View details for PubMedID 31055718
BACKGROUND: Fluoroscopy use during ERCP exposes patients and providers to deleterious effects of radiation. Formal training in fluoroscopy/radiation protection is not widely emphasized during therapeutic endoscopy training, and radiation use during GI endoscopy has not previously been characterized in the USA. In this study, we evaluated radiation training, fluoroscopy use patterns, and radiation protection practices among US therapeutic endoscopists.METHODS: An anonymous electronic survey was distributed to US therapeutic endoscopists, and responses were analyzed using descriptive statistics. State-specific requirements for fluoroscopy utilization were determined from state radiologic health branches.RESULTS: A total of 159 endoscopists (response rate 67.8%) predominantly those working in university hospitals (69.2%) with >5years of experience performing ERCP (74.9%) completed the questionnaire. Although the majority of endoscopists (61.6%) reported that they personally controlled fluoroscopy during ERCP, most (56.6%) had not received training on operating their fluoroscopy system. Only a minority (18-31%) of all respondents reported consistently utilizing modifiable fluoroscopy system parameters that minimize patient radiation exposure (pulsed fluoroscopy, frame rate modification or collimation). Endoscopists appear to undertake adequate personal radiation protective measures although use of a dosimeter was not consistent in half of respondents. The majority of states (56.8%) do not have any stated requirement for certification of non-radiologist physicians who intend to operate fluoroscopy.CONCLUSIONS: Most US gastroenterologists performing ERCP have not received formal training in operating their fluoroscopy system or in minimizing radiation exposure to themselves and to their patients. Such formal training should be included in all therapeutic endoscopy training programs, and fluoroscopy system-specific training should be offered at all hospitals.
View details for PubMedID 30911863
BACKGROUND & AIMS: Endoscopic procedures are important for diagnosis and management of many gastrointestinal, liver and biliary conditions in children. Therapeutic endoscopy procedures, including ERCP, are performed less frequently in children relative to adults. However, a formal study to evaluate institutional volumes and practice patterns for advanced therapeutic pediatric endoscopy procedures has not been previously undertaken.METHODS: A self-administered 16-question (5-minute) online survey assessing practice patterns for performance of pediatric endoscopy procedures was distributed to all registered North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) programs. Results were analyzed using descriptive statistics and thematic analysis of free-text comments.RESULTS: Respondents from 82.9% of NASPGHAN centers completed this survey. Responses revealed that EGD/colonoscopy are performed at the vast majority of centers (>90%), with most performing >50/year. Therapeutic endoscopy procedures are performed less frequently in the pediatric population, with 18.97% reporting that ERCP is not performed at their institution. Where ERCP is performed, 91.38% reported <25/year. EUS is not performed at over half (53.33%) of institutions. 71.67% of respondents do not believe their institution's current arrangement for performing pediatric therapeutic endoscopy procedures is adequate.CONCLUSIONS: Although the range of endoscopic procedures performed in children parallels that performed in adults, there are notable differences in pediatric and adult gastroenterologists' endoscopy training and procedure volumes. Our results and respondent comments suggest that pediatric patients would benefit from a partnership between pediatric and adult gastroenterologists, with adult gastroenterologists performing more complex therapeutic endoscopic procedures.
View details for PubMedID 30789864
View details for DOI 10.1007/s10620-019-05691-7
View details for PubMedID 31187327
View details for DOI 10.1053/j.gastro.2018.09.037
View details for Web of Science ID 000453401000028
BACKGROUND: The Affordable Care Act (ACA) with Medicaid expansion implemented in 2014, extended health insurance to >20-million previously uninsured individuals. However, it is unclear whether enhanced primary care access with Medicaid expansion decreased emergency department (ED) visits and hospitalizations for gastrointestinal (GI)/pancreatic/liver diseases.METHODS: We evaluated trends in GI/pancreatic/liver diagnosis-specific ED/hospital utilization over a 5-year period leading up to Medicaid expansion and a year following expansion, in California (a state that implemented Medicaid expansion) and compare these with Florida (a state that did not).RESULTS: From 2009 to 2013, GI/pancreatic/liver disease ED visits increased by 15.0% in California and 20.2% in Florida and hospitalizations for these conditions decreased by 2.6% in California and increased by 7.9% in Florida. Following Medicaid expansion, a shift from self-pay/uninsured to Medicaid insurance was seen California; in addition, a new decrease in ED visits for nausea/vomiting and GI infections, was evident, without associated change in overall ED/hospital utilization trends. Total hospitalization charges for abdominal pain, nausea/vomiting, constipation, and GI infection diagnoses decreased in California following Medicaid expansion, but increased over the same time-period in Florida.CONCLUSIONS: We observed a striking payer shift for GI/pancreatic/liver disease ED visits/hospitalizations after Medicaid expansion in California, indicating a shift in the reimbursement burden in self-pay/uninsured patients, from patients and hospitals to the government. ED visits and hospitalization charges decreased for some primary care-treatable GI diagnoses in California, but not for Florida, suggesting a trend toward lower cost of gastroenterology care, perhaps because of decreased hospital utilization for conditions amenable to outpatient management.
View details for PubMedID 30285976
BACKGROUND & AIMS: We have few population-level data on the performance of endoscopic retrograde cholangiopancreatography (ERCP) in the United States. We investigated the numbers of unplanned hospital encounters (UHEs), patient and facility factors associated with UHEs, and variation in quality and outcomes in the performance of ERCP in 3 large American states.METHODS: We collected data on 68,642 ERCPs, performed at 635 facilities in California, Florida, and New York from 2009 through 2014. The primary endpoint was number of UHEs with an ERCP-related event within 7 days of ERCP; secondary endpoints included numbers of UHE within 30 days and mortality within 30 days. Each facility was assigned a risk-standardized cohort, and variations in numbers of UHE were analyzed using multivariable analysis.RESULTS: Among all ERCPs, 5.8% resulted in an UHE within 7 days, and 10.2% by 30 days. Performance of sphincterotomy was significantly associated with a higher risk of UHE at 7 and 30 days (P<.001). Younger age, female sex, and more advanced comorbidity associated with UHE. There was substantial heterogeneity in rates of UHE among facilities: 4.2% at facilities in the lower 5th percentile and 25.2% at facilities in the 95th percentile. Increasing facility volume and ability to perform endoscopic ultrasound associated inversely with risk. The median number of ERCPs performed each year was 68.7, but 69% of facilities performed 100 or fewer ERCPs per year. Risk for UHE following sphincterotomy decreased with increasing facility volume until an inflection point of 157 ERCPs per year was reached.CONCLUSIONS: In an analysis of outcomes of 68,642 ERCPs performed in three states, we found a higher than expected number of UHEs. There is substantial unexplained variation in risk for adverse event following ERCPs among facilities-volume is the strongest predictor of risk. Annual facility volumes above approximately 150 ERCPs per year may protect against UHE.
View details for PubMedID 30243620
BACKGROUND: Residual fluid within endoscope working channels after reprocessing may promote growth of pathogens. Current reprocessing guidelines therefore recommend endoscope drying with administration of forced filtered air; however, the duration and modality of administered air are not specified. The new DriScope Aid device enables automated administration of filtered air at controlled pressure through all internal endoscope channels. We systematically compared, for the first time, the impact of manual drying and automated drying on retained working channel fluid and bioburden after reprocessing.METHODS: We assessed for residual working channel fluid after reprocessing/drying using the SteriCam borescope. Drying was performed either manually (forced filtered air) or was automated (DriScope Aid) for either 5 or 10 minutes. ATP bioluminescence testing was performed on working channel rinsates after drying, to evaluate for residual bioburden.RESULTS: Significantly more fluid droplets were evident after manual drying (4.55 ± 6.14) than with automated device-facilitated drying for either 5 minutes (0.83 ± 1.29, p=0.007) or 10 minutes (0±0, p=0.001). ATP bioluminescence values were higher for manual drying compared with automated drying at 48 hours (p=0.001) and 72 hours (p=0.014) after reprocessing.CONCLUSIONS: We demonstrate significantly fewer water droplets and delayed ATP bioluminescence values within endoscope working channels after automated drying compared with manual drying. In particular, virtually no retained fluid was evident within endoscope working channels after automated drying for 10 minutes. These findings support recommendations for automation of as many reprocessing steps as possible. Automated drying may decrease the risk of transmission of infection related to endoscopy.
View details for PubMedID 30148992
BACKGROUND: Studies from our group and others demonstrate residual fluid in 42% to 95% of endoscope working channels despite high-level disinfection (HLD) and drying. Additionally, persistent simethicone has been reported in endoscope channels despite reprocessing.METHODS: Endoscopy was performed using water or varied simethicone concentrations (0.5%, 1%, 3%) for flushing. After HLD/drying, we inspected endoscope working channels for retained fluid using the SteriCam borescope. Working channel rinsates were evaluated for adenosine triphosphate (ATP) bioluminescence. Fourier transform infrared spectroscopy was performed on fluid droplets gathered from a colonoscope in which low-concentration simethicone was used.RESULTS: Use of medium/high concentration simethicone resulted in higher mean fluid droplets (13.5/17.3 droplets, respectively) and ATP bioluminescence values (20.6/23 RLUs, respectively) compared with procedures using only water (6.3 droplets/10.9 RLUs, p<0.001). Two automated endoscope reprocessing (AER) cycles resulted in return of fluid droplet and ATP bioluminescence values to ranges similar to procedures using only water (p=0.56). Low-concentration simethicone did not increase mean residual fluid or ATP bioluminescence values compared with procedures using only water (5.8 droplets/15.6 RLUs). FTIR analysis revealed simethicone in the endoscope working channel after use of low-concentration simethicone.CONCLUSIONS: Use of medium/high concentration simethicone is associated with retention of increased fluid droplets and higher ATP bioluminescence values in endoscope working channels, compared with endoscopes in which water or low concentration simethicone was used. However, simethicone is detectable in endoscopes despite reprocessing, even when used in low concentration. Our data suggest that when simethicone is used, it should be used in the lowest concentration possible. Facilities may consider 2 AER cycles for reprocessing of endoscopes when simethicone has been used.
View details for PubMedID 30125574
View details for PubMedID 30078117
Fluoroscopy during endoscopic retrograde cholangiopancreatography (ERCP) is increasingly performed by therapeutic endoscopists, many of whom have not received formal training in modulating fluoroscopy use to minimize radiation exposure. Exposure to ionizing radiation has significant health consequences for patients and endoscopists. We aimed to evaluate whether a 20-minute educational intervention for endoscopists would improve use of fluoroscopy and decrease ERCP-associated exposure to radiation for patients.We collected data from 583 ERCPs, performed in California from June 2010 through November 2012; 331 were performed at baseline and 252 following endoscopist education. The educational intervention comprised a 20-minute video explaining best practices for fluoroscopy, coupled with implementation of a formal fluoroscopy time-out protocol before the ERCP was performed. Our primary outcome was the effect of the educational intervention on direct and surrogate markers of patient radiation exposure associated with ERCPs performed by high-volume endoscopists (HVEs) (200 or more ERCPs/year) vs low-volume endoscopists (LVEs) (fewer than 200 ERCPs/year).At baseline, total radiation dose and dose area product were significantly higher for LVEs, but there was no significant difference between HVEs and LVEs following education. Education was associated with significant reductions in median fluoroscopy time (48% reduction for HVEs vs 30% reduction for LVEs), total radiation dose (28% reduction for HVEs vs 52% for LVEs) and dose area product (35% reduction for HVEs vs 48% reduction for LVEs). All endoscopists significantly increased their use of low magnification and collimation following education.A 20-minute educational program with emphasis on ideal use of modifiable fluoroscopy machine settings results in an immediate and significant reduction in ERCP-associated patient radiation exposure for low-volume and high-volume endoscopists. Training programs should consider radiation education for advanced endoscopy fellows.
View details for PubMedID 28804031
View details for PubMedCentralID PMC5809234
View details for PubMedID 28965145
View details for PubMedCentralID PMC5856579
View details for PubMedID 28856471
View details for PubMedCentralID PMC5823722
BACKGROUND AND AIMS: Outbreaks of transmission of infection related to endoscopy despite reported adherence to reprocessing guidelines warrant scrutiny of all potential contributing factors. Recent reports from ambulatory surgery centers indicated widespread significant occult damage within endoscope working channels, raising concerns regarding the potential detrimental impact of this damage on the adequacy of endoscope reprocessing.METHODS: We inspected working channels of all 68 endoscopes at our academic institution using a novel flexible inspection endoscope. Inspections were recorded and videos reviewed by 3 investigators to evaluate and rate channel damage and/or debris. Working channel rinsates were obtained from all endoscopes, and adenosine triphosphate (ATP) bioluminescence was measured.RESULTS: Overall endoscope working channel damage was rated as minimal and/or mild and was consistent with expected wear and tear (median 1.59 on our 5-point scale). Our predominant findings included superficial scratches (98.5%) and scratches with adherent peel (76.5%). No channel perforations, stains, or burns were detected. The extent of damage was not predicted by endoscope age. Minor punctate debris was common, and a few small drops of fluid were noted in 42.6% of endoscopes after reprocessing and drying. The presence of residual fluid predicted higher ATP bioluminescence values. The presence of visualized working channel damage or debris was not associated with elevated ATP bioluminescence values.CONCLUSION: The flexible inspection endoscope enables high-resolution imaging of endoscope working channels and offers endoscopy units an additional modality for endoscope surveillance, potentially complementing bacterial cultures and ATP values. Our study, conducted in a busy academic endoscopy unit, indicated predominately mild damage to endoscope working channels, which did not correlate with elevated ATP values.
View details for PubMedID 29425885
Endoscopy has replaced many radiologic studies for the GI tract. However, ERCP remains a hybrid endoscopic-fluoroscopic procedure, which limits its portable delivery, creates delays because of fluoroscopy room unavailability, and exposes patients and providers to radiation. We evaluated fluoroscopy/radiation-free management of patients with noncomplex choledocholithiasis using direct solitary cholangioscopy (DSC).Patients underwent fluoroscopy-free biliary cannulation, sphincterotomy, and then cholangioscopy to establish location and number/size of stones and to document distance from ampulla to bifurcation to guide balloon advancement. Stones were extracted using a marked balloon catheter advanced to the bifurcation and inflated to the bile duct diameter, documented on prior imaging. Repeat cholangioscopy was performed to confirm stone clearance.Fluoroscopy-free biliary cannulation was successful in all 40 patients (100%). Advanced cannulation techniques were required in 5 patients. Papillary balloon dilation was performed in 8 patients and electrohydraulic lithotripsy in 3 patients. Discrete stones were visualized in 31 patients and stone debris/sludge in 8 patients. Fluoroscopy-free stone/debris/sludge extraction was successful in all these patients. Brief fluoroscopy was used in 2 patients (5%) to confirm stone clearance. No stone/debris/sludge was noted in 1 patient. Mild pancreatitis was noted in 2 patients (5%) and bleeding in 1 (2.5%).This study establishes the feasibility of fluoroscopy/radiation-free, cholangioscopic management of noncomplex choledocholithiasis with success and adverse event rates similar to standard ERCP. DSC represents a significant procedural advance in the management of biliary disorders that does not need to be confined to the fluoroscopy suite and can be reimagined as bedside procedures in emergency department or intensive care unit settings. (Clinical trial registration number: NCT03074201.).
View details for PubMedID 28797911
View details for PubMedCentralID PMC5801123
Biliary strictures after orthotopic liver transplantation (OLT) are typically managed by sequential ERCP procedures, with incremental dilation of the stricture and stent exchange (IDSE) and placement of new stents. This approach resolves >80% of strictures after 12 months but requires costly, lengthy ERCPs with significant patient radiation exposure. Increasing awareness of the harmful effects of radiation, escalating healthcare costs, and decreasing reimbursement for procedures mandate maximal efficiency in performing ERCP. We compared the traditional IDSE protocol with a sequential stent addition (SSA) protocol, in which additional stents are placed across the stricture during sequential ERCPs, without stent removal/exchange or stricture dilation.Patients undergoing ERCP for OLT-related anastomotic strictures from 2010 to 2016 were identified from a prospectively maintained endoscopy database. Procedure duration, fluoroscopy time, stricture resolution rates, adverse events, materials fees, and facility fees were analyzed for IDSE and SSA procedures.Seventy-seven patients underwent 277 IDSE and 132 SSA procedures. Mean fluoroscopy time was 64.5% shorter (P < .0001) and mean procedure duration 41.5% lower (P < .0001) with SSA compared with IDSE. SSA procedures required fewer accessory devices, resulting in significantly lower material (63.8%, P < .0001) and facility costs (42.8%, P < .0001) compared with IDSE. Stricture resolution was >95%, and low adverse event rates did not significantly differ.SSA results in shorter, cost-effective procedures requiring fewer accessory devices and exposing patients to less radiation. Stricture resolution rates are equivalent to IDSE, and adverse events do not differ significantly, even in this immunocompromised population.
View details for PubMedID 28757315
View details for PubMedCentralID PMC5787034
View details for PubMedID 28948439
View details for PubMedCentralID PMC5867198
View details for PubMedID 29127608
Cholecystectomy (CCY) following an episode of choledocholithiasis requiring endoscopic retrograde cholangio-pancreatography (ERCP) with stone extraction reduces recurrent biliary events, compared to expectant management. We studied practice patterns for performance of CCY following ERCP for choledocholithiasis using data from 3 large states and evaluated the effects of delaying CCY.We conducted a retrospective cohort study using the ambulatory surgery, inpatient, and emergency department databases from the states of California (years 2009-2011), New York (2011-2013), and Florida (2012-2014). We collected data from 4516 patients hospitalized with choledocholithiasis who underwent ERCP. We compared outcomes of patients who underwent CCY at index admission (early CCY), elective CCY within 60 days of discharge (delayed CCY), or did not undergo CCY (no CCY), calculating rate of recurrent biliary events (defined as an emergency department visit or unplanned hospitalization due to symptomatic cholelithiasis, cholecystitis, choledocholithiasis, cholangitis, or biliary pancreatitis), mortality, and cost by CCY cohort. We also evaluated risk factors for not undergoing CCY. The primary outcome measure was the rate of recurrent biliary events in the 365 days following discharge from index admission.Of the patients who underwent ERCP for choledocholithiasis, 41.2% underwent early CCY, 10.9% underwent delayed CCY, and 48.0% underwent no CCY. Early CCY reduced relative risk of recurrent biliary events within 60 days by 92%, compared with delayed or no CCY (P<.001). After 60 days following discharge from index admission, patients with early CCY had an 87% lower risk of recurrent biliary events than patients with no CCY (P<.001) and patients with delayed CCY had an 88% lower risk of recurrent biliary events than patients with no CCY (P<.001). A strategy of delayed CCY performed on an outpatient basis was least costly. Performance of early CCY was inversely associated with low facility volume. Hispanic race, Asian race, Medicaid insurance, and no insurance associated inversely with performance of delayed CCY.In a retrospective analysis of over 4500 patients hospitalized with choledocholithiasis, we found that CCY was not performed following ERCP for almost half of the cases. Although early and delayed CCY equally reduce the risk of subsequent recurrent biliary events, patients are at 10-fold higher risk of recurrent biliary event while waiting for a delayed CCY compared with patients who underwent early CCY. Delayed CCY is a cost-effective strategy that must be balanced against the risk of loss to follow up, particularly among patients who are ethnic minorities or have little or no health insurance.
View details for DOI 10.1053/j.gastro.2017.05.048
View details for PubMedID 28583822
Bile duct surgery (BDS), percutaneous transhepatic cholangiography (PTC), and ERCP are alternative interventions used to treat biliary disease. Our aim was to describe trends in ERCP, BDS, and PTC on a nationwide level in the United States.We used the National Inpatient Sample to estimate age-standardized utilization trends of inpatient diagnostic ERCP, therapeutic ERCP, BDS, and PTC between 1998 and 2013. We calculated average case fatality, length of stay, patient demographic profile (age, gender, payer), and hospital characteristics (hospital size and metropolitan status) for these procedures.Total biliary interventions decreased over the study period from 119.8 to 100.1 per 100,000. Diagnostic ERCP utilization decreased by 76%, and therapeutic ERCP utilization increased by 35%. BDS rates decreased by 78% and PTC rates by 24%. ERCP has almost completely supplanted surgery for the management of choledocholithiasis. Fatality from ERCP, BDS, and PTC have all decreased, whereas mean length of stay has remained stable. The proportion of Medicare-insured, Medicaid-insured, and uninsured patients undergoing biliary procedures has increased over time. Most of the increase in therapeutic ERCP and decrease in BDS occurred in large, metropolitan hospitals.Although therapeutic ERCP utilization has increased over time, the total volume of biliary interventions has decreased. BDS utilization has experienced the most dramatic decrease, possibly a consequence of the increased therapeutic capacity and safety of ERCP. ERCPs are now predominantly therapeutic in nature. Large urban hospitals are leading the shift from surgical to endoscopic therapy of the biliary system.
View details for DOI 10.1016/j.gie.2016.12.021
View details for PubMedID 28062313
The Affordable Care Act (ACA) has expanded access to health insurance for millions of Americans, but the impact of Medicaid expansion on healthcare delivery and utilization remains uncertain.To determine the early impact of the Medicaid expansion component of ACA on hospital and ED utilization in California, a state that implemented the Medicaid expansion component of ACA and Florida, a state that did not.Analyze all ED encounters and hospitalizations in California and Florida from 2009 to 2014 and evaluate trends by payer and diagnostic category. Data were collected from State Inpatient Databases, State Emergency Department Databases and the California Office of Statewide Health Planning and Development.Hospital and ED encounters.Population-based study of California and Florida state residents.Implementation of Medicaid expansion component of ACA in California in 2014.Changes in ED visits and hospitalizations by payer, percentage of patients hospitalized after an ED encounter, top diagnostic categories for ED and hospital encounters.In California, Medicaid ED visits increased 33% after Medicaid expansion implementation and self-pay visits decreased by 25% compared with a 5.7% increase in the rate of Medicaid patient ED visits and a 5.1% decrease in rate of self-pay patient visits in Florida. In addition, California experienced a 15.4% increase in Medicaid inpatient stays and a 25% decrease in self pay stays. Trends in the percentage of patients admitted to the hospital from the ED were notable; a 5.4% decrease in hospital admissions originating from the ED in California, and a 2.1% decrease in Florida from 2013 to 2014.We observed a significant shift in payer for ED visits and hospitalizations after Medicaid expansion in California without a significant change in top diagnoses or overall rate of these ED visits and hospitalizations. There appears to be a shift in reimbursement burden from patients and hospitals to the government without a dramatic shift in patterns of ED or hospital utilization.
View details for PubMedID 28771602
Recent outbreaks of duodenoscope-transmitted infections underscore the importance of adequate endoscope reprocessing. Adenosine triphosphate (ATP) bioluminescence testing allows rapid evaluation of endoscopes for bacteriologic/biologic residue. In this prospective study we evaluate the utility of ATP in bacteriologic surveillance and the effects of endoscopy staff education and dual cycles of cleaning and high-level disinfection (HLD) on endoscope reprocessing.ATP bioluminescence was measured after precleaning, manual cleaning, and HLD on rinsates from suction-biopsy channels of all endoscopes and elevator channels of duodenoscopes/linear echoendoscopes after use. ATP bioluminescence was remeasured in duodenoscopes (1) after re-education and competency testing of endoscopy staff and subsequently (2) after 2 cycles of precleaning and manual cleaning and single cycle of HLD or (3) after 2 cycles of precleaning, manual cleaning, and HLD.The ideal ATP bioluminescence benchmark of <200 relative light units (RLUs) after manual cleaning was achieved from suction-biopsy channel rinsates of all endoscopes, but 9 of 10 duodenoscope elevator channel rinsates failed to meet this benchmark. Re-education reduced RLUs in duodenoscope elevator channel rinsates after precleaning (23,218.0 vs 1340.5 RLUs, P < .01) and HLD (177.0 vs 12.0 RLUs, P < .01). After 2 cycles of manual cleaning/HLD, duodenoscope elevator channel RLUs achieved levels similar to sterile water, with corresponding negative cultures.ATP testing offers a rapid, inexpensive alternative for detection of endoscope microbial residue. Re-education of endoscopy staff and 2 cycles of cleaning and HLD decreased elevator channel RLUs to levels similar to sterile water and may therefore minimize the risk of transmission of infections by duodenoscopes.
View details for DOI 10.1016/j.gie.2016.10.035
View details for PubMedID 27818222
The clinical spectrum of Neisseria meningitidis can range from nasopharyngeal colonization to life-threatening invasive diseases such as meningitis. However, its etiologic role in invasive pyomyositis (PM) has never been reported before in the English language. In this study, we report the first case of PM in the English language and the second case in the literature caused by N meningitidis.
View details for PubMedID 27703989
View details for PubMedID 27423887
View details for PubMedID 27423886
Medulloblastoma (MB) cells arise from granule neuron precursors (GNPs) that have lost growth control. During normal development, GNPs divide in response to Sonic hedgehog (SHH), a ligand that binds to the patched (PTCH) receptor on GNPs. If one copy of the Ptch gene is lost, as in human Gorlin's syndrome and in Ptch(+/-) mice, MBs may form. Proper transduction of the SHH signal critically depends on primary cilia. Loss of primary cilia results in improper signal reception and failure to properly activate SHH target genes. KIF3a, part of a kinesin motor, is required for formation of primary cilia. Here, we use tamoxifen-induced ablation of Kif3a in GNPs of postnatal Ptch(+/-) mouse cerebella to show that KIF3a is necessary for MB formation. To investigate the importance of primary cilia in established tumors, we deleted Kif3a from cultured cells and from tumor cell grafts. The loss of Kif3a from established tumors led to their growth arrest and regression. MBs behave as if they are addicted to the presence of primary cilia. These results underscore the potential utility of agents that disrupt cilia for the treatment of Hh pathway-related MBs.
View details for DOI 10.1093/carcin/bgt041
View details for PubMedID 23389290
View details for PubMedCentralID PMC3670253
The Hedgehog (Hh) cascade controls cell proliferation, differentiation and patterning of tissues during embryogenesis but is largely suppressed in the adult. The Hh pathway can become reactivated in cancer. Here, we assimilate data from recent studies to understand how and when the Hh pathway is turned on to aid the neoplastic process. Hh signaling is now known to have a role in established tumors, enabling categorization of tumors based on the role Hh signaling plays in their growth. This categorization has relevance for prognosis and targeted therapeutics. In the first category, abnormal Hh signaling initiates the tumor. In the second category, Hh signaling helps maintain the tumor. In the third category, Hh signaling is implicated but its role is not yet defined.
View details for DOI 10.1016/j.molmed.2010.05.003
View details for Web of Science ID 000281273500001
View details for PubMedID 20696410
View details for PubMedCentralID PMC3651907
Aberrant activation of the Hedgehog (Hh) signaling pathway contributes to many forms of cancer. Primary cilia are Hh signal transduction centers. Two papers in a recent issue of Nature Medicine (Han et al., 2009; Wong et al., 2009) show that mutating cilia can increase or reduce the rates of tumorigenesis depending on how the Hh pathway is disrupted.
View details for DOI 10.1016/j.ccr.2009.09.019
View details for Web of Science ID 000270770400005
View details for PubMedID 19800572
View details for PubMedCentralID PMC3437380
Medulloblastoma (MB) can arise in the cerebellum due to genetic activation of the Sonic Hedgehog (Shh) signaling pathway. During normal cerebellum development, Shh spurs the proliferation of granule neuron precursors (GNP), the precursor cells of MB. Mutations in the Shh receptor gene patched1 (ptc1+/-) lead to increased MB incidence in humans and mice. MB tumorigenesis in mice heterozygous for ptc1+/- shows distinct steps of progression. Most ptc1+/- mice form clusters of preneoplastic cells on the surface of the mature cerebellum that actively transcribe Shh target genes. In approximately 15% of mice, these preneoplastic cells will become fast-growing, lethal tumors. It was previously shown that the loss of function of insulin-like growth factor 2 (igf2) suppresses MB formation in ptc1+/- mice. We found that igf2 is not expressed in preneoplastic lesions but is induced as these lesions progress to more advanced MB tumors. Igf2 is not required for formation of preneoplastic lesions but is necessary for progression to advanced tumors. Exogenous Igf2 protein promoted proliferation of MB precursor cells (GNP) and a MB cell line, PZp53(MED). Blocking igf2 signaling inhibited growth of PZp53(MED) cells, implicating igf2 as a potential clinical target.
View details for DOI 10.1158/0008-5472.CAN-08-2135
View details for Web of Science ID 000260698900019
View details for PubMedID 18974121
View details for PubMedCentralID PMC2597356
Because the transcription factor neuronal Per-Arnt-Sim-type signal-sensor protein-domain protein 2 (NPAS2) acts both as a sensor and an effector of intracellular energy balance, and because sleep is thought to correct an energy imbalance incurred during waking, we examined NPAS2's role in sleep homeostasis using npas2 knockout (npas2-/-) mice. We found that, under conditions of increased sleep need, i.e., at the end of the active period or after sleep deprivation (SD), NPAS2 allows for sleep to occur at times when mice are normally awake. Lack of npas2 affected electroencephalogram activity of thalamocortical origin; during non-rapid eye movement sleep (NREMS), activity in the spindle range (10-15 Hz) was reduced, and within the delta range (1-4 Hz), activity shifted toward faster frequencies. In addition, the increase in the cortical expression of the NPAS2 target gene period2 (per2) after SD was attenuated in npas2-/- mice. This implies that NPAS2 importantly contributes to the previously documented wake-dependent increase in cortical per2 expression. The data also revealed numerous sex differences in sleep; in females, sleep need accumulated at a slower rate, and REMS loss was not recovered after SD. In contrast, the rebound in NREMS time after SD was compromised only in npas2-/- males. We conclude that NPAS2 plays a role in sleep homeostasis, most likely at the level of the thalamus and cortex, where NPAS2 is abundantly expressed.
View details for DOI 10.1073/pnas.0602006103
View details for Web of Science ID 000237399900060
View details for PubMedID 16636276
View details for PubMedCentralID PMC1459027
Sleep deprivation impairs hippocampal-dependent learning, which, in turn, is associated with increased survival of newborn cells in the hippocampus. We tested whether the deleterious effects of sleep restriction on hippocampus-dependent memory were associated with reduced cell survival in the hippocampus. We show that sleep restriction impaired hippocampus-dependent learning and abolished learning-induced neurogenesis. Animals were trained in a water maze on either a spatial learning (hippocampus-dependent) task or a nonspatial (hippocampus-independent) task for 4 days. Sleep-restricted animals were kept awake for one-half of their rest phase on each of the training days. Consistent with previous reports, animals trained on the hippocampus-dependent task expressed increased survival of newborn cells in comparison with animals trained on the hippocampus-independent task. This increase was abolished by sleep restriction that caused overall reduced cell survival in all animals. Sleep restriction also selectively impaired spatial learning while performance in the nonspatial task was, surprisingly, improved. Further analysis showed that in both training groups fully rested animals applied a spatial strategy irrespective of task requirements; this strategy interfered with performance in the nonspatial task. Conversely, in sleep-restricted animals, this preferred spatial strategy was eliminated, favoring the use of nonspatial information, and hence improving performance in the nonspatial task. These findings suggest that sleep loss altered behavioral strategies to those that do not depend on the hippocampus, concomitantly reversing the neurogenic effects of hippocampus-dependent learning.
View details for DOI 10.1152/jn.00218.2005
View details for Web of Science ID 000233317100053
View details for PubMedID 16014798
Locomotor activity rhythms in a significant proportion of Siberian hamsters (Phodopus sungorus sungorus) become arrhythmic after the light-dark (LD) cycle is phase-delayed by 5 h. Arrhythmia is apparent within a few days and persists indefinitely despite the presence of the photocycle. The failure of arrhythmic hamsters to regain rhythms while housed in the LD cycle, as well as the lack of any masking of activity, suggested that the circadian system of these animals had become insensitive to light. We tested this hypothesis by examining light-induced gene expression in the suprachiasmatic nucleus (SCN). Several weeks after the phase delay, arrhythmic and re-entrained hamsters were housed in constant darkness (DD) for 24 h and administered a 30-min light pulse 2 h after predicted dark onset because light induces c-fos and per1 genes at this time in entrained animals. Brains were then removed, and tissue sections containing the SCN were processed for in situ hybridization and probed with c-fos and per1 mRNA probes made from Siberian hamster cDNA. Contrary to our prediction, light pulses induced robust expression of both c-fos and per1 in all re-entrained and arrhythmic hamsters. A separate group of animals held in DD for 10 days after the light pulse remained arrhythmic. Thus, even though the SCN of these animals responded to light, neither the LD cycle nor DD restored rhythms, as it does in other species made arrhythmic by constant light (LL). These results suggest that different mechanisms underlie arrhythmicity induced by LL or by a phase delay of the LD cycle. Whereas LL induces arrhythmicity by desynchronizing SCN neurons, phase delay-induced arrhythmicity may be due to a loss of circadian rhythms at the level of individual SCN neurons.
View details for DOI 10.1152/ajpregu.00695.2004
View details for Web of Science ID 000232528200020
View details for PubMedID 16002555
Spontaneous reentrainment to phase shifts of the photocycle is a fundamental property of all circadian systems. Siberian hamsters are, however, unique in this regard because most fail to reentrain when the LD cycle (16-h light/day) is phase delayed by 5 h. In the present study, the authors compared reentrainment responses in hamsters from 2 colonies. One colony descended from animals trapped in the wild more than 30 years ago (designated "nonentrainers"), and the other colony was outbred as recently as 13 years ago (designated "entrainers"). As reported previously, only 10% of hamsters from the nonentrainer colony reentrained to a 5-h phase delay of the LD cycle. By contrast, 75% of animals from the entrainer colony reentrained to the phase shift. Another goal of this study was to test the hypothesis that failure to reentrain was a consequence of light exposure during the middle of the night on the day of the 5-h phase delay. This hypothesis was tested by exposing animals to 2 h of light during the early, middle, or late part of the night and then subjecting them on the next day to a 3-h phase delay of the photocycle, which is a phase shift to which all hamsters normally reentrain. All animals from both colonies reentrained when light pulses occurred early in the night, but more animals from the entrainer colony, compared to the nonentrainer colony, reentrained when the light pulse occurred in the middle or late part of the night. The phenotypic variation in reentrainment responses is similar to the variation in photoperiodic responsiveness previously reported for these 2 colonies. Phenotypic variation in both traits is due to underlying differences in circadian organization and suggests a common genetic basis for reentrainment responses and photoperiodic responsiveness.
View details for DOI 10.1177/0748730404268055
View details for Web of Science ID 000225093900008
View details for PubMedID 15523114
Circadian activity rhythms of most Siberian hamsters (Phodopus sungorus sungorus) fail to reentrain to a 5-h phase shift of the light-dark (LD) cycle. Instead, their rhythms free-run at periods close to 25 h despite the continued presence of the LD cycle. This lack of behavioral reentrainment necessarily means that molecular oscillators in the master circadian pacemaker, the SCN, were unable to reentrain as well. The authors tested the hypothesis that a phase shift of the LD cycle rendered the SCN incapable of responding to photic input. Animals were exposed to a 5-h phase delay of the photocycle, and activity rhythms were monitored until a lack of reentrainment was confirmed. Hamsters were then housed in constant darkness for 24 h and administered a 30-min light pulse 2 circadian hours after activity onset. Brains were then removed, and tissue sections containing the SCN were processed for in situ hybridization. Sections were probed with Siberian hamster c-fos and per1 mRNA probes because light rapidly induces these 2 genes in the SCN during subjective night but not at other circadian phases. Light pulses induced robust expression of both genes in all animals that reentrained to the LD cycle, but no expression was observed in any animal that failed to reentrain. None of the animals exhibited an intermediate response. This finding is the first report of acute shift in a photocycle eliminating photosensitivity in the SCN and suggests that a specific pattern of light exposure may desensitize the SCN to subsequent photic input.
View details for DOI 10.1177/0748730404266771
View details for Web of Science ID 000222693400004
View details for PubMedID 15245648
