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Aneurysms with persistent patency after treatment with the Pipeline Embolization Device

Mon, 08/07/2017 - 10:00am

The Pipeline Embolization Device (PED) was approved for the treatment of intracranial aneurysms from the petrous to the superior hypophyseal segment of the internal carotid artery. However, since its approval, its use for treatment of intracranial aneurysms in other locations and non-sidewall aneurysms has grown tremendously. The authors report on a cohort of 15 patients with 16 cerebral aneurysms that incorporated an end vessel with no significant distal collaterals, which were treated with the PED. The cohort includes 7 posterior communicating artery aneurysms, 5 ophthalmic artery aneurysms, 1 superior cerebellar artery aneurysm, 1 anterior inferior cerebellar artery aneurysm, and 2 middle cerebral artery aneurysms. None of the aneurysms achieved significant occlusion at the last follow-up evaluation (mean 24 months). Based on these observations, the authors do not recommend the use of flow diverters for the treatment of this subset of cerebral aneurysms.

Two-year single-center experience with the 'Baby Trevo' stent retriever for mechanical thrombectomy in acute ischemic stroke

Mon, 08/07/2017 - 10:00am

OBJECTIVE: To evaluate the safety and efficacy of the 'Baby Trevo' (Trevo XP ProVue 3x20 mm Retriever) stent retriever for large vessel occlusions (LVOs) in acute ischemic stroke (AIS).

MATERIALS AND METHODS: We retrospectively analyzed our stroke database and included all patients treated with the Baby Trevo for distal LVOs in AIS. Patient gender, mean age, vascular risk factors, National Institutes of Health Stroke Scale (NIHSS) score at presentation, and modified Rankin Scale (mRS) score at baseline and 90-day follow-up were documented. Reperfusion rates for the vessels treated were recorded using the Thrombolysis in Cerebral Infarction (TICI) classification. Occurrence of vasospasm and new or evolving infarcts in the treated vascular territory was documented.

RESULTS: Thirty-five subjects with a mean NIHSS score of 18 were included. The Baby Trevo device was used in 38 branches of the anterior and posterior circulations. TICI 2b/3 blood flow was restored after one single pass in 20/38 (52.6%) and after two or three passes in 11 vessels. The remaining vessels required either more than three passes, showed less than a TICI 2b/3 reperfusion (n=3), or demonstrated failure to retrieve the clot (n=4). TICI 2b/3 reperfusion was achieved in 30 patients (85.7%). No vessel injuries, rupture, or significant vasospasm were seen. Overall, a mRS score of

CONCLUSIONS: Our preliminary data suggest that the 'Baby Trevo' achieves a high recanalization rate without any significant risk. Larger cohort studies are needed to validate the clinical benefit.

Live Cell Imaging: Assessing the Phototoxicity of 488 and 546 nm Light and Methods to Alleviate it

Mon, 08/07/2017 - 10:00am

In live cell imaging of fluorescent proteins, phototoxicity of the excitation light can be problematical. Cell death is obvious, but reduced cell viability can make the interpretation of observations error prone. We characterized the phototoxic consequences of 488 and 546 nm light on untransformed human cells and tested methods that have or could be used to alleviate photodamage. Unlabeled RPE1 cells were given single 0.5-2.5 min irradiations in early G1 from a mercury arc lamp on a fluorescence microscope. Four hundred eighty-eight nanometer light produced a dose-dependent decrease in the percentage of cells that progressed to mitosis, slowing of the cell cycle for some of those entering mitosis, and a approximately 12% incidence of cell death for the highest dose. For 546 nm light we found a 10-15% reduction in the percentage of cells entering mitosis, no strong dose dependency, and a approximately 2% incidence of cell death for the longest irradiations. For cells expressing GFP-centrin1 or mCherry-centrin1, fewer entered mitosis for each dose than unlabeled cells. For constant total dose 488 nm light irradiations of unlabeled cells, reducing the intensity 10-fold or spreading the exposures out as a series of 10 sec pulses at 1 min intervals produced a minor and not consistent improvement in the percentage of cells entering mitosis. Reducing oxidative processes, by culturing at approximately 3% oxygen or adding the reducing agent Trolox noticeably increased the fraction of cells entering mitosis. Thus, for long-term imaging there can be value to using RFP constructs and for GFP-tagged proteins reducing oxidative processes.

Focused peer review: the end game of peer review

Mon, 08/07/2017 - 10:00am

PURPOSE: The aim of this report is to describe the authors' experience with expanding the routine peer-review process to include misdiagnoses from all sources and the use of focused peer review (FPR) in faculty accountability and management.

METHODS: A department-wide routine peer review was conducted. Each radiologist was assigned 12 cases per month. In addition, clinically reported errors, missed diagnoses discovered outside the routine peer-review process, were identified. Cases were scored from 1 to 5. The department quality office evaluated cases with scores of 3 and 4 from both sources for further processing with FPR, a multistep continuation of the peer-review process using a tracking document. Once initiated, FPR was processed by seeking comments from the division director and the interpreting radiologist. In some cases, FPR was discontinued before completion. Completed FPR documents were submitted to the department chair for administrative action, ranging from no action to termination. All FPR cases are presented at monthly departmental morbidity and mortality conferences.

RESULTS: Routine peer review was done on 1,646 cases from a total of about 300,000 studies by 31 radiologists. Thirty-five cases from the two sources with scores of 3 and 4 were analyzed, 21 from the routine peer review and 14 clinically reported errors. The quality officer initiated 25 FPRs, rejecting 10 because errors were not considered significant. Further scrutiny lead to dropping 7 of the 12 routine and 2 of the 13 cases with clinically reported error. Sixteen FPRs were completed, 5 (31%) from routine peer review and 11 (69%) from clinically reported errors. For these 16 completed FPRs, management decisions were made by the department chair.

CONCLUSIONS: Processing of routine peer-review data together with cases of clinically reported error strengthens the peer-review process. Focused peer review can effectively contribute to the surveillance and management of faculty performance for improved patient care.

Simple measurement of aneurysm residual after treatment: the SMART scale for evaluation of intracranial aneurysms treated with flow diverters

Mon, 08/07/2017 - 10:00am

BACKGROUND: Primary endovascular reconstruction with flow diversion represents a fundamental paradigm shift in the technique of endovascular aneurysm treatment. Unlike coil embolization, often there remains residual post-procedural filling within the aneurysm with flow diverters, the curative reconstruction presumably occurring over a period of weeks. Thus, conventional grading scales for post-procedural aneurysm occlusion and recanalization are inadequate. The aim of this paper is to propose a new angiographic grading scale that addresses this fundamentally new treatment option.

METHOD: A five-point grading scale describes the location of residual flow within the aneurysm in the venous phase [grade 1: patent aneurysm with diffuse inflow; grade 2: residual filling of the aneurysm dome (saccular) or wall (fusiform); grade 3: only residual neck (saccular) or only intra-aneurysmal filling with former boundaries covered (fusiform); grade 4: complete occlusion].

FINDINGS: Grade 0 represents any aneurysm, regardless of occlusion rate with early phase, coherent inflow jet. Intra-aneurysmal flow stagnation is categorized into: (a) none, (b) capillary phase, and (c) venous phase. Prevailing parent vessel hemodynamics with in-stent stenosis (ISS) are divided into none (ISS0), mild (ISS1), moderate (ISS2), severe (ISS3), and total (ISS4) occlusion. The proposed grading scales allow assessment of the hemodynamic consequences of stent placement on endosaccular in-flow, stasis, and location of stasis as well as parent vessel hemodynamics.

CONCLUSIONS: Further studies need to show the applicability and possible predictive value of this new grading scale on the efficacy of the stent in promoting intra-aneurysmal flow stagnation, thus creating the potential to harmonize the results of future papers. This may help to optimize treatment and future device design.

Quantitative evaluation of C-arm CT cerebral blood volume in a canine model of ischemic stroke

Mon, 08/07/2017 - 10:00am

BACKGROUND AND PURPOSE: Previous studies have shown the feasibility of assessing qualitative CBV measurements in the angiography suite by using FPD-CBCT systems. We have investigated the correlation of FPD-CBCT CBV lesion volumes to the infarct volume.

MATERIALS AND METHODS: Unilateral strokes were created in 7 adult dogs. MR imaging and FPD-CBCT data were obtained after MCA occlusion. FPD-CBCT CBV and ADC maps were generated for all subjects. The animals were sacrificed immediately following the last imaging study to measure infarct volume on histology. The reliability of FPD-CBCT-based lesion volume measurements was compared with those measured histologically by using regression and Bland-Altman analysis.

RESULTS: The best correlation (R(2) = 0.72) between lesion volumes assessed with FPD-CBCT and histology was established with a threshold of mean healthy CBV - 2.5 x SD. These results were inferior to the correlation of lesion volumes measured with ADC and histology (R(2) = 0.99). Bland-Altman analysis showed that the agreement of ADC-derived lesion volumes with histology was superior to the agreement of FPD-CBCT-derived lesion volumes with histology.

CONCLUSIONS: We correlated FPD-CBCT measurements of CBV and MR ADC lesion volumes with histologically assessed infarct volume. As expected, ADC is a very accurate and precise method for determining the extent of infarction. FPD-CBCT CBV lesion volumes are correlated to the size of the infarct. Improvement of FPD-CBCT image quality provides an opportunity to establish quantitative CBV measurement in the angiography suite.

Anisotropic properties of bovine nasal cartilage

Mon, 08/07/2017 - 10:00am

To investigate the structural anisotropy in bovine septal cartilage, quantitative procedures in microscopic magnetic resonance imaging (muMRI), polarized light microscopy (PLM), and mechanical indentation were used to measure the tissue in three orthogonal planes: vertical, medial, and caudocephalic. The quantitative T2 imaging experiments in muMRI found strong anisotropy in the images of both vertical and caudocephalic planes but little anisotropy in the images from the medial plane. The PLM birefringent experiments found that the retardation values in the medial section were only about 10% of these in the vertical and caudocephalic sections and that the angle values in all three sections followed the rotation of the tissue section in the microscope stage. The stress relaxation experiments in mechanical indentation showed reduced stiffness in the medial plane compared to stiffness in either the vertical or caudocephalic planes. Collectively, the results in this project coherently indicate a marked structural anisotropy in cartilage from the nasal septum, where the long axis of the collagen fibrils is oriented in parallel with the medial axis.

Determination of cystic duct patency using hepatobiliary MRI with gadoxetate disodium: is T1 precontrast imaging necessary

Mon, 08/07/2017 - 10:00am

PURPOSE: To determine the need for precontrast T1-weighted imaging in determining cystic duct patency using hepatobiliary phase imaging with gadoxetate disodium-enhanced magnetic resonance imaging (MRI).

MATERIALS AND METHODS: MRI exams using gadoxetate disodium from October 4, 2008 to April 14, 2010 were reviewed in a retrospective fashion. Two reviewers independently reviewed only the 20-minute T1-weighted delayed postcontrast images to determine the presence of excreted contrast in the gallbladder lumen. Contrast was deemed present if hyperintense signal material was seen in the antidependent portion of the gallbladder lumen. The actual presence of contrast in the gallbladder was determined by directly comparing the pre- and postcontrast T1-weighted images using consensus review.

RESULTS: In all, 187 cases were included. Three (1.6%) were deemed indeterminate due to complete homogeneous opacification of the gallbladder. All three cases were identified as indeterminate by both reviewers. Of the remaining 184 cases, 136 filled (74%) and 48 did not fill (26%). Both reviewers correctly identified 136/136 cases of gallbladder filling. Reviewer A identified 47/48 cases of nonfilling and reviewer B identified 46/48 cases of nonfilling. Sensitivity and specificity were 100% and 98% for reviewer A and 100% and 96% for reviewer B, respectively.

CONCLUSION: The presence of excreted contrast in the gallbladder lumen can be determined using gadoxetate disodium-enhanced MRI without precontrast T1-weighted imaging.

Temporal evolution of susceptibility artifacts from coiled aneurysms on MR angiography: an in vivo canine study

Mon, 08/07/2017 - 10:00am

BACKGROUND AND PURPOSE: Intracranial aneurysms treated by coiling have a risk for recurrence, requiring surveillance imaging. MRA has emerged as an attractive technique for postcoiling aneurysm imaging. Previous research has evaluated MR imaging artifacts of the coil mass in vitro. Our aim in this study was to evaluate MR imaging artifacts of coiled aneurysms in vivo with time.

MATERIALS AND METHODS: Four sidewall aneurysms were created in each of 4 dogs. Aneurysms were embolized receiving only 1 type of coils. After embolization, the animals were transferred to MR imaging, which included axial 3D TOF MRA (TEs, 3.5, 5, and 6.9 ms), phase-contrast MRA, and coronal CE-MRA. MR imaging studies were repeated at 1, 4, 6, 8, 14, and 28 weeks. We calculated an OEF: OEF = V(A)/V(CM), where the numerator represents the volume of the MR imaging artifacts and the denominator is the true volume of the coil mass measured by 3D RA.

RESULTS: OEFs were largest immediately after embolization and showed a gradual decay until approximately 4 weeks, when there was stabilization of the size of the artifacts. By 4 weeks, there was mild coil compaction (average coil mass volume decrease of 7.8%); however, the OEFs decreased by 25% after 4 weeks (P < .001).

CONCLUSIONS: MR imaging susceptibility artifacts change with time, being maximal in the postembolization setting and decaying until 4 weeks. The clinical implications of this study are that baseline MRA for comparison with future imaging should be acquired at a minimum of 1 week after the procedure.

Protected graft copolymer (PGC) basal formulation of insulin as potentially safer alternative to Lantus(R) (insulin-glargine): a streptozotocin-induced, diabetic Sprague Dawley rats study

Mon, 08/07/2017 - 10:00am

PURPOSE: To develop a long-acting formulation of native human insulin with a similar pharmacodynamics (PD) profile as the insulin analogue insulin glargine (Lantus(R), Sanofi-Aventis) with the expectation of retaining native human insulin's superior safety profile as insulin glargine is able to activate the insulin-like growth factor 1 (IGF-1) receptor and is linked to a number of malignancies at a higher rate than regular human insulin.

METHODS: Development of protected graft copolymer (PGC) excipients that bind native human insulin non-covalently and testing blood glucose control obtained with these formulations in streptozotocin-induced diabetic Sprague Dawley rats compared to equally dosed insulin glargine.

RESULTS: PGC-formulations of native human insulin are able to control blood glucose to the same extent and for the same amount of time after s.c. injection as the insulin analogue insulin glargine. No biochemical changes were made to the insulin that would change receptor binding and activation with their possible negative effects on the safety of the insulin.

CONCLUSION: Formulation with the PGC excipient offers a viable alternative to biochemically changing insulin or other receptor binding peptides to improve PD properties.

Feasibility demonstration of frequency domain terahertz imaging in breast cancer margin determination

Mon, 08/07/2017 - 10:00am

In breast conservation surgery, surgeons attempt to remove malignant tissue along with a surrounding margin of healthy tissue. Subsequent pathological analysis determines if those margins are clear of malignant tissue, a process that typically requires at least one day. Only then can it be determined whether a follow-up surgery is necessary. This possibility of re-excision is undesirable in terms of reducing patient morbidity, emotional stress and healthcare. It has been shown that terahertz (THz) images of breast specimens can accurately differentiate between breast carcinoma, normal fibroglandular tissue, and adipose tissue. That study employed the Time-Domain Spectroscopy (TDS) technique. We are instead developing a new technique, Frequency-Domain Terahertz Imaging (FDTI). In this joint project between UMass/Amherst and UMass Medical School/Worcester (UMMS), we are investigating the feasibility of the FDTI technique for THz reflection imaging of breast cancer margins. Our system, which produces mechanically scanned images of size 2cm x 2cm, uses a THz gas laser. The system is calibrated with mixtures of water and ethanol and reflection coefficients as low as 1% have been measured. Images from phantoms and specimens cut from breast cancer lumpectomies at UMMS will be presented. Finally, there will be a discussion of a possible transition of this FDTI setup to a compact and inexpensive CMOS THz camera for use in the operating room.

Clinical evaluation of a new kyphoplasty technique with directed cement flow

Mon, 08/07/2017 - 9:59am

STUDY DESIGN: Prospective, single-center 2-year study. OBJECTIVE: The long-term clinical performance of a new cement-directing kyphoplasty system was evaluated for treatment of painful osteoporotic compression fractures.

SUMMARY OF BACKGROUND DATA: Cement leakage is a common clinical complication of vertebroplasty and kyphoplasty procedures. Balloon kyphoplasty restricts cement flow and reduces leakage by injection of high-viscosity cement into a compacted bone cavity. Biomechanical reinforcement of surrounding bone is limited, leaving the vertebral body vulnerable to continued collapse.

METHODS: The patient population consisted of 20 patients at least 50 years of age with up to 3 painful osteoporotic vertebral compression fractures between T4-L5. The cement-directing kyphoplasty system procedure was performed unipedicularly using a curved drill and reamer to create a central cavity. The cement-directing implant was positioned inside the cavity and cement was injected through it. A total of 37 levels were treated. Pain relief was assessed using a verbal pain scale. The Roland-Morris Questionnaire was used to evaluate disability. Cement leakage was determined from radiographs (anterior/posterior and lateral) obtained within 24 hours of the procedure.

RESULTS: : Significant pain relief was achieved immediately after the procedure, as shown by a decrease in the mean pain scores from 8.20 (+/-1.40) measured preoperatively to 2.85 (+/-2.13) measured postoperatively. Pain relief was sustained throughout the 2-year follow-up period. Mean Roland-Morris Questionnaire scores improved from 21.8 (+/-3.5) measured preoperatively to 11.6 (+/-5.6) measured 6 weeks postoperatively. The investigators reported 1 moderate cortical leak (2.7%) and an independent reviewer identified 8 additional minor segmental vein and cortical leaks (24.3%). None of the leaks was symptomatic.

CONCLUSIONS: Directed cement flow allows cement to fill the anterior vertebral body, stabilizing fractures and supporting biomechanical loading. Control of cement flow may help minimize the risk of posterior leakage into the basivertebral vein or spinal canal.

The Trevo device: preclinical data of a novel stroke thrombectomy device in two different animal models of arterial thrombo-occlusive disease

Mon, 08/07/2017 - 9:59am

BACKGROUND: The currently available mechanical devices fail to achieve recanalization in as many as 20-40% of proximal arterial occlusion strokes.

OBJECTIVE: The preclinical evaluation of the safety and efficacy of a novel thrombectomy device designed to achieve immediate flow restoration by quickly removing clot is reported.

METHODS: Four confirmatory animal studies were performed with the Trevo device (Concentric Medical Inc, Mountain View, California, USA) in the swine (n=2) and canine (n=1) models of arterial thrombo-occlusive disease employing autologous thrombin generated thrombi. The angiographic response and the degree of device-clot incorporation were evaluated. High resolution flat panel three-dimensional CT was performed to further define the in vivo device-thrombus-vessel interaction. Finally, samples of three swine vessels treated with six passes of the device were explanted for histopathological analysis. RESULTS: A total of 16 clots of variable hardness and consistency were implanted in a variety of vascular settings, including the swine internal maxillary, lingual and forelimb arteries as well as the canine external carotid and vertebral arteries. Thrombolysis in Myocardial Infarction (TIMI) 2-3 reperfusion was achieved in all cases immediately after device deployment. All 16 clots were retrieved after one (n=15) or two (n=1) passes with the device. Histopathological analysis demonstrated severe disruption of the intima but no hemorrhage of media or adventitia.

CONCLUSION: The experimental data suggest that the Trevo device is highly effective at achieving immediate reperfusion of occluded arteries without causing any clinically significant disruption of vascular integrity.

MR imaging of acute cervical spinal ligamentous and soft tissue trauma

Mon, 08/07/2017 - 9:59am

The increasing availability of magnetic resonance imaging (MRI) and the high sensitivity of MRI for soft tissue injury are resulting in the increased use of MRI for the evaluation of acute trauma. As cervical spine injury can have a devastating consequence, MRI is being more commonly used to evaluate cervical spine injury in the acute setting, necessitating emergent interpretation by the on-call radiologist. Unless one is formally trained in a trauma center, the MRI findings of soft tissue and ligamentous cervical spine injury may not be fully appreciated. The goal of this pictorial review is to familiarize the reader with some of the more common soft tissue, vascular, and ligamentous injuries seen on MRI of the cervical spine in the emergent setting.

Iterative reconstruction using a Monte Carlo based system transfer matrix for dedicated breast positron emission tomography

Mon, 08/07/2017 - 9:59am

To maximize sensitivity, it is desirable that ring Positron Emission Tomography (PET) systems dedicated for imaging the breast have a small bore. Unfortunately, due to parallax error this causes substantial degradation in spatial resolution for objects near the periphery of the breast. In this work, a framework for computing and incorporating an accurate system matrix into iterative reconstruction is presented in an effort to reduce spatial resolution degradation towards the periphery of the breast. The GATE Monte Carlo Simulation software was utilized to accurately model the system matrix for a breast PET system. A strategy for increasing the count statistics in the system matrix computation and for reducing the system element storage space was used by calculating only a subset of matrix elements and then estimating the rest of the elements by using the geometric symmetry of the cylindrical scanner. To implement this strategy, polar voxel basis functions were used to represent the object, resulting in a block-circulant system matrix. Simulation studies using a breast PET scanner model with ring geometry demonstrated improved contrast at 45% reduced noise level and 1.5 to 3 times resolution performance improvement when compared to MLEM reconstruction using a simple line-integral model. The GATE based system matrix reconstruction technique promises to improve resolution and noise performance and reduce image distortion at FOV periphery compared to line-integral based system matrix reconstruction.

Therapeutic plasma exchange performed in tandem with hemodialysis without supplemental calcium in the apheresis circuit

Fri, 08/04/2017 - 1:13pm

Therapeutic plasma exchange (TPE) and hemopoietic progenitor cell (HPC) collection are apheresis procedures that can safely be performed in tandem with hemodialysis. Despite the return of citrate-anticoagulated blood to the patient during HPC collection, it is not necessary to administer supplemental calcium during these procedures because the ionized calcium concentration is restored as the returning blood passes through the dialyzer. It is not known whether this applies to TPE, in which a mixture of blood and pharmaceutical albumin, an avid binder of plasma ionized calcium, is returned to the patient through the dialyzer. We report on three dialysis-dependent patients who required TPE and underwent tandem treatments without supplemental calcium in the apheresis circuit. Overall, ionized calcium fell 4-12% (P = 0.0.024) and patients reported no symptoms of hypocalcemic toxicity. Tandem hemodialysis/TPE can be performed without supplemental calcium in the apheresis circuit. Overall, ionized calcium fell 4-12% (P = 0.0.024) and patients reported no symptoms of hypocalcemic toxicity. Tandem hemodialysis/TPE can be performed without supplemental calcium in the apheresis circuit. J. Clin. Apheresis 32:154-157, 2017. © 2016 Wiley Periodicals, Inc.

A liquid calcium+vitamin D3 supplement is effective prophylaxis against hypocalcemic toxicity during apheresis platelet donation

Fri, 08/04/2017 - 1:13pm

Hypocalcemic toxicity, because of return of citrate anion to the donor, is the major toxicity of apheresis platelet donation. Oral calcium carbonate, given prophylactically at the start of donation, has shown limited ability to alleviate this toxicity. We examined whether repeated prophylactic doses of calcium carbonate, or of a liquid preparation containing calcium citrate, calcium phosphate, and vitamin D3 , would be more effective at preventing symptoms of hypocalcemic toxicity. Symptoms were reported by 48% of donors who received no prophylaxis and 60% of donors who received 1000 mg of oral calcium carbonate at the start of, and every 20 minutes during, donation (P = 0.711). Only 19.2% of donors who received the liquid preparation (1000 mg calcium, 1000 IU vitamin D3 ) reported symptoms (P = 0.040 versus no prophylaxis, P = 0.039 versus calcium carbonate). This difference was not because of gender, weight, age, or blood volume of the donor. Neither calcium preparation prevented a measurable fall in plasma ionized calcium during donation. We conclude that liquid calcium citrate/calcium phosphate/vitamin D3 provides effective prophylaxis against hypocalcemic toxicity during platelet donation, however it does not prevent a fall in plasma ionized calcium.

This bud's for you: mechanisms of cellular nucleocytoplasmic trafficking via nuclear envelope budding

Fri, 08/04/2017 - 12:03pm

The nuclear envelope (NE) physically separates the cytoplasmic and nuclear compartments. While this barrier provides advantages, it also presents a challenge for the nuclear export of large ribonucleoprotein (RNP) complexes. Decades-old dogma holds that all such border-crossing is via the nuclear pore complex (NPC). However, the diameter of the NPC central channel limits the passage of large cargos. Here, we review evidence that such large RNPs employ an endogenous NE-budding pathway, previously thought to be exclusive to the nuclear egress of Herpes viruses. We discuss this and other models proposed, the likelihood that this pathway is conserved, and the consequences of disrupting NE-budding for synapse development, localized translation of synaptic mRNAs, and laminopathies inducing accelerated aging.

The Circadian Clock Gene BMAL1 Coordinates Intestinal Regeneration

Fri, 08/04/2017 - 12:03pm

BACKGROUND and AIMS: The gastrointestinal syndrome is an illness of the intestine caused by high levels of radiation. It is characterized by extensive loss of epithelial tissue integrity, which initiates a regenerative response by intestinal stem and precursor cells. The intestine has 24-hour rhythms in many physiological functions that are believed to be outputs of the circadian clock: a molecular system that produces 24-hour rhythms in transcription/translation. Certain gastrointestinal illnesses are worsened when the circadian rhythms are disrupted, but the role of the circadian clock in gastrointestinal regeneration has not been studied.

METHODS: We tested the timing of regeneration in the mouse intestine during the gastrointestinal syndrome. The role of the circadian clock was tested genetically using the BMAL1 loss of function mouse mutant in vivo, and in vitro using intestinal organoid culture.

RESULTS: The proliferation of the intestinal epithelium follows a 24-hour rhythm during the gastrointestinal syndrome. The circadian clock runs in the intestinal epithelium during this pathologic state, and the loss of the core clock gene, BMAL1, disrupts both the circadian clock and rhythmic proliferation. Circadian activity in the intestine involves a rhythmic production of inflammatory cytokines and subsequent rhythmic activation of the JNK stress response pathway.

CONCLUSIONS: Our results show that a circadian rhythm in inflammation and regeneration occurs during the gastrointestinal syndrome. The study and treatment of radiation-induced illnesses, and other gastrointestinal illnesses, should consider 24-hour timing in physiology and pathology.