In many cases, the lack of clear guidance and regulations regarding environmental impacts contributed to elevated harms to the natural environment, workers, and the broader community.
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The association between US Army enlistment waivers and subsequent behavioral and social health outcomes and attrition from service.
Mil Med
PUBLISHED: 05-28-2013
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Soldiers granted enlistment waivers for medical concerns, misconduct, or positive alcohol/drug tests may or may not be associated with an increased likelihood of negative behavioral outcomes. Soldiers in the population examined (n = 8,943) who were granted enlistment waivers from 2003 to 2008 were significantly more likely to subsequently be screened for alcohol/substance abuse, test positive for illicit substances, or receive an Army separation for behavioral misconduct. These associations were highest among Soldiers granted waivers for nonlawful alcohol/drug violations. Soldiers granted waivers for felony offenses and serious nontraffic violations were significantly less likely to separate from the Army compared with Soldiers not granted enlistment waivers.
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Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial.
Lancet Neurol
PUBLISHED: 05-08-2013
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On the basis of mixed results from previous trials, we assessed whether therapeutic hypothermia for 48-72 h with slow rewarming improved mortality in children after brain injury.
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The epitope integration site for vaccine antigens determines virus control while maintaining efficacy in an engineered cancer vaccine.
Mol. Ther.
PUBLISHED: 04-09-2013
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Picornaviruses have been developed as potential therapies for gene delivery and vaccination. One drawback to their use is the potential for recombination and viral persistence. Therefore, the engineering strategies used must take into account the possibility for virus escape. We have developed Theilers murine encephalomyelitis virus (TMEV) as a potential vaccine vector for use in immunotherapy. This study shows that insertion of a vaccine epitope at a unique site within the TMEV leader protein can dramatically increase the type I interferon (IFN) response to infection and promote rapid viral clearance. This live virus vaccine maintains its ability to drive antigen-specific CD8(+) T-cell responses to a model antigen as well as to the weakly immunogenic tumor antigen Her2/neu. Furthermore, the epitope integration site does not affect the efficacy of this vaccine as cancer immunotherapy for treating models of melanoma and breast cancer as demonstrated by delayed tumor outgrowth and increased survival in animals implanted with these tumors. These findings show that an attenuated virus retaining limited ability to replicate nonetheless can effectively mobilize CD8(+) cellular immunity and will be important for the design of picornavirus vectors used as immunotherapy in clinical settings.
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A transactional and collaborative approach to reducing effects of bottom trawling.
Conserv. Biol.
PUBLISHED: 03-26-2013
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Private-sector financial and legal transactions have long been used to protect terrestrial habitats and working landscapes, but less commonly to address critical threats in marine environments. Transferrable and marketable fishing privileges, including permits and quotas, make it possible to use private-sector transactions as conservation strategies to address some fishery management issues. Abating the effects of bottom trawling on the seafloor and bycatch and discard associated with the practice has proven challenging. On the Central Coast of California, The Nature Conservancy (TNC), Environmental Defense Fund, local fishers and local, state, and federal authorities worked collaboratively to protect large areas of the seafloor from bottom trawling for groundfish while addressing economic impacts of trawl closures. Contingent on the adoption of trawl-closure areas by a federal regulatory agency, TNC used private funds to purchase federal groundfish trawl permits and vessels from willing sellers. Trawl-closure areas were designed collaboratively by combining regional biological diversity and fisheries data with local fishers knowledge. The private transactional strategy was designed to remedy some deficiencies in previous federal buyouts, to mitigate economic impacts from trawl closures, and to carefully align with a public regulatory process to protect "essential fish habitat" under the Magnuson-Stevens Fishery Conservation and Management Act. This collaborative effort protected 1.5 million ha (3.8 million acres) of seafloor, reduced trawl effort in the area by 50%, and set a precedent for collaborative partnerships between conservation and fishing interests. This is the first time a large conservation organization has taken an ownership position in a fishery and demonstrates how nongovernmental organizations can invest in fisheries to improve environmental and economic performance.
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Hypothermia decreases cerebrospinal fluid asymmetric dimethylarginine levels in children with traumatic brain injury.
Pediatr Crit Care Med
PUBLISHED: 02-27-2013
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Pathological increases in asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, have been implicated in endothelial dysfunction and vascular diseases. Reduced nitric oxide early after traumatic brain injury may contribute to hypoperfusion. Currently, methods to quantify asymmetric dimethylarginine in the cerebrospinal fluid have not been fully explored. We aimed to develop and validate a method to determine asymmetric dimethylarginine in the cerebrospinal fluid of a pediatric traumatic brain injury population and to use this method to assess the effects of 1) traumatic brain injury and 2) therapeutic hypothermia on this mediator.
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Baseline serum concentrations of zinc, selenium, and prolactin in critically ill children.
Pediatr Crit Care Med
PUBLISHED: 02-09-2013
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To describe serum concentrations of zinc, selenium, and prolactin in critically ill children within 72 hours of PICU admission, and to investigate relationships between these immunomodulators and lymphopenia.
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Hyperoxia and hypoxia in children resuscitated from cardiac arrest.
Pediatr Crit Care Med
PUBLISHED: 02-09-2013
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Ischemia depletes antioxidant reserves and impairs mitochondrial electron transport. Oxygen within blood reperfusing ischemic tissue can form free radicals, worsen oxidative stress, and exacerbate tissue injury (reperfusion injury). One strategy for limiting reperfusion injury is to limit delivery of "luxuriant" oxygen during or after reperfusion. Resuscitation guidelines for children with cardiac arrest recommend early weaning of supplemental oxygen as tolerated. There are currently no studies demonstrating the frequency and outcomes of hyperoxia and hypoxia after pediatric cardiac arrest.
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Brain tissue oxygen monitoring identifies cortical hypoxia and thalamic hyperoxia after experimental pediatric cardiac arrest.
Pediatr. Res.
PUBLISHED: 01-29-2013
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Background:Optimization of cerebral oxygenation after pediatric cardiac arrest (CA) may reduce neurological damage associated with the post-CA syndrome. We hypothesized that important alterations in regional partial pressure of brain tissue oxygen (PbO2) occur after resuscitation from CA and that clinically relevant interventions such as hyperoxia and blood pressure augmentation would influence PbO2.Methods:Cortical and thalamic PbO2 were monitored in immature rats subjected to asphyxial CA (9 or 12?min asphyxia) and sham-operated rats using oxygen sensors.Results:Thalamus and cortex showed similar baseline PbO2. Post-resuscitation there was early and sustained cortical hypoxia in an insult-duration fashion. In contrast, thalamic PbO2 initially increased four-fold, and afterwards returned to baseline values. PbO2 was FiO2-dependent, and the response to oxygen was more pronounced after a 9?min vs. 12?min CA. After a 12?min CA, PbO2 was modestly affected by blood pressure augmentation using epinephrine in the thalamus but not cortex.Conclusion:After asphyxial pediatric CA, there is marked regional variability of cerebral oxygenation. Cortical hypoxia is pronounced and appears early, while thalamic hyperoxia is followed by normoxia. Compromised PbO2 in the cortex may represent a relevant and clinically measurable therapeutic target aimed at improving neurological outcome after pediatric CA.Pediatric Research (2013); doi:10.1038/pr.2013.220.
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Pediatric traumatic brain injury in 2012: the year with new guidelines and common data elements.
Crit Care Clin
PUBLISHED: 01-04-2013
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Traumatic brain injury (TBI) remains the leading cause of death of children in the developing world. In 2012, several international efforts were completed to aid clinicians and researchers in advancing the field of pediatric TBI. The second edition of the Guidelines for the Medical Management of Traumatic Brain Injury in Infants, Children and Adolescents updated those published in 2003. This article highlights the processes involved in developing the Guidelines, contrasts the new guidelines with the previous edition, and delineates new research efforts needed to advance knowledge. The impact of common data elements within these potential new research fields is reviewed.
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Can inferred provenance and its visualisation be used to detect erroneous annotation? A case study using UniProtKB.
PLoS ONE
PUBLISHED: 01-01-2013
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A constant influx of new data poses a challenge in keeping the annotation in biological databases current. Most biological databases contain significant quantities of textual annotation, which often contains the richest source of knowledge. Many databases reuse existing knowledge; during the curation process annotations are often propagated between entries. However, this is often not made explicit. Therefore, it can be hard, potentially impossible, for a reader to identify where an annotation originated from. Within this work we attempt to identify annotation provenance and track its subsequent propagation. Specifically, we exploit annotation reuse within the UniProt Knowledgebase (UniProtKB), at the level of individual sentences. We describe a visualisation approach for the provenance and propagation of sentences in UniProtKB which enables a large-scale statistical analysis. Initially levels of sentence reuse within UniProtKB were analysed, showing that reuse is heavily prevalent, which enables the tracking of provenance and propagation. By analysing sentences throughout UniProtKB, a number of interesting propagation patterns were identified, covering over [Formula: see text] sentences. Over [Formula: see text] sentences remain in the database after they have been removed from the entries where they originally occurred. Analysing a subset of these sentences suggest that approximately [Formula: see text] are erroneous, whilst [Formula: see text] appear to be inconsistent. These results suggest that being able to visualise sentence propagation and provenance can aid in the determination of the accuracy and quality of textual annotation. Source code and supplementary data are available from the authors website at http://homepages.cs.ncl.ac.uk/m.j.bell1/sentence_analysis/.
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Predictive habitat modelling as a tool to assess the change in distribution and extent of an OSPAR priority habitat under an increased ocean temperature scenario: consequences for marine protected area networks and management.
PLoS ONE
PUBLISHED: 01-01-2013
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The aims of this study were to determine the extent and distribution of an OSPAR priority habitat under current baseline ocean temperatures; to illustrate the prospect for habitat loss under a changing ocean temperature scenario; and to demonstrate the potential application of predictive habitat mapping in "future-proofing" conservation and biodiversity management. Maxent modelling and GIS environmental envelope analysis of the biogenic bed forming species, Modiolus modiolus was carried out. The Maxent model was tested and validated using 75%/25% training/test occurrence records and validated against two sampling biases (the whole study area and a 20km buffer). The model was compared to the envelope analysis and the area under the receiver operating characteristic curve (Area Under the curve; AUC) was evaluated. The performance of the Maxent model was rated as good to excellent on all replicated runs and low variation in the runs was recorded from the AUC values. The extent of "most suitable", "less suitable" and "unsuitable" habitat was calculated for the baseline year (2009) and the projected increased ocean temperature scenarios (2030, 2050, 2080 and 2100). A loss of 100% of "most suitable" habitat was reported by 2080. Maintaining a suitable level of protection of marine habitats/species of conservation importance may require management of the decline and migration rather than maintenance of present extent. Methods applied in this study provide the initial application of a plausible "conservation management tool".
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The potential for bio-mediators and biomarkers in pediatric traumatic brain injury and neurocritical care.
Front Neurol
PUBLISHED: 01-01-2013
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The use of biomarkers of brain injury in pediatric neurocritical care has been explored for at least 15?years. Two general lines of research on biomarkers in pediatric brain injury have been pursued: (1) studies of "bio-mediators" in cerebrospinal fluid (CSF) of children after traumatic brain injury (TBI) to explore the components of the secondary injury cascades in an attempt to identify potential therapeutic targets and (2) studies of the release of structural proteins into the CSF, serum, or urine in order to diagnose, monitor, and/or prognosticate in patients with TBI or other pediatric neurocritical care conditions. Unique age-related differences in brain biology, disease processes, and clinical applications mandate the development and testing of brain injury bio-mediators and biomarkers specifically in pediatric neurocritical care applications. Finally, although much of the early work on biomarkers of brain injury in pediatrics has focused on TBI, new applications are emerging across a wide range of conditions specifically for pediatric neurocritical care including abusive head trauma, cardiopulmonary arrest, septic shock, extracorporeal membrane oxygenation, hydrocephalus, and cardiac surgery. The potential scope of the utility of biomarkers in pediatric neurocritical care is thus also discussed.
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The kinase activity of the Helicobacter pylori Asp-tRNA(Asn)/Glu-tRNA(Gln) amidotransferase is sensitive to distal mutations in its putative ammonia tunnel.
Biochemistry
PUBLISHED: 12-29-2011
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The Helicobacter pylori (Hp) Asp-tRNA(Asn)/Glu-tRNA(Gln) amidotransferase (AdT) plays important roles in indirect aminoacylation and translational fidelity. AdT has two active sites, in two separate subunits. Kinetic studies have suggested that interdomain communication occurs between these subunits; however, this mechanism is not well understood. To explore domain-domain communication in AdT, we adapted an assay and optimized it to kinetically characterize the kinase activity of Hp AdT. This assay was applied to the analysis of a series of point mutations at conserved positions throughout the putative AdT ammonia tunnel that connects the two active sites. Several mutations that caused significant decreases in AdTs kinase activity (reduced by 55-75%) were identified. Mutations at Thr149 (37 Å distal to the GatB kinase active site) and Lys89 (located at the interface of GatA and GatB) were detrimental to AdTs kinase activity, suggesting that these mutations have disrupted interdomain communication between the two active sites. Models of wild-type AdT, a valine mutation at Thr149, and an arginine mutation at Lys89 were subjected to molecular dynamics simulations. A comparison of wild-type, T149V, and K89R AdT simulation results unmasks 59 common residues that are likely involved in connecting the two active sites.
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Common data elements for pediatric traumatic brain injury: recommendations from the biospecimens and biomarkers workgroup.
J. Neurotrauma
PUBLISHED: 11-22-2011
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Biospecimens represent a critically important resource in pediatric brain injury research. Data from these specimens can be used to identify and classify injury, understand the molecular mechanisms underlying different types of brain injury, and ultimately identify therapeutic targets to tailor treatments for individual patient needs. To realize the full potential of biospecimens in pediatric traumatic brain injury (TBI), standardization and adoption of best practice guidelines are needed to ensure the quality and consistency of specimens. Multiple groups, including the National Cancer Institute (NCI), the International Society for Biological and Environmental Repositories (ISBER), and the Organisation for Economic Co-operation and Development (OECD), have previously published best practice guidelines for biospecimen resources. Recommendations have also been provided by the Biospecimens and Biomarkers Workgroup of the interagency TBI Common Data Elements (CDE) initiative. The recommendations from all of these sources, however, focus exclusively on adult biospecimen collection. There are no published pediatric-specific biospecimen collection guidelines. An additional workgroup was formed to specifically address this gap. The aim of the Pediatric TBI CDE Biospecimens and Biomarkers Workgroup was to provide recommendations for best practice guidelines to standardize the quality and accessibility of biospecimens for pediatric brain injury research in general, and for pediatric TBI research in particular. Consensus recommendations were developed by review of previously published adult-specific recommendations, including the recommendations of the original TBI Common Data Elements Biospecimens and Biomarkers Workgroup, and by participation in the interagency workshop "Common Data Elements for TBI Research: Pediatric Considerations," held in Houston, Texas in March of 2010. These recommendations represent expert opinion on this subject. The authors of this article were members of the Biospecimens Workgroup. We hope that with adoption of these best practices, future investigators will be able to obtain biospecimens in a consistent way that meets the needs of pediatric patients, and helps to accelerate acquisition of pediatric-specific biomarker data.
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Brain injuries and neurological system failure are the most common proximate causes of death in children admitted to a pediatric intensive care unit.
Pediatr Crit Care Med
PUBLISHED: 11-09-2011
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Mortality rates from critical illness in children have declined over the past several decades, now averaging between 2% and 5% in most pediatric intensive care units. Although these rates, and mortality rates from specific disorders, are widely understood, the impact of acute neurologic injuries in such children who die and the role of these injuries in the cause of death are not well understood. We hypothesized that neurologic injuries are an important cause of death in children.
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Common data elements for pediatric traumatic brain injury: recommendations from the working group on demographics and clinical assessment.
J. Neurotrauma
PUBLISHED: 11-07-2011
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The Common Data Elements (CDEs) initiative is a National Institutes of Health (NIH) interagency effort to standardize naming, definitions, and data structure for clinical research variables. Comparisons of the results of clinical studies of neurological disorders have been hampered by variability in data coding, definitions, and procedures for sample collection. The CDE project objective is to enable comparison of future clinical trials results in major neurological disorders, including traumatic brain injury (TBI), stroke, multiple sclerosis, and epilepsy. As part of this effort, recommendations for CDEs for research on TBI were developed through a 2009 multi-agency initiative. Following the initial recommendations of the Working Group on Demographics and Clinical Assessment, a separate workgroup developed recommendations on the coding of clinical and demographic variables specific to pediatric TBI studies for subjects younger than 18 years. This article summarizes the selection of measures by the Pediatric TBI Demographics and Clinical Assessment Working Group. The variables are grouped into modules which are grouped into categories. For consistency with other CDE working groups, each variable was classified by priority (core, supplemental, and emerging). Templates were produced to summarize coding formats, guide selection of data points, and provide procedural recommendations. This proposed standardization, together with the products of the other pediatric TBI working groups in imaging, biomarkers, and outcome assessment, will facilitate multi-center studies, comparison of results across studies, and high-quality meta-analyses of individual patient data.
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Use of the Sheffield telescopic intramedullary rod system for the management of osteogenesis imperfecta: clinical outcomes at an average follow-up of nineteen years.
J Bone Joint Surg Am
PUBLISHED: 11-04-2011
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Elongating intramedullary rods have been used in the management of osteogenesis imperfecta for the past fifty years. The complication rates reported in many reviews of the available techniques have been high. This study reviews the long-term functional outcomes and complications following the use of the Sheffield system of telescopic intramedullary rods.
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The association between deployment-related posttraumatic growth among U.S. Army soldiers and negative behavioral health conditions.
J Clin Psychol
PUBLISHED: 10-31-2011
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This study assessed posttraumatic growth (PTG) in a sample of U.S. Army Soldiers using the Post-Traumatic Growth Inventory (PTGI), and the relationship between PTG and negative behavioral health (BH) conditions.
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Q fever diagnosis in domestic ruminants: comparison between complement fixation and commercial enzyme-linked immunosorbent assays.
J. Vet. Diagn. Invest.
PUBLISHED: 09-13-2011
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Q fever is an important zoonotic disease caused by infection with the bacterium Coxiella burnetii. Veterinary diagnostic laboratories, including the Veterinary Laboratories Agency (VLA) in England and Wales, have traditionally relied on the complement fixation test (CFT) for serological diagnosis. However, Q fever has assumed greater significance in recent years following several large human outbreaks linked to exposure to infected ruminants and it is essential that more reliable tests are introduced to detect the presence of C. burnetii infection in animals. The objective of the current study was to evaluate the performance of 3 commercially available enzyme-linked immunosorbent assays (ELISAs) for detection of antibodies to C. burnetii and to compare the findings with the CFT using a sample panel of 548 sera from sheep, goats, and cattle, including animals of known disease status. The statistical analysis using TAGS (test accuracy in the absence of a gold standard) software and receiver operating characteristic techniques demonstrated that the 3 ELISAs all showed improved sensitivity over the CFT. The test based on ovine antigen demonstrated the best overall performance and therefore, the VLA has adopted this test for routine use.
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Non-invasive diagnosis of pulmonary hypertension: ESC/ERS Guidelines with Updated Commentary of the Cologne Consensus Conference 2011.
Int. J. Cardiol.
PUBLISHED: 08-24-2011
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The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the diagnosis of pulmonary hypertension. However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the non-invasive diagnosis of pulmonary hypertension. This manuscript describes in detail the results and recommendations of the working group which were last updated in October 2011.
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Sustained hyperaemia stimulus is necessary to induce flow-mediated dilation of the human brachial artery.
Clin Physiol Funct Imaging
PUBLISHED: 07-19-2011
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We studied the relative importance of the magnitude and duration of the shear stimulus to induce flow-mediated dilation (FMD) in the brachial artery of 10 healthy men by ultrasound imaging. The shear stress stimulus was induced by different durations of reactive hyperaemia following 15-min forearm occlusion. The control condition of continuous postocclusion hyperaemia was compared to 20, 40 and 60?s of reactive hyperaemia followed by reapplication of circulatory arrest for 2?min and a second cuff release. In response to the first cuff release, peak shear rate was not different between conditions; total shear during the first minute was reduced in the 40?s and further reduced in the 20?s conditions. FMD in control (10·0?±?3·0%), 60?s (10·5?±?3·2%) and 40?s (7·8?±?3·6%) were greater than the 20-s condition (2·9?±?2·8%). At second cuff release, peak shear of the 20-s condition was slightly reduced from the first release, but 40 and 60-s conditions were progressively reduced. Total shear to peak dilation was reduced after the second cuff release for the 20 and 40-s conditions and further after the 60-s condition. FMD was maintained in the 20-s condition (8·3?±?3·7%) but reduced in the 40-s (3·7?±?1·7%) and 60-s conditions (1·5?±?2·6%). FMD was not related to peak shear rate after the first occlusion (r?=?0·003) but was after the second cuff release (r?=?0·32, P?=?0·004). The FMD response was correlated with the total shear to time of peak diameter after the first (r?=?0·35, P<0·001) and the second (r?=?0·25, P?=?0·009) cuff release.
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Donation after cardiocirculatory death: a call for a moratorium pending full public disclosure and fully informed consent.
Philos Ethics Humanit Med
PUBLISHED: 07-15-2011
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Many believe that the ethical problems of donation after cardiocirculatory death (DCD) have been "worked out" and that it is unclear why DCD should be resisted. In this paper we will argue that DCD donors may not yet be dead, and therefore that organ donation during DCD may violate the dead donor rule. We first present a description of the process of DCD and the standard ethical rationale for the practice. We then present our concerns with DCD, including the following: irreversibility of absent circulation has not occurred and the many attempts to claim it has have all failed; conflicts of interest at all steps in the DCD process, including the decision to withdraw life support before DCD, are simply unavoidable; potentially harmful premortem interventions to preserve organ utility are not justifiable, even with the help of the principle of double effect; claims that DCD conforms with the intent of the law and current accepted medical standards are misleading and inaccurate; and consensus statements by respected medical groups do not change these arguments due to their low quality including being plagued by conflict of interest. Moreover, some arguments in favor of DCD, while likely true, are "straw-man arguments," such as the great benefit of organ donation. The truth is that honesty and trustworthiness require that we face these problems instead of avoiding them. We believe that DCD is not ethically allowable because it abandons the dead donor rule, has unavoidable conflicts of interests, and implements premortem interventions which can hasten death. These important points have not been, but need to be fully disclosed to the public and incorporated into fully informed consent. These are tall orders, and require open public debate. Until this debate occurs, we call for a moratorium on the practice of DCD.
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Methods for the enhancement of fingermarks in blood.
Forensic Sci. Int.
PUBLISHED: 04-01-2011
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Fingermarks formed in or by blood often require specific development techniques. This review examines techniques and materials that may be used to enhance and record fingermarks deposited in blood or fingermarks generated by blood-contaminated papillary ridges. A large number of techniques are presented here and are discussed from a chemical as well as practical perspective. It is concluded that an optimized sequence of techniques targeting both latent (non-bloody) and bloody fingermarks must be applied to detect and enhance the maximum number of marks, and therefore optimize the information content from exhibits that may bear marks in blood.
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Translating biomarkers research to clinical care: applications and issues for rehabilomics.
PM R
PUBLISHED: 03-23-2011
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Traumatic brain injury is a leading cause of morbidity and mortality in adults and children in the United States. Despite steady improvement in our understanding of the pathophysiology of acquired brain injuries, there has been remarkably little improvement in brain injury therapies and/or pharmacologic treatments over the past decade. One of the reasons may be the inability to properly stratify subjects for clinical trials and/or to have real-time assessment of the effectiveness of a given intervention. It has been recognized for several decades that serum biomarkers may allow for more objective subject stratification as well as act as surrogate markers of treatment efficacy. Despite numerous studies, however, biomarkers are not currently part of clinical practice in either acquired brain injury or other neurologic or musculoskeletal disorders. The goals of this review article, therefore, are to use traumatic brain injury as a example to discuss the use of biomarkers in clinical and randomized controlled trials; to briefly discuss the field of neuroproteomics and its interface with neurologic interventions; and to provide an overview of the collaborative pathway between academia and industry, which needs to be an integral part of the translation of biomarkers from the bench to the bedside in any clinical population. Introduction of the concept of rehabilomics and implications of biomarker use for the physical medicine and rehabilitation physician also are discussed.
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The kinematic features of motorcycles in congested urban networks.
Accid Anal Prev
PUBLISHED: 03-11-2011
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The aim of this paper is to compare the kinematic features of motorcycles with those of passenger cars in urban traffic. The hypothesis that motorcycles capability to swerve in urban traffic contributes to their seemingly assertive behaviour is examined. Data for this study were collected in afternoon peak hours at Central London using video recorders. Detailed information on the trajectories of 2109 vehicles (including 477 motorcycles and 1293 passenger cars) was extracted from the video images and the observable kinematic features were analysed. In addition, a model describing the longitudinal following behaviour of motorcycles was employed to analyse the impacts of motorcycles swerving behaviour. The model was calibrated using Markov Chain Monte Carlo (MCMC) numerical methods. The observable kinematic features show that in comparison to passenger cars, motorcycles have shorter safety gaps, higher speeds and severer acceleration and deceleration rates reflecting their generally much higher power to weight ratios and usage of available braking power. However, the data also support the hypothesis that motorcyclists maintain a considerable safety margin as they have the ability to avoid a collision by swerving away.
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Theilers murine encephalomyelitis virus as a vaccine candidate for immunotherapy.
PLoS ONE
PUBLISHED: 03-02-2011
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The induction of sterilizing T-cell responses to tumors is a major goal in the development of T-cell vaccines for treating cancer. Although specific components of anti-viral CD8+ immunity are well characterized, we still lack the ability to mimic viral CD8+ T-cell responses in therapeutic settings for treating cancers. Infection with the picornavirus Theilers murine encephalomyelitis virus (TMEV) induces a strong sterilizing CD8+ T-cell response. In the absence of sterilizing immunity, the virus causes a persistent infection. We capitalized on the ability of TMEV to induce strong cellular immunity even under conditions of immune deficiency by modifying the virus to evaluate its potential as a T-cell vaccine. The introduction of defined CD8+ T-cell epitopes into the leader sequence of the TMEV genome generates an attenuated vaccine strain that can efficiently drive CD8+ T-cell responses to the targeted antigen. This virus activates T-cells in a manner that is capable of inducing targeted tissue damage and glucose dysregulation in an adoptive T-cell transfer model of diabetes mellitus. As a therapeutic vaccine for the treatment of established melanoma, epitope-modified TMEV can induce strong cytotoxic T-cell responses and promote infiltration of the T-cells into established tumors, ultimately leading to a delay in tumor growth and improved survival of vaccinated animals. We propose that epitope-modified TMEV is an excellent candidate for further development as a human T-cell vaccine for use in immunotherapy.
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The immediate placement of dental implants into extraction sites with periapical lesions: a retrospective chart review.
J. Oral Maxillofac. Surg.
PUBLISHED: 01-18-2011
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The purpose of this study was to evaluate the success of dental implants placed immediately into extraction sites in the presence of chronic periapical pathology.
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Herbicide resistances in Amaranthus tuberculatus: a call for new options.
J. Agric. Food Chem.
PUBLISHED: 11-12-2010
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Amaranthus tuberculatus is a major weed of crop fields in the midwestern United States. Making this weed particularly problematic to manage is its demonstrated ability to evolve resistance to herbicides. Herbicides to which A. tuberculatus has evolved resistance are photosystem II inhibitors, acetolactate synthase inhibitors, protoporphyrinogen oxidase inhibitors, and glyphosate. Many populations of A. tuberculatus contain more than one of these resistances, severely limiting the options for effective herbicide control. A survey of multiple-herbicide resistance in A. tuberculatus revealed that all populations resistant to glyphosate contained resistance to acetolactate synthase inhibitors, and 40% contained resistance to protoporphyrinogen oxidase inhibitors. The occurrences of multiple-herbicide resistances in A. tuberculatus illustrate the need for continued herbicide discovery efforts and/or the development of new strategies for weed management.
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Physiological responses and air consumption during simulated firefighting tasks in a subway system.
Appl Physiol Nutr Metab
PUBLISHED: 10-22-2010
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Professional firefighters (33 men, 3 women), ranging in age from 30 to 53 years, participated in a simulation of a subway system search and rescue while breathing from their self-contained breathing apparatus (SCBA). We tested the hypothesis that during this task, established by expert firefighters to be of moderate intensity, the rate of air consumption would exceed the capacity of a nominal 30-min cylinder. Oxygen uptake, carbon dioxide output, and air consumption were measured with a portable breath-by-breath gas exchange analysis system, which was fully integrated with the expired port of the SCBA. The task involved descending a flight of stairs, walking, performing a search and rescue, retreat walking, then ascending a single flight of stairs to a safe exit. This scenario required between 9:56 and 13:24 min:s (mean, 12:10 ± 1:10 min:s) to complete, with an average oxygen uptake of 24.3 ± 4.5 mL kg(-1) min(-1) (47 ± 10 % peak oxygen uptake) and heart rate of 76% ± 7% of maximum. The highest energy requirement was during the final single-flight stair climb (30.4 ± 5.4 mL kg(-1) min(-1)). The average respiratory exchange ratio (carbon dioxide output/oxygen uptake) throughout the scenario was 0.95 ± 0.08, indicating a high carbon dioxide output for a relatively moderate average energy requirement. Air consumption from the nominal "30-min" cylinder averaged 51% (range, 26%-68%); however, extrapolation of these rates of consumption suggested that the low-air alarm, signalling that only 25% of the air remains, would have occurred as early as 11 min for an individual with the highest rate of air consumption, and at 16 min for the group average. These data suggest that even the moderate physical demands of walking combined with search and rescue while wearing full protective gear and breathing through the SCBA impose considerable physiological strain on professional firefighters. As well, the rate of air consumption in these tasks classed as moderate, compared with high-rise firefighting, would have depleted the air supply well before the nominal time used to describe the cylinders.
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Endothelin-1 is increased in cerebrospinal fluid and associated with unfavorable outcomes in children after severe traumatic brain injury.
J. Neurotrauma
PUBLISHED: 09-17-2010
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Severe pediatric traumatic brain injury (TBI) is associated with unfavorable outcomes secondary to injury from activation of the inflammatory cascade, the release of excitotoxic neurotransmitters, and changes in the reactivity of cerebral vessels, causing ischemia. Hypoperfusion of injured brain tissues after TBI is also associated with unfavorable outcomes. Therapeutic hypothermia is an investigational treatment strategy for use in patients with severe TBI that has shown differential effects on various cerebrospinal fluid (CSF) mediators in pediatric patients. Endothelin-1 (ET-1) is a powerful vasoconstrictor that exerts its effects on the cerebrovascular endothelium for sustained periods after TBI. The purpose of this study was to determine if CSF concentrations of ET-1 are increased after severe TBI in children, and if they are associated with demographics and outcomes that are affected by therapeutic hypothermia. This was an ancillary study to a prospective, randomized-controlled trial of early hypothermia in a tertiary care pediatric intensive care unit. Children (n?=?34, age 3 months-15 years) suffering from severe TBI were randomized to hypothermia (n?=?19) and normothermia (n?=?15) as part of the efficacy study. Children undergoing diagnostic lumbar puncture (n?=?11) to rule out infection were used as controls. Patients received either mild to moderate hypothermia (32-33°C) or normothermia as part of their treatment protocol. CSF was serially collected during the first 5 days after TBI. ET-1 concentrations were quantitated in patient and control CSF samples by a validated ELISA in duplicate with a limit of quantification of 0.195?pg/mL. CSF ET-1 concentrations were increased by two- to threefold in children after TBI compared to controls, and the increase was sustained for up to 5 days post-TBI. This relationship was not affected by hypothermia, and there were no differences in ET-1 response between children with inflicted and accidental TBI. Group-based trajectory analysis revealed two distinct groups with similar ET-1 levels over time. Univariate analysis showed a significant association between ET-1 levels and Glasgow Outcome Scale (GOS) scores, for which higher ET-1 levels over time were associated with unfavorable outcomes. ET-1 is increased in children with severe TBI and is associated with unfavorable outcomes. This increase in ET-1 may mediate the hypoperfusion or cerebrovascular dysfunction accompanying severe TBI in children. Importantly, hypothermia does not affect the brains ET-1 response as measured in the CSF.
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Placental inflammation and fetal hemodynamics in a rat model of chorioamnionitis.
Pediatr. Res.
PUBLISHED: 08-26-2010
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The relative contributions of inflammation and ischemia to the pathogenesis of periventricular leukomalacia (PVL) have not been elucidated. We hypothesized that fetal cardiovascular function and cerebral blood flow velocity (BFV) would be decreased in a rat model of chorioamnionitis. We also tested whether placental inflammation was related to proximity to the cervix in our model of chorioamnionitis [intracervical lipopolysaccharide (LPS) or vehicle (PBS) injection]. On embryonic d 15, Sprague-Dawley rats underwent baseline maternal and fetal echocardiography, followed by LPS or PBS injection, then serial echocardiographic evaluations until embryonic day (ED) 21. One hour after birth, pups had middle cerebral artery (MCA) BFV measured. Placentas of LPS-exposed pups exhibited uniform, higher inflammation grades (p < 0.001). All fetal BFVs increased with advancing GA (p < 0.001) whereas resistance index (RI) decreased (p < 0.001). There was no difference in fetal BFV between the groups other than a reduced gestation-related increase in descending aorta BFV in LPS-exposed rats (p < 0.05). Newborn pups exposed to LPS had lower heart rate (p = 0.006) and MCA BFV (p = 0.024) and higher RI (p = 0.003) and pulsatility index (PI; p = 0.004). In conclusion, intracervical LPS injection produces an inflammation independent of placental position, a blunted increase in gestation-related aortic BFV, and a decrease in MCA BFV in newborn pups.
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Quo vadis 2010? - carpe diem: challenges and opportunities in pediatric traumatic brain injury.
Dev. Neurosci.
PUBLISHED: 07-30-2010
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Traumatic brain injury (TBI) in infants and children remains a public health problem of enormous magnitude. It is a complex and heterogeneous condition that presents many diagnostic, therapeutic and prognostic challenges. A number of investigative teams are studying pediatric TBI both in experimental models and in clinical studies at the bedside. This review builds on work presented in a prior supplement to Developmental Neuroscience that was published in 2006, and addresses several active areas of research on this topic, including (1) the application of novel imaging methods, (2) the use of serum and/or CSF biomarkers of injury, (3) advances in neuromonitoring, (4) the development and testing of novel therapies, (5) developments in modeling pediatric TBI, (6) the consideration of a new approach to classification of pediatric TBI, and (7) assessing the potential impact of the development of pediatric and neonatal neurocritical care services on the management and outcome of pediatric TBI.
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Avoiding flexor tendon repair rupture with intraoperative total active movement examination.
Plast. Reconstr. Surg.
PUBLISHED: 05-14-2010
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Wide-awake flexor tendon repair in tourniquet-free unsedated patients permits intraoperative Total Active Movement examination (iTAMe) of the freshly repaired flexor tendon. This technique has permitted the intraoperative observation of tendon repair gapping induced by active movement when the core suture is tied too loosely. The gap can be repaired intraoperatively to decrease postoperative tendon repair rupture rates. The authors record their rupture rate in the first 15 years of experience with iTAMe.
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The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell survival.
J. Immunol.
PUBLISHED: 05-07-2010
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The expression of pathogen recognition receptors in human FOXP3+ T regulatory cells is established, yet the function of these receptors is currently obscure. In the process of studying the function of both peripheral and lamina propria FOXP3+ lymphocytes in patients with the human inflammatory bowel disease Crohns disease, we observed a clear deficiency in the quantity of FOXP3+ lymphocytes in patients with disease-associated polymorphisms in the pathogen recognition receptor gene NOD2. Subsequently, we determined that the NOD2 ligand, muramyl dipeptide (MDP), activates NF-kappaB in primary human FOXP3+ T cells. This activation is functionally relevant, as MDP-stimulated human FOXP3+ T cells are protected from death receptor Fas-mediated apoptosis. Importantly, apoptosis protection was not evident in MDP-stimulated FOXP3+ T cells isolated from a patient with the disease-associated polymorphism. Thus, we propose that one function of pathogen recognition receptors in human T regulatory cells is the protection against death receptor-mediated apoptosis in a Fas ligand-rich environment, such as that of the inflamed intestinal subepithelial space.
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The investigation of a relative contrast index model for fingerprint quantification.
Forensic Sci. Int.
PUBLISHED: 05-03-2010
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The quantification of fingerprint contrast is a relatively new concept in fingerprint enhancement research. It has emerged as a mode of fingerprint assessment to reduce the potential biased of visual qualitative assessment. Subjective qualitative methods that are currently reported in the literature include; side-by-side assessment, assigning a score to a treatment based on visible criteria and stating observed results without presenting supporting validation. These qualitative methods often do not state clearly the visual assessment parameters and produce a degree of ambiguity when defining the enhancement results. The relative contrast index model was constructed to empirically quantify the difference in contrast between fingerprint ridges and valleys, using measurements gained from a microspectrophotometer. This paper seeks to further investigate this recent research and test the model using three different microspectrophotometers. Data from these separate sources will determine whether the theoretical aspects of the model would pragmatically produce reliable and repeatable results across a range of microspectrophotometers found in forensic laboratories.
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Closed reduction and stabilization of supracondylar fractures of the humerus in children: the crucial factor of surgical experience.
J Pediatr Orthop B
PUBLISHED: 05-01-2010
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We reviewed the outcome following operative management of displaced (Gartland II and III) supracondylar fractures of the humerus in children over a 2-year period and tried to correlate the outcome with various factors including experience of the treating surgeon. Of the 71 children who formed the study group, 62 (87.3%) had a good outcome irrespective of the treatment modality. Closed reduction followed by plaster immobilization or percutaneous pinning resulted in a better outcome than open reduction. There was a direct involvement of the consultant in the primary management of these injuries in 17 cases (24%), none of which had a poor outcome. Of the 54 cases in whom the primary management was carried out independently by trainees without any consultant supervision, nine patients (17%) developed complications or needed reoperations. The proportion of unsatisfactory outcomes increased to 20.3% when failure to achieve a satisfactory reduction by closed means was also considered as a perioperative complication. There is a learning curve associated with percutaneous pinning after closed reduction and experience of the surgeon seems to be one of the factors that have an influence on the outcome.
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?-Synuclein levels are elevated in cerebrospinal fluid following traumatic brain injury in infants and children: the effect of therapeutic hypothermia.
Dev. Neurosci.
PUBLISHED: 04-06-2010
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?-Synuclein is one of the most abundant proteins in presynaptic terminals. Normal expression of ?-synuclein is essential for neuronal survival and it prevents the initiation of apoptosis in neurons through covalent cross-linking of cytochrome c released from mitochondria. Exocytosis of ?-synuclein occurs with neuronal mitochondrial dysfunction, making its detection in cerebrospinal fluid (CSF) of children after severe traumatic brain injury (TBI) a potentially important marker of injury. Experimental therapeutic hypothermia (TH) improves mitochondrial function and attenuates cell death, and therefore may also affect CSF ?-synuclein concentrations. We assessed ?-synuclein levels in CSF of 47 infants and children with severe TBI using a commercial ELISA for detection of monomeric protein. 23 patients were randomized to TH based on published protocols where cooling (32-33°C) was initiated within 6-24 h, maintained for 48 h, and then followed by slow rewarming. CSF samples were obtained continuously via an intraventricular catheter for 6 days after TBI. Control CSF (n = 9) was sampled from children receiving lumbar puncture for CSF analysis of infection that was proven negative. Associations of initial Glasgow Coma Scale (GCS) score, age, gender, treatment, mechanism of injury and Glasgow Outcome Scale (GOS) score with CSF ?-synuclein were compared by multivariate regression analysis. CSF ?-synuclein levels were elevated in TBI patients compared to controls (p = 0.0093), with a temporal profile showing an early, approximately 5-fold increase on days 1-3 followed by a delayed, >10-fold increase on days 4-6 versus control. ?-Synuclein levels were higher in patients treated with normothermia versus hypothermia (p = 0.0033), in patients aged <4 years versus ?4 years (p < 0.0001), in females versus males (p = 0.0007), in nonaccidental TBI versus accidental TBI victims (p = 0.0003), and in patients with global versus focal injury on computed tomography of the brain (p = 0.046). Comparisons of CSF ?-synuclein levels with initial GCS and GOS scores were not statistically significant. Further studies are needed to evaluate the conformational status of ?-synuclein in CSF, and whether TH affects ?-synuclein aggregation.
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Relationship of intracranial pressure and cerebral perfusion pressure with outcome in young children after severe traumatic brain injury.
Dev. Neurosci.
PUBLISHED: 03-22-2010
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Traumatic brain injury (TBI) is the most common cause of death for children less than 18 years of age. Current standards of care for children with severe TBI include monitoring of intracranial pressure (ICP), and goal-directed therapies to minimize ICP and optimize cerebral perfusion pressure (CPP; the mathematical difference between the mean arterial pressure and ICP). Current guidelines for ICP and CPP thresholds suggest that age-based thresholds should be adopted, but few studies have included the youngest children affected by TBI (those <2 years of age). We performed a retrospective analysis of our pediatric neurotrauma database to determine if ICP and CPP thresholds associated with favorable neurological outcome could be determined, or if the number of episodic alterations in the parameters (ICP >15 or >20 mm Hg; CPP <40 mm Hg, <45 mm Hg or <50 mm Hg) was different between children with favorable and unfavorable outcomes (based on dichotomous Glasgow Outcome Scale score at 6 months after TBI). Data from 22 children (of whom 81% had suffered from inflicted childhood neurotrauma) were analyzed in the first 7 days. Children with unfavorable outcome had more hourly readings of CPP of <45 mm Hg compared to children with favorable outcome [median (25-75%): 2 (1-31) vs. 0 (0-2); p <0.05]. There was no difference between the number of hourly readings of ICP of >20 mm Hg between the outcome groups [median (25-75%): favorable 0 (0-1) vs. unfavorable 1 (0-4); p = 0.17]. To our knowledge, this is the first exploratory report to test if CPP and ICP thresholds can be established for this young population of children after TBI, and it suggests a CPP target threshold of 45 mm Hg. Despite good ICP control in this population, there was still a 50% incidence of unfavorable outcome, suggesting that there may be unique physiologic parameters that need to be targeted in infants with severe TBI. A prospective study is needed to fully determine what goals should be targeted for this vulnerable population.
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Rates of hospital-acquired respiratory illness in Bangladeshi tertiary care hospitals: results from a low-cost pilot surveillance strategy.
Clin. Infect. Dis.
PUBLISHED: 03-10-2010
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Patients hospitalized in resource-poor health care settings are at increased risk for hospital-acquired respiratory infections due to inadequate infrastructure.
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How I cool children in neurocritical care.
Neurocrit Care
PUBLISHED: 02-11-2010
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Brain injury is the leading cause of death in our pediatric ICU [Au et al. Crit Care Med 36:A128, 2008]. Clinical care for brain injury remains largely supportive. Therapeutic hypothermia has been shown to be effective in improving neurological outcome after adult ventricular-arrhythmia-induced cardiac arrest and neonatal asphyxia, and is under investigation as a neuroprotectant after cardiac arrest and traumatic brain injury in children in our ICU and other centers. To induce hypothermia in children comatose after cardiac arrest we target 32-34 degrees C using cooling blankets and intravenous iced saline as primary methods for induction, for 24-72 h duration with vigilant re-warming. The objective of this article is to share our hypothermia protocol for cooling children with acute brain injury.
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Adenosine A1 receptor activation as a brake on the microglial response after experimental traumatic brain injury in mice.
J. Neurotrauma
PUBLISHED: 02-04-2010
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We reported that adenosine A(1) receptor (A(1)AR) knockout (KO) mice develop lethal status epilepticus after experimental traumatic brain injury (TBI), which is not seen in wild-type (WT) mice. Studies in epilepsy, multiple sclerosis, and neuro-oncology suggest enhanced neuro-inflammation and/or neuronal death in A(1)AR KO. We hypothesized that A(1)AR deficiency exacerbates the microglial response and neuronal damage after TBI. A(1)AR KO and WT littermates were subjected to mild controlled cortical impact (3 m/sec; 0.5 mm depth) to left parietal cortex, an injury level below the acute seizure threshold in the KO. At 24 h or 7 days, mice were sacrificed and serial sections prepared. Iba-1 immunostaining was used to quantify microglia at 7 days. To assess neuronal injury, sections were stained with Fluoro-Jade C (FJC) at 24 h to evaluate neuronal death in the hippocampus and cresyl violet staining at 7 days to analyze cortical lesion volumes. We also studied the effects of adenosine receptor agonists and antagonists on (3)H-thymidine uptake (proliferation index) by BV-2 cells (immortalized mouse microglial). There was no neuronal death in CA1 or CA3 quantified by FJC. A(1)AR KO mice exhibited enhanced microglial response; specifically, Iba-1 + microglia were increased 20-50% more in A(1)AR KO versus WT in ipsilateral cortex, CA3, and thalamus, and contralateral cortex, CA1, and thalamus (p < 0.05). However, contusion and cortical volumes did not differ between KO and WT. Pharmacological studies in cultured BV-2 cells indicated that A(1)AR activation inhibits microglial proliferation. A(1)AR activation is an endogenous inhibitor of the microglial response to TBI, likely via inhibition of proliferation, and this may represent a therapeutic avenue to modulate microglia after TBI.
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Severe hypernatremia in a hospitalized child: munchausen by proxy.
Pediatr. Neurol.
PUBLISHED: 01-28-2010
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An 8-week-old infant presented to a referring institution with profuse diarrhea and infectious enteritis for 1 week. He was initially treated for suspected Salmonella spp. sepsis and meningitis, because the organism was found in the stool, but the childs illness progressed, manifested by paroxysmal profuse diarrhea and increased urine output. After several weeks, he suffered a sagittal venous thrombosis and intracranial hemorrhage. Subsequently the child was transferred to a tertiary center for intestinal evaluation. The patients diarrhea and excessive diuresis resolved, and his sodium normalized soon after transfer. Four days later, however, after his mother arrived, he immediately developed severe hypernatremia (serum sodium concentration [Na(+)] = 214 mEq/L), with resumption of diarrhea and excessive diuresis. A gastric aspirate during the crisis demonstrated an extremely high sodium content, [Na(+)] = 1416 mEq/L, consistent with salt intoxication. Surveillance of the mother revealed that she manipulated the indwelling nasogastric tube; confronted, she admitted to salt administration. This case describes one of the ways that Munchausen syndrome by proxy can manifest with profound neurologic sequelae, and highlights the need for close observation and swift intervention when sufficient cause is present.
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Peripheral nerve gap repair facilitated by a dynamic tension device.
Can J Plast Surg
PUBLISHED: 01-26-2010
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End-to-end neurorrhaphy remains the gold standard for transected nerve repair. However, the current dogma is that to be successful, nerve repairs must be tension free. Therefore, nerve gaps are most commonly repaired with grafts. While there is evidence that nerves can regenerate successfully after initial approximation under a tensile force, the amount of tension that deters regeneration of human nerves remains unclear. The present paper describes a case in which a favourable functional outcome was obtained following repair of a median nerve gap that was reduced by a dynamic tension device. The case provides some evidence that modest separations between stumps can be overcome by dynamic tension, enabling primary end-to-end repair of nerve gaps.
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Neurological sequelae of 2009 influenza A (H1N1) in children: a case series observed during a pandemic.
Pediatr Crit Care Med
PUBLISHED: 01-19-2010
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To outline a series of cases demonstrating neurologic complications in children with Influenza infection. The ongoing 2009 influenza A (H1N1) presents significant challenges to the field of pediatric critical care and requires increased awareness of new presentations and sequelae of infection. Since World Health Organization declared a H1N1 pandemic, much attention has been focused on its respiratory manifestations of the illness, but limited information regarding neurologic complications has been reported.
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Adaptive evolution of pelvic reduction in sticklebacks by recurrent deletion of a Pitx1 enhancer.
Science
PUBLISHED: 12-10-2009
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The molecular mechanisms underlying major phenotypic changes that have evolved repeatedly in nature are generally unknown. Pelvic loss in different natural populations of threespine stickleback fish has occurred through regulatory mutations deleting a tissue-specific enhancer of the Pituitary homeobox transcription factor 1 (Pitx1) gene. The high prevalence of deletion mutations at Pitx1 may be influenced by inherent structural features of the locus. Although Pitx1 null mutations are lethal in laboratory animals, Pitx1 regulatory mutations show molecular signatures of positive selection in pelvic-reduced populations. These studies illustrate how major expression and morphological changes can arise from single mutational leaps in natural populations, producing new adaptive alleles via recurrent regulatory alterations in a key developmental control gene.
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Structure-guided expansion of kinase fragment libraries driven by support vector machine models.
Biochim. Biophys. Acta
PUBLISHED: 09-16-2009
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This work outlines a new de novo design process for the creation of novel kinase inhibitor libraries. It relies on a profiling paradigm that generates a substantial amount of kinase inhibitor data from which highly predictive QSAR models can be constructed. In addition, a broad diversity of X-ray structure information is needed for binding mode prediction. This is important for scaffold and substituent site selection. Borrowing from FBDD, the process involves fragmentation of known actives, proposition of binding mode hypotheses for the fragments, and model-driven recombination using a pharmacophore derived from known kinase inhibitor structures. The support vector machine method, using Merck atom pair derived fingerprint descriptors, was used to build models from activity from 6 kinase assays. These models were qualified prospectively by selecting and testing compounds from the internal compound collection. Overall hit and enrichment rates of 82% and 2.5%, respectively, qualified the models for use in library design. Using the process, 7 novel libraries were designed, synthesized and tested against these same 6 kinases. The results showed excellent results, yielding a 92% hit rate for the 179 compounds that made up the 7 libraries. The results of one library designed to include known literature compounds, as well as an analysis of overall substituent frequency, are discussed.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.