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1.  Atrial fibrillation after esophagectomy: an indicator of postoperative morbidity 
Purpose
The relevance of new-onset atrial fibrillation (AF) after esophagectomy remains poorly defined. This study’s primary goal is to better define the incidence, clinical patterns, and outcomes associated with the development of AF after esophagectomy.
Methods
The study is a retrospective review of patients undergoing esophagectomy at a single academic center between May 1996 and December 2007. Patients with new-onset AF were evaluated by univariate and multivariate analyses for risk factors associated with AF onset and outcomes.
Results
New-onset AF was noted in 32 of 156 (20.5%) patients after esophagectomy. Most (16/32, 50%) developed AF within 48 h, and 28 of 32 (87.5%) developed new AF within 72 h of surgery. Pulmonary complications were more frequent in patients with AF than those without AF (59.4% vs. 15.3%, P < 0.01) and usually immediately preceded or occurred concurrently with AF. Anastomotic leaks were significantly more common in patients with AF than those without (28.1% vs. 6.45%, P < 0.01) and were identified, on average, 4.2 days after the onset of AF. In the multivariate analysis, anastomotic leaks, pulmonary complications, and number of complications were significantly associated with AF. Although 60-day survival was worse for patients developing AF (P < 0.01), multivariate analysis suggests that non-AF complications were the independent predictor of mortality.
Conclusion
New-onset AF after esophagectomy is associated with anastomotic leaks, pulmonary complications, and decreased 60-day survival. Although pulmonary complications typically occurred coincident with the onset of AF, anastomotic leaks were usually diagnosed 4 days after AF onset. New postesophagectomy AF should prompt vigilance for the presence of other concurrent complications.
doi:10.1007/s11748-010-0713-9
PMCID: PMC4069196  PMID: 21674306
Esophagectomy; Atrial fibrillation; Anastomotic leak
2.  Comorbidity-Polypharmacy Score: A Novel Adjunct In Post-Emergency Department Trauma Triage 
The Journal of surgical research  2012;181(1):16-19.
OBJECTIVE
Post-emergency department (ED) triage of older trauma patients continues to be challenging as morbidity and mortality for any given level of injury severity tend to increase with age. The Comorbidity-Polypharmacy Score (CPS) combines the number of pre-injury medications with the number of comorbidities to estimate the severity of co-morbid conditions. This retrospective study examines the relationship between CPS and triage accuracy for older (≥45 years) patients admitted for traumatic injury.
METHODS
Patients ≥ 45 years old presenting to level 1 trauma center from 2005 to 2008 were included. Basic data included patient demographics, injury severity score (ISS), morbidity/mortality, and functional outcome measures. CPS was calculated by adding total numbers of co-morbid conditions and pre-injury medications. Patients were divided into 3 triage groups: undertriage, appropriate triage, and over-triage. Under-triage criteria included initial admission to the floor or step-down unit followed by an unplanned transfer to ICU within 24 hours of admission. Over-triage was defined as initial ICU admission for <1 day without stated need for ICU level of care (i.e., lack of evidence for tracheal intubation/mechanical ventilation, injury-related hemorrhage, or other traditional ICU indications such as intracranial bleeding). All other patients were presumed to be correctly triaged. The three triage groups were then analyzed looking for contributors to mis-triage.
RESULTS
Charts for 711 patients were evaluated (mean age 63.5, 55.7% male, mean ISS 9.02). Of those, 11 (1.55%) met criteria for “under-triage” and 14 (1.97%) were “over-triaged”. The remaining 686 patients had no evidence of mis-triage. The three groups were similar in terms of injury severity and age. The groups were significantly different with respect to CPS, with undertriage CPS scores (14.9±6.80) being nearly three times higher than the overtriage CPS scores (5.14±3.48). There were more similarities between appropriate and overtriage groups, with the undertriage group being characterized by greater number of complications, and lower functional outcomes at discharge (all, p<0.05). The undertriage group had significantly higher mortality (27%) than the appropriate and over-triage groups (6% and 0%, respectively).
CONCLUSION
In the era of medication reconciliation, the CPS is easy to obtain and calculate in patients who are not critically injured. This study suggests that CPS may be a promising adjunct in identifying older trauma patients who are more likely to be under-triaged. The significance of our findings is especially important when considering that injury severity in the undertiage group was similar to injury severity in the other groups. Further evaluation of CPS as a triage tool in acute trauma is warranted.
doi:10.1016/j.jss.2012.05.042
PMCID: PMC3717608  PMID: 22683074
Trauma triage; Level of care; Undertriage; Overtriage; Older trauma patient; Comorbidity-polypharmacy score
3.  Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB24 
PLoS Genetics  2014;10(2):e1003991.
Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia.
Author Summary
Neurodegenerative diseases are one of the most important causes of decline in an aging population. An important subset of these diseases are known as the hereditary ataxias, familial neurodegenerative diseases that affect the cerebellum causing progressive gait disturbance in both humans and dogs. We identified a mutation in RAB24, a gene associated with autophagy, in Old English Sheepdogs and Gordon Setters with hereditary ataxia. Autophagy is a process by which cell proteins and organelles are removed and recycled and its critical role in maintenance of the continued health of cells is becoming clear. We evaluated the brains of affected dogs and identified accumulations of autophagosomes within the cerebellum, suggesting a defect in the autophagy pathway. Our results suggest that a defect in the autophagy pathway results in neuronal death in a naturally occurring disease in dogs. The autophagy pathway should be investigated in human hereditary ataxia and may represent a therapeutic target in neurodegenerative diseases.
doi:10.1371/journal.pgen.1003991
PMCID: PMC3916225  PMID: 24516392
4.  A new dosing protocol reduces dexmedetomidine-associated hypotension in critically ill surgical patients☆,☆☆,★ 
Journal of critical care  2009;24(4):568-574.
Background
Although no ideal sedative exists, dexmedetomidine is unique because it produces sedation and analgesia without decreasing the respiratory drive. Hemodynamic responses to dexmedetomidine are variable and dependent on the patient population. Our initial experience was associated with an unacceptable incidence of hypotension and bradycardia. We evaluated occurrence of hypotension and bradycardia in critically ill surgical patients receiving dexmedetomidine before and after implementation of a dosing protocol.
Methods
This is a retrospective chart review of all admissions to a university medical center–based, 44-bed surgical intensive care unit pre and post protocol implementation.
Results
Forty-four patients received dexmedetomidine including 19 historic controls and 25 dosed via protocol. Both groups had comparable demographics and initial and maximum dosages of dexmedetomidine. Use of the dosing protocol resulted in fewer dosage changes (mean ± standard deviation, 4.8 ± 3.8 compared to 7.8 ± 3.9; P = .014) and fewer episodes of hypotension (16% vs 68.4%; P = .0006) but did not influence bradycardic episodes (20% vs 15.5%; P > .99).
Conclusion
We found that use of a protocol that increases the time interval between dosage adjustments may reduce dexmedetomidine-associated hypotension.
doi:10.1016/j.jcrc.2009.05.015
PMCID: PMC3725302  PMID: 19682844
Dexmedetomidine; Intensive care unit; Hypotension
5.  The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis 
Introduction
X-linked adrenoleukodystrophy (X-ALD) is a complex disorder with variable expressivity that affects the nervous, adrenocortical and male reproductive systems. Although ABCD1 mutations are known to provide the genetic basis for X-ALD, its pathogenesis is not fully elucidated. While elevated very long chain fatty acid (VLCFA) levels in blood and reduced VLCFA catabolic activity in cultured fibroblasts are biomarkers used to identify ABCD1 mutation carriers, the roles peroxisomal lipid metabolism play in disease etiology are unknown.
Methods
Primary skin fibroblasts from two male patients with the childhood cerebral form of the disease (CCALD) caused by ABCD1 frameshift or missense mutations and three healthy donors were transduced with retroviral vectors expressing the OCT4, SOX2, KLF4 and c-MYC factors. Candidate induced pluripotent stem cells (iPSCs) were subject to global gene expression, DNA methylation, DNA copy number variation, and genotyping analysis and tested for pluripotency through in vitro differentiation and teratoma formation. Saturated VLCFA (sVLCFA) and plasmalogen levels in primary fibroblasts and iPSCs from healthy donors as well as CCALD patients were determined through mass spectroscopy.
Results
Skin fibroblasts from CCALD patients and healthy donors were reprogrammed into validated iPSCs. Unlike fibroblasts, CCALD patient iPSCs show differentially expressed genes (DEGs) relevant to both peroxisome abundance and neuroinflammation. Also, in contrast to fibroblasts, iPSCs from patients showed no significant difference in sVLCFA levels relative to those from controls. In all cell types, the plasmalogen levels tested did not correlate with ABCD1 mutation status.
Conclusion
Normal ABCD1 gene function is not required for reprogramming skin fibroblasts into iPSCs or maintaining pluripotency. Relative to DEGs found in fibroblasts, DEGs uncovered in comparisons of CCALD patient and control iPSCs are more consistent with major hypotheses regarding disease pathogenesis. These DEGs were independent of differences in sVLCFA levels, which did not vary according to ABCD1 mutation status. The highlighted genes provide new leads for pathogenic mechanisms that can be explored in animal models and human tissue specimens. We suggest that these iPSC resources will have applications that include assisting efforts to identify genetic and environmental modifiers and screening for therapeutic interventions tailored towards affected cell populations and patient genotypes.
doi:10.1186/scrt130
PMCID: PMC3580430  PMID: 23036268
6.  A founder mutation in the PEX6 gene is responsible for increased incidence of Zellweger syndrome in a French Canadian population 
BMC Medical Genetics  2012;13:72.
Background
Zellweger syndrome (ZS) is a peroxisome biogenesis disorder due to mutations in any one of 13 PEX genes. Increased incidence of ZS has been suspected in French-Canadians of the Saguenay-Lac-St-Jean region (SLSJ) of Quebec, but this remains unsolved.
Methods
We identified 5 ZS patients from SLSJ diagnosed by peroxisome dysfunction between 1990–2010 and sequenced all coding exons of known PEX genes in one patient using Next Generation Sequencing (NGS) for diagnostic confirmation.
Results
A homozygous mutation (c.802_815del, p.[Val207_Gln294del, Val76_Gln294del]) in PEX6 was identified and then shown in 4 other patients. Parental heterozygosity was confirmed in all. Incidence of ZS was estimated to 1 in 12,191 live births, with a carrier frequency of 1 in 55. In addition, we present data suggesting that this mutation abolishes a SF2/ASF splice enhancer binding site, resulting in the use of two alternative cryptic donor splice sites and predicted to encode an internally deleted in-frame protein.
Conclusion
We report increased incidence of ZS in French-Canadians of SLSJ caused by a PEX6 founder mutation. To our knowledge, this is the highest reported incidence of ZS worldwide. These findings have implications for carrier screening and support the utility of NGS for molecular confirmation of peroxisomal disorders.
doi:10.1186/1471-2350-13-72
PMCID: PMC3483250  PMID: 22894767
Zellweger syndrome; Founder effect; Peroxisome biogenesis disorders; Next generation sequencing
7.  Levodopa Response Reveals Sepiapterin Reductase Deficiency in a Female Heterozygote with Adrenoleukodystrophy 
JIMD Reports  2011;3:79-82.
We report a 4-year-old girl heterozygous for X-linked adrenoleukodystrophy (ALD) who displayed dopa-responsive motor symptoms and was subsequently diagnosed with sepiapterin reductase deficiency (SPR; OMIM 182125). Her father and paternal uncle had known ALD, and she was found to have elevated plasma very long chain fatty acids and a mutation in the ABCD1 gene. She had language delay, severe hypotonia and abnormal eye movements and responded dramatically to a trial of levodopa (4 mg/kg per day). Two mutations within the gene for sepiapterin reductase were found and cultured skin fibroblasts demonstrated near zero activity of the enzyme. This case illustrates the importance of treatment trials that may give rise to biochemical clues to the underlying diagnosis, and the need to continue to search for diagnoses despite a misleading family history.
doi:10.1007/8904_2011_65
PMCID: PMC3509860  PMID: 23430877
8.  Nonsense suppressor therapies rescue peroxisome lipid metabolism and assembly in cells from patients with specific PEX gene mutations 
Journal of cellular biochemistry  2011;112(5):1250-1258.
Peroxisome biogenesis disorders (PBDs) are multisystemic autosomal recessive disorders resulting from mutations in PEX genes required for normal peroxisome assembly and metabolic activities. Here, we evaluated the potential effectiveness of aminoglycoside G418 (geneticin) and PTC124 (ataluren) nonsense suppression therapies for the treatment of PBD patients with disease-causing nonsense mutations. PBD patient skin fibroblasts producing stable PEX2 or PEX12 nonsense transcripts and Chinese hamster ovary (CHO) cells with a Pex2 nonsense allele all showed dramatic improvements in peroxisomal very long chain fatty acid catabolism and plasmalogen biosynthesis in response to G418 treatments. Cell imaging assays provided complementary confirmatory evidence of improved peroxisome assembly in G418-treated patient fibroblasts. In contrast, we observed no appreciable rescue of peroxisome lipid metabolism or assembly for any patient fibroblast or CHO cell culture treated with various doses of PTC124. Additionally, PTC124 did not show measurable nonsense suppression in immunoblot assays that directly evaluated the read-through of PEX7 nonsense alleles found in PBD patients with rhizomelic chondrodysplasia punctata type 1 (RCDP1). Overall, our results support the continued development of safe and effective nonsense suppressor therapies that could benefit a significant subset of individuals with PBDs. Furthermore, we suggest that the described cell culture assay systems could be useful for evaluating and screening for novel nonsense suppressor therapies.
doi:10.1002/jcb.22979
PMCID: PMC3136445  PMID: 21465523
peroxisome biogenesis disorder; ataluren; geneticin; nonsense mutation
9.  Pre-injury polypharmacy as a predictor of outcomes in trauma patients 
Background:
One of the hallmarks of modern medicine is the improving management of chronic health conditions. Long-term control of chronic disease entails increasing utilization of multiple medications and resultant polypharmacy. The goal of this study is to improve our understanding of the impact of polypharmacy on outcomes in trauma patients 45 years and older.
Materials and Methods:
Patients of age ≥45 years were identified from a Level I trauma center institutional registry. Detailed review of patient records included the following variables: Home medications, comorbid conditions, injury severity score (ISS), Glasgow coma scale (GCS), morbidity, mortality, hospital length of stay (LOS), intensive care unit (ICU) LOS, functional outcome measures (FOM), and discharge destination. Polypharmacy was defined by the number of medications: 0–4 (minor), 5–9 (major), or ≥10 (severe). Age- and ISS-adjusted analysis of variance and multivariate analyses were performed for these groups. Comorbidity–polypharmacy score (CPS) was defined as the number of pre-admission medications plus comorbidities. Statistical significance was set at alpha = 0.05.
Results:
A total of 323 patients were examined (mean age 62.3 years, 56.1% males, median ISS 9). Study patients were using an average of 4.74 pre-injury medications, with the number of medications per patient increasing from 3.39 for the 45–54 years age group to 5.68 for the 75+ year age group. Age- and ISS-adjusted mortality was similar in the three polypharmacy groups. In multivariate analysis only age and ISS were independently predictive of mortality. Increasing polypharmacy was associated with more comorbidities, lower arrival GCS, more complications, and lower FOM scores for self-feeding and expression-communication. In addition, hospital and ICU LOS were longer for patients with severe polypharmacy. Multivariate analysis shows age, female gender, total number of injuries, number of complications, and CPS are independently associated with discharge to a facility (all, P < 0.02).
Conclusion:
Over 40% of trauma patients 45 years and older were receiving 5 or more medications at the time of their injury. Although these patients do not appear to have higher mortality, they are at increased risk for complications, lower functional outcomes, and longer hospital and intensive care stays. CPS may be useful when quantifying the severity of associated comorbid conditions in the context of traumatic injury and warrants further investigation.
doi:10.4103/2229-5151.84793
PMCID: PMC3249840  PMID: 22229132
Comorbid conditions; outcome prediction; polypharmacy; trauma outcomes
10.  Cultural and religious aspects of palliative care 
For most clinicians and patients, the discussion of palliative care is a difficult topic. It is complicated by both the clinician's and patient's belief systems, which are frequently heavily influenced by cultural and religious upbringing. This article discusses the impact of some of those differences on attitudes toward end of life decisions. Several different religions and cultures have been evaluated for their impact on perceptions of palliative care and the authors will share some examples.
doi:10.4103/2229-5151.84804
PMCID: PMC3249849  PMID: 22229141
Culture; end-of-life care; palliative care; religion
11.  Human and great ape red blood cells differ in plasmalogen levels and composition 
Background
Plasmalogens are ether phospholipids required for normal mammalian developmental, physiological, and cognitive functions. They have been proposed to act as membrane antioxidants and reservoirs of polyunsaturated fatty acids as well as influence intracellular signaling and membrane dynamics. Plasmalogens are particularly enriched in cells and tissues of the human nervous, immune, and cardiovascular systems. Humans with severely reduced plasmalogen levels have reduced life spans, abnormal neurological development, skeletal dysplasia, impaired respiration, and cataracts. Plasmalogen deficiency is also found in the brain tissue of individuals with Alzheimer disease.
Results
In a human and great ape cohort, we measured the red blood cell (RBC) levels of the most abundant types of plasmalogens. Total RBC plasmalogen levels were lower in humans than bonobos, chimpanzees, and gorillas, but higher than orangutans. There were especially pronounced cross-species differences in the levels of plasmalogens with a C16:0 moiety at the sn-1 position. Humans on Western or vegan diets had comparable total RBC plasmalogen levels, but the latter group showed moderately higher levels of plasmalogens with a C18:1 moiety at the sn-1 position. We did not find robust sex-specific differences in human or chimpanzee RBC plasmalogen levels or composition. Furthermore, human and great ape skin fibroblasts showed only modest differences in peroxisomal plasmalogen biosynthetic activity. Human and chimpanzee microarray data indicated that genes involved in plasmalogen biosynthesis show cross-species differential expression in multiple tissues.
Conclusion
We propose that the observed differences in human and great ape RBC plasmalogens are primarily caused by their rates of biosynthesis and/or turnover. Gene expression data raise the possibility that other human and great ape cells and tissues differ in plasmalogen levels. Based on the phenotypes of humans and rodents with plasmalogen disorders, we propose that cross-species differences in tissue plasmalogen levels could influence organ functions and processes ranging from cognition to reproduction to aging.
doi:10.1186/1476-511X-10-101
PMCID: PMC3129581  PMID: 21679470
12.  A Pex7 hypomorphic mouse model for plasmalogen deficiency affecting the lens and skeleton 
Molecular genetics and metabolism  2009;99(4):408-416.
Rhizomelic chondrodysplasia punctata type 1 is a peroxisome biogenesis disorder with the clinical features of rhizomelia, abnormal epiphyseal calcifications, congenital cataracts, and profound growth and developmental delays. It is a rare autosomal recessive disorder, caused by defects in the peroxisome receptor, Pex7. The pathology results from a deficiency of plasmalogens, a critical class of ether phospholipids whose functions are largely unknown. To study plasmalogens in an animal model, avoid early mortality and facilitate therapeutic investigations in this disease, we engineered a hypomorphic mouse model in which Pex7 transcript levels are reduced to less than 5% of wild type. These mice are born in expected ratios, are fertile and have a normal life span. However, they are petite and develop early cataracts. Further investigations showed delayed endochondral ossification and abnormalities in lens fibers. The biochemical features of reduced Pex7 function were reproduced in this model, including tissue plasmalogen deficiency, phytanic acid accumulation, reduced import of Pex7 ligands and consequent defects in plasmalogen biosynthesis and phytanic acid oxidation. Dietary supplementation with batyl alcohol, a plasmalogen precursor, recovered ether phospholipids in blood, but did not alter the clinical phenotype. The relatively mild phenotype of these mice mimics patients with milder pex7 defects, and highlights the skeleton and lens as sensitive markers of plasmalogen deficiency. The role of plasmalogens in the normal function of these tissues at various ages can now be studied and additional therapeutic interventions tested in this model.
doi:10.1016/j.ymgme.2009.12.005
PMCID: PMC2839039  PMID: 20060764
Pex7; mouse models; Peroxisome Biogenesis Disorder; Rhizomelic Chondrodysplasia Punctata; plasmalogens; phytanic acid
13.  The impact of antiplatelet therapy on pelvic fracture outcomes 
Introduction:
Despite increasing use of antiplatelet agents (APA), little is known regarding the effect of these agents on the orthopedic trauma patient. This study reviews clinical outcomes of patients with pelvic fractures (Pfx) who were using pre-injury APA. Specifically, we focused on the influence of APA on postinjury bleeding, transfusions, and outcomes after Pfx.
Methods:
Patients with Pfx admitted during a 37-month period beginning January 2006 were divided into APA and non-APA groups. Pelvic injuries were graded using pelvic fracture severity score (PFSS)–a combination of Young–Burgess (pelvic ring), Letournel–Judet (acetabular), and Denis (sacral fracture) classifications. Other clinical data included demographics, co-morbid conditions, medications, injury severity score (ISS), associated injuries, morbidity/mortality, hemoglobin trends, blood product use, imaging studies, procedures, and resource utilization. Multivariate analyses for predictors of early/late transfusions, pelvic surgery, and mortality were performed.
Results:
A total of 109 patients >45 years with Pfx were identified, with 37 using preinjury APA (29 on aspirin [ASA], 8 on clopidogrel, 5 on high-dose/scheduled non-steroidal anti-inflammatory agents [NSAID], and 8 using >1 APAs). Patients in the APA groups were older than patients in the non-APA group (70 vs. 63 years, P < 0.01). The two groups were similar in gender distribution, PFSS and ISS. Patients in the APA group had more comorbidities, lower hemoglobin levels at 24 h, and received more packed red blood cell (PRBC) transfusions during the first 24 h of hospitalization (all, P < 0.05). There were no differences in platelet or late (>24 h) PRBC transfusions, blood loss/transfusions during pelvic surgery, lengths of stay, post-ED/discharge disposition, or mortality. In multivariate analysis, predictors of early PRBC transfusion included higher ISS/PFSS, pre-injury ASA use, and lower admission hemoglobin (all, P < 0.03). Predictors of late PRBC transfusion included the number of complications, gender, PFSS, and any APA use (all, P < 0.05). Mortality was associated with pelvic hematoma/contrast extravasation on imaging, number of complications, and higher PFSS/ISS (all, P < 0.04).
Conclusions:
Results of this study support the contention that preinjury use of APA does not independently affect morbidity or mortality in trauma patients with Pfx. Despite no clinically significant difference in early postinjury blood loss, pre-injury use of APA was associated with increased likelihood of receiving PRBC transfusion within 24 h of admission. Furthermore, multivariate analyses demonstrated that among different APA, only preinjury ASA (vs. clopidogrel or NSAID) was associated with early PRBC transfusions. Late transfusion was associated with the use of any APA, complications, higher PFSS, and need for pelvic surgery.
doi:10.4103/0974-2700.76841
PMCID: PMC3097583  PMID: 21633571
Antiplatelet therapy; injury severity; pelvic fractures; pelvic severity score; trauma outcomes
14.  Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions 
BMC Physiology  2010;10:19.
Background
It has been proposed that anatomical differences in human and great ape guts arose in response to species-specific diets and energy demands. To investigate functional genomic consequences of these differences, we compared their physiological levels of phytanic acid, a branched chain fatty acid that can be derived from the microbial degradation of chlorophyll in ruminant guts. Humans who accumulate large stores of phytanic acid commonly develop cerebellar ataxia, peripheral polyneuropathy, and retinitis pigmentosa in addition to other medical conditions. Furthermore, phytanic acid is an activator of the PPAR-alpha transcription factor that influences the expression of genes relevant to lipid metabolism.
Results
Despite their trace dietary phytanic acid intake, all great ape species had elevated red blood cell (RBC) phytanic acid levels relative to humans on diverse diets. Unlike humans, chimpanzees showed sexual dimorphism in RBC phytanic acid levels, which were higher in males relative to females. Cultured skin fibroblasts from all species had a robust capacity to degrade phytanic acid. We provide indirect evidence that great apes, in contrast to humans, derive significant amounts of phytanic acid from the hindgut fermentation of plant materials. This would represent a novel reduction of metabolic activity in humans relative to the great apes.
Conclusion
We identified differences in the physiological levels of phytanic acid in humans and great apes and propose this is causally related to their gut anatomies and microbiomes. Phytanic acid levels could contribute to cross-species and sex-specific differences in human and great ape transcriptomes, especially those related to lipid metabolism. Based on the medical conditions caused by phytanic acid accumulation, we suggest that differences in phytanic acid metabolism could influence the functions of human and great ape nervous, cardiovascular, and skeletal systems.
doi:10.1186/1472-6793-10-19
PMCID: PMC2964658  PMID: 20932325
15.  Identification of Novel Mutations and Sequence Variation in the Zellweger Syndrome Spectrum of Peroxisome Biogenesis Disorders 
Human mutation  2009;30(3):E467-E480.
Peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive neurodegenerative disorders that affect multiple organ systems. Approximately 80% of PBD patients are classified in the Zellweger syndrome spectrum (PBD-ZSS). Mutations in the PEX1, PEX6, PEX10, PEX12, or PEX26 genes are found in approximately 90% of PBD-ZSS patients. Here, we sequenced the coding regions and splice junctions of these five genes in 58 PBD-ZSS cases previously subjected to targeted sequencing of a limited number of PEX gene exons. In our cohort, 71 unique sequence variants were identified, including 18 novel mutations predicted to disrupt protein function and 2 novel silent variants. We identified 4 patients who had two deleterious mutations in one PEX gene and a third deleterious mutation in a second PEX gene. For two such patients, we conducted cell fusion complementation analyses to identify the defective gene responsible for aberrant peroxisome assembly. Overall, we provide empirical data to estimate the relative fraction of disease-causing alleles that occur in the coding and splice junction sequences of these five PEX genes and the frequency of cases where mutations occur in multiple PEX genes. This information is beneficial for efforts aimed at establishing rapid and sensitive clinical diagnostics for PBD-ZSS patients and interpreting the results from these genetic tests.
doi:10.1002/humu.20932
PMCID: PMC2649967  PMID: 19105186
peroxisome biogenesis disorders; Zellweger syndrome; PBD-ZSS; neonatal adrenoleukodystrophy; infantile Refsum disease; PEX1; PEX6; PEX10; PEX12
16.  The complicated management of a patient following transarterial chemoembolization for metastatic carcinoid 
Background
Transarterial Chemoembolization (TACE) has been recognized as a successful way of managing symptomatic and/or progressive hepatic carcinoid metastases not amenable to surgical resection. Although it is a fairly safe procedure, it is not without its complications.
Case presentation
This is a case of a 53 year-old woman with a patent foramen ovale (PFO) and mild pulmonary hypertension who underwent TACE for progressive carcinoid liver metastases. She developed acute heart failure, due to a severe inflammatory response; this resulted in pneumatosis intestinalis due to non-occlusive mesenteric ischemia. We describe the successful non-operative management of her pneumatosis intestinalis and the role of a PFO in this patient's heart failure.
Conclusion
TACE remains an effective and safe treatment for metastatic carcinoid not amenable to resection, this case illustrates the complexity of complications that can arise. A multi-disciplinary approach including ready access to advanced critical care facilities is recommended in managing such complex patients.
doi:10.1186/1477-7819-6-125
PMCID: PMC2605455  PMID: 19032771
17.  Bap31 enhances the ER export and quality control of human class I MHC molecules 
The assembly of class I MHC molecules and their export from the endoplasmic reticulum is governed by chaperones and accessory proteins. We present evidence that the putative cargo receptor protein Bap31 participates in the transport and the quality control of human class I molecules. Transfection of the human adenocarcinoma cell line HeLa with YFP-Bap31 chimeras increased surface levels of class I in a dose-dependent manner, by as much as 3.7-fold. The increase in surface class I resulted from an increase in the rate of export of newly-synthesized class I molecules to the cell surface and from an increase in the stability of the exported molecules. We propose that Bap31 performs quality control on class I molecules in two distinct phases: first, by exporting peptide-loaded class I molecules to the ERGIC and second, by retrieving class I molecules which have lost peptides in the acidic post-ER environment. This function of Bap31 is conditional or redundant, since we find that Bap31 deficiency does not reduce surface class I levels. Overexpression of the Bap31 homolog, Bap29, decreases surface class levels in HeLa, indicating that it does not substitute for Bap31.
PMCID: PMC1978250  PMID: 17056546
MHC; trafficking; presentation

Results 1-18 (18)