Mice with a conditional deletion of Talpid3 (KIAA0586) – a model for Joubert syndrome

Joubert syndrome (JS) is a ciliopathy associated with mutations in numerous genes encoding cilia components. TALPID3 encoded by KIAA0856 in man (2700049A03Rik in mouse) is a centrosomal protein essential for the assembly of primary cilia. Mutations in KIAA0856 have been recently identified in JS patients. Herein, we describe a novel mouse JS model with a conditional deletion of the conserved exons 11–12 of Talpid3 in the central nervous system which recapitulates the complete cerebellar phenotype seen in JS. Talpid3 mutant mice exhibit key hallmarks of JS including progressive ataxia, severely hypoplastic cerebellar hemispheres and vermis, together with abnormal decussation of the superior cerebellar peduncles. The Purkinje cell layer is disorganised with abnormal dendritic arborisation. The external granule layer (EGL) is thinner, lacks primary cilia, and has a reduced level of proliferation. Furthermore, we describe novel cellular defects including ectopic clusters of mature granule neurons, and abnormal parallel fibre-derived synapses and disorientation of cells in the EGL. The defective glial scaffold results in abnormal granule cell migration which manifests as ectopic clusters of granule neurons. In addition, we show a reduction in Wnt7a expression suggesting that defects may arise not only from deficiencies in the Hedgehog (Hh) pathway but also due to the additional roles of Talpid3. The Talpid3 conditional knockout mouse is a novel JS model which fully recapitulates the JS cerebellar phenotype. These findings reveal a role for Talpid3 in granule precursor cell migration in the cerebellum (either direct or indirect) which together with defective Hh signalling underlies the JS phenotype. Our findings also illustrate the utility of creating conditional mouse models to assist in unravelling the molecular and cellular mechanisms underlying JS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Exploratory Study of Apparent Diffusion Coefficient Histogram Metrics in Assessing Pancreatic Malignancy

PurposeTo evaluate whole-lesion 3D-histogram apparent diffusion coefficient (ADC) metrics for assessment of pancreatic malignancy.MethodsForty-two pancreatic malignancies (36 pancreatic adenocarcinoma [PDAC], 6 pancreatic neuroendocrine [PanNET]) underwent abdominal magnetic resonance imaging (MRI) with diffusion-weighted imaging before endoscopic ultrasound biopsy or surgical resection. Two radiologists independently placed 3D volumes of interest to derive whole-lesion histogram ADC metrics. Mann-Whitney tests and receiver operating characteristic analyses were used to assess metrics’ diagnostic performance for lesion histology, T-stage, N-stage, and grade.ResultsWhole-lesion ADC histogram metrics lower in PDACs than PanNETs for both readers (P ≤ .026) were mean ADC (area under the curve [AUC] = 0.787-0.792), mean of the bottom 10th percentile (mean_0-10) (AUC = 0.787-0.880), mean of the 10th-25th percentile (mean_10-25) (AUC = 0.884-0.917) and mean of the 25th-50th percentile (mean_25-50) (AUC = 0.829-0.829). For mean_10-25 (metric with highest AUC for identifying PDAC), for reader 1 a threshold > 0.94 × 10^?3 mm²/s achieved sensitivity 94% and specificity 83%, and for reader 2 a threshold > 0.82 achieved sensitivity 97% and specificity 67%. Metrics lower in nodal status ≥ N₁ than N₀ for both readers (P ≤ .043) were mean_0-10 (AUC = 0.789-0.822) and mean_10-25 (AUC = 0.800-0.822). For mean_10-25 (metric with highest AUC for identifying N₀), for reader 1 a threshold <1.17 achieved sensitivity 87% and specificity 67%, and for reader 2 a threshold <1.04 achieved sensitivity 87% and specificity 83%. No metric was associated with T-stage (P > .195) or grade (P > .215).ConclusionVolumetric ADC histogram metrics may serve as non-invasive biomarkers of pancreatic malignancy. Mean_10-25 outperformed standard mean for lesion histology and nodal status, supporting the role of histogram analysis.     

Evidence of impaired pain modulation in adolescents with idiopathic scoliosis and chronic back pain

BACKGROUND CONTEXT

Although 40% of adolescent idiopathic scoliosis (AIS) patients present with chronic back pain, the pathophysiology and underlying pain mechanisms remain poorly understood. We hypothesized that development of chronic pain syndrome in AIS is associated with alterations in pain modulatory mechanisms.

Elevated glycohemoglobin HbA1c is associated with low back pain in nonoverweight diabetics

Background Context

Low back pain (LBP) is a common complaint in clinical practice of multifactorial origin. Although obesity has been thought to contribute to LBP primarily by altering the distribution of mechanical loads on the spine, the additional contribution of obesity-related conditions such as diabetes mellitus (DM) to LBP has not been thoroughly examined.

Assessing the CT findings and clinical course of ED patients with first-time versus recurrent acute pancreatitis

Study objectives

The primary objective of this study was to compare Emergency Department patients with first-time versus recurrent acute pancreatitis.