Reprogramming by drug-like molecules leads to regeneration of cochlear hair cell-like cells in adult mice.

Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance to hearing recovery in patients with permanent hearing loss. In mature mammalian cochlea, co-activation of Myc and Notch1 reprograms supporting cells (SC) and promotes HC regeneration. Understanding of the underlying mechanisms may aid the development of a clinically relevant approach to achieve HC regeneration in the nontransgenic mature cochlea. By single-cell RNAseq, we show that MYC/NICD "rejuvenates" the adult mouse cochlea by activating multiple pathways including Wnt and cyclase activator of cyclic AMP (cAMP), whose blockade suppresses HC-like cell regeneration despite Myc/Notch activation. We screened and identified a combination (the cocktail) of drug-like molecules composing of small molecules and small interfering RNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. We show that the cocktail effectively replaces Myc and Notch1 transgenes and reprograms fully mature wild-type (WT) SCs for HC-like cells regeneration in vitro. Finally, we demonstrate the cocktail is capable of reprogramming adult cochlea for HC-like cells regeneration in WT mice with HC loss in vivo. Our study identifies a strategy by a clinically relevant approach to reprogram mature inner ear for HC-like cells regeneration, laying the foundation for hearing restoration by HC regeneration.

Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents.

Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.

Rescue of auditory function by a single administration of AAV-TMPRSS3 gene therapy in aged mice of human recessive deafness DFNB8.

Patients with mutations in the TMPRSS3 gene suffer from recessive deafness DFNB8/DFNB10. For these patients, cochlear implantation is the only treatment option. Poor cochlear implantation outcomes are seen in some patients. To develop biological treatment for TMPRSS3 patients, we generated a knockin mouse model with a frequent human DFNB8 TMPRSS3 mutation. The Tmprss3A306T/A306T homozygous mice display delayed onset progressive hearing loss similar to human DFNB8 patients. Using AAV2 as a vector to carry a human TMPRSS3 gene, AAV2-hTMPRSS3 injection in the adult knockin mouse inner ear results in TMPRSS3 expression in the hair cells and the spiral ganglion neurons. A single AAV2-hTMPRSS3 injection in Tmprss3A306T/A306T mice of an average age of 18.5 months leads to sustained rescue of the auditory function to a level similar to wild-type mice. AAV2-hTMPRSS3 delivery rescues the hair cells and the spiral ganglions neurons. This study demonstrates successful gene therapy in an aged mouse model of human genetic deafness. It lays the foundation to develop AAV2-hTMPRSS3 gene therapy to treat DFNB8 patients, as a standalone therapy or in combination with cochlear implantation.

Primary bone tumor detection and classification in full-field bone radiographs via YOLO deep learning model.

OBJECTIVES: Automatic bone lesions detection and classifications present a critical challenge and are essential to support radiologists in making an accurate diagnosis of bone lesions. In this paper, we aimed to develop a novel deep learning model called You Only Look Once (YOLO) to handle detecting and classifying bone lesions on full-field radiographs with limited manual intervention. METHODS: In this retrospective study, we used 1085 bone tumor radiographs and 345 normal bone radiographs from two centers between January 2009 and December 2020 to train and test our YOLO deep learning (DL) model. The trained model detected bone lesions and then classified these radiographs into normal, benign, intermediate, or malignant types. The intersection over union (IoU) was used to assess the model's performance in the detection task. Confusion matrices and Cohen's kappa scores were used for evaluating classification performance. Two radiologists compared diagnostic performance with the trained model using the external validation set. RESULTS: In the detection task, the model achieved accuracies of 86.36% and 85.37% in the internal and external validation sets, respectively. In the DL model, radiologist 1 and radiologist 2 achieved Cohen's kappa scores of 0.8187, 0.7927, and 0.9077 for four-way classification in the external validation set, respectively. The YOLO DL model illustrated a significantly higher accuracy for intermediate bone tumor classification than radiologist 1 (95.73% vs 88.08%, p = 0.004). CONCLUSIONS: The developed YOLO DL model could be used to assist radiologists at all stages of bone lesion detection and classification in full-field bone radiographs. KEY POINTS: • YOLO DL model can automatically detect bone neoplasms from full-field radiographs in one shot and then simultaneously classify radiographs into normal, benign, intermediate, or malignant. • The dataset used in this retrospective study includes normal bone radiographs. • YOLO can detect even some challenging cases with small volumes.

Gene editing in a Myo6 semi-dominant mouse model rescues auditory function.

Myosin VI（MYO6） is an unconventional myosin that is vital for auditory and vestibular function. Pathogenic variants in the human MYO6 gene cause autosomal-dominant or -recessive forms of hearing loss. Effective treatments for Myo6 mutation causing hearing loss are limited. We studied whether adeno-associated virus (AAV)-PHP.eB vector-mediated in vivo delivery of Staphylococcus aureus Cas9 (SaCas9-KKH)-single-guide RNA (sgRNA) complexes could ameliorate hearing loss in a Myo6WT/C442Y mouse model that recapitulated the phenotypes of human patients. The in vivo editing efficiency of the AAV-SaCas9-KKH-Myo6-g2 system on Myo6C442Y is 4.05% on average in Myo6WT/C442Y mice, which was ∼17-fold greater than editing efficiency of Myo6WT alleles. Rescue of auditory function was observed up to 5 months post AAV-SaCas9-KKH-Myo6-g2 injection in Myo6WT/C442Y mice. Meanwhile, shorter latencies of auditory brainstem response (ABR) wave I, lower distortion product otoacoustic emission (DPOAE) thresholds, increased cell survival rates, more regular hair bundle morphology, and recovery of inward calcium levels were also observed in the AAV-SaCas9-KKH-Myo6-g2-treated ears compared to untreated ears. These findings provide further reference for in vivo genome editing as a therapeutic treatment for various semi-dominant forms of hearing loss and other semi-dominant diseases.

Mebendazole-Induced Blood-Testis Barrier Injury in Mice Testes by Disrupting Microtubules in Addition to Triggering Programmed Cell Death.

Mebendazole (MBZ) is a synthetic benzimidazole known for its antiparasitic properties. In recent years, growing evidence showed that MBZ was also used as an anti-tumor agent. However, whether (and to what extent) this drug treatment affected the male reproductive system was not well-understood. In this study, male C57BL/6 mice were injected with 40 mg/kg/day of MBZ. The treatment was for 3 and 7 days. Our results showed that the injected mice exhibited an abnormal spermatogenic phase with a significant decrease in sperm. We further detected microtubule disruption and transient functional destruction of the blood-testes barrier (BTB) in the MBZ-injected mice testes (BTB). Our data confirmed that MBZ suppressed the expression of the BTB junction-associated proteins and disrupted the Sertoli cells' function in vivo. Moreover, MBZ-treated mice demonstrated an aberrant caspase-3 signalling pathway, which resulted in the apoptosis of the germ cells. Here, we present our data, indicating that MBZ impairs BTB by reducing the expression of the microtubules' and BTB junction-associated proteins. The last leads to activating the caspase-3 pathway, which triggers extensive germ cell apoptosis.

MRI Evaluation of Various Elbow, Forearm, and Wrist Neuropathies: A Pictorial Review.

Upper extremity entrapment neuropathies are common and can cause pain, sensory loss, and muscle weakness leading to functional disability. We conducted a retrospective review from January 2007 until March 2020 of the magnetic resonance imaging (MRI) features of intrinsic and extrinsic causes of wrist, forearm, and elbow neuropathies of 637 patients who received a diagnosis of neuropathy by means of clinical and electrodiagnostic testing. We discuss cases with varying intrinsic and extrinsic nerve pathologies, including postoperative examples, affecting the median, radial, and ulnar nerve.Our collection of cases demonstrates a diversity of intrinsic and extrinsic causative factors. Intrinsic pathologies include neuritis as well as tumors arising from the nerve. Extrinsic causes resulting in nerve entrapment include masses, acute and chronic posttraumatic cases, anatomical variants, inflammatory and crystal deposition, calcium pyrophosphate deposition disease, and dialysis-related amyloidosis. Finally, we review postsurgical cases, such as carpal tunnel release and ulnar nerve transposition.Although upper extremity neuropathies tend to have a typical clinical presentation, imaging, particularly MRI, plays a vital role in evaluating the etiology and severity of each neuropathy and ultimately helps guide clinical management.

Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration of Infection.

In this retrospective study, chest CTs of 121 symptomatic patients infected with coronavirus disease-19 (COVID-19) from four centers in China from January 18, 2020 to February 2, 2020 were reviewed for common CT findings in relationship to the time between symptom onset and the initial CT scan (i.e. early, 0-2 days (36 patients), intermediate 3-5 days (33 patients), late 6-12 days (25 patients)). The hallmarks of COVID-19 infection on imaging were bilateral and peripheral ground-glass and consolidative pulmonary opacities. Notably, 20/36 (56%) of early patients had a normal CT. With a longer time after the onset of symptoms, CT findings were more frequent, including consolidation, bilateral and peripheral disease, greater total lung involvement, linear opacities, "crazy-paving" pattern and the "reverse halo" sign. Bilateral lung involvement was observed in 10/36 early patients (28%), 25/33 intermediate patients (76%), and 22/25 late patients (88%).

CT Imaging Features of 2019 Novel Coronavirus (2019-nCoV).

In this retrospective case series, chest CT scans of 21 symptomatic patients from China infected with the 2019 novel coronavirus (2019-nCoV) were reviewed, with emphasis on identifying and characterizing the most common findings. Typical CT findings included bilateral pulmonary parenchymal ground-glass and consolidative pulmonary opacities, sometimes with a rounded morphology and a peripheral lung distribution. Notably, lung cavitation, discrete pulmonary nodules, pleural effusions, and lymphadenopathy were absent. Follow-up imaging in a subset of patients during the study time window often demonstrated mild or moderate progression of disease, as manifested by increasing extent and density of lung opacities.

In vivo evaluation of human patellar tendon microstructure and microcirculation with diffusion MRI.

BACKGROUND: Patellar tendon (PT) microstructure integrity and microcirculation status play a crucial role in the progression of tendinopathy and tendon repair. PURPOSE: To assess the feasibility and robustness of stimulated-echo based diffusion-weighted MRI with readout-segmented echo-planar imaging (ste-RS-EPI) for noninvasive assessment of microstructure and microcirculation of human PT. STUDY TYPE: Prospective. SUBJECTS: Fifteen healthy volunteers. FIELD STRENGTH/SEQUENCE: PT diffusion tensor imaging (DTI) and intravoxel incoherent motion (IVIM) were acquired with an ste-RS-EPI protocol on a 3T MRI scanner. ASSESSMENT: Subjects were positioned with their PT at the magic angle. DTI-derived parameters including axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) were estimated with b-values of 0 and 800 s/mm2 and 12 diffusion directions. IVIM-derived parameters, f p , D* × f p , V b , and D* × V b were assessed in the central-third and the outer-two thirds of the PT with b-values of 0, 20, 30, 60, 80, 120, 200, 400, and 600 s/mm2 in three orthogonal directions. STATISTICAL TESTS: Paired t-tests were used to evaluate differences in IVIM parameters between the central-third and outer-two thirds regions of the patellar tendon. Paired t-tests and within-subject coefficient of variation were used to assess the intra- and intersession reproducibility of PT DTI and IVIM parameters. RESULTS: DTI parameters for healthy PT were 1.54 ± 0.09 × 10-3 mm2 /s, 1.01 ± 0.05 × 10-3 mm2 /s, 1.18 ± 0.06 × 10-3 mm2 /s, and 0.30 ± 0.04 for AD, RD, MD, and FA, respectively. Significantly higher (P < 0.05) IVIM parameters f p and D* × f p were observed in the outer-two thirds (6.1% ± 2.4% and 95.2 ± 49.6, respectively) compared with the central-third (3.8% ± 2.3% and 48.6 ± 35.2, respectively) of the PT. DATA CONCLUSION: Diffusion MRI of PT with an ste-RS-EPI protocol is clinically feasible. Both DTI- and IVIM-derived parameters of the PT demonstrated good test-retest reproducibility and interrater reliability. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:780-790.

CT image visual quantitative evaluation and clinical classification of coronavirus disease (COVID-19).

OBJECTIVES: To explore the relationship between the imaging manifestations and clinical classification of COVID-19. METHODS: We conducted a retrospective single-center study on patients with COVID-19 from Jan. 18, 2020 to Feb. 7, 2020 in Zhuhai, China. Patients were divided into 3 types based on Chinese guideline: mild (patients with minimal symptoms and negative CT findings), common, and severe-critical (patients with positive CT findings and different extent of clinical manifestations). CT visual quantitative evaluation was based on summing up the acute lung inflammatory lesions involving each lobe, which was scored as 0 (0%), 1 (1-25%), 2 (26-50%), 3 (51-75%), or 4 (76-100%), respectively. The total severity score (TSS) was reached by summing the five lobe scores. The consistency of two observers was evaluated. The TSS was compared with the clinical classification. ROC was used to test the diagnosis ability of TSS for severe-critical type. RESULTS: This study included 78 patients, 38 males and 40 females. There were 24 mild (30.8%), 46 common (59.0%), and 8 severe-critical (10.2%) cases, respectively. The median TSS of severe-critical-type group was significantly higher than common type (p < 0.001). The ICC value of the two observers was 0.976 (95% CI 0.962-0.985). ROC analysis showed the area under the curve (AUC) of TSS for diagnosing severe-critical type was 0.918. The TSS cutoff of 7.5 had 82.6% sensitivity and 100% specificity. CONCLUSIONS: The proportion of clinical mild-type patients with COVID-19 was relatively high; CT was not suitable for independent screening tool. The CT visual quantitative analysis has high consistency and can reflect the clinical classification of COVID-19. KEY POINTS: • CT visual quantitative evaluation has high consistency (ICC value of 0.976) among the observers. The median TSS of severe-critical type group was significantly higher than common type (p < 0.001). • ROC analysis showed the area under the curve (AUC) of TSS for diagnosing severe-critical type was 0.918 (95% CI 0.843-0.994). The TSS cutoff of 7.5 had 82.6% sensitivity and 100% specificity. • The proportion of confirmed COVID-19 patients with normal chest CT was relatively high (30.8%); CT was not a suitable screening modality.

Prediction of Abnormal Bone Density and Osteoporosis From Lumbar Spine MR Using Modified Dixon Quant in 257 Subjects With Quantitative Computed Tomography as Reference.

BACKGROUND: Bone marrow fat increases when bone mass decreases, which could be attributed to the fact that adipogenesis competes with osteogenesis. Bone marrow fat has the potential to predict abnormal bone density and osteoporosis. PURPOSE: To investigate the predictive value of using vertebral bone marrow fat fraction(BMFF) obtained from modified Dixon(mDixon) Quant in the determination of abnormal bone density and osteoporosis. STUDY TYPE: Prospective. POPULATION: 257 subjects (age: 20-79 years old; BMI: 16.6-32.9 kg/m2 ;181 females,76 males) without known spinal tumor, history of trauma, dysplasia, spinal surgery or hormone therapy. FIELD STRENGTH/SEQUENCE: 3.0T/mDixon. ASSESSMENT: BMFF was measured at the L1, L2 and L3 vertebral body on fat fraction maps of the lumbar spine. Bone mineral density (BMD) was obtained using quantitative computed tomography, which served as the reference standard. STATISTICAL TESTS: The BMFF between the three groups (normal bone density, osteopenia and osteoporosis) was tested using one-way analysis of variance in SPSS. The correlation and partial correlation of BMFF and BMD were analyzed before and after controlling for age, sex and BMI. Logistic regression analysis using independent training and validation data was conducted to evaluate the performance of predicting abnormal BMD or osteoporosis using BMFF. RESULTS: There was a significant difference in vertebral BMFF between the three groups (P < 0.001). Moderate inverse correlation was found between vertebral BMFF and BMD after controlling age, sex and BMI (r = -0.529; P < 0.001). The mean area under the curve, sensitivity, specificity and negative predictive value (NPV) for predicting abnormal bone density were 0.940, 0.877, 0.896, and 0.890, respectively. The corresponding results for predicting subjects with osteoporosis were 0.896, 0.848, 0.853, and 0.969, respectively. DATA CONCLUSION: mDixon Quant is a fast, simple, noninvasive and nonionizing method to access vertebral BMFF and has a high predictive power for identifying abnormal bone density and osteoporosis. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:390-399.

Bone microarchitectural parameters can detect oxytocin induced changes prior to bone density on mitigating bone deterioration in rabbit osteoporosis model using micro-CT.

BACKGROUND: This study is aimed to determine the efficacy of X-Ray Microtomography (micro-CT) in predicting oxytocin (OT) treatment response in rabbit osteoporosis(OP) model. METHODS: Sixty-five rabbits were randomly divided into three groups: control group, ovariectomy (OVX) -vehicle and OVX-oxytocin group. The controls underwent sham surgery. OVX-vehicle and OVX-oxytocin groups were subjected to bilateral OVX. The rabbits in OVX-oxytocin group were injected with oxytocin. In the 0th, 4th, 8th, 10th and 12th weeks post OVX operation, bone mineral density (BMD) and bone micro-architectural parameters were measured in three groups. RESULTS: Bone mineral density (BMD), bone volume fraction (BV/TV), Trabecular Number (Tb.N), and Trabecular Thickness (Tb.Th) decreased, while Trabecular Spacing (Tb.Sp) and Structure Model Index (SMI) increased overtime in all the three groups. In OVX-oxytocin group, the bone deterioration tendency is slowing down compared with that of the OVX-vehicle group. The BMD of the OVX-oxytocin group was significantly lower than those in the OVX-vehicle group at 12th week (P = 0.017). BV/TV and Tb.Sp in OVX-oxytocin group changed significantly from 8th week (P = 0.043) and 12th week (P = 0.014), which is earlier than that of BMD and other bone micro-architectural parameters. CONCLUSION: BV/TV and Tb.Sp changed prior to BMD and other bone micro-architectural parameters with oxytocin intervention, which indicate that they are more sensitive markers for predicting early osteoporosis and treatment monitoring when using micro-CT to evaluate osteoporosis rabbit model.

Abbreviated quantitative UTE imaging in anterior cruciate ligament reconstruction.

BACKGROUND: Existing ultrashort echo time magnetic resonance imaging (UTE MRI) methods require prohibitively long acquisition times (~ 20-40 min) to quantitatively assess the clinically relevant fast decay T2* component in ligaments and tendons. The purpose of this study was to evaluate the feasibility and clinical translatability of a novel abbreviated quantitative UTE MRI paradigm for monitoring graft remodeling after anterior cruciate ligament (ACL) reconstruction. METHODS: Eight patients who had Graftlink™ hamstring autograft reconstruction were recruited for this prospective study. A 3D double-echo UTE sequence at 3.0 Tesla was performed at 3- and 6-months post-surgery. An abbreviated UTE MRI paradigm was established based on numerical simulations and in vivo validation from healthy knees. This proposed approach was used to assess the T2* for fast decay component ([Formula: see text]) and bound water signal fraction (fbw) of ACL graft in regions of interest drawn by a radiologist. RESULTS: Compared to the conventional bi-exponential model, the abbreviated UTE MRI paradigm achieved low relative estimation bias for [Formula: see text] and fbw over a range of clinically relevant values for ACL grafts. A decrease in [Formula: see text] of the intra-articular graft was observed in 7 of the 8 ACL reconstruction patients from 3- to 6-months (- 0.11 ± 0.16 ms, P = 0.10). Increases in [Formula: see text] and fbw from 3- to 6-months were observed in the tibial intra-bone graft ([Formula: see text]: 0.19 ± 0.18 ms, P < 0.05; Δfbw: 4% ± 4%, P < 0.05). Lower [Formula: see text] (- 0.09 ± 0.11 ms, P < 0.05) was observed at 3-months when comparing the intra-bone graft to the graft/bone interface in the femoral tunnel. The same comparisons at the 6-months also yielded relatively lower [Formula: see text] (- 0.09 ± 0.12 ms, P < 0.05). CONCLUSION: The proposed abbreviated 3D UTE MRI paradigm is capable of assessing the ACL graft remodeling process in a clinically translatable acquisition time. Longitudinal changes in [Formula: see text] and fbw of the ACL graft were observed.

Correlation of bone marrow cellularity and metabolic activity in healthy volunteers with simultaneous PET/MR imaging.

OBJECTIVE: To evaluate the correlation between bone marrow cellularity (BMC) and metabolic activity in healthy subjects and to see whether yellow marrow is indeed metabolically quiescent. Because metabolic activity can be assumed to reflect vascularity, we assessed the relationship between regional metabolic activity and geographic frequency of metastases as noted in the literature. MATERIALS AND METHODS: Two hundred and twenty locations (ten in each side of the pelvis and proximal femur) were evaluated in 11 consecutive healthy volunteers with simultaneous PET/MR. BMC was calculated through precise water-fat fraction quantification with a 6-echo gradient echo. We analyzed correlations between cellularity and SUVr, age, and R2*. We also looked at the relation between our results and the reported prevalence of metastases. RESULTS: There was moderate but statistically significant correlation between BMC and metabolic activity (r = 0.636, p < 0.0001). Interestingly, the iliac and sacrum had higher metabolic activity relative to cellularity, whereas the femoral neck and lesser trochanter showed lower SUVr than other regions with the similar cellularity. The relatively lower metabolic status of the femoral neck conflicted with its reported high frequency of metastasis. Excluding regions with almost no remaining red marrow, cellularity showed inverse relationship with age (r = 0.476, p < 0.0001) and direct relationship with R2* (r = 0.532, p < 0.0010). CONCLUSIONS: Metabolic activity of bone marrow was largely dependent on BMC while yellow marrow seems metabolically quiescent. The discrepancy between the assumed vascularity as determined by metabolic activity and reported sites of metastasis suggested that the process of bone metastasis may not depend entirely on vascularity.

Diffusion tensor imaging of human Achilles tendon by stimulated echo readout-segmented EPI (ste-RS-EPI).

PURPOSE: Healing, regeneration, and remodeling of the injured Achilles tendon are associated with notable changes in tendon architecture. However, assessing Achilles microstructural properties with conventional diffusion tension imaging (DTI) remains a challenge because of very short T2 / T 2 * values of the tendon. Hence, the objective of this study was to develop a novel Achilles tendon DTI protocol for a non-invasive investigation of the changes of microstructural integrity in tendinopathy. METHODS: A novel stimulated echo readout-segmented EPI (ste-RS-EPI) DTI sequence was proposed to achieve a TE of ∼14-20 ms for typical b-values of 400-800 s/mm2 on clinical 3T MRI scanners. To further boost tendon MR signal, the Achilles was positioned at the magic angle (∼55 °) with respect to the scanner B0 field. The sensitivity of the developed protocol was evaluated in 19 healthy participants and 6 patients with clinically confirmed tendinopathy. RESULTS: Compared to spin echo RS-EPI DTI protocol, ste-RS-EPI provided an ∼100-200% increase in Achilles MR signal. Tendinopathic Achilles demonstrated a high degree of microstructural disruption based on DTI tractography analysis, with significantly lower (P < 0.05) axial diffusivity (1.20 ± 0.19 vs. 1.39 ± 0.10 × 10-3 mm2 /s), radial diffusivity (0.72 ± 0.11 vs. 0.81 ± 0.08 × 10-3 mm2 /s), and mean diffusivity (0.87 ± 0.14 vs. 1.00 ± 0.07 × 10-3 mm2 /s), but no significant difference in fractional anisotropy (0.38 ± 0.04 vs. 0.38 ± 0.05; P = 0.86). CONCLUSION: Achilles tendon ste-RS-EPI DTI can non-invasively detect the tendinopathy-induced changes to microstructural integrity, consistent with the disruption of collagen arrangement and increased cellularity. This study demonstrated the robustness and sensitivity of the proposed protocol in Achilles tendinopathy.

Intravoxel incoherent motion (IVIM) imaging in human achilles tendon.

BACKGROUND: Limited microcirculation has been implicated in Achilles tendinopathy and may affect healing and disease progression. Existing invasive and noninvasive approaches to evaluate tendon microcirculation lack sensitivity and spatial coverage. PURPOSE: To develop a novel Achilles tendon intravoxel incoherent motion (IVIM) MRI protocol to overcome the limitations from low tendon T2 /T2 * value and low intratendinous blood volume and blood velocity to evaluate tendon microcirculation. STUDY TYPE: Prospective. SUBJECTS: Sixteen healthy male participants (age 31.0 ± 2.1) were recruited. FIELD STRENGTH/SEQUENCE: A stimulated echo readout-segmented echo planar imaging (ste-RS-EPI) IVIM sequence at 3.0T. ASSESSMENT: The feasibility of the proposed ste-RS-EPI IVIM protocol combined with Achilles tendon magic angle effect was evaluated. The sensitivity of the protocol was assessed by an exercise-induced intratendinous hemodynamic response in healthy participants. The vascular origin of the observed IVIM signal was validated by varying the diffusion mixing time and echo time. STATISTICAL TESTS: Two-tailed t-tests were used to evaluate differences (P < 0.05 was considered significant). RESULTS: Consistent with known tendon hypovascularity, the midportion Achilles tendon at baseline showed significantly lower IVIM-derived perfusion fraction (fp ) (3.1 ± 0.9%) compared to the proximal and distal Achilles tendon (6.0 ± 1.8% and 6.1 ± 2.0%, respectively; P < 0.01). Similarly, the midportion Achilles tendon exhibited significantly lower baseline blood flow index (D*×fp ) (40.9 ± 19.2, 18.3 ± 5.3, and 32.0 ± 9.4 in proximal, midportion, and distal Achilles tendon, respectively; P < 0.01). Eccentric heel-raise exercise led to ∼2 times increase of Achilles tendon blood flow in healthy participants. Consistent with its vascular origin, the estimated fp demonstrated a high dependency to IVIM protocol parameters, while the T1 /T2 -corrected absolute intratendinous microvascular blood volume fraction (Vb ) did not vary. DATA CONCLUSION: Achilles tendon ste-RS-EPI IVIM noninvasively assessed baseline values and exercise-induced changes to tendon microcirculation in healthy tendon. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1690-1699.

Birth injuries to growth plates: A sheep in wolves' clothing.

Growth plate injuries (Salter-Harris type 1 or physeal fractures) of the long bones in the newborn are easily misdiagnosed as joint fractures with dislocations due to their nonossified epiphyses on plain radiographs. Diagnosis with musculoskeletal ultrasound (US) is advantageous due to its ability to visualize the nonossified epiphysis. We present two cases of humeral growth plate fractures in newborns, one at the shoulder (proximal humerus) and the other at the elbow (distal humerus). These cases emphasize the importance of quick and noninvasive diagnosis with US to avoid unnecessary intervention. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45:511-514, 2017.

Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss.

Hereditary hearing loss is characterized by a high degree of genetic heterogeneity. Here we present OTOGL mutations, a homozygous one base pair deletion (c.1430 delT) causing a frameshift (p.Val477Glufs(∗)25) in a large consanguineous family and two compound heterozygous mutations, c.547C>T (p.Arg183(∗)) and c.5238+5G>A, in a nonconsanguineous family with moderate nonsyndromic sensorineural hearing loss. OTOGL maps to the DFNB84 locus at 12q21.31 and encodes otogelin-like, which has structural similarities to the epithelial-secreted mucin protein family. We demonstrate that Otogl is expressed in the inner ear of vertebrates with a transcription level that is high in embryonic, lower in neonatal, and much lower in adult stages. Otogelin-like is localized to the acellular membranes of the cochlea and the vestibular system and to a variety of inner ear cells located underneath these membranes. Knocking down of otogl with morpholinos in zebrafish leads to sensorineural hearing loss and anatomical changes in the inner ear, supporting that otogelin-like is essential for normal inner ear function. We propose that OTOGL mutations affect the production and/or function of acellular structures of the inner ear, which ultimately leads to sensorineural hearing loss.

Hair cell overexpression of Islet1 reduces age-related and noise-induced hearing loss.

Isl1 is a LIM-homeodomain transcription factor that is critical in the development and differentiation of multiple tissues. In the mouse inner ear, Isl1 is expressed in the prosensory region of otocyst, in young hair cells and supporting cells, and is no longer expressed in postnatal auditory hair cells. To evaluate how continuous Isl1 expression in postnatal hair cells affects hair cell development and cochlear function, we created a transgenic mouse model in which the Pou4f3 promoter drives Isl1 overexpression specifically in hair cells. Isl1 overexpressing hair cells develop normally, as seen by morphology and cochlear functions (auditory brainstem response and otoacoustic emissions). As the mice aged to 17 months, wild-type (WT) controls showed the progressive threshold elevation and outer hair cell loss characteristic of the age-related hearing loss (ARHL) in the background strain (C57BL/6J). In contrast, the Isl1 transgenic mice showed significantly less threshold elevation with survival of hair cells. Further, the Isl1 overexpression protected the ear from noise-induced hearing loss (NIHL): both ABR threshold shifts and hair cell death were significantly reduced when compared with WT littermates. Our model suggests a common mechanism underlying ARHL and NIHL, and provides evidence that hair cell-specific Isl1 expression can promote hair cell survival and therefore minimize the hearing impairment that normally occurs with aging and/or acoustic overexposure.