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1.  Endoscopic Anterior Skull Base Surgery: Intraoperative Considerations of the Crista Galli 
Skull Base  2011;21(2):83-86.
We sought to measure the anatomic dimensions of the crista galli in a consecutive series of patients undergoing the endoscopic transcribriform approach for anterior skull base tumors at a tertiary academic university hospital. We performed a retrospective chart review of patients undergoing purely endoscopic transcribriform surgery for sinonasal and skull base lesions. Main outcome measures included radiological dimensions of the crista galli. A total of 12 patients were identified and treated by the senior authors at the University of Pennsylvania. The average crista galli dimensions were 12.7 ± 2.4 mm (anterior-posterior) and 12.9 ± 2.5 mm (cranial-caudal dimension). Knowledge of the dimensions of the crista galli is important in preoperative planning for both instrumentation and access.
PMCID: PMC3312591  PMID: 22451806
Endoscopic skull base surgery; transcribriform; crista galli; radiology; anatomy
2.  Endoscopic Transcranial and Intracranial Resection: Case Series and Design of a Perioperative Management Protocol 
Skull Base  2011;21(1):13-22.
Purely endoscopic resections of transcranial/intracranial pathology represent an exciting minimally invasive option for some patients. There is an abundance of literature on surgical techniques, though very little deals with perioperative management, which is critical for good outcomes. We present a detailed case review and a perioperative management protocol with specific reference to skull base and neuroanatomy. We performed a retrospective chart review and analysis of outcomes and complications by approach and design and prospective employment of a perioperative management protocol in a major tertiary care referral hospital. We included patients undergoing endoscopic skull base approaches by the two senior surgeons from September 2005 to April 2009, selecting of transcranial/intracranial cases for detailed review. Our main outcome measures included perioperative morbidity, mortality, and complications; degree of resection; recurrence rate; and survival. Fifteen patients met study criteria. No perioperative mortality occurred. There were two major and four minor complications. Mean follow-up was 15 months; 11/13 patients with malignancies had no evidence of disease. A perioperative management protocol was designed from these data and has resulted in decreased lumbar drainage and increased fluid/electrolyte monitoring. Endoscopic transcranial/intracranial anterior skull base surgery is both safe and effective when a complete understanding of the surgery and perioperative management is achieved.
PMCID: PMC3312415  PMID: 22451795
Extended endonasal approach; endoscopic; anterior skull base; skull base neoplasm
4.  Nuclear Lamins and Neurobiology 
Molecular and Cellular Biology  2014;34(15):2776-2785.
Much of the work on nuclear lamins during the past 15 years has focused on mutations in LMNA (the gene for prelamin A and lamin C) that cause particular muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. These disorders, often called “laminopathies,” mainly affect mesenchymal tissues (e.g., striated muscle, bone, and fibrous tissue). Recently, however, a series of papers have identified important roles for nuclear lamins in the central nervous system. Studies of knockout mice uncovered a key role for B-type lamins (lamins B1 and B2) in neuronal migration in the developing brain. Also, duplications of LMNB1 (the gene for lamin B1) have been shown to cause autosome-dominant leukodystrophy. Finally, recent studies have uncovered a peculiar pattern of nuclear lamin expression in the brain. Lamin C transcripts are present at high levels in the brain, but prelamin A expression levels are very low—due to regulation of prelamin A transcripts by microRNA 9. This form of prelamin A regulation likely explains why “prelamin A diseases” such as Hutchinson-Gilford progeria syndrome spare the central nervous system. In this review, we summarize recent progress in elucidating links between nuclear lamins and neurobiology.
PMCID: PMC4135577  PMID: 24842906
5.  Bone Morphogenetic Protein-4 Enhances Vascular Endothelial Growth Factor Secretion by Human Retinal Pigment Epithelial Cells 
Journal of cellular biochemistry  2006;98(5):1196-1202.
Retinal pigment epithelial (RPE) cells secrete vascular endothelial growth factor (VEGF), a cytokine known to promote angiogenesis. Results from RNase protection assays (RPAs) show that RPE from non-diabetic human donors and from adult retinal pigment epithelium-19 (ARPE-19) cells expressed significant bone morphogenetic protein-4 (BMP-4) message. In addition, ARPE-19 cells cultured in high glucose (25 mM), compared to those in physiological glucose (5.5 mM) released significantly more BMP-4 into the conditioned media (CM). However, the effect of BMP-4 on the release of VEGF by ARPE-19 cells has not been studied. Accordingly, ARPE-19 cells were treated with BMP-4 to determine VEGF secretion. BMP-4 and VEGF levels in the CM and cell lysates were measured by enzyme-linked immunosorbent assay (ELISA). Cells treated with exogenous BMP-4 had higher VEGF in the CM and this treatment effect was dose- and time-dependent, while cell lysates had low levels of VEGF. Addition of cycloheximide (CHX) or actinomycin-D (ACT) significantly reduced VEGF secretion from cells treated with BMP-4, suggesting that the BMP-4-induced secretion of VEGF requires new RNA and protein synthesis. Our results suggest that BMP-4 may play a role in the regulation of ocular angiogenesis associated with diabetic retinopathy (DR) by stimulating VEGF release from RPE cells.
PMCID: PMC4306351  PMID: 16514669
retinal pigment epithelium; ARPE-19; bone morphogenetic protein; vascular endothelial growth factor; angiogenesis; diabetic retinopathy
6.  A Nonhuman Primate Scrub Typhus Model: Protective Immune Responses Induced by pKarp47 DNA Vaccination in Cynomolgus Macaques 
We developed an intradermal (ID) challenge cynomolgus macaque (Macaca fascicularis) model of scrub typhus, the leading cause of treatable undifferentiated febrile illness in tropical Asia, caused by the obligate intracellular bacterium, Orientia tsutsugamushi. A well-characterized animal model is required for the development of clinically relevant diagnostic assays and evaluation of therapeutic agents and candidate vaccines. We investigated scrub typhus disease pathophysiology and evaluated two O. tsutsugamushi 47-kDa, Ag-based candidate vaccines, a DNA plasmid vaccine (pKarp47), and a virus-vectored vaccine (Kp47/47-Venezuelan equine encephalitis virus replicon particle) for safety, immunogenicity, and efficacy against homologous ID challenge with O. tsutsugamushi Karp. Control cynomolgus macaques developed fever, classic eschars, lymphadenopathy, bacteremia, altered liver function, increased WBC counts, pathogen-specific Ab (IgM and IgG), and cell-mediated immune responses. Vaccinated macaques receiving the DNA plasmid pKarp47 vaccine had significantly increased O. tsutsugamushi–specific, IFN-γ–producing PBMCs (p = 0.04), reduced eschar frequency and bacteremia duration (p ≤ 0.01), delayed bacteremia onset (p < 0.05), reduced circulating bacterial biomass (p = 0.01), and greater reduction of liver transaminase levels (p < 0.03) than controls. This study demonstrates a vaccine-induced immune response capable of conferring sterile immunity against high-dose homologous ID challenge of O. tsutsugamushi in a nonhuman primate model, and it provides insight into cell-mediated immune control of O. tsutsugamushi and dissemination dynamics, highlights the importance of bacteremia indices for evaluation of both natural and vaccine-induced immune responses, and importantly, to our knowledge, has determined the first phenotypic correlates of immune protection in scrub typhus. We conclude that this model is suitable for detailed investigations into vaccine-induced immune responses and correlates of immunity for scrub typhus.
PMCID: PMC4319312  PMID: 25601925
7.  Salmonella enterica Serovar Enteritidis Ghosts Carrying the Escherichia coli Heat-Labile Enterotoxin B Subunit Are Capable of Inducing Enhanced Protective Immune Responses 
The Escherichia coli heat-labile enterotoxin B subunit (LTB) is a potent vaccine adjuvant. Salmonella enterica serovar Enteritidis ghosts carrying LTB (S. Enteritidis-LTB ghosts) were genetically constructed using a novel plasmid, pJHL187-LTB, designed for the coexpression of the LTB and E lysis proteins. S. Enteritidis-LTB ghosts were characterized using scanning electron microscopy to visualize their transmembrane tunnel structures. The expression of LTB in S. Enteritidis-LTB ghost preparations was confirmed by immunoblot and enzyme-linked immunosorbent assays. The parenteral adjuvant activity of LTB was demonstrated by immunizing chickens with either S. Enteritidis-LTB ghosts or S. Enteritidis ghosts. Chickens were intramuscularly primed at 5 weeks of age and subsequently boosted at 8 weeks of age. In total, 60 chickens were equally divided into three groups (n = 20 for each): group A, nonvaccinated control; group B, immunized with S. Enteritidis-LTB ghosts; and group C, immunized with S. Enteritidis ghosts. Compared with the nonimmunized chickens (group A), the immunized chickens (groups B and C) exhibited increased titers of plasma IgG and intestinal secretory IgA antibodies. The CD3+ CD4+ subpopulation of T cells was also significantly increased in both immunized groups. Among the immunized chickens, those in group B exhibited significantly increased titers of specific plasma IgG and intestinal secretory IgA (sIgA) antibodies compared with those in group C, indicating the immunomodulatory effects of the LTB adjuvant. Furthermore, both immunized groups exhibited decreased bacterial loads in their feces and internal organs. These results indicate that parenteral immunization with S. Enteritidis-LTB ghosts can stimulate superior induction of systemic and mucosal immune responses compared to immunization with S. Enteritidis ghosts alone, thus conferring efficient protection against salmonellosis.
PMCID: PMC4054236  PMID: 24671556
8.  Tendon to bone healing and its implications for surgery 
Entheses are complex structures which act to reduce stress concentrations between tendon and skeleton tissues. Understanding the development and function of the enthesis organ has implications for surgical repair, particularly in regards to healing and the regulation of tendon to bone engraftment. In this paper we review the development and function of entheses as well as the enthesis organ concept. Next we examine the process of tendon to bone healing and how this can be regulated, before addressing implications for surgical repair and post-operative care.
PMCID: PMC4241426  PMID: 25489553
tendon; fibrous enthesis; fibrocartilaginous enthesis; healing; surgical repair
9.  Field Detection of Tembusu Virus in Western Thailand by RT-PCR and Vector Competence Determination of Select Culex Mosquitoes for Transmission of the Virus 
Tembusu virus (TMUV; Ntaya serocomplex) was detected in two pools of mosquitoes captured near Sangkhlaburi, Thailand, as well as from sera from sentinel ducks from the same area. Although TMUV has been isolated from several mosquito species in Asia, no studies have ever shown competent vectors for this virus. Therefore, we allowed mosquitoes captured near Sangkhlaburi to feed on young chickens that had been infected with TMUV. These mosquitoes were tested approximately 2 weeks later to determine infection, dissemination, and transmission rates. Culex vishnui developed high viral titers after feeding on TMUV-infected chicks and readily transmitted virus to naïve chickens. In contrast, Cx. fuscocephala seemed less susceptible to infection, and more importantly, zero of five fuscocephala with a disseminated infection transmitted virus by bite, indicating a salivary gland barrier. These results provide evidence for the involvement of Culex mosquitoes in the transmission of TMUV in the environment.
PMCID: PMC3820315  PMID: 24043687
11.  Clinical Targeting of Mutated and Wild-Type Protein Tyrosine Kinases in Cancer 
Molecular and Cellular Biology  2014;34(10):1722-1732.
Clinical therapies for cancer have evolved from toxic, nontargeted agents to manageable, highly targeted therapies. Protein tyrosine kinases are a family of signaling molecules implicated in nearly every cancer type and are the foundation for the development of modern targeted agents. Recent genomic analyses have identified activating mutations, translocations, and amplifications of tyrosine kinases. Selective targeting of these genetically altered tyrosine kinases has resulted in significant clinical advances, including increased patient survival. This indicates that altered protein tyrosine kinases are the main drivers of many different cancers. However, lost during analyses of genetic lesions are the contributions of activated, wild-type kinases on tumor-dependent pathways. New approaches in phosphoproteomic technologies have identified several wild-type tyrosine kinase activation states, suggesting that non-genetically altered kinases can be essential “nodes” for signal transduction. Here, we summarize the evidence supporting the common mechanisms of protein tyrosine kinase activation in cancer and provide a personal perspective on the kinases BCR-ABL and BTK, as well as nonmutated kinase targets in prostate cancer, through our work. We outline the mechanisms of tyrosine kinase activation in the absence of direct mutation and discuss whether non-genetically altered tyrosine kinases or their associated downstream signaling pathways can be effectively targeted.
PMCID: PMC4019040  PMID: 24567371
12.  Independent Risk Factors for Urinary Tract Infection and for Subsequent Bacteremia or Acute Cellular Rejection: A Single Center Report of 1166 Kidney Allograft Recipients 
Transplantation  2013;96(8):10.1097/TP.0b013e3182a04997.
Urinary tract infection (UTI) is a frequent, serious complication in kidney allograft recipients.
We reviewed the records of 1166 kidney allograft recipients who received their allografts at our institution between January 2005 to December 2010 and determined the incidence of UTI during the first three months after transplantation (early UTI). We utilized Cox proportional hazard models to determine the risk factors for early UTI and whether early UTI was an independent risk factor for subsequent bacteremia or acute cellular rejection (ACR).
UTI, defined as ≥105 bacterial colony forming units per milliliter of urine, developed in 247 (21%) of the 1166 recipients. Independent risk factors for the first episode of UTI were: female gender (hazard ratio [HR]: 2.9, 95% Confidence Intervals (CI): 2.2–3.7, P<0.001), prolonged use of Foley catheter (HR: 3.9, 95% CI: 2.8–5.4, P<0.001), ureteral stent (HR 1.4, 95% CI: 1.1–1.8, P=0.01), age (HR: 1.1, 95% CI: 1.0–1.2, P=0.03), and delayed graft function (HR:1.4, 95% CI: 1.0–1.9, P=0.06). Trimethoprim/sulfamethoxazole prophylaxis was associated with a reduced risk of UTI (HR: 0.6, 95% CI: 0.3–0.9, P=0.02). UTI was an independent risk factor for subsequent bacteremia (HR: 2.4, 95% CI: 1.2–4.8, P=0.01). Untreated, but not treated, UTI was associated with an increased risk of ACR (HR: 2.8, 95% CI: 1.3–6.2, P=0.01).
Female gender, prolonged use of Foley catheter, ureteral stent, age, and delayed graft function are independent risk factors for early UTI. UTI is independently associated with the development of bacteremia, and untreated UTI is associated with subsequent ACR.
PMCID: PMC3833249  PMID: 23917724
Urinary Tract Infection; Bacteremia; Acute Rejection; Kidney Transplantation
13.  Change in the immunophenotype of a somatotroph adenoma resulting in gigantism 
Examining the pathologic progression of a pituitary adenoma from the point of a prepubescent child to an adult with gigantism affords us an opportunity to consider why patients may develop secretory or functioning tumors and raises questions about whether therapeutic interventions and surveillance strategies could be made to avoid irreversible phenotypic changes.
Case Description:
A patient underwent a sublabial transsphenoidal resection for a clinically non-functioning macroadenoma in 1999. He underwent radiation treatment and was transiently given growth hormone (GH) supplementation as an adolescent. His growth rapidly traversed several percentiles and he was found to have elevated GH levels. The patient became symptomatic and was taken for a second neurosurgical procedure. Pathology and immunohistochemical staining demonstrated a significantly higher proportion of somatotroph cells and dense granularity; he was diagnosed with a functional somatotroph adenoma.
While it is likely that the described observations reflect the manifestations of a functional somatotroph adenoma in development, it is possible that pubertal growth, GH supplementation, its removal, or radiation therapy contributed to the described endocrine and pathologic changes.
PMCID: PMC4228498  PMID: 25396071
Gigantism; growth hormone; non-functional adenoma; pituitary adenoma; somatotroph adenoma
14.  Non communicable disease multimorbidity and associated health care utilization and expenditures in India: cross-sectional study 
Non communicable disease (NCD) multimorbidity is increasingly becoming common in high income settings but little is known about its epidemiology and associated impacts on citizens and health systems in low and middle-income countries (LMICs). We aim to examine the socio-demographic distribution of NCD multimorbidity (≥2 diseases) and its implications for health care utilization and out-of-pocket expenditure (OOPE) in India.
We analyzed cross-sectional nationally representative data from the World Health Organisaion Study on Global Ageing and Adult Health (WHO-SAGE), conducted in India during 2007. Multiple logistic regression was used to determine socio-demographic predictors of self-reported multimorbidity. A two part model was used to assess the relationship between number of NCDs and health care utilization including OOPE.
28.5% of the sample population had at least one NCD and 8.9% had NCD multimorbidity. The prevalence of multimorbidity increased from 1.3% in 18–29 year olds to 30.6% in those aged 70 years and above. Mean outpatient visits in the preceding 12 months increased from 2.2 to 6.2 and the percentage reporting an overnight hospital stay in the past 3 years increased from 9% to 29% in those with no NCD and ≥2 NCDs respectively (p <0.001).
OOPE incurred during the last outpatient visit increased from INR 272.1 (95% CI = 249.0-295.2) in respondents with no NCDs to INR 454.1 (95% CI = 407.8-500.4) in respondents with ≥2 NCDs. However, we did not find an increase in OOPE during the last inpatient visit with number of NCDs (7865.9 INR for those with zero NCDs compared with 7301.3 for those with ≥2 NCDs). For both outpatient and inpatient OOPE, medicine constitutes the largest proportion of spending (70.7% for outpatient, 53.6% for inpatient visit), followed by spending for health care provider (14.0% for outpatient, 12.2% for inpatient visit).
NCD multimorbidity is common in the Indian adult population and is associated with substantially higher healthcare utilization and OOPE. Strategies to address the growing burden of NCDs in LMICs should include efforts to improve the management of patients with multimorbidity and reduce associated financial burden to individuals and households.
PMCID: PMC4283077  PMID: 25274447
Non-communicable disease (NCD); Multimorbidity; Health care utilization; Out-of-pocket expenditure (OOPE); WHO-SAGE; India
15.  Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB-EFNB1 complex 
Cancer research  2013;73(18):5787-5797.
Most head and neck squamous cell carcinomas (HNSCC) over-express ERBB1/EGFR, but EGFR- targeted therapies have yielded disappointing clinical results in treatment of this cancer. Here we describe a novel interaction between EGFR and the ligand EphrinB1 (EFNB1), and we show that EFNB1 phosphorylation and downstream signaling persists in the presence of cetuximab. Mechanistically, cetuximab drives a shift in EGFR dimerization partners within the signaling complex, suggesting that targeted drugs may trigger partner rearrangements that allow persistent pathway activation. EFNB1 attenuation slowed tumor growth and increased survival in a murine model of HNSCC, suggesting a substantial contribution of EFNB1 signaling to HNSCC development. Together, our findings suggest that EFNB1 is part of the EGFR signaling complex and may mediate drug resistance in HNSCC as well as other solid tumors.
PMCID: PMC4048035  PMID: 23811940
EphrinB1; cetuximab; MAP Kinase; head and neck cancer; ErbB
16.  Improving Access to Psychological Therapies and antidepressant prescribing rates in England: a longitudinal time-series analysis 
The British Journal of General Practice  2013;63(614):e649-e653.
Antidepressant prescribing rates in England have been increasing since the 1970s. The impact of the Improving Access to Psychological Therapies (IAPT) initiative on antidepressant prescribing rates is unknown.
To investigate the impact of the establishment of IAPT services on antidepressant prescribing rates in primary care trusts (PCTs) in England.
Design and setting
A longitudinal time-series analysis, using PCT-level data from 2008 to 2011 set in England.
A time-series analysis was conducted using PCT-level prescription data, dates of establishment of IAPT services, and covariate data for age, sex, and socioeconomic status. Statistical analysis was carried out using analysis of variance and a random-effect negative binomial model.
Antidepressant prescribing rates in England increased by 10% per year during the study period (adjusted rate ratio = 1.10, 95% CI = 1.09 to 1.10). The implementation of IAPT services had no significant effect on antidepressant prescribing (adjusted rate ratio = 0.99, 95% CI = 0.99 to 1.00).
Introduction of a large-scale initiative to increase provision of psychological therapies has not curbed the long-term increased prescribing of antidepressants in England.
PMCID: PMC3750805  PMID: 23998846
antidepressive agents; cognitive behavioural therapy; depression; general practice; primary health care
17.  The Kety-Schmidt Technique for Quantitative Perfusion and Oxygen Metabolism Measurements in the MR Environment 
AJNR. American journal of neuroradiology  2012;34(9):10.3174/ajnr.A3270.
The Kety-Schmidt technique provides quantitative measurement of whole brain cerebral blood flow (CBF). CBF is measured as the area between the arterial and venous washout curves of a diffusible tracer. Oxygen extraction and metabolism may be calculated from arterial and venous samples. In this report we present a method for performing these measurements in an MR environment. This technique could be useful for validation of MR methods of hemodynamic and metabolic measurements in humans.
PMCID: PMC3868472  PMID: 22997166
18.  Molecular weight dependent tissue factor pathway inhibitor release by heparin and heparin oligosaccharides 
Thrombosis research  2006;119(5):653-661.
Heparin and low molecular weight heparins exert their vascular effects by mobilizing tissue factor pathway inhibitor (TFPI) from the vascular endothelium into the blood circulation. We compared the influence of molecular weight on the TFPI release by heparin and its fractions in a non-human primate model. Primates were treated with unfractionated heparin, a low molecular weight heparin (gammaparin), or a heparin-derived oligosaccharide mixture (C3). Endothelial TFPI release was determined using both immunologic and functional assays. After intravenous administration, all agents significantly increased TFPI levels ( p < 0.05) in a dose dependent manner. The increase produced by unfractionated heparin and gammaparin was greater than that by C3 at an equal dosage (p < 0.05). With subcutaneous injection, all agents produced less TFPI release. Repeated administration of heparin-derived oligosaccharides gradually increased TFPI release. A 1.89 fold increase in TFPI levels was observed 4 days after C3 treatment (2.5 mg/ kg). Our findings indicated that TFPI release is dependent on the molecular weight of heparin and its derivatives. Heparin oligosaccharides exert their vascular effects through increased TFPI release after long-term repeated administration.
PMCID: PMC4142645  PMID: 16824584
19.  Rhes Suppression Enhances Disease Phenotypes in Huntington’s Disease Mice 
In Huntington’s disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had increased anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as a therapy for HD.
PMCID: PMC4139702  PMID: 25062765
Huntington disease; Rhes; rasd2; neurodegenerative disease; genetic therapies; RNA interference
21.  Reciprocal knock-in mice to investigate the functional redundancy of lamin B1 and lamin B2 
Molecular Biology of the Cell  2014;25(10):1666-1675.
To assess the redundancy of lamins B1 and B2, knock-in lines were created that produce lamin B2 from the Lmnb1 locus and lamin B1 from the Lmnb2 locus. Both lines developed severe neurodevelopmental abnormalities, indicating that the abnormalities elicited by the loss of one B-type lamin cannot be prevented by increased synthesis of the other.
Lamins B1 and B2 (B-type lamins) have very similar sequences and are expressed ubiquitously. In addition, both Lmnb1- and Lmnb2-deficient mice die soon after birth with neuronal layering abnormalities in the cerebral cortex, a consequence of defective neuronal migration. The similarities in amino acid sequences, expression patterns, and knockout phenotypes raise the question of whether the two proteins have redundant functions. To investigate this topic, we generated “reciprocal knock-in mice”—mice that make lamin B2 from the Lmnb1 locus (Lmnb1B2/B2) and mice that make lamin B1 from the Lmnb2 locus (Lmnb2B1/B1). Lmnb1B2/B2 mice produced increased amounts of lamin B2 but no lamin B1; they died soon after birth with neuronal layering abnormalities in the cerebral cortex. However, the defects in Lmnb1B2/B2 mice were less severe than those in Lmnb1-knockout mice, indicating that increased amounts of lamin B2 partially ameliorate the abnormalities associated with lamin B1 deficiency. Similarly, increased amounts of lamin B1 in Lmnb2B1/B1 mice did not prevent the neurodevelopmental defects elicited by lamin B2 deficiency. We conclude that lamins B1 and B2 have unique roles in the developing brain and that increased production of one B-type lamin does not fully complement loss of the other.
PMCID: PMC4019497  PMID: 24672053
22.  Heparin Oligosaccharides as Potential Therapeutic Agents in Senile Dementia 
Current pharmaceutical design  2007;13(15):1607-1616.
Heparin is a glycosaminoglycan mixture currently used in prophylaxis and treatment of thrombosis. Heparin possesses non-anticoagulant properties, including modulation of various proteases, interactions with fibroblast growth factors, and anti-inflammatory actions. Senile dementia of Alzheimer’s type is accompanied by inflammatory responses contributing to irreversible changes in neuronal viability and brain function. Vascular factors are also involved in the pathogenesis of senile dementia. Inflammation, endogenous proteoglycans, and assembly of senile plagues and neurofibrillary tangles contribute directly and indirectly to further neuronal damage. Neuron salvage can be achieved by anti-inflammation and the competitive inhibition of proteoglycans accumulation. The complexity of the pathology of senile dementia provides numerous potential targets for therapeutic interventions designed to modulate inflammation and proteoglycan assembly. Heparin and related oligosaccharides are known to exhibit anti-inflammatory effects as well as inhibitory effects on proteoglycan assembly and may prove useful as neuroprotective agents.
PMCID: PMC4114250  PMID: 17504153
23.  Noninvasive Prognostication of Polyomavirus BK-Associated Nephropathy 
Transplantation  2013;96(2):131-138.
BK virus associated nephropathy (BKVN) is associated with an increased risk of graft failure.
Levels of mRNAs encoding proteins implicated in inflammation and fibrosis were measured in urine collected at the time of biopsy diagnosis of BKVN in 29 kidney graft recipients, and analyzed for prognosticating graft failure using logistic regression.
Ten of 29 BKVN patients had graft failure within 36 months of BKVN diagnosis and the remaining 19 patients did not. Serum creatinine level, BKVN biopsy stage and urinary cell levels of mRNA for PAI-1, vimentin, TIMP-1, fibronectin, granzyme B or perforin were associated with graft failure. A combination of PAI-1 mRNA level, BKVN biopsy stage and creatinine level (P=0.0015, by logistic regression) and a combination of PAI-1 mRNA level and creatinine level (P=0.001) were the best fitting models for prognosticating graft failure, and PAI-1 mRNA level was the only independent predictor (OR=2.8; 95% CI: 1.1 to 6.8, P=0.03) by multivariable analysis. The AUC for the combination of PAI-1 mRNA, biopsy and creatinine was 0.92 (95% CI: 0.80 to 1.0, P<0.001) by ROC curve analysis, and the AUC was 0.92 (95% CI: 0.80 to 1.0, P<0.001) for the combination of PAI-mRNA and creatinine. Graft outcome was correctly predicted in 27 of 29 BKVN patients by either model.
Urinary cell level of PAI-1 mRNA, measured at the time of BKVN diagnosis, is an independent prognosticator of graft failure and a prediction model of serum creatinine and PAI mRNA is as accurate as the model that includes the biopsy result.
PMCID: PMC3950314  PMID: 23778650
BK virus nephropathy; Messenger RNA; Kidney transplantation; PCR assay
24.  Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of HPV+ cancer 
The increasing incidence of human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (OSSC) demands development of novel therapies. Despite presenting at a more advanced stage, HPV(+) OSCC’s have a better prognosis than their HPV(−) counterparts. We have previously demonstrated that clearance of HPV(+) OSCC during treatment with radiation and chemotherapy requires an immune response which is likely responsible for the improved clinical outcomes. To further elucidate the mechanism of immune-mediated clearance, we asked whether radiation therapy induces tumor cell changes that allow the body to recognize and aid in tumor clearance. Here, we describe a radiation-induced change in tumor surface protein expression that is critical for immune-mediated clearance. Radiation therapy decreases surface expression of CD47, a self marker. CD47 is frequently over-expressed in HNSCC and radiation induces a decrease of CD47 in a dose dependent manner. We show both in vitro and in vivo that tumor cell CD47 protein levels are restored over time following sub-lethal radiation exposure and that protein levels on adjacent, normal tissues remain unaffected. Furthermore, reduction of tumor cell CD47 increases phagocytosis of these cells by dendritic cells and leads to increased IFNγ and granzyme production from mixed lymphocytes. Finally, decreasing tumor cell CD47 in combination with standard radiation and chemotherapy results in improved immune-mediated tumor clearance in vivo. These findings help define an important mechanism of radiation related immune clearance and suggest that decreasing CD47 specifically on tumor cells may be a good therapeutic target for HPV related disease.
PMCID: PMC3972896  PMID: 23292955
HPV; CD47; radiation; immune; HNSCC; OSCC
25.  Use of the bootstrap method to develop a physical fitness test for public safety officers who serve as both police officers and firefighters 
Physical fitness testing is a common tool for motivating employees with strenuous occupations to reach and maintain a minimum level of fitness. Nevertheless, the use of such tests can be hampered by several factors, including required compliance with US antidiscrimination laws. The Highland Park (Texas) Department of Public Safety implemented testing in 1991, but no single test adequately evaluated its sworn employees, who are cross-trained and serve as police officers and firefighters. In 2010, the department's fitness experts worked with exercise physiologists from Baylor Heart and Vascular Hospital to develop and evaluate a single test that would be equitable regardless of race/ethnicity, disability, sex, or age >50 years. The new test comprised a series of exercises to assess overall fitness, followed by two sequences of job-specific tasks related to firefighting and police work, respectively. The study group of 50 public safety officers took the test; raw data (e.g., the number of repetitions performed or the time required to complete a task) were collected during three quarterly testing sessions. The statistical bootstrap method was then used to determine the levels of performance that would correlate with 0, 1, 2, or 3 points for each task. A sensitivity analysis was done to determine the overall minimum passing score of 17 points. The new physical fitness test and scoring system have been incorporated into the department's policies and procedures as part of the town's overall employee fitness program.
PMCID: PMC4059562  PMID: 24982558

Results 1-25 (197)