Structural determinants of dual incretin receptor agonism by tirzepatide.

SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.

Class B1 GPCRs: Insights into Multi-Receptor Pharmacology for the Treatment of Metabolic Disease.

The secretin-like, class B1 sub-family of seven transmembrane-spanning G protein coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and utilize a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via a large N-terminal extracellular domain that forms a hydrophobic ligand binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogues of several class B1 ligands for therapeutic use. Among the most successful of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multi-functional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of poly-pharmacologic ligands. Further, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complex with either native ligands or multi-functional agonists are provided, supporting the pharmacological basis of such therapeutic agents.

Cost-effectiveness of budesonide-formoterol vs inhaled epinephrine in US adults with mild asthma.

BACKGROUND: The management of mild asthma has lacked an over-the-counter (OTC) option aside from inhaled epinephrine, which is available in the United States. However, inhaled epinephrine use without an inhaled corticosteroid may increase the risk of asthma death. OBJECTIVE: To compare the cost-effectiveness of OTC as-needed budesonide-formoterol as a plausible alternative to inhaled epinephrine. METHODS: We developed a probabilistic Markov model to compare OTC as-needed budesonide-formoterol inhaler use vs inhaled epinephrine use in adults with mild asthma from a US societal perspective over a lifetime horizon, with a 3% annual discount rate (2022 US dollars). Inputs were derived from the SYmbicort Given as-needed in Mild Asthma (SYGMA) trials, published literature, and commercial costs. Outcomes were quality-adjusted life-years (QALY), costs, incremental net monetary benefit (INMB), severe asthma exacerbations, well-controlled asthma days, and asthma-related deaths. Microsimulation was used to evaluate underinsured Americans living with mild asthma (n = 5,250,000). RESULTS: Inhaled epinephrine was dominated (with lower QALYs gains at a higher cost) by both as-needed budesonide-formoterol (INMB, $15,541 at a willingness-to-pay of $100,000 per QALY) and the no-OTC inhaler option (INMB, $1023). Adults using as-needed budesonide-formoterol had 145 more well-controlled asthma days, 2.79 fewer severe exacerbations, and an absolute risk reduction of 0.23% for asthma-related death compared with inhaled epinephrine over a patient lifetime. As-needed budesonide-formoterol remained dominant in all sensitivity and scenario analyses, with a 100% probability of being cost-effective compared with inhaled epinephrine in probabilistic sensitivity analysis. CONCLUSION: If made available, OTC as-needed budesonide-formoterol for treating mild asthma in underinsured adults without HCP management improves asthma outcomes, prevents fatalities, and is cost-saving.

Quantitative and Radiological Assessment of Post-cardiac-Arrest Comatose Patients with Diffusion-Weighted Magnetic Resonance Imaging.

BACKGROUND: Although magnetic resonance imaging, particularly diffusion-weighted imaging, has increasingly been used as part of a multimodal approach to prognostication in patients who are comatose after cardiac arrest, the performance of quantitative analysis of apparent diffusion coefficient (ADC) maps, as compared to standard radiologist impression, has not been well characterized. This retrospective study evaluated quantitative ADC analysis to the identification of anoxic brain injury by diffusion abnormalities on standard clinical magnetic resonance imaging reports. METHODS: The cohort included 204 previously described comatose patients after cardiac arrest. Clinical outcome was assessed by (1) 3-6 month post-cardiac-arrest cerebral performance category and (2) coma recovery to following commands. Radiological evaluation was obtained from clinical reports and characterized as diffuse, cortex only, deep gray matter structures only, or no anoxic injury. Quantitative analyses of ADC maps were obtained in specific regions of interest (ROIs), whole cortex, and whole brain. A subgroup analysis of 172 was performed after eliminating images with artifacts and preexisting lesions. RESULTS: Radiological assessment outperformed quantitative assessment over all evaluated regions (area under the curve [AUC] 0.80 for radiological interpretation and 0.70 for the occipital region, the best performing ROI, p = 0.011); agreement was substantial for all regions. Radiological assessment still outperformed quantitative analysis in the subgroup analysis, though by smaller margins and with substantial to near-perfect agreement. When assessing for coma recovery only, the difference was no longer significant (AUC 0.83 vs. 0.81 for the occipital region, p = 0.70). CONCLUSIONS: Although quantitative analysis eliminates interrater differences in the interpretation of abnormal diffusion imaging and avoids bias from other prediction modalities, clinical radiologist interpretation has a higher predictive value for outcome. Agreement between radiological and quantitative analysis improved when using high-quality scans and when assessing for coma recovery using following commands. Quantitative assessment may thus be more subject to variability in both clinical management and scan quality than radiological assessment.

Hyper-entanglement between pulse modes and frequency bins.

Hyper-entanglement between two or more photonic degrees of freedom (DOF) can enhance and enable new quantum protocols by allowing each DOF to perform the task it is optimally suited for. Here we demonstrate the generation of photon pairs hyper-entangled between pulse modes and frequency bins. The pulse modes are generated via parametric downconversion in a domain-engineered crystal and subsequently entangled to two frequency bins via a spectral mapping technique. The resulting hyper-entangled state is characterized and verified via measurement of its joint spectral intensity and non-classical two-photon interference patterns from which we infer its spectral phase. The protocol combines the robustness to loss, intrinsic high dimensionality and compatibility with standard fiber-optic networks of the energy-time DOF with the ability of hyper-entanglement to increase the capacity and efficiency of the quantum channel, already exploited in recent experimental applications in both quantum information and quantum computation.

Structural insights into probe-dependent positive allosterism of the GLP-1 receptor.

Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a 'molecular glue'. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric Gs. The modulator binds high in the helical bundle at an interface between TM1 and TM2, allowing access to the peptide ligand. Pharmacological characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36) versus oxyntomodulin that is driven by a single residue. Our findings expand protein-protein modulation drug discovery to uncompetitive, active state stabilizers for peptide hormone receptors.

Persistent opioid use in patients with multiple myeloma post-ASCT.

PURPOSE: Bone pain is a common presenting symptom of multiple myeloma (MM) and is frequently treated with opioids in addition to myeloma directed therapy. With improved response and survival with modern myeloma therapy, it is important to re-examine the role of opioids in managing symptomatic myeloma. PATIENTS AND METHODS: We performed a retrospective analysis of patients with myeloma at Rutgers Cancer Institute of New Jersey (RCINJ) who received an ASCT between January 1, 2012, and December 30, 2017, and who had subsequent follow-up (a total of 138 patients). We sought information specifically from the visits after induction therapy but prior to ASCT, at 100 days and 1-year post-ASCT follow-up visits. We compared opioid users and non-users in relation to treatment response, co-morbid conditions, and symptoms. We also examined amounts, duration, and odds of continued opioid use. RESULTS: At the time of the first analysis (before transplant), 34.8% of patients were using opioids and opioid use was more frequent in younger patients and, as expected, in patients with bone lesions. At 1 year, 31.9% of patients were still using opioids and continued opioid use was not correlated with disease response. Of the patients using opioids at the time of transplant, 58% either maintained their opioid dose or increased it at 1-year post-transplant. CONCLUSIONS: This retrospective analysis shows that despite a small decrease in opioid use over time, opioid use remains frequent in MM patients and is correlated with younger age and bone involvement but not with response to therapy. Over half the patients using opioids at the time of transplant continued or increased opioid use over the following year. With increasing survival in myeloma patients, further attention is required to distinguish cancer pain from chronic pain in cancer patients.

Optimised domain-engineered crystals for pure telecom photon sources.

The ideal photon-pair source for building up multi-qubit states needs to produce indistinguishable photons with high efficiency. Indistinguishability is crucial for minimising errors in two-photon interference, central to building larger states, while high heralding rates will be needed to overcome unfavourable loss scaling. Domain engineering in parametric down-conversion sources negates the need for lossy spectral filtering allowing one to satisfy these conditions inherently within the source design. Here, we present a telecom-wavelength parametric down-conversion photon source that operates on the achievable limit of domain engineering. We generate photons from independent sources which achieve two-photon interference visibilities of up to 98.6 ± 1.1% without narrow-band filtering. As a consequence, we reach net heralding efficiencies of up to 67.5%, which corresponds to collection efficiencies exceeding 90%.

Synthetic protease-activated class B GPCRs.

G-protein coupled receptors (GPCRs) are the ligand detection machinery of a majority of extracellular signaling systems in metazoans. Novel chemical and biological tools to probe the structure-function relationships of GPCRs have impacted both basic and applied GPCR research. To better understand the structure-function of class B GPCRs, we generated receptor-ligand fusion chimeric proteins that can be activated by exogenous enzyme application. As a prototype, fusion proteins of the glucagon-like peptide-1 receptor (GLP-1R) with GLP-1(7-36) and exendin-4(1-39) peptides incorporating enterokinase-cleavable N-termini were generated. These receptors are predicted to generate fusion protein neo-epitopes upon proteolysis with enterokinase that are identical to the N-termini of GLP-1 agonists. This system was validated by measuring enterokinase-dependent GLP-1R mediated cAMP accumulation, and a structure-activity relationship for both linker length and peptide sequence was observed. Moreover, our results show this approach can be used in physiologically relevant cell systems, as GLP-1R-ligand chimeras were shown to induce glucose-dependent insulin secretion in insulinoma cells upon exposure to enterokinase. This approach suggests new strategies for understanding the structure-function of peptide-binding GPCRs.

Post-modification of Cellulose Nanocrystal Aerogels with Thiol-Ene Click Chemistry.

The functionalization of cellulose nanocrystal (CNC) aerogels was achieved through a two-step synthetic procedure. CNC aerogels were prepared under hydrothermal conditions, followed by solvent exchange and critical point drying. The CNC aerogels were functionalized with a methacrylate group and then underwent thiol-ene click chemistry to impart a range of functionalities onto the surface of the CNC aerogel. The use of the functionalized aerogels as oil absorbents was then investigated, with the most hydrophobic CNC aerogel, 1 H,1 H,2 H,2 H-perfluorodecanethiol-functionalized CNC aerogel, exhibiting the highest absorption of xylenes at 2.9 mL g-1.

COMPARISON OF 3 MM × 3 MM VERSUS 6 MM × 6 MM OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY SCAN SIZES IN THE EVALUATION OF NON-PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To evaluate the utility of different optical coherence tomography angiography scan protocols in evaluating retinal changes in non-proliferative diabetic retinopathy. METHODS: Patients were imaged with the RTVue XR Avanti OCT 3 mm × 3 mm and 6 mm × 6 mm "Angio Retina" scan protocols. Ability to clearly delineate the foveal avascular zone (FAZ), FAZ remodeling, microaneurysms, capillary nonperfusion, motion, and doubling artifacts were evaluated. RESULTS: Forty-six eyes from 27 patients were enrolled. Eighty-nine percent of 3 mm × 3 mm versus 59% of 6 mm × 6 mm scans clearly delineated the FAZ (P = 0.001). Eighty percent of 3 mm × 3 mm versus 43% of 6 mm × 6 mm scans demonstrated FAZ remodeling (P = 0.0002). Microaneurysms were detected by 57% of 6 mm × 6 mm and 35% of 3 mm × 3 mm scans (P = 0.003). Capillary nonperfusion was detected in 87% of 3 mm × 3 mm scans versus 89% of 6 mm × 6 mm scans (P = 0.99). No significant differences were noted in the incidence of artifacts between the scan sizes (motion artifact P = 0.29 and doubling artifact P = 0.29). CONCLUSION: 3 mm × 3 mm scan delineated FAZ and remodeling better than 6 mm × 6 mm scan, likely because of its higher scan density. 6 mm × 6 mm scans detected microaneurysms more readily than 3 mm × 3 mm, likely because of its larger scan area. There were utility for both 3 mm × 3 mm and 6 mm × 6 mm scans when evaluating these patients.

RESOLUTION, DEPTH OF FIELD, AND PHYSICIAN SATISFACTION DURING DIGITALLY ASSISTED VITREORETINAL SURGERY.

PURPOSE: To evaluate depth of field, lateral resolution, and image quality of a heads-up 3D visualization system for vitreoretinal surgery using physician survey and optical measurement outcomes. METHODS: Depth of field and lateral resolution were compared between the standard ocular viewing system and the digital 3D system at ×5, ×13, and ×18 magnification by 6 retinal surgeons. Optical techniques were used as well as a survey of surgeon impression. Surgeon impression surveys were performed after 6 weeks of surgical use of the device. RESULTS: Physician questionnaire survey scores for depth of field at high magnification were better for the digital 3D system and equivalent for all other categories. Measured lateral resolution was 36.7 mm and 16.6 mm at ×5 magnification (P < 0.001), 14.3 mm and 6.4 mm at ×13 magnification (P < 0.001), and 9.8 mm and 4.2 mm (P < 0.001) at ×18 magnification for the digital 3D and oculars, respectively. Measured depth of field was 4.00 mm and 6.78 mm at ×5 magnification (P = 0.027), 0.72 mm and 0.86 mm at ×13 (P = 0.311), and 0.28 mm and 0.40 mm at ×18 magnification (P = 0.235) for the oculars and digital 3D, respectively. CONCLUSION: Lateral resolution of the digital 3D system was half that of the ocular viewing system and there was some improvement in depth of field with the digital system. Surgeon impression suggested that the digital system was superior when evaluating depth of field at high magnification.

Determination of L-AP4-bound human mGlu8 receptor amino terminal domain structure and the molecular basis for L-AP4's group III mGlu receptor functional potency and selectivity.

L-2-Amino-4-phosphonobutyric acid (L-AP4) is a known potent and selective agonist for the Group III mGlu receptors. However, it does not show any selectivity among the individual group III mGlu subtypes. In order to understand the molecular basis for this group selectivity, we solved the first human mGlu8 amino terminal domain (ATD) crystal structures in complex with L-glu and L-AP4. In comparison with other published L-glu-bound mGlu ATD structures, we have observed L-glu binds in a significantly different manner in mGlu1. Furthermore, these new structures provided evidence that both the electronic and steric nature of the distal phosphate of L-AP4 contribute to its exquisite Group III functional agonist potency and selectivity.

Pharmacological management of cerebral venous sinus thrombosis with full-dose IV heparin infusion and its clinical outcomes.

OBJECTIVE: To report a case of successful use of unfractionated heparin (UFH) infusion to treat cerebral venous sinus thrombosis (CVST). CASE SUMMARY: A 54-year-old female with a history of ovarian cancer addressed through palliative care, presents to the Emergency Department complaining of nausea, vomiting and headache for the last 72h. The patient was on a home regimen of enoxaparin 1.5mg/kg subcutaneously daily for recent pulmonary embolism and deep vein thrombosis that developed while on warfarin therapy previously. CT scan showed superior sagittal sinus thrombosis. UFH infusion was initiated and continued for 48h until the headache dissipated. DISCUSSION: Stable CVST may be treated with UFH infusion; however, there is limited literature that describes UFH dosing for CVST management. CONCLUSIONS: UFH may be considered as one of the pharmacological agents to manage CVST. The dosing for UFH bolus and infusion is similar to treatment dose for pulmonary embolism/deep vein thrombosis management with goal anti-Xa between 0.3 and 0.7units/mL.

Ganglion Cell Complex Loss in Chiasmal Compression by Brain Tumors.

BACKGROUND: Patterns of ganglion cell complex (GCC) loss detected by optical coherence tomography provide an objective measure of optic nerve injury. These patterns aid in early diagnosis and localization of chiasmal lesions. METHODS: Twenty-three patients with chiasmal compression seen between 2010 and 2015 were imaged with the Cirrus high-definition optical coherence tomography macular cube 512 × 128, retinal nerve fiber layer (RNFL) scan protocols and automated (30-2 Humphrey) visual fields (VFs). Age-matched controls were included for comparison. Generalized estimating equations were performed comparing RNFL and GCC thicknesses between patients and their controls. Effect size (d) was calculated to assess the magnitude of difference between patients and controls. The average GCC and RNFL thicknesses also were correlated with VF mean deviation (MD). Pre operative average GCC thickness was correlated to post operative VF MD. RESULTS: Patterns of GCC thinning corresponded to VF defects. The average GCC thickness was 67 ± 9 µm in patients and 86 ± 5 µm in controls (P < 0.001). The effect size was the greatest for GCC thickness (d = 2.72). The mean deviation was better correlated with GCC thickness (r =0.25) than RNFL thicknesses (r =0.15). Postoperatively, VF MD improved in 7 of 8 patients with persistent nasal GCC thinning. Six patients had no VF defect and showed statistically significant loss of GCC compared with controls (P = 0.001). CONCLUSIONS: Distinct patterns of GCC loss were identified in patients with chiasmal compression. Binasal GCC loss was typical and could be seen with minimal or no detectable VF loss. Thinning of the GCC may be detected before loss of the RNFL in some patients. After decompression, the majority of patients showed improvement in VF despite persistent GCC loss. Patients with less GCC loss before decompression had better postoperative VFs. Therefore, GCC analysis may be an objective method to diagnose and follow patients with chiasmal lesions.

Efficient and pure femtosecond-pulse-length source of polarization-entangled photons.

We present a source of polarization entangled photon pairs based on spontaneous parametric downconversion engineered for frequency uncorrelated telecom photon generation. Our source provides photon pairs that display, simultaneously, the key properties for high-performance quantum information and fundamental quantum science tasks. Specifically, the source provides for high heralding efficiency, high quantum state purity and high entangled state fidelity at the same time. Among different tests we apply to our source we observe almost perfect non-classical interference between photons from independent sources with a visibility of (100 ± 5)%.

Pipeline Embolization Device for the treatment of cervical carotid and vertebral dissecting aneurysms.

We present three patients with dissecting and saccular aneurysms affecting the cervical carotid and vertebral arteries treated with flow diversion using the Pipeline Embolization Device (ev3 Endovascular Inc/Covidien, Plymouth, Minn). The device was successfully deployed in all three patients without complication. Follow-up imaging studies at 8 to 18 months revealed complete occlusion of all three aneurysms. This device may be a valuable alternative to stent-graft devices in the treatment of cervical aneurysms since it is delivered through a microcatheter that is better able to negotiate tortuous anatomy of cervical carotid and vertebral arteries.

Agreement and reproducibility of retinal pigment epithelial detachment volumetric measurements through optical coherence tomography.

PURPOSE: To assess the agreement and reproducibility of retinal pigment epithelial detachment (RPED) volumetric measurements using a commercially available optical coherence tomography software available for the Zeiss Cirrus HD-OCT. METHODS: Twelve eyes of 10 patients with a diagnosis of neovascular age-related macular degeneration with RPED, seen at the New England Eye Center between October 2012 and December 2012, were enrolled in the study. Three separate scans per affected eye were obtained using the "Macular Cube 512 × 128" protocol. "Retinal pigment epithelial (RPE) elevation analysis" software was used to measure RPED volumes in the central 3-mm and 5-mm circles by calculating the volume between the "RPE fit" and "true RPE" lines. All 128 raster scans for each eye were exported into the AMIRA software for manual segmentation of RPED volumes in the central 3-mm and 5-mm circles. Interscan reproducibility and manual-to-automated agreement were assessed by intraclass correlation coefficient. Incidence of automated segmentation line error for both RPE fit and true RPE lines in the central 1 mm region was calculated. RESULTS: Average RPED volumes through automated segmentation software were 0.14 mm3 and 0.21 mm3 in the central 3-mm and 5-mm circles, respectively. Manual segmentation yielded average RPED volumes of 0.50 mm3 in the 3-mm circles and 0.92 mm3 in the 5-mm circles. Manual segmentation yielded significantly greater RPED volumes compared with automated measurements (P < 0.05). Intraclass correlation coefficients across the 3 automated measurements were 0.954 and 0.983 for volume in the 3-mm and 5-mm circles, respectively. Intraclass correlation coefficients between the manual and automatic volumes were 0.296 and 0.337 for the 3-mm and 5-mm circles, respectively. In the central 1 mm region, 11 of the 12 scans had breakdown in RPE fit line, whereas 8 of the 12 scans showed true RPE line breakdown. CONCLUSION: Automated "RPED elevation" software demonstrated high interscan reproducibility. However, it showed low agreement with manual measurements from high rates of segmentation line breakdown, especially at the level of the RPE fit line (91.7%). Manual measurements resulted in greater volumes compared with automated measurements.

Structural studies of several clinically important oncology drugs in complex with human serum albumin.

BACKGROUND: Serum albumin is a major pharmacokinetic effector of drugs. To gain further insight into albumin binding chemistry, the crystal structures of six oncology agents were determined in complex with human serum albumin at resolutions of 2.8 to 2.0Å: camptothecin, 9-amino-camptothecin, etoposide, teniposide, bicalutamide and idarubicin. METHODS: Protein crystal growth and low temperature X-ray crystallography RESULTS: These large, complex drugs are all bound within the subdomain IB binding region which can be described as a hydrophobic groove formed by α-helices h7, h8 and h9 covered by the extended polypeptide L1. L1 creates a binding cavity with two access sites, one between loop L1 and α-helices h7 and h8 (distal site: IBd) and the other between L1 and α-helix h9 (proximal site: IBp). Camptothecin (2.4Å) and 9 amino camptothecin (2.0Å) are clearly bound as the open lactone form (IBp). Idarubicin (2.8Å) binds in a DNA like dimer complex via an intermolecular π stacking arrangement in IBd. Bicalutamide (2.4Å) is bound in a folded intramolecular π stacking arrangement between two aromatic rings in IBd similar to idarubicin. Teniposide (2.7Å) and etoposide (2.7Å), despite small chemical differences, are bound in two distinctly different sites at or near IB. Teniposide is internalized via primarily hydrophobic interactions and spans through both openings (IBp-d). Etoposide is bound between the exterior of IB and IIA and exhibits an extensive hydrogen bonding network. CONCLUSIONS: Subdomain IB is a major binding site for complex heterocyclic molecules. GENERAL SIGNIFICANCE: The structures have important implications for drug design and development. This article is part of a Special Issue entitled Serum Albumin.

Eagle jugular syndrome presenting with intracranial hypertension - Diagnosis and illustration of pathophysiology by multi-modality imaging.

Eagle jugular syndrome is an uncommon condition caused by compression of an elongated styloid process onto the internal jugular vein. Its presentation is non-specific but may represent in severe clinical consequences including venous thrombosis and intracranial haemorrhage. Thorough understanding of local anatomy is important in understanding the pathogenesis and establishing the diagnosis. Our case reported here illustrates the use of multimodality imaging, including dynamic Computer tomography manoeuvre, in identifying the site of obstruction and guidance towards successful surgical treatment.