Ether Bond Cleavage of a Phenylcoumaran ß-5 Lignin Model Compound and Polymeric Lignin Catalysed by a LigE-type Etherase from Agrobacterium sp.

A LigE-type beta-etherase enzyme from lignin-degrading Agrobacterium sp. has been identified, which assists degradation of polymeric lignins. Testing against lignin dimer model compounds revealed that it does not catalyse the previously reported reaction of Sphingobium SYK-6 LigE, but instead shows activity for a ß-5 phenylcoumaran lignin dimer. The reaction products did not contain glutathione, indicating a catalytic role for reduced glutathione in this enzyme. Three reaction products were identified: the major product was a cis-stilbene arising from C-C fragmentation involving loss of formaldehyde; two minor products were an alkene arising from elimination of glutathione, and an oxidised ketone, proposed to arise from reaction of an intermediate with molecular oxygen. Testing of the recombinant enzyme against a soda lignin revealed the formation of new signals by two-dimensional NMR analysis, whose chemical shifts are consistent with the formation of a stilbene unit in polymeric lignin.

The pharmacologic and toxicologic characterization of the potent and selective KRAS G12D inhibitors ERAS-4693 and ERAS-5024.

Two potent and selective KRASG12D inhibitors, ERAS-4693 and ERAS-5024, were generated as possible clinical candidates to treat patients harboring G12D mutations in solid tumors. Both molecules exhibited strong anti-tumor activity in the KRASG12D mutant PDAC xenograft mouse models while ERAS-5024 also showed tumor growth inhibition when administered on an intermittent dosing regimen. Acute dose-limiting toxicity consistent with an allergic reaction was observed for both molecules shortly after administration at doses just above those which demonstrated anti-tumor activity, indicative of a narrow therapeutic index. A series of studies were subsequently conducted to identify a common underlying mechanism for the observed toxicity, including CETSA® (Cellular Thermal Shift Assay) as well as several functional off-target screens. Both ERAS-4693 and ERAS-5024 were identified to agonize MRGPRX2 which has been linked to pseudo-allergic reactions. In vivo toxicologic characterization of both molecules included repeat-dose studies in the rat and dog. Dose-limiting toxicities were observed in both species with ERAS-4693 and ERAS-5024 and plasma exposure levels at the maximum tolerated doses were generally below that which caused strong anti-tumor activity, supporting the initial observation of a narrow therapeutic index. Additional overlapping toxicities included a reduction in reticulocytes and clinical pathological changes suggestive of an inflammatory response. Furthermore, increases in plasma histamine were observed in dogs administered ERAS-5024, supporting the hypothesis that MRGPRX2 agonism may be the cause of the pseudo-allergic reaction. This work highlights the importance of balancing both the safety and efficacy of KRASG12D inhibitors as this class of molecules begins to enter clinical development.

A rare case of a gabapentin-induced cardiomyopathy.

WHAT IS KNOWN AND OBJECTIVE: Gabapentin, a γ-aminobutyric acid derivative, is used for the treatment of partial onset seizures, postherpetic neuralgia, diabetic neuropathy and a host of other neurological disorders. CASE DESCRIPTION: A 44-year-old woman with spinal stenosis was prescribed gabapentin for pain. Two months after initiating therapy, she was diagnosed with a new-onset non-ischaemic cardiomyopathy with an ejection fraction of 36% measured on a transthoracic echocardiogram. WHAT IS NEW AND CONCLUSION: A patient with suspected gabapentin-induced cardiomyopathy is reported. However, to date, gabapentin therapy has not been associated with risk of the developing a cardiomyopathy.

Clinical signs, imaging findings, and outcome in twelve cats with internal ophthalmoparesis/ophthalmoplegia.

OBJECTIVE: To retrospectively evaluate the clinical signs, imaging findings, and outcome of feline internal ophthalmoparesis/ophthalmoplegia. PROCEDURE: Medical records were reviewed from 2008 to 2015. Inclusion criteria included cats that presented with internal ophthalmoparesis/ophthalmoplegia, underwent diagnostic imaging, and had follow-up information available. RESULTS: Twelve cases of feline internal ophthalmoparesis/ophthalmoplegia were identified. Nine cats were unilaterally affected, and three cats were bilaterally affected. Affected cats had a median age of 10.54 years (range 5.75 to 13.17), and both sexes of varying breeds were affected (nine males; three females). Clinical signs including abnormal mental status (n = 9; 75%) and additional neurologic abnormalities (n = 10; 83%) were observed. Magnetic resonance imaging and/or computed tomography (MRI/CT) of the head were performed in ten cats, revealing a mass lesion in all cases with varying locations. Multicentric lymphoma was diagnosed in two cats via abdominal ultrasound and cytology. All twelve cats were euthanized due to deterioration of clinical signs and/or quality-of-life concerns. Median time from diagnosis to euthanasia was 3.5 days (range 0 to 80 days). CONCLUSIONS: Feline internal ophthalmoparesis/ophthalmoplegia rarely presents as the sole clinical sign in a referral hospital. Advanced imaging (MRI/CT) may be necessary to reach a definitive diagnosis in these cases. However, abdominal ultrasound would be advocated in cats with systemic clinical signs as a less expensive and less invasive diagnostic test to further investigate the possible etiology of internal ophthalmoparesis/ophthalmoplegia prior to advanced imaging. Feline cases with internal ophthalmoparesis/ophthalmoplegia associated with other intracranial signs and/or systemic clinical signs have a poor prognosis.

Rabbits with naturally occurring cataracts referred for phacoemulsification and intraocular lens implantation: a preliminary study of 12 cases.

OBJECTIVE: To describe the presentation of 15 rabbits with naturally occurring cataracts referred for phacoemulsification surgery, the procedure in 13 cases and the follow-up in 12. ANIMALS INCLUDED: Fifteen rabbits (30 eyes), nine of which stopped following visual cues in association with cataract progression. MATERIALS AND METHODS: Rabbits underwent preoperative ophthalmic and ocular ultrasound examination. RESULTS: Thirteen rabbits (22 eyes) had mature cataracts. Ten were bilateral and three unilateral. Two rabbits had an anterior chamber abscess. The cataract in one of these was incipient. One rabbit had bilateral immature cataracts. One rabbit had a subluxated lens, and one had a retinal detachment. Thirteen rabbits (22 eyes) underwent phacoemulsification. Eighteen, 13.5-mm capsular tension rings (CTRs) and seventeen, 13-mm IOLs (Acrivet® , Berlin, Germany) were fitted including one 41D 60V-model, and three 49D and thirteen 58D 20S-models. Intraoperative complications included one unilateral posterior-capsular tear, one lens subluxation, and one expulsive choroidal hemorrhage. One rabbit died during anesthetic recovery. Nine cases were PCR-tested for Encephalitozoon cuniculi, and only three were positive. The median follow-up time was 12 months (4-24 months). Rabbits that were not following visual cues preoperatively did so postoperatively, and surgery resulted in a clear visual axis for the follow-up period in every case except in two, due to reasons other than the surgery. CONCLUSIONS: Phacoemulsification with CTR and IOL implantation offers good long-term results and can improve the quality of life of pet rabbits. Retinal detachment, lens luxation, expulsive choroidal hemorrhage, and anesthetic death are potential complications.

Calculation of posterior chamber intraocular lens (IOL) size and dioptric power for use in pet rabbits undergoing phacoemulsification.

OBJECTIVES: To calculate the size and dioptric power of a posterior chamber intraocular lens (IOL) to achieve emmetropia in adult rabbits and to compare the dioptric power calculation results using a proprietary predictive formula to a retinoscopy-based method. ANIMALS STUDIED: Three wild rabbit cadavers, seven pet rabbits with cataracts and ten healthy pet rabbits. MATERIALS AND METHODS: Implant size was calculated using a capsular tension ring (CTR) (Acrivet® , Berlin, Germany). Published and cadaveric biometric data were used in the predictive formula. An IOL power-escalation study compared the predicted values to the refraction results of one pet rabbit (P1) fitted with a + 41D canine IOL (Acrivet® ) and six pet rabbits (P2-P7) fitted with prototype IOLs (Acrivet® ). Retinoscopy of 10 healthy pet rabbits served as controls. RESULTS: A 13.5 mm CTR fitted in all rabbits and permitted the use of a 13 mm IOL. The predicted IOL power ranged between +24D and +25D. The +41D IOL resulted in a refraction error of +8D. Progressive recalculation through a calibration formula led to the insertion of three +49D IOLs in two pet rabbits and a refraction of +6D to +8D, followed by seven +58D IOLs in four pet rabbits and a refraction median of 0D (range: -1.5D to +1D). CONCLUSIONS: A 13 mm prototype IOL of +58D achieves emmetropia and is of adequate size for rabbits. The combined use of a CTR and retinoscopy is a useful method to calculate the size and refractive power of a new, species-specific, veterinary IOL.

Computed tomographic morphometry of tympanic bulla shape and position in brachycephalic and mesaticephalic dog breeds.

Anatomic variations in skull morphology have been previously described for brachycephalic dogs; however there is little published information on interbreed variations in tympanic bulla morphology. This retrospective observational study aimed to (1) provide detailed descriptions of the computed tomographic (CT) morphology of tympanic bullae in a sample of dogs representing four brachycephalic breeds (Pugs, French Bulldogs, English Bulldog, and Cavalier King Charles Spaniels) versus two mesaticephalic breeds (Labrador retrievers and Jack Russell Terriers); and (2) test associations between tympanic bulla morphology and presence of middle ear effusion. Archived head CT scans for the above dog breeds were retrieved and a single observer measured tympanic bulla shape (width:height ratio), wall thickness, position relative to the temporomandibular joint, and relative volume (volume:body weight ratio). A total of 127 dogs were sampled. Cavalier King Charles Spaniels had significantly flatter tympanic bullae (greater width:height ratios) versus Pugs, English Bulldogs, Labrador retrievers, and Jack Russell terriers. French Bulldogs and Pugs had significantly more overlap between tympanic bullae and temporomandibular joints versus other breeds. All brachycephalic breeds had significantly lower tympanic bulla volume:weight ratios versus Labrador retrievers. Soft tissue attenuating material (middle ear effusion) was present in the middle ear of 48/100 (48%) of brachycephalic breeds, but no significant association was found between tympanic bulla CT measurements and presence of this material. Findings indicated that there are significant interbreed variations in tympanic bulla morphology, however no significant relationship between tympanic bulla morphology and presence of middle ear effusion could be identified.

IMPROVING CONSPICUITY OF THE CANINE GASTROINTESTINAL WALL USING DUAL PHASE CONTRAST-ENHANCED COMPUTED TOMOGRAPHY: A RETROSPECTIVE CROSS-SECTIONAL STUDY.

Gastrointestinal (GI) disease is a common clinical complaint in small animal patients; computed tomography (CT) examinations enable a global overview of the GI tract and associated structures. Previously, the GI wall has been reportedly identified from serosa to mucosa in 77% of standard postcontrast CT studies and wall layers seen in ultrasound have not been distinguished. Inconsistent strong contrast enhancement of the inner layer of the GI mucosal surface was noted on dual phase CT studies acquired in our institution, which increased the visibility of the GI tract and disease processes. The aim of this retrospective, observational, cross-sectional study was to determine the optimal portal vein attenuation for maximizing GI wall conspicuity using dual phase contrast-enhanced CT. Patients with abdominal CT for a non-GI related disease were included. In a pilot study, 175 GI segments from 35 CT studies were graded for presence of mucosal surface enhancement (MSE). The strongest mucosal surface enhancement grade correlated with portal vein attenuation of 43-150 HU; this value was used as inclusion criterion in the main study. A total of 441 GI segments were evaluated in 42 CT studies postcontrast for GI wall conspicuity. The GI wall was conspicuous in 56.7% precontrast, 84.5% at 30s, and 77.3% late postcontrast; 4.7% of segments were removed due to motion blur. At 30 s distinct mucosal surface enhancement was seen in the small intestine and gastric mucosal surface enhancement was poor. Findings supported the use of dual phase contrast-enhanced CT for improving conspicuity of the GI wall.

Differential diagnoses, investigation, and management of a periocular swelling close to the nasolacrimal duct in a horse - A case report of Dacryops.

To describe the differential diagnoses, investigation, and management of a periocular swelling close to the nasolacrimal duct in a horse that was consistent with a nasolacrimal duct dacryops (lacrimal cyst). A 16-year-old gelding, Connemara cross presented with a history of a periocular swelling rostroventral medial to the right eye that had been sampled by the referring veterinary surgeon. A cystic lesion was diagnosed following standing computed tomography. Surgical removal of the cystic lesion was performed, and the tissue was submitted for histopathologic and immunohistochemical examination. Surgical removal of the cyst was curative, and there was no recurrence of clinical signs 7 months later. There was a small amount of mineralized material in the center of the cyst. Histopathologic and immunohistochemical examination confirmed a nasolacrimal duct cyst. Dacryops can form in horses as well as other species and appears to have a favorable outcome if surgically removed.

TRUNCATION ARTIFACT IN MAGNETIC RESONANCE IMAGES OF THE CANINE SPINAL CORD.

The truncation artifact in magnetic resonance (MR) images is a line of abnormal signal intensity that occurs parallel to an interface between tissues of markedly different signal intensity. In order to demonstrate the truncation artifact in sagittal images of the canine spinal cord and the effect of changing spatial resolution, we conducted an experimental in vitro study. A section of fixed canine spinal cord was imaged using a 1.5T magnet. Spatial resolution was increased by increasing the acquisition matrix and reconstruction matrix, producing series of T2-weighted (T2w) images with the following pixel sizes: A, 1.6 (vertical) × 2.2 mm2 (horizontal); B, 1.2 × 1.7 mm2 ; C, 0.8 × 1.1 mm2 ; D, 0.4 × 0. 6 mm2 . Plots of mean pixel value across the cord showed variations in signal intensity compatible with truncation artifact, which appeared as a single, wide central hyperintense zone in low-resolution images and as multiple narrower zones in high spatial resolution images. Even in images obtained using the highest spatial resolution available for the MR system, the edge of the spinal cord was not accurately defined and the central canal was not visible. The experiment was repeated using an unfixed spinal cord specimen with focal compression applied to mimic a pathologic lesion. Slight hyperintensity was observed within the spinal cord at the site of compression although the cord was normal histologically. Results of this study suggest that caution should be applied when interpreting hyperintensity affecting the spinal cord in T2w sagittal images of clinical patients because of the possibility that the abnormal signal could represent a truncation artifact.

Computed tomographic findings in 15 dogs with eosinophilic bronchopneumopathy.

Eosinophilic bronchopneumopathy is a disease characterized by the infiltration of the lung and bronchial mucosa by eosinophils. The aim of the present study was to describe the CT findings in a large series of dogs with confirmed diagnosis of eosinophilic bronchopneumopathy. Computed tomographic scans of 15 dogs with confirmed diagnosis of eosinophilic bronchopneumopathy were evaluated retrospectively by two boarded radiologists who reached a consensus. Abnormalities were identified in 14/15 (93%) dogs, including pulmonary parenchymal abnormalities in 14/15 (93%) dogs, bronchial wall thickening in 13 (87%) dogs, which was considered marked in eight (53%), plugging of the bronchial lumen by mucus/debris in 11 (73%) dogs, and bronchiectasis in nine (60%) dogs. Pulmonary nodules were identified in 5/15 (33%) dogs including one dog with a mass. All dogs with a nodular lung pattern had additional abnormalities. Lymphadenopathy was present in 10 dogs (67%). Lesions associated with eosinophilic bronchopneumopathy are variable and heterogeneous and encompass a wider variety of computed tomographic features than reported previously. Computed tomographic images were abnormal in the majority of affected dogs, hence CT is a useful modality to characterize the nature and distribution of thoracic lesions in dogs with eosinophilic bronchopneumopathy.

X-ray attenuation of the liver and kidney in cats considered at varying risk of hepatic lipidosis.

X-ray attenuation of the liver has been measured using computed tomography (CT) and reported to decrease in cats with experimentally induced hepatic lipidosis. To assess the clinical utility of this technique, medical records and noncontrast CT scans of a series of cats were retrospectively reviewed. A total of 112 cats met inclusion criteria and were stratified into three hepatic lipidosis risk groups. Group 1 cats were considered low-risk based on no history of inappetence or weight loss, and normal serum chemistry values; Group 2 cats were considered intermediate risk based on weight loss, serum hepatic enzymes above normal limits, or reasonably controlled diabetes mellitus; and Group 3 cats were considered high risk based on poorly controlled diabetes mellitus due to hypersomatotropism. Mean CT attenuation values (Hounsfield units, HU) were measured using regions of interest placed within the liver and cranial pole of the right kidney. Hepatic and renal attenuation were weakly positively correlated with each other (r = 0.2, P = 0.03) and weakly negatively correlated with body weight (r = -0.21, P = 0.05, and r = -0.34, P = 0.001, respectively). Mean (SD) hepatic and renal cortical attenuation values were 70.7 (8.7) HU and 49.6 (9.2) HU for Group 1 cats, 71.4 (7.9) HU and 48.6 (9.1) HU for Group 2, and 68.9 (7.6) HU and 47.6 (7.2) HU for Group 3. There were no significant differences in hepatic or renal attenuation among groups. Findings indicated that CT measures of X-ray attenuation in the liver and kidney may not be accurate predictors of naturally occurring hepatic lipidosis in cats.

Appearance of the canine meninges in subtraction magnetic resonance images.

The canine meninges are not visible as discrete structures in noncontrast magnetic resonance (MR) images, and are incompletely visualized in T1-weighted, postgadolinium images, reportedly appearing as short, thin curvilinear segments with minimal enhancement. Subtraction imaging facilitates detection of enhancement of tissues, hence may increase the conspicuity of meninges. The aim of the present study was to describe qualitatively the appearance of canine meninges in subtraction MR images obtained using a dynamic technique. Images were reviewed of 10 consecutive dogs that had dynamic pre- and postgadolinium T1W imaging of the brain that was interpreted as normal, and had normal cerebrospinal fluid. Image-anatomic correlation was facilitated by dissection and histologic examination of two canine cadavers. Meningeal enhancement was relatively inconspicuous in postgadolinium T1-weighted images, but was clearly visible in subtraction images of all dogs. Enhancement was visible as faint, small-rounded foci compatible with vessels seen end on within the sulci, a series of larger rounded foci compatible with vessels of variable caliber on the dorsal aspect of the cerebral cortex, and a continuous thin zone of moderate enhancement around the brain. Superimposition of color-encoded subtraction images on pregadolinium T1- and T2-weighted images facilitated localization of the origin of enhancement, which appeared to be predominantly dural, with relatively few leptomeningeal structures visible. Dynamic subtraction MR imaging should be considered for inclusion in clinical brain MR protocols because of the possibility that its use may increase sensitivity for lesions affecting the meninges.

Depletion of SAM leading to loss of heterochromatin drives muscle stem cell ageing.

The global loss of heterochromatin during ageing has been observed in eukaryotes from yeast to humans, and this has been proposed as one of the causes of ageing. However, the cause of this age-associated loss of heterochromatin has remained enigmatic. Here we show that heterochromatin markers, including histone H3K9 di/tri-methylation and HP1, decrease with age in muscle stem cells (MuSCs) as a consequence of the depletion of the methyl donor S-adenosylmethionine (SAM). We find that restoration of intracellular SAM in aged MuSCs restores heterochromatin content to youthful levels and rejuvenates age-associated features, including DNA damage accumulation, increased cell death, and defective muscle regeneration. SAM is not only a methyl group donor for transmethylation, but it is also an aminopropyl donor for polyamine synthesis. Excessive consumption of SAM in polyamine synthesis may reduce its availability for transmethylation. Consistent with this premise, we observe that perturbation of increased polyamine synthesis by inhibiting spermidine synthase restores intracellular SAM content and heterochromatin formation, leading to improvements in aged MuSC function and regenerative capacity in male and female mice. Together, our studies demonstrate a direct causal link between polyamine metabolism and epigenetic dysregulation during murine MuSC ageing.

Primary androgen deprivation (AD) followed by active surveillance (AS) for newly diagnosed prostate cancer (PC): A retrospective study.

BACKGROUND: Active surveillance (AS) is only recommended for Low-Risk prostate cancer (PC) with <34% biopsies positive. Studies describing the long-term outcome of men treated with androgen deprivation (AD) followed by AS are sparse. MATERIALS AND METHODS: One hundred two men were treated with 12 months of AD in a medical oncology clinic specializing in PC between 1998 and 2007 and were followed for a median of 7.25 years. The biopsy complete response rate after AD and the incidence of disease progression while on subsequent AS was assessed. Baseline age, D'Amico risk category, PSA velocity, percentage core biopsies, and prostate volume were evaluated as potential predictors of disease progression. RESULTS: D'Amico risk category for the 102 men: Low: n = 22, Intermediate: n = 30, and High: n = 50. Medians: Age 67.3, PSA 7.8, Gleason 3 + 4, >50% core biopsies positive, stage T1c. Seventy men had a clear biopsy and 31 of these had disease progression leading to additional treatment after a median of 52 months. D'Amico risk category of the 57 men with a positive biopsy after AD or disease progression on AS was: Low: n = 4 (18%), Intermediate: n = 16 (53%), and High: n = 37 (74%). No PC deaths occurred. Three men had clinical progression. In stepwise logistic regression analysis only higher D'Amico risk category and lower prostate volume predicted disease progression. CONCLUSIONS: Despite a high prevalence of ≥50% core biopsies positive at baseline, AD induces durable remissions in most men with Low-Risk and about half with Intermediate-Risk PC.

Variations in magnetic resonance venographic anatomy of the dorsal dural venous sinus system in 51 dogs.

Variations in intracranial dural venous sinus anatomy have been widely reported in humans, but there have been no studies reporting this in dogs. The purpose of this retrospective study was to describe variations in magnetic resonance (MR) venographic anatomy of the dorsal dural venous sinus system in a sample population of dogs with structurally normal brains. Medical records were searched for dogs with complete phase contrast, intracranial MR venograms and a diagnosis of idiopathic epilepsy. Magnetic resonance venograms were retrieved for each dog and characteristics of the dorsal dural sinuses, symmetry of the transverse sinuses and other anatomic variations were recorded. A total of 51 dogs were included. Transverse sinus asymmetry was present in 58.8% of the dogs, with transverse sinus hypoplasia seen in 39.2%, and aplasia in 23.5% of dogs. For 70.6% of dogs, at least one anatomic variation in the dorsal sagittal sinus was observed, including deviation from the midline (33.3%) and collateral branches from either the dorsal sagittal sinus or dorsal cerebral veins (54.9%). In 5 dogs (9.8%) a vessel was also identified running from the proximal transverse sinus to the distal sigmoid sinus, in a similar location to the occipital sinus previously reported in children. Findings from this study indicated that, as in humans, anatomic variations are common in the intracranial dural venous sinus system of dogs. These anatomic variations should be taken into consideration for surgical planning or diagnosis of cerebrovascular disease.

Structure-Based Design and Synthesis of Potent and Selective KRAS G12D Inhibitors.

KRAS G12D mutation has been found in approximately 45% of pancreatic ductal adenocarcinoma (PDAC) cases, making it an attractive therapeutic target. Through structure-based drug design, a series of potent and selective KRAS G12D inhibitors were designed. The lead compound, ERAS-5024, inhibited ERK1/2 phosphorylation and cell proliferation in three-dimensional Cell-Titer Glo assays in AsPC-1 PDAC cells with single-digit nanomolar potency and caused tumor regression in the in vivo efficacy studies. We describe here the details of the design and synthesis program that led to the discovery of ERAS-5024.

Photoacoustic angiography of the breast.

PURPOSE: The authors report a noninvasive technique and instrumentation for visualizing vasculature in the breast in three dimensions without using either ionizing radiation or exogenous contrast agents, such as iodine or gadolinium. Vasculature is visualized by virtue of its high hemoglobin content compared to surrounding breast parenchyma. The technique is compatible with dynamic contrast-enhanced studies. METHODS: Photoacoustic sonic waves were stimulated in the breast with a pulsed laser operating at 800 nm and a mean exposure of 20 mJ/pulse over an area of approximately 20 cm2. These waves were subsequently detected by a hemispherical array of piezoelectric transducers, the temporal signals from which were filtered and backprojected to form three-dimensional images with nearly uniform k-space sampling. RESULTS: Three-dimensional vascular images of a human volunteer demonstrated a clear visualization of vascular anatomy with submillimeter spatial resolution to a maximum depth of 40 mm using a 24 s image acquisition protocol. Spatial resolution was nearly isotropic and approached 250 microm over a 64 x 64 x 50 mm field of view. CONCLUSIONS: The authors have successfully visualized submillimeter breast vasculature to a depth of 40 mm using an illumination intensity that is 32 times less than the maximum permissible exposure according to the American National Standard for Safe Use of Lasers. Clearly, the authors can achieve greater penetration depth in the breast by increasing the intensity and the cross-sectional area of the illumination beam. Given the 24 s image acquisition time without contrast agent, dynamic, contrast-enhanced, photoacoustic breast imaging using optically absorbing contrast agents is conceivable in the future.

Evaluation of the Effects of Synovial Multipotent Cells on Deep Digital Flexor Tendon Repair in a Large Animal Model of Intra-Synovial Tendinopathy.

Intra-synovial tendon injuries are a common orthopedic problem with limited treatment options. The synovium is a specialized connective tissue forming the inner encapsulating lining of diarthrodial joints and intra-synovial tendons. It contains multipotent mesenchymal stromal cells that render it a viable source of progenitors for tendon repair. This study evaluated the effects of autologous implantation of cells derived from normal synovium (synovial membrane cells [SMCs]) in augmenting repair in an ovine model of intra-synovial tendon injury. For this purpose, synovial biopsies were taken from the right digital flexor tendon sheath following creation of a defect to the lateral deep digital flexor tendon. Mononuclear cells were isolated by partial enzymatic digestion and assessed for MSC characteristics. Cell tracking and tendon repair were assessed by implanting 5 × 106 cells into the digital flexor tendon sheath under ultrasound guidance with the effects evaluated using magnetic resonance imaging and histopathology. Synovial biopsies yielded an average 4.0 × 105 ± 2.7 × 105 SMCs that exhibited a fibroblastic morphology, variable osteogenic, and adipogenic responses but were ubiquitously strongly chondrogenic. SMCs displayed high expression of CD29 with CD271NEGATIVE and MHC-IILOW cell-surface marker profiles, and variable expression of CD73, CD90, CD105, CD166, and MHC-I. Implanted SMCs demonstrated engraftment within the synovium, though a lack of repair of the tendon lesion over 24 weeks was observed. We conclude healthy synovium is a viable source of multipotent cells, but that the heterogeneity of synovium underlies the variability between different SMC populations, which while capable of engraftment and persistence within the synovium exhibit limited capacity of influencing tendon repair. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:128-138, 2020.