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1.  Mutations in NGLY1 Cause an Inherited Disorder of the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway 
The endoplasmic reticulum-associated degradation (ERAD) pathway is responsible for the translocation of misfolded proteins across the ER membrane into the cytosol for subsequent degradation by the proteasome. In order to understand the spectrum of clinical and molecular findings in a complex neurological syndrome, we studied a series of eight patients with inherited deficiency of N-glycanase 1 (NGLY1), a novel disorder of cytosolic ERAD dysfunction.
Whole-genome, whole-exome or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data.
All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypo- or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele.
NGLY1 deficiency is a novel autosomal recessive disorder of the ERAD pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a more broad range of mutations are detected.
PMCID: PMC4243708  PMID: 24651605
NGLY1; alacrima; choreoathetosis; seizures; liver disease
2.  Clearance of Human IgG1-Sensitised Red Blood Cells In Vivo in Humans Relates to the In Vitro Properties of Antibodies from Alternative Cell Lines 
PLoS ONE  2014;9(10):e109463.
We previously produced a recombinant version of the human anti-RhD antibody Fog-1 in the rat myeloma cell line, YB2/0. When human, autologous RhD-positive red blood cells (RBC) were sensitised with this IgG1 antibody and re-injected, they were cleared much more rapidly from the circulation than had been seen earlier with the original human-mouse heterohybridoma-produced Fog-1. Since the IgG have the same amino acid sequence, this disparity is likely to be due to alternative glycosylation that results from the rat and mouse cell lines. By comparing the in vitro properties of YB2/0-produced Fog-1 IgG1 and the same antibody produced in the mouse myeloma cell line NS0, we now have a unique opportunity to pinpoint the cause of the difference in ability to clear RBC in vivo. Using transfected cell lines that express single human FcγR, we showed that IgG1 made in YB2/0 and NS0 cell lines bound equally well to receptors of the FcγRI and FcγRII classes but that the YB2/0 antibody was superior in FcγRIII binding. When measuring complexed IgG binding, the difference was 45-fold for FcγRIIIa 158F, 20-fold for FcγRIIIa 158V and approximately 40-fold for FcγRIIIb. The dissimilarity was greater at 100-fold in monomeric IgG binding assays with FcγRIIIa. When used to sensitise RBC, the YB2/0 IgG1 generated 100-fold greater human NK cell antibody-dependent cell-mediated cytotoxicity and had a 103-fold advantage over the NS0 antibody in activating NK cells, as detected by CD54 levels. In assays of monocyte activation and macrophage adherence/phagocytosis, where FcγRI plays major roles, RBC sensitised with the two antibodies produced much more similar results. Thus, the alternative glycosylation profiles of the Fog-1 antibodies affect only FcγRIII binding and FcγRIII-mediated functions. Relating this to the in vivo studies confirms the importance of FcγRIII in RBC clearance.
PMCID: PMC4193810  PMID: 25302805
3.  Performance comparison of exome DNA sequencing technologies 
Nature biotechnology  2011;29(10):908-914.
Whole exome sequencing by high-throughput sequencing of target-enriched genomic DNA (exome-seq) has become common in basic and translational research as a means of interrogating the interpretable part of the human genome at relatively low cost. Presented here is a comparison of three major commercial exome sequencing platforms from Agilent, Illumina and Nimblegen applied to the same human blood sample. The Nimblegen platform, which is the only one to use high-density overlapping baits, provides increased efficiency of enrichment and sensitivity for detecting variants but covers fewer genomic regions than the other platforms. As a result, Nimblegen requires the least amount of sequencing to sensitively detect small variants, but Agilent and Illumina are able to detect a greater total number of variants with additional sequencing. Illumina in particular captures the untranslated regions, which are missing from the Nimblegen and Agilent platforms. Exome sequencing and whole genome sequencing (WGS) of the same sample were also compared, demonstrating that exome-seq allows for the detection of additional small variants missed by WGS. These data suggest that WGS experiments benefit from being supplemented with targeted exome-seq data. This study serves to assist the community in selecting the optimal exome-seq platform for their experiments, as well as proving that exome-seq is capable of identifying important coding variations that are missed by a typical WGS experiment.
PMCID: PMC4127531  PMID: 21947028
4.  Performance comparison of whole-genome sequencing platforms 
Nature biotechnology  2011;30(1):78-82.
Whole-genome sequencing is becoming commonplace, but the accuracy and completeness of variant calling by the most widely used platforms from Illumina and Complete Genomics have not been reported. Here we sequenced the genome of an individual with both technologies to a high average coverage of ~76×, and compared their performance with respect to sequence coverage and calling of single-nucleotide variants (SNVs), insertions and deletions (indels). Although 88.1% of the ~3.7 million unique SNVs were concordant between platforms, there were tens of thousands of platform-specific calls located in genes and other genomic regions. In contrast, 26.5% of indels were concordant between platforms. Target enrichment validated 92.7% of the concordant SNVs, whereas validation by genotyping array revealed a sensitivity of 99.3%. The validation experiments also suggested that >60% of the platform-specific variants were indeed present in the genome. Our results have important implications for understanding the accuracy and completeness of the genome sequencing platforms.
PMCID: PMC4076012  PMID: 22178993
5.  Deciphering a neuronal circuit that mediates loss of appetite 
Nature  2012;483(7391):594-597.
Hypothalamic neurons that co-express agouti-related protein (AgRP), neuropeptide Y (NPY), and γ-amino-butyric acid (GABA) are known to promote feeding and weight gain by integration of various nutritional, hormonal, and neuronal signals1,2. Ablation of these neurons leads to cessation of feeding that is accompanied by Fos activation in most regions where they project3–6. Previous experiments indicate that the ensuing starvation is due to aberrant activation of the parabrachial nucleus (PBN) and it could be prevented by facilitating GABAA receptor signaling in the PBN within a critical adaptation period5. We hypothesized that loss of GABAergic inhibition from AgRP neurons to the PBN leads to abnormal activation of the PBN, which in turn inhibits feeding. However, the source of the excitatory inputs to the PBN was unknown. Here we show that glutamatergic neurons in the nucleus tractus solitarius (NTS) and caudal serotonergic neurons control the excitability of PBN neurons and inhibit feeding. Blockade of 5-HT3 receptor signaling in the rostral NTS by either chronic administration of ondansetron or genetic inactivation of Tph2 in caudal serotonergic neurons that project to the NTS protects against starvation when AgRP neurons are ablated. Moreover, genetic inactivation of glutamatergic signaling by the NTS onto N-methyl D-aspartate (NMDA)-type glutamate receptors in the PBN prevents starvation. We also demonstrate that suppressing glutamatergic output of the PBN reinstates normal appetite after AgRP neuron ablation, whereas it promotes weight gain without AgRP neuron ablation. Hence, we identify the PBN as an important hub that integrates signals from several brain regions to bidirectionally modulate feeding and body weight.
PMCID: PMC4000532  PMID: 22419158
6.  Access to the US Department of Veterans Affairs health system: self-reported barriers to care among returnees of Operations Enduring Freedom and Iraqi Freedom 
The U.S. Department of Veterans Affairs (VA) implemented the Polytrauma System of Care to meet the health care needs of military and veterans with multiple injuries returning from combat operations in Afghanistan and Iraq. Studies are needed to systematically assess barriers to use of comprehensive and exclusive VA healthcare services from the perspective of veterans with polytrauma and with other complex health outcomes following their service in Afghanistan and Iraq. These perspectives can inform policy with regard to the optimal delivery of care to returning veterans.
We studied combat veterans (n = 359) from two polytrauma rehabilitation centers using structured clinical interviews and qualitative open-ended questions, augmented with data collected from electronic health records. Our outcomes included several measures of exclusive utilization of VA care with our primary exposure as reported access barriers to care.
Nearly two thirds of the veterans reported one or more barriers to their exclusive use of VA healthcare services. These barriers predicted differences in exclusive use of VA healthcare services. Experiencing any barriers doubled the returnees’ odds of not using VA exclusively, the geographic distance to VA barrier resulted in a 7 fold increase in the returnees odds of not using VA, and reporting a wait time barrier doubled the returnee’s odds of not using VA. There were no striking differences in access barriers for veterans with polytrauma compared to other returning veterans, suggesting the barriers may be uniform barriers that predict differences in using the VA exclusively for health care.
This study provides an initial description of utilization of VA polytrauma rehabilitation and other medical care for veteran returnees from all military services who were involved in combat operations in Afghanistan or Iraq. Our findings indicate that these veterans reported important stigmatization and barriers to receiving services exclusively from the VA, including mutable health delivery system factors.
PMCID: PMC3893594  PMID: 24289747
Access to care; Health/psychiatric services; Veterans/psychology; VA health system
7.  Conceptualizing and Treating Comorbid Chronic Pain and PTSD 
Pain Research and Treatment  2013;2013:174728.
The purpose of this paper is to review the rationale for concurrent, evidence-based treatment of chronic pain and posttraumatic stress disorder (PTSD). To meet this end, we review pertinent definitions and extant theories related to the two conditions and their correlations with each other. We then synthesize theoretical components into a proposal of a comprehensive conceptual framework for understanding the relationship and clinical complexity of overlapping chronic pain and PTSD. We conclude with an example of an integrated treatment model designed specifically to address a fundamental factor associated with pain and PTSD: avoidance.
PMCID: PMC3684116  PMID: 23819047
8.  Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes 
Cell  2012;148(6):1293-1307.
Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here we present an integrative Personal Omics Profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14-month period. Our iPOP analysis revealed various medical risks, including Type II diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high coverage genomic and transcriptomic data, which provide the basis of our iPOP, discovered extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and disease states by connecting genomic information with additional dynamic omics activity.
PMCID: PMC3341616  PMID: 22424236
9.  Quantification of the effects of antibodies on the extra- and intracellular dynamics of Salmonella enterica 
Antibodies are known to be essential in controlling Salmonella infection, but their exact role remains elusive. We recently developed an in vitro model to investigate the relative efficiency of four different human immunoglobulin G (IgG) subclasses in modulating the interaction of the bacteria with human phagocytes. Our results indicated that different IgG subclasses affect the efficacy of Salmonella uptake by human phagocytes. In this study, we aim to quantify the effects of IgG on intracellular dynamics of infection by combining distributions of bacterial numbers per phagocyte observed by fluorescence microscopy with a mathematical model that simulates the in vitro dynamics. We then use maximum likelihood to estimate the model parameters and compare them across IgG subclasses. The analysis reveals heterogeneity in the division rates of the bacteria, strongly suggesting that a subpopulation of intracellular Salmonella, while visible under the microscope, is not dividing. Clear differences in the observed distributions among the four IgG subclasses are best explained by variations in phagocytosis and intracellular dynamics. We propose and compare potential factors affecting the replication and death of bacteria within phagocytes, and we discuss these results in the light of recent findings on dormancy of Salmonella.
PMCID: PMC3565705  PMID: 23235264
bacteriology; Salmonella enterica; infection dynamics; antibodies; mathematical model; likelihood
10.  Who should be prioritized for renal transplantation?: Analysis of key stakeholder preferences using discrete choice experiments 
BMC Nephrology  2012;13:152.
Policies for allocating deceased donor kidneys have recently shifted from allocation based on Human Leucocyte Antigen (HLA) tissue matching in the UK and USA. Newer allocation algorithms incorporate waiting time as a primary factor, and in the UK, young adults are also favoured. However, there is little contemporary UK research on the views of stakeholders in the transplant process to inform future allocation policy. This research project aimed to address this issue.
Discrete Choice Experiment (DCE) questionnaires were used to establish priorities for kidney transplantation among different stakeholder groups in the UK. Questionnaires were targeted at patients, carers, donors / relatives of deceased donors, and healthcare professionals. Attributes considered included: waiting time; donor-recipient HLA match; whether a recipient had dependents; diseases affecting life expectancy; and diseases affecting quality of life.
Responses were obtained from 908 patients (including 98 ethnic minorities); 41 carers; 48 donors / relatives of deceased donors; and 113 healthcare professionals. The patient group demonstrated statistically different preferences for every attribute (i.e. significantly different from zero) so implying that changes in given attributes affected preferences, except when prioritizing those with no rather than moderate diseases affecting quality of life. The attributes valued highly related to waiting time, tissue match, prioritizing those with dependents, and prioritizing those with moderate rather than severe diseases affecting life expectancy. Some preferences differed between healthcare professionals and patients, and ethnic minority and non-ethnic minority patients. Only non-ethnic minority patients and healthcare professionals clearly prioritized those with better tissue matches.
Our econometric results are broadly supportive of the 2006 shift in UK transplant policy which emphasized prioritizing the young and long waiters. However, our findings suggest the need for a further review in the light of observed differences in preferences amongst ethnic minorities, and also because those with dependents may be a further priority.
PMCID: PMC3576250  PMID: 23173887
Renal transplant; Allocation; Choice experiment; Stakeholder
11.  Integrative genomics identifies molecular alterations that challenge the linear model of melanoma progression 
Cancer research  2011;71(7):2561-2571.
Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathological and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (SNP 6.0, Affymetrix) with gene expression array (U133A 2.0, Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N=114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P<0.05, Spearman’s rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene methylthioadenosine phosphorylase (MTAP) in SSM resulted in reduced cell growth. The differential expression of another metabolic related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM.
PMCID: PMC3070783  PMID: 21343389
melanoma; nodular; genomics; SNP array; DNA copy number
12.  Overexpression or knockdown of rat tryptophan hyroxylase-2 has opposing effects on anxiety behavior in an estrogen-dependent manner 
Neuroscience  2010;176:120-131.
Previous studies showed that chronic estrogen treatment increases tryptophan hydroxylase-2 (TpH2) mRNA in the caudal dorsal raphe nucleus (DRN), and this increase was associated with decreased anxiety. The present study explored the interaction of estrogen and targeted, bidirectional manipulation of TpH2 expression in the caudal DRN by knockdown or viral overexpression, to decrease or increase tryptophan hydroxylase expression respectively, on anxiety behavior. Rats were ovariectomized and replaced with empty or estradiol capsules (OVX, OVX/E, respectively). Animals received microinfusions of either antisense TpH2 or control morpholino oligonucleotides into caudal DRN and were later tested in the open field test. A separate group of animals were microinfused with TpH2-GFP or GFP-only herpes simplex viral vectors into caudal DRN and tested in the open field. The bidirectional impact of manipulations on TpH2 expression was confirmed using a combination of quantitative protein and mRNA measurements; TpH2 expression changes were limited to discrete subregions of DRN that were targeted by the manipulations. Estradiol decreased anxiety in all behavioral measures. In the OVX/E group, TpH2 knockdown significantly decreased time spent in the center of the open field, but not in the OVX group, suggesting that TpH2 knockdown reduced the anxiolytic effects of estrogen. Conversely, TpH2 overexpression in the OVX group mimicked the effects of estrogen, as measured by increased time spent in the center of the open field. These results suggest that estrogen and TpH2 in the caudal DRN have a critical interaction in regulating anxiety-like behavior.
PMCID: PMC3038592  PMID: 21182901
Serotonin; raphe; Herpes virus vector; Gene transfer; mRNA; estradiol
13.  Dynamic, adaptive changes in MAO-A binding after alterations in substrate availability: an in vivo [11C]-harmine positron emission tomography study 
Monoamine oxidase A (MAO-A) is an important target in the pathophysiology and therapeutics of major depressive disorder, aggression, and neurodegenerative conditions. We measured the effect of changes in MAO-A substrate on MAO-A binding in regions implicated in affective and neurodegenerative disease with [11C]-harmine positron emission tomography in healthy volunteers. Monoamine oxidase A VT, an index of MAO-A density, was decreased (mean: 14%±9%) following tryptophan depletion in prefrontal cortex (P<0.031), and elevated (mean: 17%±11%) in striatum following carbidopa–levodopa administration (P<0.007). These findings suggest an adaptive role for MAO-A in maintaining monoamine neurotransmitter homeostasis by rapidly compensating fluctuating monoamine levels.
PMCID: PMC3293124  PMID: 22186668
brain imaging; depression; dopamine; Parkinson's disease; positron emission tomography; 5-HT
14.  Correction: Defining Natural History: Assessment of the Ability of College Students to Aid in Characterizing Clinical Progression of Niemann-Pick Disease, Type C 
PLoS ONE  2011;6(11):10.1371/annotation/642295d5-8e46-467d-a9f9-2c6ee94116a9.
PMCID: PMC3206956
15.  Defining Natural History: Assessment of the Ability of College Students to Aid in Characterizing Clinical Progression of Niemann-Pick Disease, Type C 
PLoS ONE  2011;6(10):e23666.
Niemann-Pick Disease, type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease.
PMCID: PMC3184943  PMID: 21984891
16.  The Reality of Pervasive Transcription 
PLoS Biology  2011;9(7):e1000625.
Despite recent controversies, the evidence that the majority of the human genome is transcribed into RNA remains strong.
PMCID: PMC3134446  PMID: 21765801
17.  Using Enhanced and Integrated Services to Improve Response to Standard Methadone Treatment: Changing the Clinical Infrastructure of Treatment Networks 
Outcomes are presented from opioid-dependent outpatients (N = 81) participating in a new community-based initiative designed to improve access to enhanced substance abuse and psychiatric services in the publicly-supported methadone maintenance treatment network in Baltimore, Maryland. The initiative, entitled Community Access to Specialized Treatment (CAST), is located at the Addiction Treatment Services (ATS), a program within this network. Network programs referred patients engaged in unremitting drug use and at risk for discharge to CAST, where they received methadone substitution, individual and group counseling within an adaptive platform, behavioral contingencies to reinforce adherence, and on-site psychiatric evaluation and care. Patients returned to their referring program after producing at least two consecutive weeks of drug-negative urine samples and full counseling adherence. CAST was well-utilized by the community. Patients had high rates of adherence to scheduled individual and group counseling services (93% and 73%, respectively); 43% of referrals successfully completed the program in an average of 101 days. This community-wide service delivery approach is a novel alternative to integrating intensive substance abuse and psychiatric care at each program within a treatment network.
PMCID: PMC2815257  PMID: 19717272
opioid dependence; substance abuse treatment; treatment systems
18.  Complete Bacteriophage Transfer in a Bacterial Endosymbiont (Wolbachia) Determined by Targeted Genome Capture 
Bacteriophage flux can cause the majority of genetic diversity in free-living bacteria. This tenet of bacterial genome evolution generally does not extend to obligate intracellular bacteria owing to their reduced contact with other microbes and a predominance of gene deletion over gene transfer. However, recent studies suggest intracellular coinfections in the same host can facilitate exchange of mobile elements between obligate intracellular bacteria—a means by which these bacteria can partially mitigate the reductive forces of the intracellular lifestyle. To test whether bacteriophages transfer as single genes or larger regions between coinfections, we sequenced the genome of the obligate intracellular Wolbachia strain wVitB from the parasitic wasp Nasonia vitripennis and compared it against the prophage sequences of the divergent wVitA coinfection. We applied, for the first time, a targeted sequence capture array to specifically trap the symbiont's DNA from a heterogeneous mixture of eukaryotic, bacterial, and viral DNA. The tiled array successfully captured the genome with 98.3% efficiency. Examination of the genome sequence revealed the largest transfer of bacteriophage and flanking genes (52.2 kb) to date between two obligate intracellular coinfections. The mobile element transfer occurred in the recent evolutionary past based on the 99.9% average nucleotide identity of the phage sequences between the two strains. In addition to discovering an evolutionary recent and large-scale horizontal phage transfer between coinfecting obligate intracellular bacteria, we demonstrate that “targeted genome capture” can enrich target DNA to alleviate the problem of isolating symbiotic microbes that are difficult to culture or purify from the conglomerate of organisms inside eukaryotes.
PMCID: PMC3068000  PMID: 21292630
horizontal gene transfer; endosymbiont; intracellular
19.  Children from Baffin Island have a disproportionate burden of tuberculosis in Canada: data from the Children's Hospital of Eastern Ontario (1998-2008) 
BMC Pediatrics  2010;10:102.
The Children's Hospital of Eastern Ontario (CHEO) provides services to children in Baffin Island, through the Baffin Island Pediatric Health Initiative. Tuberculosis (TB) remains a major public health problem in that region. The objective of our study was to describe the origin and clinical characteristics of patients with TB disease at CHEO, since the inception of the Baffin Island Pediatric Health Initiative.
All charts with a discharge diagnosis of TB disease during the first 10 years of the Baffin Island program were reviewed. Patients meeting a pre-determined case definition were included in analyses. A standard medical record abstraction form was used for patient data collection.
Twenty patients met our case definition. Seven (35%) were Canadian-born children from Baffin Island. Seven resided in Ontario, 4 in Quebec, and 2 were visiting from other countries. All 7 children residing in Ontario were born in African countries. Endothoracic disease occurred in 16 patients (80%), including 9 with primary pulmonary TB, and 3 with sputum smear positive "adult-type" disease. Extrathoracic disease was present in 6 children (30%), including 3 with CNS disease. Three children had disease in 2 separate sites.
While Baffin Island makes up 1% of the hospital catchment population, they contributed 35% of TB patients, and the only TB death. While TB in foreign-born children is due in part to epidemics abroad, the problem in Baffin Island is a reflection of disease burden and transmission within Canada.
PMCID: PMC3022791  PMID: 21192806
20.  Systematic Review of the Literature on Pain in Patients with Polytrauma Including Traumatic Brain Injury 
Pain medicine (Malden, Mass.)  2009;10(7):1200-1217.
To review the literature addressing the assessment and management of pain in patients with polytraumatic injuries including traumatic brain injury (TBI) and blast-related headache, and to identify patient, clinician and systems factors associated with pain-related outcomes.
Systematic review.
We conducted searches in MEDLINE of literature published from 1950 through July 2008. Due to a limited number of studies using controls or comparators, we included observational and rigorous qualitative studies. We systematically rated the quality of systematic reviews, cohort, and case-control design studies.
One systematic review, 93 observational studies, and one qualitative research study met inclusion criteria. The literature search yielded no published studies that assessed measures of pain intensity or pain-related functional interference among patients with cognitive deficits due to TBI, that compared patients with blast-related headache with patients with other types of headache, or that assessed treatments for blast-related headache pain. Studies on the association between TBI severity and pain reported mixed findings. There was limited evidence that the following factors are associated with pain among TBI patients: severity, location, and multiplicity of injuries; insomnia; fatigue; depression; and post-traumatic stress disorder.
Very little evidence is currently available to guide pain assessment and treatment approaches in patients with polytrauma. Further research employing systematic observational as well as controlled intervention designs is clearly indicated.
PMCID: PMC2995299  PMID: 19818031
Pain; Multiple Trauma; Blast Injuries; Traumatic Brain Injury; Veterans
21.  lncRNAdb: a reference database for long noncoding RNAs 
Nucleic Acids Research  2010;39(Database issue):D146-D151.
Large numbers of long RNAs with little or no protein-coding potential [long noncoding RNAs (lncRNAs)] are being identified in eukaryotes. In parallel, increasing data describing the expression profiles, molecular features and functions of individual lncRNAs in a variety of systems are accumulating. To enable the systematic compilation and updating of this information, we have developed a database (lncRNAdb) containing a comprehensive list of lncRNAs that have been shown to have, or to be associated with, biological functions in eukaryotes, as well as messenger RNAs that have regulatory roles. Each entry contains referenced information about the RNA, including sequences, structural information, genomic context, expression, subcellular localization, conservation, functional evidence and other relevant information. lncRNAdb can be searched by querying published RNA names and aliases, sequences, species and associated protein-coding genes, as well as terms contained in the annotations, such as the tissues in which the transcripts are expressed and associated diseases. In addition, lncRNAdb is linked to the UCSC Genome Browser for visualization and Noncoding RNA Expression Database (NRED) for expression information from a variety of sources. lncRNAdb provides a platform for the ongoing collation of the literature pertaining to lncRNAs and their association with other genomic elements. lncRNAdb can be accessed at:
PMCID: PMC3013714  PMID: 21112873
22.  Behavioural and spermatogenic hybrid male breakdown in Nasonia 
Heredity  2010;104(3):289-301.
Several reproductive barriers exists within the Nasonia species complex, including allopatry, premating behavioural isolation, postzygotic inviability and Wolbachia-induced cytoplasmic incompatibility. Here we show that hybrid males suffer two additional reproductive disadvantages, an inability to properly court females and decreased sperm production. Hybrid behavioural sterility, characterized by a reduced ability of hybrids to perform necessary courtship behaviours, occurs in hybrids between two species of Nasonia. Hybrid males produced in crosses between N. vitripennis and N. giraulti courted females at a reduced frequency (23-69%), compared to wild-type N. vitripennis and N. giraulti males (>93%). Reduced courtship frequency was not a simple function of inactivity among hybrids. A strong effect of cytoplasmic (mitochondrial) background was also found in N. vitripennis and N. giraulti crosses; F2 hybrids with giraulti cytoplasm showing reduced ability at most stages of courtship. Hybrids produced between a younger species pair, N. giraulti and N. longicornis, were behaviourally fertile. All males possessed motile sperm, but sperm production is greatly reduced in hybrids between the older species pair, N. vitripennis and N. giraulti. This effect on hybrid males, lowered sperm counts rather than non-functional sperm, is different from most described cases of hybrid male sterility and may represent an earlier stage of hybrid sperm breakdown. The results add to previous studies of F2 hybrid inviability and behavioural sterility, and indicated that Wolbachia induced hybrid incompatibility has arisen early in species divergence, relative to behavioural sterility and spermatogenic infertility.
PMCID: PMC2872237  PMID: 20087395
Nasonia; courtship behaviour; spermatogenesis; hybrid sterility; speciation
23.  Description of a Developmental Criterion-Referenced Assessment for Promoting Competence in Internal Medicine Residents 
End-of- rotation global evaluations can be subjective, produce inflated grades, lack interrater reliability, and offer information that lacks value. This article outlines the generation of a unique developmental criterion-referenced assessment that applies adult learning theory and the learner, manager, teacher model, and represents an innovative application to the American Board of Internal Medicine (ABIM) 9-point scale.
We describe the process used by Southern Illinois University School of Medicine to develop rotation-specific, criterion-based evaluation anchors that evolved into an effective faculty development exercise.
The intervention gave faculty a clearer understanding of the 6 Accreditation Council for Graduate Medical Education competencies, each rotation's educational goals, and how rotation design affects meaningful work-based assessment. We also describe easily attainable successes in evaluation design and pitfalls that other institutions may be able to avoid. Shifting the evaluation emphasis on the residents' development of competence has made the expectations of rotation faculty more transparent, has facilitated conversations between program director and residents, and has improved the specificity of the tool for feedback. Our findings showed the new approach reduced grade inflation compared with the ABIM end-of-rotation global evaluation form.
We offer the new developmental criterion-referenced assessment as a unique application of the competences to the ABIM 9-point scale as a transferable model for improving the validity and reliability of resident evaluations across graduate medical education programs.
PMCID: PMC2931180  PMID: 21975710
24.  Development of the Objective Structured System-Interaction Examination 
Study Objective
The purpose of this study was to develop an objective method of evaluating resident competency in systems-based practice.
Study Design
Faculty developed a 12-station examination, the Objective Structured System-Interaction Examination (OSSIE), patterned after the Objective Structured Clinical Examinations (OSCEs), to evaluate residents' ability to effectively work within the complex medical system of care. Scenarios consisted of multiple situations, such as patient hand-offs, consultations, complicated discharges, and family meetings, in which residents interacted with simulated professionals, simulated patients, and simulated family members to demonstrate the systems-based skills. Twelve second-year residents participated in the OSSIE.
Along with the standardized professionals, a faculty member provided the resident with immediate feedback and completed an evaluation form designed specifically to assess systems-based practice. Residents, faculty, and staff evaluated the OSSIE and felt it provided a rich learning experience and was a beneficial means of formative assessment. The residents' third-year learning experiences were adapted to meet their needs, and suggestions were offered for curriculum revision.
The OSSIE is unique in that it uses standardized professionals, involves scenarios in a variety of settings, and incorporates current technology, including an electronic health record and a state-of-the-art simulation laboratory, into the examination. Challenges to implementation include faculty time, scheduling of residents, and availability of resources.
By using the OSSIE, faculty are able to assess, provide constructive feedback, and tailor training opportunities to improve resident competence in systems-based practice. Reliability and validity of an instrument developed for use with the OSSIE are currently being determined.
PMCID: PMC2931182  PMID: 21975711
25.  Interleukin-6 Attenuates Insulin-Mediated Increases in Endothelial Cell Signaling but Augments Skeletal Muscle Insulin Action via Differential Effects on Tumor Necrosis Factor-α Expression 
Diabetes  2009;58(5):1086-1095.
The cytokine interleukin-6 (IL-6) stimulates AMP-activated protein kinase (AMPK) and insulin signaling in skeletal muscle, both of which result in the activation of endothelial nitric oxide synthase (eNOS). We hypothesized that IL-6 promotes endothelial cell signaling and capillary recruitment in vivo, contributing to increased glucose uptake.
The effect of IL-6 with and without insulin on AMPK, insulin, and eNOS signaling in and nitric oxide (NO) release from human aortic endothelial cells (HAECs) was examined. The physiological significance of these in vitro signaling events was assessed by measuring capillary recruitment in rats during control and euglycemic-hyperinsulinemic clamps with or without IL-6 infusion.
IL-6 blunted increases in insulin signaling, eNOS phosphorylation (Ser1177), and NO production and reduced phosphorylation of AMPK in HAEC in vitro and capillary recruitment in vivo. In contrast, IL-6 increased Akt phosphorylation (Ser473) in hindlimb skeletal muscle and enhanced whole-body glucose disappearance and glucose uptake during the clamp. The differences in endothelial cell and skeletal muscle signaling were mediated by the cell-specific, additive effects of IL-6 and insulin because this treatment markedly increased tumor necrosis factor (TNF)-α protein expression in HAECs without any effect on TNF-α in skeletal muscle. When HAECs were incubated with a TNF-α–neutralizing antibody, the negative effects of IL-6 on eNOS signaling were abolished.
In the presence of insulin, IL-6 contributes to aberrant endothelial cell signaling because of increased TNF-α expression.
PMCID: PMC2671037  PMID: 19188427

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