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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
3.  Impact of Pay for Performance on Prescribing of Long-Acting Reversible Contraception in Primary Care: An Interrupted Time Series Study 
PLoS ONE  2014;9(4):e92205.
The aim of this study was to evaluate the impact of Quality and Outcomes Framework (QOF), a major pay-for-performance programme in the United Kingdom, on prescribing of long-acting reversible contraceptives (LARC) in primary care.
Negative binomial interrupted time series analysis using practice level prescribing data from April 2007 to March 2012. The main outcome measure was the prescribing rate of long-acting reversible contraceptives (LARC), including hormonal and non hormonal intrauterine devices and systems (IUDs and IUSs), injectable contraceptives and hormonal implants.
Prescribing rates of Long-Acting Reversible Contraception (LARC) were stable before the introduction of contraceptive targets to the QOF and increased afterwards by 4% annually (rate ratios  = 1.04, 95% CI = 1.03, 1.06). The increase in LARC prescribing was mainly driven by increases in injectables (increased by 6% annually), which was the most commonly prescribed LARC method. Of other types of LARC, the QOF indicator was associated with a step increase of 20% in implant prescribing (RR =  1.20, 95% CI =  1.09, 1.32). This change is equivalent to an additional 110 thousand women being prescribed with LARC had QOF points not been introduced.
Pay for performance incentives for contraceptive counselling in primary care with women seeking contraceptive advice has increased uptake of LARC methods.
PMCID: PMC3973652  PMID: 24694949
4.  The Relationship between Waterpipe and Cigarette Smoking in Low and Middle Income Countries: Cross-Sectional Analysis of the Global Adult Tobacco Survey 
PLoS ONE  2014;9(3):e93097.
Waterpipe tobacco smoking is receiving growing attention due to accumulating evidence suggesting increasing prevalence in some populations and deleterious health effects. Nevertheless, the relationship between waterpipe and cigarette smoking remain unknown, particularly in low and middle income countries.
Materials and Methods
We analysed waterpipe and cigarette smoking using data from Global Adult Tobacco Survey, a household survey of adults aged ≥15 years conducted between 2008–2010 in LMICs. Factors associated with waterpipe and cigarette use were assessed using multiple logistic regression. Factors associated with the quantity of waterpipe and cigarette smoking were assessed using log-linear regression models.
After adjusting for age, gender, residence, education, occupation and smokeless tobacco use, waterpipe smoking was significantly higher among cigarette users than in non-cigarette users in India (5.6% vs. 0.6%, AOR 13.12, 95% CI 7.41–23.23) and Russia (6.7% vs. 0.2%, AOR 27.73, 95% CI 11.41–67.43), but inversely associated in Egypt (2.6% vs. 3.4%, AOR 0.21, 95% CI 0.15–0.30) and not associated in Vietnam (13.3% vs. 4.7%, AOR 0.96, 95% CI 0.74–1.23). Compared to non-cigarette smokers, waterpipe smokers who also used cigarettes had more waterpipe smoking sessions per week in Russia (1.3 vs. 2.9, beta coefficient 0.31, 95% CI 0.06, 0.57), but less in Egypt (18.2 vs. 10.7, beta coefficient −0.45, 95% CI −0.73, −0.17) and Vietnam (102.0 vs. 79.3, beta coefficient −0.31, 95% CI −0.56, −0.06) and similar amounts in India (29.4 vs. 32.6, beta coefficient −0.12, 95% CI −0.46, 0.22).
Waterpipe smoking is low in most LMICs but important country-level differences in use, including concurrent cigarette smoking, should be taken into account when designing and evaluating tobacco control interventions.
PMCID: PMC3963998  PMID: 24664109
5.  Glucose-Neopentyl Glycol (GNG) Amphiphiles for Membrane Protein Solubilization, Stabilization and Crystallization 
The development of a new class of surfactants for membrane protein manipulation, “GNG amphiphiles”, is reported. These amphiphiles display promising behavior for membrane proteins, as demonstrated recently by the high resolution structure of a sodium-pumping pyrophosphatase reported by Kellosalo et al.
PMCID: PMC3578972  PMID: 23165475
6.  HIV-Infected Kidney Graft Recipients Managed With an Early Corticosteroid Withdrawal Protocol: Clinical Outcomes and Messenger RNA Profiles1 
Transplantation  2013;95(5):711-720.
The outcome of HIV-infected kidney transplant recipients managed with an early corticosteroid withdrawal protocol is not known.
Eleven consecutive HIV-infected patients with undetectable plasma HIV RNA and >200/mm3 CD4+ T-cells underwent deceased (n=8) or living donor (n=3) kidney transplantation at our center. All were managed with an early corticosteroid withdrawal protocol; 9 of 11 received anti-thymocyte globulin and 2 received basiliximab induction. We analyzed patient and graft outcomes, acute rejection (AR) rate, HIV progression, BKV replication, infections and urinary cell mRNA profiles.
The median follow-up was 44.5 months (range: 26-73). The incidence of AR was 9% at one year and patient and allograft survival rates were 100% and 91%, respectively. Estimated glomerular filtration rate at one year (mean ± SD) was 78±39 ml/min/1.73m2. Plasma HIV RNA was undetectable at 24 months and none had BKV replication. Six of the 11 kidney recipients developed eight infections requiring hospitalization. Urinary cell levels of mRNA for complement components and complement regulatory proteins, cell lineage specific proteins CD3, CD4, CD8, CTLA4, Foxp3, chemokine IP-10, cytotoxic perforin and granzyme B and BKV–VP1 mRNA were not different (P>0.05) between HIV-infected patients and HIV-negative recipients (n=22) with stable graft function and normal biopsy results.
An early steroid withdrawal regimen with anti-thymocyte globulin induction was associated with excellent graft and patient outcomes in HIV-infected recipients of kidney allografts. Their urinary cell mRNA profiles are indistinguishable from those of HIV negative patients with stable graft function and normal biopsy results.
PMCID: PMC3644872  PMID: 23503504
Kidney transplantation; HIV; Gene expression; Tacrolimus
7.  SUMO-2 and PIAS1 Modulate Insoluble Mutant Huntingtin Protein Accumulation 
Cell reports  2013;4(2):362-375.
A key feature in Huntington disease (HD) is the accumulation of mutant Huntingtin (HTT) protein, which may be regulated by posttranslational modifications. Here, we define the primary sites of SUMO modification in the amino-terminal domain of HTT, show modification downstream of this domain, and demonstrate that HTT is modified by the stress-inducible SUMO-2. A systematic study of E3 SUMO ligases demonstrates that PIAS1 is an E3 SUMO ligase for both HTT SUMO-1 and SUMO-2 modification and that reduction of dPIAS in a mutant HTT Drosophila model is protective. SUMO-2 modification regulates accumulation of insoluble HTT in HeLa cells in a manner that mimics proteasome inhibition and can be modulated by overexpression and acute knockdown of PIAS1. Finally, the accumulation of SUMO-2-modified proteins in the insoluble fraction of HD postmortem striata implicates SUMO-2 modification in the age-related pathogenic accumulation of mutant HTT and other cellular proteins that occurs during HD progression.
PMCID: PMC3931302  PMID: 23871671
8.  Evaluation of a Field-Portable DNA Microarray Platform and Nucleic Acid Amplification Strategies for the Detection of Arboviruses, Arthropods, and Bloodmeals 
Highly multiplexed assays, such as microarrays, can benefit arbovirus surveillance by allowing researchers to screen for hundreds of targets at once. We evaluated amplification strategies and the practicality of a portable DNA microarray platform to analyze virus-infected mosquitoes. The prototype microarray design used here targeted the non-structural protein 5, ribosomal RNA, and cytochrome b genes for the detection of flaviviruses, mosquitoes, and bloodmeals, respectively. We identified 13 of 14 flaviviruses from virus inoculated mosquitoes and cultured cells. Additionally, we differentiated between four mosquito genera and eight whole blood samples. The microarray platform was field evaluated in Thailand and successfully identified flaviviruses (Culex flavivirus, dengue-3, and Japanese encephalitis viruses), differentiated between mosquito genera (Aedes, Armigeres, Culex, and Mansonia), and detected mammalian bloodmeals (human and dog). We showed that the microarray platform and amplification strategies described here can be used to discern specific information on a wide variety of viruses and their vectors.
PMCID: PMC3583313  PMID: 23249687
9.  Identification of a cKit+ Colonic Crypt Base Secretory Cell That Supports Lgr5+ Stem Cells in Mice 
Gastroenterology  2012;142(5):1195-1205.e6.
Background & Aims
Paneth cells contribute to the small intestinal niche of Lgr5+ stem cells. Although the colon also contains Lgr5+ stem cells, it does not contain Paneth cells. We investigated the existence of colonic Paneth-like cells that have a distinct transcriptional signature and support Lgr5+ stem cells.
We used multicolor fluorescence-activated cell sorting to isolate different subregions of colon crypts, based on known markers, from dissociated colonic epithelium of mice. We performed multiplexed single-cell gene expression analysis with quantitative reverse transcriptase polymerase chain reaction followed by hierarchical clustering analysis to characterize distinct cell types. We used immunostaining and fluorescence-activated cell sorting analyses with in vivo administration of a Notch inhibitor and in vitro organoid cultures to characterize different cell types.
Multicolor fluorescence-activated cell sorting could isolate distinct regions of colonic crypts. Four major epithelial subtypes or transcriptional states were revealed by gene expression analysis of selected populations of single cells. One of these, the goblet cells, contained a distinct cKit/CD117+ crypt base subpopulation that expressed Dll1, Dll4, and epidermal growth factor, similar to Paneth cells, which were also marked by cKit. In the colon, cKit+ goblet cells were interdigitated with Lgr5+ stem cells. In vivo, this colonic cKit+ population was regulated by Notch signaling; administration of a γ-secretase inhibitor to mice increased the number of cKit+ cells. When isolated from mouse colon, cKit+ cells promoted formation of organoids from Lgr5+ stem cells, which expressed Kitl/stem cell factor, the ligand for cKit. When organoids were depleted of cKit+ cells using a toxin-conjugated antibody, organoid formation decreased.
cKit marks small intestinal Paneth cells and a subset of colonic goblet cells that are regulated by Notch signaling and support Lgr5+stem cells.
PMCID: PMC3911891  PMID: 22333952
Cancer; Inflammatory Bowel Disease; Intestine; Regenerate
10.  Nuclear lamins in the brain—new insights into function and regulation 
Molecular neurobiology  2012;47(1):290-301.
The nuclear lamina is an intermediate filament meshwork composed largely of four nuclear lamins—lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins). Located immediately adjacent to the inner nuclear membrane, the nuclear lamina provides a structural scaffolding for the cell nucleus. It also interacts with both nuclear membrane proteins and the chromatin and is thought to participate in many important functions within the cell nucleus. Defects in A-type lamins cause cardiomyopathy, muscular dystrophy, peripheral neuropathy, lipodystrophy, and progeroid disorders. In contrast, the only bona fide link between the B-type lamins and human disease is a rare demyelinating disease of the central nervous system—adult-onset autosomal-dominant leukoencephalopathy, caused by a duplication of the gene for lamin B1. However, this leukoencephalopathy is not the only association between the brain and B-type nuclear lamins. Studies of conventional and tissue-specific knockout mice have demonstrated that B-type lamins play essential roles in neuronal migration in the developing brain and in neuronal survival. The importance of A-type lamin expression in the brain is unclear, but it is intriguing that the adult brain preferentially expresses lamin C rather than lamin A, very likely due to microRNA-mediated removal of prelamin A transcripts. Here, we review recent studies on nuclear lamins, focusing on the function and regulation of the nuclear lamins in the central nervous system.
PMCID: PMC3538886  PMID: 23065386
Nuclear lamina; brain development; A-type lamins; B-type lamins; differential gene expression
11.  Conducting Functional Communication Training via Telehealth to Reduce the Problem Behavior of Young Children with Autism 
Functional communication training (FCT) was conducted by parents of 17 young children with autism spectrum disorders who displayed problem behavior. All procedures were conducted at regional clinics located an average of 15 miles from the families’ homes. Parents received coaching via telehealth from behavior consultants who were located an average of 222 miles from the regional clinics. Parents first conducted functional analyses with telehealth consultation (Wacker, Lee, et al., in press) and then conducted FCT that was matched to the identified function of problem behavior. Parent assistants located at the regional clinics received brief training in the procedures and supported the families during the clinic visits. FCT, conducted within a nonconcurrent multiple baseline design, reduced problem behavior by an average of 93.5%. Results suggested that FCT can be conducted by parents via telehealth when experienced applied behavior analysts provide consultation.
PMCID: PMC3608527  PMID: 23543855
functional communication training; telehealth; autism spectrum disorders; problem behavior
12.  Association between being employed in a smoke-free workplace and living in a smoke-free home: Evidence from 15 low and middle income countries☆ 
Preventive Medicine  2014;59(100):47-53.
To assess whether being employed in a smoke-free workplace is associated with living in a smoke-free home in 15 low and middle income countries (LMICs).
Country-specific individual level analyses of cross-sectional Global Adult Tobacco Survey data (2008–2011) from 15 LMICs was conducted using multiple logistic regression. The dependent variable was living in a smoke-free home; the independent variable was being employed in a smoke-free workplace. Analyses were adjusted for age, gender, residence, region, education, occupation, current smoking, current smokeless tobacco use and number of household members. Individual country results were combined in a random effects meta-analysis.
In each country, the percentage of participants employed in a smoke-free workplace who reported living in a smoke-free home was higher than those employed in a workplace not smoke-free. The adjusted odds ratios (AORs) of living in a smoke-free home among participants employed in a smoke-free workplace (vs. those employed where smoking occurred) were statistically significant in 13 of the 15 countries, ranging from 1.12 [95% CI 0.79–1.58] in Uruguay to 2.29 [1.37–3.83] in China. The pooled AOR was 1.61 [1.46–1.79].
In LMICs, employment in a smoke-free workplace is associated with living in a smoke-free home. Accelerated implementation of comprehensive smoke-free policies is likely to result in substantial population health benefits in these settings.
•Individual level Global Adult Tobacco Survey data analyzed for 15 LMICs (2008–2010)•Studied association of smoke-free workplace policy with living in smoke-free home•Implementation of smoke-free workplace policy varies greatly across LMICs.•Smoke-free homes 60% more likely with employment in smoke-free workplaces in LMICs•100% smoke-free policy in LMICs changes social norms around exposing others to SHS.
PMCID: PMC3898883  PMID: 24287123
Smoke-free policy; Secondhand smoke; Tobacco; Workplace; Low- and middle-income countries; GATS
13.  Directing driver attention with augmented reality cues 
This simulator study evaluated the effects of augmented reality (AR) cues designed to direct the attention of experienced drivers to roadside hazards. Twenty-seven healthy middle-aged licensed drivers with a range of attention capacity participated in a 54 mile (1.5 hour) drive in an interactive fixed-base driving simulator. Each participant received AR cues to potential roadside hazards in six simulated straight (9 mile long) rural roadway segments. Drivers were evaluated on response time for detecting a potentially hazardous event, detection accuracy for target (hazard) and non-target objects, and headway with respect to the hazards. Results showed no negative outcomes associated with interference. AR cues did not impair perception of non-target objects, including for drivers with lower attentional capacity. Results showed near significant response time benefits for AR cued hazards. AR cueing increased response rate for detecting pedestrians and warning signs but not vehicles. AR system false alarms and misses did not impair driver responses to potential hazards.
PMCID: PMC3891797  PMID: 24436635
Highlighting Cues; Augmented Reality; Driver Distraction; Driver Inattention; Driving
14.  Visual search for features and conjunctions following declines in the useful field of view 
Experimental aging research  2012;38(4):10.1080/0361073X.2012.699370.
Background/Study Context
Typical measures for assessing the useful field (UFOV) of view involve many components of attention. The objective of the current experiment was to examine differences in visual search efficiency for older individuals with and without UFOV impairment.
The authors used a computerized screening instrument to assess the useful field of view and to characterize participants as having an impaired or normal UFOV. Participants also performed two visual search tasks, a feature search (e.g., search for a green target among red distractors) or a conjunction search (e.g., a green target with a gap on its left or right side among red distractors with gaps on the left or right and green distractors with gaps on the top or bottom).
Visual search performance did not differ between UFOV impaired and unimpaired individuals when searching for a basic feature. However, search efficiency was lower for impaired individuals than unimpaired individuals when searching for a conjunction of features.
The results suggest that UFOV decline in normal aging is associated with conjunction search. This finding suggests that the underlying cause of UFOV decline may arise from an overall decline in attentional efficiency. Because the useful field of view is a reliable predictor of driving safety, the results suggest that decline in the everyday visual behavior of older adults might arise from attentional declines.
PMCID: PMC3823497  PMID: 22830667
15.  Foster Kennedy Syndrome Due to Meningioma Growth during Pregnancy 
Tumors of the olfactory groove may cause unilateral optic atrophy with contralateral papilledema and anosmia (Foster Kennedy syndrome). We describe a case of a young pregnant woman with Foster Kennedy syndrome due to an olfactory groove meningioma.
PMCID: PMC3822324  PMID: 24273529
Foster Kennedy syndrome; meningioma; pregnancy; optic disk atrophy; papilledema; anosmia
16.  Cross-Sectional Study on Attitudes among General Practitioners towards Pneumococcal Vaccination for Middle-Aged and Elderly Population in Hong Kong 
PLoS ONE  2013;8(11):e78210.
To study the attitudes among general practitioners towards pneumococcal vaccination for middle-aged (50–64) and elderly population (over 65) in Hong Kong and the factors affecting their decision to advise pneumococcal vaccination for those age groups.
Cross-sectional study of general practitioners in private practice in Hong Kong.
Members of Hong Kong Medical Association delivering general practice services in private sector.
Measuring Tool
Self-administered questionnaire.
Main Outcome Measures
Intention to recommend pneumococcal vaccination, barriers against pneumococcal vaccination.
53.4% of the respondents would actively recommend pneumococcal vaccination to elderly patients but only 18.8% would recommend for middle-aged patients. Consultation not related to pneumococcal vaccine was the main reason for not recommending pneumococcal vaccine (43.6%). Rarity of pneumonia in their daily practice was another reason with 68.4% of respondents attending five or less patients with pneumonia each year. In multivariate analysis, factors such as respondents would get vaccination when reaching age 50 (ORm 10.1), and attending 6 pneumonia cases or more per year (ORm 2.28) were found to be associated with increasing likelihood for recommending vaccination to the middle-aged. While concerns of marketing a product (ORm 0.41), consultation not related to vaccination (ORm 0.45) and limited time (ORm 0.38) were factors that reduced the likelihood.
Public policy is needed to increase the awareness of impact of pneumococcal pneumonia and the availability of preventive measures.
PMCID: PMC3818320  PMID: 24223775
17.  Venezuelan Equine Encephalitis Virus Replicon Particle Vaccine Protects Nonhuman Primates from Intramuscular and Aerosol Challenge with Ebolavirus 
Journal of Virology  2013;87(9):4952-4964.
There are no vaccines or therapeutics currently approved for the prevention or treatment of ebolavirus infection. Previously, a replicon vaccine based on Venezuelan equine encephalitis virus (VEEV) demonstrated protective efficacy against Marburg virus in nonhuman primates. Here, we report the protective efficacy of Sudan virus (SUDV)- and Ebola virus (EBOV)-specific VEEV replicon particle (VRP) vaccines in nonhuman primates. VRP vaccines were developed to express the glycoprotein (GP) of either SUDV or EBOV. A single intramuscular vaccination of cynomolgus macaques with VRP expressing SUDV GP provided complete protection against intramuscular challenge with SUDV. Vaccination against SUDV and subsequent survival of SUDV challenge did not fully protect cynomolgus macaques against intramuscular EBOV back-challenge. However, a single simultaneous intramuscular vaccination with VRP expressing SUDV GP combined with VRP expressing EBOV GP did provide complete protection against intramuscular challenge with either SUDV or EBOV in cynomolgus macaques. Finally, intramuscular vaccination with VRP expressing SUDV GP completely protected cynomolgus macaques when challenged with aerosolized SUDV, although complete protection against aerosol challenge required two vaccinations with this vaccine.
PMCID: PMC3624300  PMID: 23408633
18.  Development of a Biosafety Enhanced and Immunogenic Salmonella Enteritidis Ghost Using an Antibiotic Resistance Gene Free Plasmid Carrying a Bacteriophage Lysis System 
PLoS ONE  2013;8(10):e78193.
In the development of genetically inactivated bacterial vaccines, plasmid retention often requires the antibiotic resistance gene markers, the presence of which can cause the potential biosafety hazards such as the horizontal spread of resistance genes. The new lysis plasmid was constructed by utilizing the approach of balanced-lethal systems based on auxotrophic gene Aspartate semialdehyde dehydrogenase (asd). The PhiX174 lysis gene E and λPR37-cI857 temperature-sensitive regulatory system was cloned in the asd gene positive plasmid and this novel approach allowed the production of antibiotic resistance marker free Salmonella Enteritidis (S. Enteritidis) ghost. The immunogenic potential of the biosafety enhanced antibiotic resistance gene free S. Enteritidis ghost was evaluated in chickens by employing the prime-boost vaccination strategy using a combination of oral and intramuscular routes. A total of 75 two-week-old chickens were equally divided into five groups: group A (non-immunized control), group B (intramuscularly primed and boosted), group C (primed intramuscularly and boosted orally), group D (primed and boosted orally), and group E (primed orally and boosted intramuscularly). Chickens from all immunized groups demonstrated significant increases in plasma IgG, intestinal secretory IgA levels, and antigen-specific lymphocyte proliferative response. After a virulent S. Enteritidis challenge, all immunized groups showed fewer gross lesions and decreased bacterial recovery from organs in comparison with the non-immunized control group. Among the immunized chickens, groups B and D chickens showed optimized protection, indicating that the prime-booster immunization with the ghost via intramuscular or oral route is efficient. Taken together, our results demonstrate that an antibiotic resistance gene free lysis plasmid was successfully constructed and utilized for production of safety enhanced S. Enteritidis ghost, which can be used as a safe and effective vaccine against virulent S. Enteritidis infections.
PMCID: PMC3799721  PMID: 24205152
19.  The impact of diphenhydramine and promethazine in patients undergoing advanced upper endoscopic procedures 
Endoscopic retrograde cholangiopancreatography (ERCP ) and endoscopic ultrasound (EUS) procedures are more complex and longer duration than standard endoscopy, requiring deeper levels of sedation. While prior studies have compared standard sedation (meperidine and midazolam) to propofol, no randomized, controlled trials have evaluated the use of adjunct sedatives in these procedures.
To prospectively compare the use of promethazine and diphenhydramine as adjunct sedatives to standard sedation in patients undergoing advanced endoscopic procedures.
This was a prospective, randomized, placebo-controlled study in a single, tertiary-care referral center. Promethazine (P), diphenhydramine (B), or normal saline (NS) were given as adjunct sedatives along with meperidine and midazolam in adult patients undergoing upper EUS and/or ERCP procedures. The main outcome measurement was sedation failure.
292 patients (P: 97, B: 93, NS: 102) were randomized over 36 months. No significant differences in sedation failures (P: 8, B: 13, NS: 11, p=0.449) or in the times needed to achieve adequate sedation (P: 11.8 minutes, B: 12.9 minutes, NS: 14.0 minutes, p=0.054) were seen between the groups. Sedation using P (43.7 minutes) was associated with a significantly longer recovery time compared to B (28.0 minutes) or NS (24.5 minutes).
The use of promethazine and diphenhydramine as adjunct sedatives did not improve sedation failure rates or reduce the time needed to achieve sedation in patients undergoing upper EUS or ERCP. Patients with anticipated sedation difficulties should proceed directly to propofol-based sedation.
PMCID: PMC3896573  PMID: 24498528
promethazine; diphenhydramine; endoscopic retrograde cholangiopancreatography; endoscopic ultrasound; sedation
20.  Autoimmune pancreatitis diagnosed using endoscopic ultrasound and a novel 19-gauge histology needle 
PMCID: PMC3896580  PMID: 24498535
autoimmune pancreatitis; endoscopic ultrasound; fine needle biopsy
21.  Dysregulation of the complement cascade in the hSOD1G93A transgenic mouse model of amyotrophic lateral sclerosis 
Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS); however, a comprehensive examination of complement expression in this disease has not been performed. This study therefore aimed to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5 and CD88) and regulators (CD55 and CD59a) in the lumbar spinal cord of hSOD1G93A mice during defined disease stages.
hSOD1G93A and wild-type mice were examined at four different ages of disease progression. mRNA and protein expression of complement components and regulators were examined using quantitative PCR, western blotting and ELISA. Localisation of complement components within lumbar spinal cord was investigated using immunohistochemistry. Statistical differences between hSOD1G93A and wild-type mice were analysed using a two-tailed t-test at each stage of disease progression.
We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1G93A mice. CD88 was also increased during disease progression, with immunolocalisation demonstrating expression on motor neurons and increasing expression on microglia surrounding the regions of motor neuron death.
These results indicate that local complement activation and increased expression of CD88 may contribute to motor neuron death and ALS pathology in the hSOD1G93A mouse. Hence, reducing complement-induced inflammation could be an important therapeutic strategy to treat ALS.
PMCID: PMC3850877  PMID: 24067070
C1q; C4; Factor B; C3; C5; CD55; CD88; Motor neuron disease; Neuroinflammation
22.  EUS compared with endoscopy plus transabdominal US in the initial diagnostic evaluation of patients with upper abdominal pain 
Gastrointestinal endoscopy  2010;72(5):967-974.
Primary upper endoscopy (EGD) and transabdominal US (TUS) are often performed in patients with upper abdominal pain.
Primary: Determine whether the combination of EGD and EUS was equivalent to EGD plus TUS in the diagnostic evaluation of upper abdominal pain. Secondary: Compare EUS versus TUS in detecting abdominal lesions, and compare EGD by using an oblique-viewing echoendoscope versus the standard, forward-viewing endoscope in detecting mucosal lesions.
Prospective, paired design.
Six academic endoscopy centers.
This study involved patients with upper abdominal pain referred for endoscopy.
All patients had EGD, EUS, and TUS. The EGD was done using both an oblique-viewing echoendoscope and the standard, forward-viewing endoscope (randomized order) by two separate endoscopists in a blinded fashion, followed by EUS. TUS was performed within 4 weeks of EGD/EUS, also in a blinded fashion. Follow-up: telephone interviews and chart reviews.
Main Outcome Measurements
Diagnose possible etiology of upper abdominal pain and detect clinically significant lesions.
A diagnosis of the etiology of upper abdominal pain was made in 66 of 172 patients (38%). The diagnostic rate was 42 of 66 patients (64%) for EGD plus EUS versus 41 of 66 patients (62%) for EGD plus TUS, which was statistically equivalent (McNemar test; P = .27). One hundred ninety-eight lesions were diagnosed with either EUS or TUS. EUS was superior to TUS for visualizing the pancreas (P < .0001) and for diagnosing chronic pancreatitis (P = .03). Two biliary stones were detected only by EUS. Two hundred fifty-one mucosal lesions were similarly diagnosed with EGD with either the standard, forward-viewing endoscope or the oblique-viewing echoendoscope (kappa = 0.48 [95% CI, .43-.54]). EGD with the standard, forward-viewing endoscope was preferred for biopsies.
No cost analysis.
The combination of EGD with EUS is equivalent to EGD plus TUS for diagnosing a potential etiology of upper abdominal pain. EUS is superior to TUS for detecting chronic pancreatitis. EGD combined with EUS should be considered in the first-line diagnostic evaluation of patients with upper abdominal pain.
PMCID: PMC3775486  PMID: 20650452
23.  Sleep Syncope: Treatment with a Permanent Pacemaker 
Vasovagal syncope usually occurs during upright posture, but Jardine et al. have described a variant that occurs at night. During “sleep syncope”, patients are awakened from sleep with nausea, abdominal cramping or a sense of impending diarrhea, get up, and faint in the bathroom. We report on a patient with recurrent sleep syncope (with physical injury) in whom an asystolic pause was documented during one of her “sleep syncope” spells. Implantation of a dual chamber pacemaker (5 year follow-up) “cured” her of further syncope. This is the 1st report of pacemaker use for this unusual form of reflex syncope.
PMCID: PMC3774786  PMID: 22433038
syncope; sleep; pacemaker
24.  A Host-guest Relationship in Bone Morphogenetic Protein Receptor-II Defines Specificity in Ligand-Receptor Recognition 
Biochemistry  2012;51(35):6968-6980.
One of the most intriguing questions confronting the Bone Morphogenetic Protein family is the mechanism of ligand recognition, since there are more ligands than receptors. Crystal structures of two type II receptors ActR-II and BMPR-II are essentially identical, and a loop structure (A-loop) has been suggested to play a role in determining ligand specificity. Solution biophysical study showed mutations of several A-loop residues in these two receptors exert different ligand binding effects. Thus, the issues of mechanism of ligand recognition and specificity remain unresolved. We examined effects of mutations of residues Y40, G47, and S107 in BMPR-II receptor. These residues are not identified in contact with the ligand in the BMP-7-BMPR-II complex, but are found mutated in genetic diseases. They are likely to be useful in identifying their roles in differentiating the various BMP ligands. Spectroscopic probing revealed little mutation-induced structural change in BMPR-II. Ligand binding studies revealed that Y40 plays a significant role in differentiating three distinct ligands; G47 and S107 affect ligand binding to a lesser extent. The role of the A-loop in ActR-II or BMPR-II is dependent on the host sequence of the receptor extracellular domain (ECD) in which it is embedded, suggesting a host-guest relationship between the A-loop and the rest of the ECD. Computational analysis demonstrated a long-range connectivity between Y40, G47, and S107 and other locations in BMPR-II. An integration of these results on functional energetics and protein structures clearly demonstrate, for the first time, an intra-domain communication network within BMPR-II.
PMCID: PMC3481545  PMID: 22894880
25.  Fully Endoscopic Microvascular Decompression: Our Early Experience 
Minimally Invasive Surgery  2013;2013:739432.
Background. Microvascular decompression (MVD) is a widely accepted treatment for neurovascular disorders associated with facial pain and spasm. The endoscope has rapidly become a standard tool in neurosurgical procedures; however, its adoption in lateral approaches to the posterior fossa has been slower. The endoscope is used primarily to assist conventional microscopic techniques. We are interested in developing fully endoscopic approaches to the cerebellopontine angle, and here, we describe our preliminary experience with this procedure for MVD. Methods. A retrospective review of our two-year experience from 2011 to 2012, transitioning from using conventional microscopic techniques to endoscope-assisted microsurgery to fully endoscopic MVD, is provided. We also reviewed our preliminary outcomes during this transition. Results. There was no difference in the surgical duration of these three procedures. In addition, the majority of procedures performed in 2012 were fully endoscopic, suggesting the ease of incorporating this solo tool into practice. Pain outcomes of fully endoscopic MVD appear to be very similar to those of both conventional and endoscope-assisted MVDs. Complications occurred in all groups at equally low rates. Conclusion. Fully endoscopic MVD is both safe and effective. By enhancing visualization of structures within the cerebellopontine angle, endoscopy may prove to be a valuable adjunct or alternative to conventional microscopic approaches.
PMCID: PMC3776375  PMID: 24083024

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