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Objective: The objective of this study was to determine the anatomical relationship of the congenital calcaneal bursae in the bovine, and describe the computed tomography (CT), endoscopic and gross anatomy of these bursae., Study Design: Ex vivo experimental., Sample Population: Eighteen clinically normal cadaver bovine hindlimbs., Methods: Intrasynovial injection of iodinated contrast and methylene blue into the intertendinous calcaneal bursa (ICB) (n = 16) or gastrocnemius calcaneal bursa (GCB) (n = 2). Limbs were imaged post-contrast injection using multidetector CT. Endoscopic examination of the ICB was performed on two randomly selected limbs. All limbs underwent gross anatomical dissection., Results: The anatomy of the congenital calcaneal bursae was consistent between CT imaging, endoscopic examination and gross dissection. The ICB and GCB were two separate synovial structures with no communication in all limbs. The distal and proximal extent of the ICB, defined as the distance from the point of tuber calcanei to the distal/proximal aspect of the ICB, was (median [IQR]) 7.4 (7.4 to 7.8) cm distally and 5.4 (4.7 to 6.0) cm proximally., Conclusion: Positive contrast CT and gross anatomical dissection revealed no communication between the congenital calcaneal bursae in any limb. Routine bursoscopy allowed complete endoscopic examination of the ICB. The proximal extent of the ICB is shorter than the distal extent. The use of a collective term for these bursae should be avoided in the bovine, as the ICB and the GCB are two separate synovial structures with no communication., Clinical Significance: Knowledge of distinct anatomy and relationship between the congenital calcaneal bursae in the bovine may facilitate diagnosis and treatment of disorders affecting the region of tuber calcanei, including septic bursitis and osteomyelitis., (© 2023 The Authors. Veterinary Surgery published by Wiley Periodicals LLC on behalf of American College of Veterinary Surgeons.)

Objective: To determine long term outcomes of nonracing equines athletes treated for short incomplete proximal sagittal fractures of the proximal phalanx (SIPSFP1) by lag screw fixation., Study Design: Retrospective study., Sample Population: Thirty-one horses., Methods: Medical records from horses with an SIPSFP1 (2008-2014) were reviewed. Long-term (≥12 months) outcomes were assessed with telephone interviews and clinical and radiographic examinations., Results: Warmblood was the predominant breed in cases included in the study. Among horses with long-term interview information, 27 of 31 returned to previous athletic activity level. In total, 15 horses with 19 fractures had clinical and radiographic assessment after a minimum of 12 months. Among those, nine of 15 horses were sound at the trot, and six of 15 were mildly lame. Complete radiographic healing was confirmed in six limbs, and the facture line was evident in 13. The position of the proximal screw was not associated with radiographic fracture healing or return to soundness., Conclusion: Most horses treated for SIPSFP1 with lag screw fixation returned to previous activity levels, although radiographic fracture healing remained incomplete 12 months or more after surgery., Clinical Significance: Lag screw fixation is a valid treatment for horses not used for racing that are experiencing an SIPSFP1 and results in a high rate of return to intended use, although complete radiographic fracture healing cannot be expected., (© 2019 The American College of Veterinary Surgeons.)

Magnetic resonance imaging fat suppression techniques are commonly used for diagnosis of canine spinal disease, however, studies comparing different techniques are currently lacking. This retrospective, methods comparison study aimed to evaluate water excitation and STIR MRI pulse sequences for visualization of canine lumbar spinal nerve roots. For inclusion, all dogs had to have dorsal planar MRI studies of the lumbar spine using both sequences. Visual grading analysis was used for scoring the following five criteria: degree of fat suppression; nerve root visualization; subjective tissue contrast; presence of noise; and overall better image quality. Scores were independently recorded by three board-certified veterinary radiologists on two separate occasions, 3-6 weeks apart. A total of 90 dogs were sampled. A two-tailed t-test showed that there were significant differences in all scored parameters (P < 0.00001), with the exception of noise (P = 0.47343), and that the water excitation sequence scored higher in all cases excluding noise. A Gwets AC kappa for intraobserver and interobserver reliability showed "almost perfect" agreement for the nerve roots in both tests (intra: k = 0.88; inter: k = 0.90). Intraobserver agreement was "substantial" for the degree of fat suppression (k = 0.68), subjective tissue contrast (k = 0.75), and overall better image quality (k = 0.76) and it was "fair" for the noise (k = 0.46). Interobserver agreement was "moderate" for the degree of fat suppression (k = 0.53), subjective tissue contrast (k = 0.63), and overall better image quality (k = 0.66) and "slight" for noise (k = 0.25). These findings supported using the water excitation pulse sequence for fat-suppressed MRI of canine lumbar spinal nerve roots., (© 2019 American College of Veterinary Radiology.)

The requirement to pack the sulcus of the equine foot as an aid to diagnostic interpretation before acquisition of dorsoproximal-palmarodistal oblique projections is debatable. The purpose of this study was to investigate the benefit of packing the sulcus in the assessment of normal anatomy. 23 cadaver limbs were radiographed in a podoblock (https://www.podoblock.com/products-page/podoblock/podoblock/) A non-packed image (NP) and a packed image (P) of the same foot were acquired. The image quality of P was graded against the reference NP by five observers, where -1=P was superior, 0=no difference between P and NP, and +1=NP was superior. Four anatomical criteria were used: the distal solar margin of the distal phalanx (DP), the vascular channels of DP, the palmar aspect of the distal interphalangeal joint and the articulation of the navicular bone with DP. A total Visual Grading Analysis Score of 0.28 indicates a preference for NP images. Packing was of benefit in only 10.8 per cent of cases. While judicious high-quality packing may be of benefit in a minority of cases, the routine packing of the sulcus in equine radiography was not found to be of benefit in the assessment of anatomical features in this study., Competing Interests: Competing interests: Not required., (© British Veterinary Association 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Juvenile bovine patients who present with clinical signs of lameness are commonly evaluated using radiographic techniques both within a hospital setting and in a farm environment. The radiographic development of the juvenile bovine skeleton is currently poorly documented. In this study, the limbs of four heifer calves were sequentially radiographed to assess development of the juvenile bovine appendicular skeleton in the first 12 months of life. Images were acquired at three weeks, three months, six months, nine months and one year of age. The normal radiographic anatomy of the fore limbs and hindlimbs and the changes over the first 12 months are described. The majority of physes remain open throughout this period, with the exception of the proximal physes of the proximal and middle phalanges, the proximal radial physis, and the proximal humeral physis which close radiographically between 9 months and 12 months of age, and fusion of the fourth and central tarsal bones occurs between 9 months and 12 months of age. The results of this study may aid in differentiating normal and abnormal anatomy in the juvenile bovine limb., (British Veterinary Association.)

OBJECTIVE To determine the size of the left and right kidneys by use of CT in dogs of various breeds without evidence of renal disease. DESIGN Retrospective, observational study. ANIMALS 21 client-owned dogs. PROCEDURES Renal length, diameter of the abdominal aorta, and length of the L2 vertebral body were measured independently on multiplanar reformatted non-contrast-enhanced CT images by 3 observers at 3 time points. Intraobserver and interobserver agreement for renal length were determined. Associations of renal length with body weight, aorta diameter, and L2 vertebral body length were assessed by calculation of Pearson correlation coefficients and 95% confidence intervals. Renal measurements were normalized to patient size by calculating renal length-to-aorta diameter and renal length-to-L2 vertebral body length ratios for comparison with previously published radiographic and ultrasonographic measurements. RESULTS All kidneys were identified and measured on CT images by all observers. Intraobserver and interobserver agreement were excellent. Body weight, aorta diameter, and length of the L2 vertebral body were significantly correlated with renal length. Renal length-to-aorta diameter and renal length-to-L2 vertebral body length ratios (7.4 and 2.7, respectively) fell within the ranges of previously published values for these measurements. CONCLUSIONS AND CLINICAL RELEVANCE As CT becomes more widely available in general practice, knowledge of typical renal measurements and anatomic ratios obtained with this modality in dogs may be useful. A prospective study with a larger population of dogs, ideally including formulation of a reference range, is needed.

Pyoderma gangrenosum (PG) is a rare inflammatory neutrophilic dermatosis often misdiagnosed. It is uncommon in infants and children accounting for 4% of cases. A one-year-old male in paediatric ICU ventilated for bronchopneumonia was referred with ulcerated areas on his neck and axilla corresponding to sites of recent removal of central and arterial lines. Examination revealed areas of deep ulceration with violaceous undermined borders in keeping with PG. This was supported by a skin biopsy showing a neutrophilic infiltrate in the deeper dermis. Topical clobetasol propionate was commenced and a dramatic improvement within 24 hours noted. Blood results showed a leucocytosis of 29.7; a differential WCC showed toxic granulation in neutrophils with myeloid left shift; immunoglobulins showed elevated IgG 23 and IgA 4.86. The elevated WCC made us consider a leukaemic trigger; however, they settled with treatment of the underlying infection. PG in children is more likely to have an atypical distribution involving the head and neck (26.6%) or buttocks (15%). An interesting feature in this case is the presence of pathergy, a term used to describe the induction or exacerbation of PG at sites of iatrogenic or incidental trauma. It is seen in 31% of patients with PG., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-β (Aβ) production by shifting endoproteolytic amyloid-β protein precursor (AβPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aβ production in awake and freely moving AβPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aβ concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aβ levels while treatment with the M1 antagonist dicyclomine increased ISF Aβ levels reaching significance within 120 minutes of treatment. The reduction in Aβ levels was associated with PKCα and ERK activation resulting in increased levels of the α-secretase ADAM17 and a shift in AβPP processing toward the non-amyloidogenic processing pathway. In contrast, treatment with the M1 receptor antagonist dicyclomine caused a decrease in levels of phosphorylated ERK that was independent of PKCα, and led to an elevation of β-secretase levels associated with increased amyloidogenic AβPP processing. The results of this study demonstrate rapid effects of in vivo M1 receptor modulation on the ISF pool of Aβ and suggest that intracerebral microdialysis with retrodialysis is a useful technical approach for monitoring acute treatment effects of muscarinic receptor modulators on AβPP/Aβ metabolism.

Keratoacantnoma centrifugum marginatum (KCM) is a rare variant of keratoacantnoma, with > 40 cases reported world wide. Spontaneous resolution of KCM is very rare. To our knowledge, this is the first case of KCM with spontaneous resolution as documented by serial photographs., (© 2014 British Association of Dermatologists.)

Soluble oligomeric amyloid β peptide (Aβ) generated from processing of the amyloid precursor protein (APP) plays a central role in the pathogenesis of Alzheimer's Disease (AD) and through actions at glutamatergic synapses affects excitability and plasticity. The physiological control of APP processing is not fully understood but stimulation of synaptic NMDA receptors (NMDAR) can suppress Aβ levels through an ERK-dependent increase in α-secretase activity. AMPA-type glutamate receptors (AMPAR) couple to ERK phosphorylation independently of NMDAR activation raising the possibility that stimulation of AMPAR might similarly promote non-amyloidogenic APP processing. We have tested this hypothesis by investigating whether AMPAR directly regulate APP processing in cultured mouse cortical neurons, by analyzing APP C-terminal fragments (CTFs), soluble APP (sAPP), Aβ levels, and cleavage of an APP-GAL4 reporter protein. We report that direct stimulation of AMPAR increases non-amyloidogenic α-secretase-mediated APP processing and inhibits Aβ production. Processing was blocked by the matrix metalloproteinase inhibitor TAPI-1 but was only partially dependent on Ca(2+) influx and ERK activity. AMPAR can therefore, be added to the repertoire of receptors that couple to non-amyloidogenic APP processing at glutamatergic synapses and thus pharmacological targeting of AMPAR could potentially influence the development and progression of Aβ pathology in AD.

Notch signaling is an evolutionarily conserved pathway, which is fundamental for neuronal development and specification. In the last decade, increasing evidence has pointed out an important role of this pathway beyond embryonic development, indicating that Notch also displays a critical function in the mature brain of vertebrates and invertebrates. This pathway appears to be involved in neural progenitor regulation, neuronal connectivity, synaptic plasticity and learning/memory. In addition, Notch appears to be aberrantly regulated in neurodegenerative diseases, including Alzheimer's disease and ischemic injury. The molecular mechanisms by which Notch displays these functions in the mature brain are not fully understood, but are currently the subject of intense research. In this review, we will discuss old and novel Notch targets and molecular mediators that contribute to Notch function in the mature brain and will summarize recent findings that explore the two facets of Notch signaling in brain physiology and pathology., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This is a study of the interaction between the two NMDA neurotransmitter receptor subtypes, NR1/NR2A and NR1/NR2B, and amyloid precursor protein (APP) 695, the major APP variant expressed in neurones. APP695 co-immunoprecipitated with assembled NR1-1a/NR2A and NR1-1a/NR2B NMDA receptors following expression in mammalian cells. Single NR1-1a, NR1-2a, NR1-4b(c-Myc), or NR2 subunit transfections revealed that co-association of APP695 with assembled NMDA receptors was mediated via the NR1 subunit; it was independent of the NR1 C1, C2, and C2' cassettes and, the use of an NR1-2a(c-Myc)-trafficking mutant suggested that interaction between the two proteins occurs in the endoplasmic reticulum. The use of antibodies directed against extracellular and intracellular NR2 subunit epitopes for immunoprecipitations suggested that APP/NMDA receptor association was mediated via N-terminal domains. Anti-APP antibodies immunoprecipitated NR1, NR2A, and NR2B immunoreactive bands from detergent extracts of mammalian brain; reciprocally, anti-NR1 or anti-NR2A antibodies co-immunoprecipitated APP immunoreactivity. Immune pellets from brain were sensitive to endoglycosidase H suggesting that, as for heterologous expression, APP and NMDA receptor association occurs in the endoplasmic reticulum. Co-expression of APP695 in mammalian cells resulted in enhanced cell surface expression of both NR1-1a/NR2A and NR1-1a/NR2B NMDA receptors with no increase in total subunit expression. These findings are further evidence for a role of APP in intracellular trafficking mechanisms. Further, they provide a link between two major brain proteins that have both been implicated in Alzheimer's disease.

Altered amyloid precursor protein (APP) processing leading to increased production and oligomerization of Abeta may contribute to Alzheimer's disease (AD). Understanding how APP processing is regulated under physiological conditions may provide new insights into AD pathogenesis. Recent reports demonstrate that excitatory neural activity regulates APP metabolism and Abeta levels, although understanding of the molecular mechanisms involved is incomplete. We have investigated whether NMDA receptor activity regulates APP metabolism in primary cultured cortical neurons. We report that a pool of APP is localized to the postsynaptic compartment in cortical neurons and observed partial overlap of APP with both NR1 and PSD-95. NMDA receptor stimulation increased nonamyloidogenic alpha-secretase-mediated APP processing, as measured by a 2.5-fold increase in cellular alpha-C-terminal fragment (C83) levels after glutamate or NMDA treatment. This increase was blocked by the NMDA receptor antagonists d-AP5 and MK801 but not by the AMPA receptor antagonist CNQX or the L-type calcium channel blocker nifedipine, was prevented by chelation of extracellular calcium, and was blocked by the alpha-secretase inhibitor TAPI-1. Cotreatment of cortical neurons with bicuculline and 4-AP, which stimulates glutamate release and activates synaptic NMDA receptors, evoked an MK801-sensitive increase in C83 levels. Furthermore, NMDA receptor stimulation caused a twofold increase in the amount of soluble APP detected in the neuronal culture medium. Finally, NMDA receptor activity inhibited both Abeta1-40 release and Gal4-dependent luciferase activity induced by beta-gamma-secretase-mediated cleavage of an APP-Gal4 fusion protein. Altogether, these data suggest that calcium influx through synaptic NMDA receptors promotes nonamyloidogenic alpha-secretase-mediated APP processing.

Background: Proteus syndrome is a rare, sporadic overgrowth disorder for which the underlying genetic defect remains unknown. Although the clinical course is well-described there is no systematic histopathological description of the lesional pathology., Objective: To describe the histopathological features encountered in a series of patients with Proteus syndrome from a single centre., Methods: Patients with Proteus syndrome who had undergone therapeutic surgical resection or biopsy were identified from a database and the histopathological findings were reviewed, with particular regard to descriptive features of the underlying tissue abnormality., Results: There were 18 surgical specimens from nine patients, median age 4 years (range 1-9), classified into four main categories: soft-tissue swellings (lipomatous lesions), vascular anomalies (vascular malformation and haemangioma), macrodactyly (hamartomatous overgrowth) and others (sebaceous naevus and nonspecific features). In all cases, the clinical features of overgrowth were due to increased amounts of disorganized tissue, indicating a hamartomatous-type defect in which normal tissue constituents were present, but with an abnormal distribution and architecture. Vascular malformations represented a prominent category of lesions, accounting for 50% of the specimens, predominantly comprising lymphatic and lymphovascular malformations. No malignancy or cytological atypia was identified in any case., Conclusions: The histopathological features of lesions resected from children with Proteus syndrome predominantly include hamartomatous mixed connective tissue lesions, benign neoplasms such as lipomata, and lymphatic-rich vascular malformations.

Background: The incidence of skin cancer, both melanoma and nonmelanoma skin cancer (NMSC), is rising throughout the world. The evaluation of trends in skin cancer will allow better planning of the future development of skin cancer services., Objectives: Using data collected from the Northern Ireland Cancer Registry (NICR), the incidence of the three major cutaneous cancers, basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM), was determined and the workload associated with their management assessed., Methods: The records of patients with a first diagnosis of BCC, SCC or MM occurring between 1993 and 2002 were retrieved from the NICR database. The annual age- and sex-adjusted incidence rates of all three skin cancers were computed per 100 000 person-years by direct standardization according to the European Standard Population. Trends in incidence were estimated by calculating the estimated annual percentage change using Microsoft Excel. For patients registered with the NICR as having BCC, SCC or MM, the number of pathological reports where malignant samples had been examined was counted and then summed to provide the number of specimens examined each year between 1993 and 2004., Results: For all three cancers the age-specific rates for both males and females increased with age, except for MM in men aged 75 years and over, where the rates were seen to decrease. Over the 12-year period there was a 62% increase in the overall number of skin cancer samples processed by local pathology laboratories and a 20% increase in the number of patients. These data highlight the fact that many patients will have more than one skin cancer, which reinforces the benefit in collecting data for both patient and sample numbers in order to obtain a true reflection of the workload. The data have also shown that more affluent men and women have higher rates of BCC and MM than their less affluent counterparts., Conclusions: In view of the data presented it is clear that management of NMSC and MM will impose significant demands on services in the years ahead. This will impact on the entire multidisciplinary team. Future planning, in terms of manpower and resources, will prove essential if we are to remain in a position to manage our patients with these malignant tumours appropriately.