The prognosis for return to athletic function for Thoroughbred racehorses in Hong Kong with injuries to the palmaroproximal aspect of the metacarpus diagnosed using low-field magnetic resonance imaging.

OBJECTIVE: To evaluate and compare the prognosis for Thoroughbred racehorses to return to galloping and racing with injuries to the palmaroproximal metacarpus diagnosed with MRI. ANIMALS: 29 flat racing Thoroughbreds at the Hong Kong Jockey Club that underwent MRI between 2014 and 2022. METHODS: Clinical, radiographic, ultrasonographic, and MRI reports were collected from veterinary clinical records, and these were combined with training and racing data. Horses were categorized on the basis of MRI diagnosis: (1) proximal suspensory ligament (PSL) involvement only, (2) PSL and concurrent proximal third metacarpal (MC3) bone involvement, and (3) proximal MC3 bone involvement only. The following were compared for prognosis for return to athletic function: return to galloping or racing, and reinjury. RESULTS: Overall, the prognosis for return to athletic function was fair, with 92% (22/24; P = .53) and 67% (16/24; P = .73) of horses returning to galloping and racing, respectively. There was a relatively low reinjury rate, with 18% (4/22) of horses reinjuring. Horses with concurrent injury to both the PSL and proximal MC3 bone (Category 2) took longer to return to gallop (median, 116; IQR, 100.5 to 160), when compared with horses having only PSL injury (median, 69; IQR, 43 to 80; P = .04). Of the 4 horses that reinjured, 3 (75%) were horses in Category 2. CLINICAL RELEVANCE: The findings from this study suggest that injuries involving both PSL and proximal MC3 bone concurrently require a longer rehabilitation period than those with PSL involvement alone.

Current management of avascular necrosis of the metacarpal head: a comprehensive literature review.

BACKGROUND: Avascular necrosis (AVN) of the metacarpal head is a rare disease that may lead to progressive destruction of the metacarpophalangeal joint and hand function. This study aimed to describe the epidemiology, possible risk factors, clinical presentation, diagnostic workup, and treatment of the rare condition of avascular necrosis of the metacarpal head. METHODS: Articles were searched using the subject words "Dieterich disease","Mauclaire's disease", and "avascular necrosis of metacarpal head" in the PubMed and Scopus databases. Studies were retained for review after meeting the inclusion criteria. Those outcomes relevant to diagnose and assessing AVN of the metacarpal head and those related to curative management were extracted. RESULTS: The literature search revealed 45 studies with 55 patients. Although the aetiology of osteonecrosis has not been clearly delineated, AVN of the metacarpal head most commonly arises from trauma but other risk factors may also be involved. Plain radiographs are often negative and therefore likely to be missed. Early-stage osteonecrosis of the metacarpal head was best assessed using MRI. Given the rarity of this condition, there is no clear consensus on the treatment. CONCLUSIONS: Avascular necrosis of the metacarpal head should be considered in the differential diagnosis of painful metacarpophalangeal joints. An early understanding of this unusual disease will provide an optimal clinical outcome, restoring joint activity, and resolving pain. Nonoperative treatment cannot cure all patients. Surgical management is based on the patient and lesion characteristics.

Morphological analysis of third metacarpus cartilage and subchondral bone in Thoroughbred racehorses: An ex vivo study.

Racehorses are exposed to repetitive overload during training and competition, causing joint hyperextension, tissue fatigue, and ultimately skeletal failure. Some degree of bone changes, such as sclerosis, are expected in equine athletes, as adaptation to the biomechanical rigors of training and racing. Understanding the imaging characteristics of the equine joint surface and subchondral bone would allow earlier detection of injuries or adaptation, improving prognosis and training programs. This study sought to describe the joint surface structural patterns and the periarticular structures of the third metacarpal bone (MC3). Both forelimbs of eight horses engaged in daily training programs, aged 3-5 years, which were euthanized for reasons unrelated to the metacarpophalangeal (MCP) joints, were collected. Specimens were evaluated through macroscopic inspection, radiography, ultrasonography, and microscopic examinations, such as optical microscopy and microtomography. Analysis of the microtomography images showed that 50% of the samples had higher trabecular thickness in the lateral condyle. Comparison of each imaging examination revealed that ultrasound images were most closely related to the histological examination (p = .29) in terms of sensitivity, while macroscopic and radiographic examinations differed most between evaluators. Finally, the irregularities and modifications observed in the articular cartilage surface and subchondral bone were normal adaptations of the anatomical structures of trained racehorses, which should be considered during clinical examination.

DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation.

BACKGROUND: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2. METHODS: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed. RESULTS: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin. CONCLUSIONS: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.

Singleton-Merten syndrome: A rare cause of femoral head necrosis.

Singleton-Merten syndrome (SMS) is a type I interferonopathy. In this report, we disclose the first-to the best of our knowledge-direct association of SMS with femoral head necrosis (FHN). The following case report presents the condition of a 38-year-old male suffering from SMS with FHN, characterized by acute symptoms and rapid disease progression. As per the recommendations of the Association Research Circulation Osseous (ARCO) and the S3-guidelines, we successfully treated the FHN with core decompression. Our histological results correlate with the changes described in medical literature in patients with SMS and MDA5-knockout in vivo experiments such as osteopenia, widened medullary cavity, and thin cortical bone. Moreover, the conducted immunohistochemistry shows strong CD56 positivity of the osteoblasts and osteocytes, as well as significant CD68 and CD163 positivity of the middle-sized osteoclasts. Collectively, these findings suggest an underlying syndrome in the FHN. A six-month post-operative follow-up revealed complete recovery with the absence of the initial symptoms and ability to resume normal daily activities. Taken together, our findings suggest that SMS is an additional cause of FHN in young adults. Early detection and adequate treatment using well-established joint-preserving techniques demonstrate a favorable improvement of the patient's clinical condition.

Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants.

The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signaling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (Lässig et al., 2015), revealing how ATP turnover helps RIG-I distinguish viral from self-RNA and explaining why a mutation in a motif that slows down ATP hydrolysis causes the autoimmune disease Singleton-Merten syndrome (SMS). Here we show that a different, mechanistically unexplained SMS variant, C268F, which is localized in the ATP-binding P-loop, can signal independently of ATP but is still dependent on RNA. The structure of RIG-I C268F in complex with double-stranded RNA reveals that C268F helps induce a structural conformation in RIG-I that is similar to that induced by ATP. Our results uncover an unexpected mechanism to explain how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP.

Limb bone histology records birth in mammals.

The annual cyclicality of cortical bone growth marks (BGMs) allows reconstruction of some important life history traits, such as longevity, growth rate or age at maturity. Little attention has been paid, however, to non-cyclical BGMs, though some record key life history events such as hatching (egg-laying vertebrates), metamorphosis (amphibians), or weaning (suggested for Microcebus and the hedgehog). Here, we investigate the relationship between non-cyclical BGMs and a stressful biological event in mammals: the moment of birth. In the present study, we histologically examine ontogenetic series of femora, tibiae and metapodia in several extant representatives of the genus Equus (E. hemionus, E. quagga and E. grevyi). Our analysis reveals the presence of a non-cyclical growth mark that is deposited around the moment of birth, analogous to the neonatal line described for teeth. We therefore refer to it as neonatal line. The presence of this feature within the bone cross-section agrees with a period of growth arrest in newborn foals regulated by the endocrine system. The neonatal line is accompanied by modifications in bone tissue type and vascularization, and has been identified in all bones studied and at different ontogenetic ages. Our discovery of a non-cyclical BGM related to the moment of birth in mammals is an important step towards the histological reconstruction of life histories in extant and fossil equids.

Subchondral bone morphology in the metacarpus of racehorses in training changes with distance from the articular surface but not with age.

The repetitive large loads generated during high-speed training and racing commonly cause subchondral bone injuries in the metacarpal condyles of racehorses. Adaptive bone modelling leads to focal sclerosis at the site of highest loading in the palmar aspect of the metacarpal condyles. Information on whether and how adaptive modelling of subchondral bone changes during the career of a racehorse is sparse. The aim of this cross-sectional study was to describe the changes in subchondral bone micromorphology in the area of highest loading in the palmar aspect of the metacarpal condyle in thoroughbred racehorses as a function of age and training. Bone morphology parameters derived from micro-CT images were evaluated using principal component analysis and mixed-effects linear regression models. The largest differences in micromorphology were observed in untrained horses between the age of 16 and 20 months. Age and duration of a training period had no influence on tissue mineral density, bone volume fraction or number and area of closed pores to a depth of 5.1 mm from the articular surface in 2- to 4-year-old racehorses in training. Horses with subchondral bone injuries had more pores in cross-section compared with horses without subchondral bone injuries. Differences in bone volume fraction were due to the volume of less mineralised bone. Tissue mineral density increased and bone volume fraction decreased with increasing distance from the articular surface up to 5.1 mm from the articular surface. Further research is required to elucidate the biomechanical and pathophysiological consequences of these gradients of micromorphological parameters in the subchondral bone.

Transcriptomic and behavioural characterisation of a mouse model of burn pain identify the cholecystokinin 2 receptor as an analgesic target.

Burn injury is a cause of significant mortality and morbidity worldwide and is frequently associated with severe and long-lasting pain that remains difficult to manage throughout recovery. We characterised a mouse model of burn-induced pain using pharmacological and transcriptomic approaches. Mechanical allodynia elicited by burn injury was partially reversed by meloxicam (5 mg/kg), gabapentin (100 mg/kg) and oxycodone (3 and 10 mg/kg), while thermal allodynia and gait abnormalities were only significantly improved by amitriptyline (3 mg/kg) and oxycodone (10 mg/kg). The need for relatively high opioid doses to elicit analgesia suggested a degree of opioid resistance, similar to that shown clinically in burn patients. We thus assessed the gene expression changes in dorsal root ganglion neurons and pathophysiological mechanisms underpinning burn injury-induced pain using a transcriptomic approach. Burn injury was associated with significantly increased expression of genes associated with axon guidance, neuropeptide signalling, behavioural defence response and extracellular signalling, confirming a mixed neuropathic and inflammatory aetiology. Notably, among the pain-related genes that were upregulated post-injury was the cholecystokinin 2 receptor (Cckbr), a G protein-coupled receptor known as a pain target involved in reducing opioid effectiveness. Indeed, the clinically used cholecystokinin receptor antagonist proglumide (30 mg/kg) was effective at reversing mechanical allodynia, with additional analgesia evident in combination with low-dose oxycodone (1 mg/kg), including significant reversal of thermal allodynia. These findings highlight the complex pathophysiological mechanisms underpinning burn injury-induced pain and suggest that cholecystokinin-2 receptor antagonists may be useful clinically as adjuvants to decrease opioid requirements and improve analgesic management.

Acquired dermal melanocytosis confined to the palm with a review of published cases of acquired dermal melanocytosis on the hands.

Acquired dermal melanocytosis (ADM) classically occurs on the face. However, extrafacial ADM including palmar ADM has been reported on rare occasions. We present the first report of ADM confined to the palm without ADM lesions in other regions in a 30-year-old Japanese woman. The patient presented with several interspersed macules up to 1 cm in diameter with poorly defined margins, containing faint slate-gray spots 1-2 mm in diameter, on the left palm near the first and second fingers and on the palmar side of the first finger near the metacarpophalangeal joint. These slate-gray spots were prominent on and around palmar creases and on wrinkles on the metacarpophalangeal joint. The patient was right hand-dominant. Histopathological examination revealed scattered spindle-shaped cells with melanin granules and melanophages in the upper to middle dermis. Pigment-bearing spindle-shaped cells were demonstrated to be dermal melanocytes because of positive staining for Melan-A after melanin removal. We review the published work for ADM on the hands.

Unusual cutaneous features associated with a heterozygous gain-of-function mutation in IFIH1: overlap between Aicardi-Goutières and Singleton-Merten syndromes.

Cutaneous lesions described as chilblain lupus occur in the context of familial chilblain lupus or Aicardi-Goutières syndrome. To date, seven genes related to Aicardi-Goutières syndrome have been described. The most recently described encodes the cytosolic double-stranded RNA receptor IFIH1 (also known as MDA5), a key component of the antiviral type I interferon-mediated innate immune response. Enhanced type I interferon signalling secondary to gain-of-function mutations in IFIH1 can result in a range of neuroinflammatory phenotypes including classical Aicardi-Goutières syndrome. It is of note that none of the patients with a neurological phenotype so far described with mutations in this gene was reported to demonstrate cutaneous involvement. We present a family segregating a heterozygous pathogenic mutation in IFIH1 showing dermatological involvement as a prominent feature, variably associated with neurological disturbance and premature tooth loss. All three affected individuals exhibited increased expression of interferon-stimulated genes in whole blood, and the mutant protein resulted in enhanced interferon signalling in vitro, both in the basal state and following ligand stimulation. Our results further extend the phenotypic spectrum associated with mutations in IFIH1, indicating that the disease can be confined predominantly to the skin, while also highlighting phenotypic overlap with both Aicardi-Goutières syndrome and Singleton-Merten syndrome.

Association of catastrophic biaxial fracture of the proximal sesamoid bones with bony changes of the metacarpophalangeal joint identified by standing magnetic resonance imaging in cadaveric forelimbs of Thoroughbred racehorses.

OBJECTIVE: To compare bony changes in the metacarpophalangeal joint (MCPJ) of racehorses with (cases) and without (controls) biaxial proximal sesamoid bone (PSB) fracture as determined by 2 grading scales applied to images of cadaveric forelimbs obtained by means of standing MRI (sMRI). DESIGN: Case-control study. SAMPLE: Forelimbs from 74 Thoroughbred racehorses (21 cases and 53 controls) that were euthanized at a Florida racetrack. PROCEDURES: Both forelimbs were harvested from cases and controls. Each forelimb underwent sMRI to obtain images of the MCPJ. Two grading scales were described and used for image evaluation; one assessed the density of the PSBs, and the other assessed the integrity of the subchondral bone (SCB) plate at the distopalmar aspect of the third metacarpal bone (MC3). Logistic regression was used to compare the grades between case and control limbs. RESULTS: Biaxial PSB fracture was associated with a total PSB grade (sum of lateral and medial PSB grades) ≥ 5 for the fractured limb, total MC3 SCB grade (sum of lateral and medial MC3 SCB grades) ≥ 5 for the contralateral limb, and the presence of orthopedic disease in the contralateral MC3. CONCLUSIONS AND CLINICAL RELEVANCE: For cases with biaxial PSB fracture, the density of the PSBs in the affected limb was greater and the MC3 of the contralateral limb was more likely to have orthopedic disease, compared with those for controls. Further evaluation of sMRI as a screening tool for identification of racehorses at risk of biaxial PSB fracture is warranted.

Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome.

Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.

Transforming growth factor-ß (TGF-ß) expression is increased in the subsynovial connective tissue in a rabbit model of carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is an idiopathic disease that results from increased fibrosis of the subsynovial connective tissue (SSCT). A recent study found overexpression of both transforming growth factor-ß (TGF-ß) and connective tissue growth factor (CTGF) in the SSCT of CTS patients. This study investigated TGF-ß and CTGF expression in a rabbit model of CTS, in which SSCT fibrosis is induced by a surgical injury. Levels of TGF-ß1 and CTGF at 6, 12, 24 weeks after injury were determined by immunohistochemistry A significant increase in TGF-ß1 and a concomitant significant increase in CTGF were found at 6 weeks, in addition to higher cell density compared to normal (all p<0.05), Interestingly, CTGF expression was reduced at 12 and 24 weeks, suggesting that an initial insult results in a time limited response. We conclude that this rabbit model mimics the fibrosis found in human CTS, and may be useful to study pathogenetic mechanisms of CTS in vivo.

Identification of cartilage injury using quantitative multiphoton microscopy.

OBJECTIVE: Cartilage injury can lead to post-traumatic osteoarthritis (PTOA). Immediate post-trauma cellular and structural changes are not widely understood. Furthermore, current cellular-resolution cartilage imaging techniques require sectioning of cartilage and/or use of dyes not suitable for patient imaging. In this study, we used multiphoton microscopy (MPM) data with FDA-approved sodium fluorescein to identify and evaluate the pattern of chondrocyte death after traumatic injury. METHOD: Mature equine distal metacarpal or metatarsal osteochondral blocks (OCBs) were injured by 30 MPa compressive loading delivered over 1 s. Injured and control sites were imaged unfixed and in situ 1 h post-injury with sodium fluorescein using rasterized z-scanning. MPM data was quantified in MATLAB, reconstructed in 3-D, and projected in 2-D to determine the damage pattern. RESULTS: MPM images (600 per sample) were reconstructed and analyzed for cell death. The overall distribution of cell death appeared to cluster into circular (n = 7) or elliptical (n = 4) patterns (p = 0.006). Dead cells were prevalent near cracks in the matrix, with only 26.3% (SE = 5.0%, p < 0.0001) of chondrocytes near cracks being viable. CONCLUSION: This study demonstrates the first application of MPM for evaluating cellular-scale cartilage injury in situ in live tissue, with clinical potential for detecting early cartilage damage. With this technique, we were able to uniquely observe two death patterns resulting from the same compressive loading, which may be related to local variability in matrix structure. These results also demonstrate proof-of-concept MPM diagnostic use in detecting subtle and early cartilage damage not detectable in any other way.

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