Objective comparison of a sit to stand test to the walk test for the identification of unilateral lameness caused by cranial cruciate ligament disease in dogs.

OBJECTIVE: The purpose of this study was to evaluate a sit to stand test with the walk test for the identification of unilateral cranial cruciate ligament rupture in dogs. MATERIALS AND METHODS: Peak vertical force and vertical impulse were measured on a pressure-sensitive walkway, during a sit to stand test and walk test, and in 10 dogs with unilateral cranial cruciate ligament rupture and 18 non-lame dogs. Data collected were used to calculate symmetry indices (SI) of ipsilateral and contralateral hindlimbs (HL), diagonal limb pairs (DLP) and ipsilateral limb pairs (ILP). RESULTS: The symmetry indices of peak vertical force of HL during the walk test and sit to stand test were 100% and 90% sensitive for discriminating lame and non-lame dogs respectively. The symmetry indices of vertical impulse of HLs during the walk test and sit to stand test were 100% and 50% sensitive for discriminating lame and non-lame dogs respectively. Analysis of ipsilateral and diagonal limb pairs did not improve the discrimination in either test. The time taken to collect data from the sit to stand test data was shorter than for the walk test. CLINICAL SIGNIFICANCE: Whilst the sit to stand test required a shorter time for collection of data than the walk test, it did not accurately identify all dogs with lameness associated with CCLR, and thus has relatively limited clinical utility in its tested form.

Ordinal models to analyze strategy sophistication: Evidence from a learning trajectory efficacy study.

Investigators often rely on the proportion of correct responses in an assessment when describing the impact of early mathematics interventions on child outcomes. Here, we propose a shift in focus to the relative sophistication of problem-solving strategies and offer methodological guidance to researchers interested in working with strategies. We leverage data from a randomized teaching experiment with a kindergarten sample whose details are outlined in Clements et al. (2020). First, we describe our problem-solving strategy data, including how strategies were coded in ways that are amenable to analysis. Second, we explore what kinds of ordinal statistical models best fit the nature of arithmetic strategies, describe what each model implies about problem-solving behavior, and how to interpret model parameters. Third, we discuss the effect of "treatment", operationalized as instruction aligned with an arithmetic Learning Trajectory (LT). We show that arithmetic strategy development is best described as a sequential stepwise process and that children who receive LT instruction use more sophisticated strategies at post-assessment, relative to their peers in a teach-to-target skill condition. We introduce latent strategy sophistication as an analogous metric to traditional Rasch factor scores and demonstrate a moderate correlation them (r = 0.58). Our work suggests strategy sophistication carries information that is unique from, but complimentary to traditional correctness-based Rasch scores, motivating its expanded use in intervention studies.

Femoral condylar fractures in four continental giant breed rabbits.

Four male neutered continental giant rabbits aged between 10 and 30 months were presented with femoral condylar fractures, which developed without an observed traumatic injury. Stabilisation of the condylar fracture was achieved with screw fixation in all cases, which was supplemented with additional fixation in three cases. Complications consequent to the surgical intervention occurred in two cases: a femoral fracture and loss of fixation. Three rabbits were reported to have recovered normal limb function, and the rabbit that developed a femoral fracture as a consequence of its surgical intervention was treated with amputation.

Pulmonary Lymphangioleiomyomatosis originates in the pleural mesothelial cell population.

Lymphangioleiomyomatosis (LAM) is a cystic lung disease mainly affecting women, in which degradation of the lung parenchyma is associated with a cell of unknown provenance, known as a LAM cell. LAM cells carry TSC2 mutations and can be identified in the lung parenchyma by their expression of both smooth muscle actin and antigens characteristic of melanocytes and melanocytic tumors. The nature of the cell-of-origin of LAM is controversial, and despite continued research effort remains elusive. Further, it has not been possible to culture pulmonary LAM cells in vitro, and current research relies on cells and animal models which may not recapitulate all features of the disease. We noted aberrant expression of melanoma antigens in pleural mesothelial cells in lung tissue from LAM patients, indicating that these cells could be the precursors of parenchymal LAM cells. We hypothesise that loss of tuberin function following TSC2 mutation in the mesothelial cell lineage gives rise to the cell-of-origin of pulmonary LAM (P-LAM), and of other associated conditions commonly noted in LAM patients. The unique properties of mesothelial cells provide a straightforward explanation of the diverse presentation of LAM.

Presentation, treatment and outcome of long-bone fractures in pet rabbits (Oryctolagus cuniculus).

OBJECTIVES: To describe the incidence, aetiology, characteristics, assessment, management and outcome of long-bone fractures in rabbits presenting to a single institution. MATERIALS AND METHODS: Medical records of pet rabbits diagnosed with long-bone fractures over a 12-year period were analysed. Patient signalment, fracture aetiology, fracture location, fracture description, time from fracture occurrence to veterinary presentation, fixation method, postoperative complications, clinical outcome and follow-up were recorded. RESULTS: Twenty-eight pet rabbits that sustained 30 fractures were included in the study [femoral (n=12), tibial (n=6), metacarpal/metatarsal/phalangeal (n=5), radial and ulnar (n=4) and tarsal (n=3)]. Twenty-one (75%) of the rabbits were less than 2 years of age, including seven (25%) under 6 months of age. Twenty-five fractures had no identifiable cause and five were traumatic. Only one fracture was open. Surgical stabilisation was performed in 22 fractures, four were non-surgically managed, two had the affected limb amputated, one underwent digital amputation and one was euthanased. Postoperative complications occurred in nine fractures [major (n=6), minor (n=3)]. The frequency of complications or attainment of a functional recovery was not notably different between the different methods of fixation. Overall, 24 rabbits recovered, two were euthanased and four underwent limb amputation. CLINICAL SIGNIFICANCE: Fractures in rabbits typically occur in young animals and they usually lack an obvious aetiology. The majority of the rabbits treated achieved a functional recovery, although the postoperative complication rate was high in fractures treated surgically (41%).

An in vitro study of the effect of the optimal irrigation solution conditions during canine articular surgery.

OBJECTIVES: To establish whether chondrocyte viability, matrix degradation and the induction of proteolytic gene expression in canine cartilage is independent of irrigation fluid osmolality and time following exposure to the irrigation fluid. METHODS: Canine cartilage explants were exposed to one of three different solution types i) Culture medium (270-280 mOsmol/kg) ii) NaCl 0.9% (302 mOsmol/kg) iii) NaCl 0.9% with sucrose (600 mOsmol/kg). Chondrocyte viability and selected proteolytic gene expression were measured at two time points; immediately following exposure and 24 h following exposure. The media samples at 24 h following exposure were assessed for sulphated glycosaminoglycan (sGAG) release. RESULTS: In all samples, no cell death was observed across the superficial or deeper layers of the cartilage. When adjusting for time, gene expression was not shown to be dependent on solution type. However for all solution types, Matrix Metalloproteinase 13 (MMP13) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS5) expression was significantly decreased in cartilage samples at 24 h post exposure comparatively to samples tested immediately post exposure. No significant differences were identified in the relative sGAG release between the solution types. CLINICAL SIGNIFCANCE: Arthroscopic solution irrigation of cartilage explants had no effect on cell viability or proteinase production. At present there is no indication to optimise irrigation fluid osmolarity, as conventional arthroscopic solution was not deleterious to healthy cartilage in this model.

A dust-enshrouded tidal disruption event with a resolved radio jet in a galaxy merger.

Tidal disruption events (TDEs) are transient flares produced when a star is ripped apart by the gravitational field of a supermassive black hole (SMBH). We have observed a transient source in the western nucleus of the merging galaxy pair Arp 299 that radiated >1.5 × 1052 erg at infrared and radio wavelengths but was not luminous at optical or x-ray wavelengths. We interpret this as a TDE with much of its emission reradiated at infrared wavelengths by dust. Efficient reprocessing by dense gas and dust may explain the difference between theoretical predictions and observed luminosities of TDEs. The radio observations resolve an expanding and decelerating jet, probing the jet formation and evolution around a SMBH.

Gait in ducks (Anas platyrhynchos) and chickens (Gallus gallus) - similarities in adaptation to high growth rate.

Genetic selection for increased growth rate and muscle mass in broiler chickens has been accompanied by mobility issues and poor gait. There are concerns that the Pekin duck, which is on a similar selection trajectory (for production traits) to the broiler chicken, may encounter gait problems in the future. In order to understand how gait has been altered by selection, the walking ability of divergent lines of high- and low-growth chickens and ducks was objectively measured using a pressure platform, which recorded various components of their gait. In both species, lines which had been selected for large breast muscle mass moved at a slower velocity and with a greater step width than their lighter conspecifics. These high-growth lines also spent more time supported by two feet in order to improve balance when compared with their lighter, low-growth conspecifics. We demonstrate that chicken and duck lines which have been subjected to intense selection for high growth rates and meat yields have adapted their gait in similar ways. A greater understanding of which components of gait have been altered in selected lines with impaired walking ability may lead to more effective breeding strategies to improve gait in poultry.

Cumulative incidence and risk factors for limber tail in the Dogslife labrador retriever cohort.

Limber tail is a condition that typically affects larger working breeds causing tail limpness and pain, resolving without veterinary intervention. It is poorly understood and the disease burden has not been well characterised. Data collected from owners of the Dogslife cohort of Labrador Retrievers have been used to describe incidents and a case-control study was undertaken to elucidate risk factors with 38 cases and 86 controls. The cumulative incidence of unexplained tail limpness was 9.7 per cent. Swimming is not a necessary precursor for limber tail, but it is a risk factor (OR=4.7) and working dogs were more susceptible than non-working dogs (OR=5.1). Higher latitudes were shown to be a risk factor for developing the condition and the case dogs were more related to each other than might be expected by chance. This suggests that dogs may have an underlying genetic predisposition to developing the condition. This study is the first, large-scale investigation of limber tail and the findings reveal an unexpectedly high illness burden. Anecdotally, accepted risk factors have been confirmed and the extent of their impact has been quantified. Identifying latitude and a potential underlying genetic predisposition suggests avenues for future work on this painful and distressing condition.

The NAD(+) salvage pathway modulates cancer cell viability via p73.

The involvement of the nicotinamide adenine dinucleotide (NAD(+)) salvage pathway in cancer cell survival is poorly understood. Here we show that the NAD(+) salvage pathway modulates cancer cell survival through the rarely mutated tumour suppressor p73. Our data show that pharmacological inhibition or knockdown of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD(+) salvage pathway, enhances autophagy and decreases survival of cancer cells in a p53-independent manner. Such NAMPT inhibition stabilizes p73 independently of p53 through increased acetylation and decreased ubiquitination, resulting in enhanced autophagy and cell death. These effects of NAMPT inhibition can be effectively reversed using nicotinamide mononucleotide (NMN), the enzymatic product of NAMPT. Similarly, knockdown of p73 also decreases NAMPT inhibition-induced autophagy and cell death, whereas overexpression of p73 alone enhances these effects. We show that the breast cancer cell lines (MCF-7, MDA-MB-231 and MDA-MB-468) harbour significantly higher levels of NAMPT and lower levels of p73 than does the normal cell line (MCF-10A), and that NAMPT inhibition is cytotoxic exclusively to the cancer cells. Furthermore, data from 176 breast cancer patients demonstrate that higher levels of NAMPT and lower levels of p73 correlate with poorer patient survival, and that high-grade tumours have significantly higher NAMPT/p73 mRNA ratios. Therefore, the inverse relationship between NAMPT and p73 demonstrable in vitro is also reflected from the clinical data. Taken together, our studies reveal a new NAMPT-p73 nexus that likely has important implications for cancer diagnosis, prognosis and treatment.

Dogslife: A cohort study of Labrador Retrievers in the UK.

Studies of animals that visit primary and secondary veterinary centres dominate companion animal epidemiology. Dogslife is a research initiative that collects data directly from owners about the health and lifestyle of Kennel Club (KC) registered Labrador Retrievers (LR) in the UK. The ultimate aim is to seek associations between canine lifestyle and health. A selection of data from Dogslife regarding the height, weight and lifestyle of 4307 LR up to four years of age is reported here. The majority of the dogs were household pets, living with at least one other pet, in families or households with more than one adult. The dogs typically ate diets of dried food and daily meal frequency decreased as the dogs aged. Working dogs spent more time exercising than pets, and dogs in Wales and Scotland were exercised more than their counterparts in England. Dogs in households with children spent less time exercising than dogs in other types of households. There was considerable variation in height and weight measurements indicative of a highly heterogeneous population. The average male height at the shoulders was 2-3cm taller than the UK breed standard. Dog weights continued to increase between one and four years of age. Those with chocolate coloured coats were heavier than their yellow and black counterparts. Greater dog weight was also associated with dogs whose owners reported restricting their dog's exercise due to where they lived. These findings highlight the utility of wide public engagement in the collation of phenotypic measures, providing a unique insight into the physical development and lifestyle of a cohort of LRs. In combination with concurrently collected data on the health of the cohort, phenotypic data from the Dogslife Project will contribute to understanding the relationship between dog lifestyle and health.

Bilateral calcaneal stress fractures in two cats.

Two cats that developed bilateral calcaneal stress fractures are reported. One cat developed lameness associated with incomplete fractures at the base of both calcanei, both of which progressed to acute, complete fractures 2 months later. The second cat presented with acute complete calcaneal fracture, with evidence of remodelling of the contralateral calcaneus, which subsequently fractured two years later. The calcaneal fractures were successfully stabilised with lateral bone plates in each case. Stress fractures were suspected because of the bilateral nature, the simple and similar configuration, the consistent location of the fractures, the absence of other signs of trauma in both cases and the suspected insidious onset of the lameness. The feline calcaneus is susceptible to stress fracture, and cats presenting with calcaneal fractures without evidence of trauma should be evaluated for concurrent skeletal pathology.

Gemcitabine enhances the efficacy of reovirus-based oncotherapy through anti-tumour immunological mechanisms.

BACKGROUND: Reovirus preferentially infects and kills cancer cells and is currently undergoing clinical trials internationally. While oncolysis is the primary mode of tumour elimination, increasing evidence illustrates that reovirus additionally stimulates anti-tumour immunity with a capacity to target existing and possibly relapsing cancer cells. These virus-induced anti-tumour immune activities largely determine the efficacy of oncotherapy. On the other hand, anti-viral immune responses can negatively affect oncotherapy. Hence, the strategic management of anti-tumour and anti-viral immune responses through complementary therapeutics is crucial to achieve the maximum anti-cancer benefits of oncotherapy. METHODS: Intra-peritoneal injection of mouse ovarian surface epithelial cells (ID8 cells) into wild-type C57BL/6 mice was treated with a therapeutic regimen of reovirus and/or gemcitabine and then analysed for prolonged survival, disease pathology, and various immunological parameters. Furthermore, in vitro analyses were conducted to assess apoptosis, viral spread, and viral production during reovirus and/or gemcitabine treatment. RESULTS: We demonstrate that reovirus and gemcitabine combination treatment postpones peritoneal carcinomatosis development and prolongs the survival of cancer-bearing hosts. Importantly, these anti-cancer benefits are generated through various immunological mechanisms, including: (1) inhibition of myeloid-derived suppressor cells recruitment to the tumour microenvironment, (2) downmodulation of pro-MDSC factors, and (3) accelerated development of anti-tumour T-cell responses. CONCLUSION: The complementation of reovirus with gemcitabine further potentiates virus-initiated anti-cancer immunity and enhances the efficacy of oncotherapy. In the context of ongoing clinical trials, our findings represent clinically relevant information capable of enhancing cancer outcomes.

Gemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy.

Gemcitabine is a chemotherapeutic that is widely used for the treatment of a variety of haematological malignancies and has become the standard chemotherapy for the treatment of advanced pancreatic cancer. Combinational gemcitabine regimes (e.g.with doxorubicin) are being tested in clinical trials to treat a variety of cancers, including colon cancer. The limited success of these trials has prompted us to pursue a better understanding of gemcitabine's mechanism of cell killing, which could dramatically improve the therapeutic potential of this agent. For comparison, we included gamma irradiation that triggers robust cell cycle arrest and Cr(VI), which is a highly toxic chemical that induces a robust p53-dependent apoptotic response. Gemcitabine induced a potent p53-dependent apoptosis that correlated with the accumulation of pro-apoptotic proteins such as PUMA and Bax. This is accompanied by a drastic reduction in p2l and 14-3-3σ protein levels, thereby significantly sensitizing the cells to apoptosis. In vitro and in vivo studies demonstrated that gemcitabine required PUMA transcription to instigate an apoptotic programme. This was in contrast to Cr(VI)-induced apoptosis that required Bax and was independent of transcription. An examination of clinical colon and pancreatic cancer tissues shows higher p53, p21, 14-3-3σ and Bax expression compared with matched normal tissues, yet there is a near absence of PUMA protein. This may explain why gemcitabine shows only limited efficacy in the treatment of these cancers. Our results raise the possibility that targeting the Bax-dependent cell death pathway, rather than the PUMA pathway, could result in significantly improved patient outcome and prognosis for these cancers.

The rapid assembly of an elliptical galaxy of 400 billion solar masses at a redshift of 2.3.

Stellar archaeology shows that massive elliptical galaxies formed rapidly about ten billion years ago with star-formation rates of above several hundred solar masses per year. Their progenitors are probably the submillimetre bright galaxies at redshifts z greater than 2. Although the mean molecular gas mass (5 × 10(10) solar masses) of the submillimetre bright galaxies can explain the formation of typical elliptical galaxies, it is inadequate to form elliptical galaxies that already have stellar masses above 2 × 10(11) solar masses at z ≈ 2. Here we report multi-wavelength high-resolution observations of a rare merger of two massive submillimetre bright galaxies at z = 2.3. The system is seen to be forming stars at a rate of 2,000 solar masses per year. The star-formation efficiency is an order of magnitude greater than that of normal galaxies, so the gas reservoir will be exhausted and star formation will be quenched in only around 200 million years. At a projected separation of 19 kiloparsecs, the two massive starbursts are about to merge and form a passive elliptical galaxy with a stellar mass of about 4 × 10(11) solar masses. We conclude that gas-rich major galaxy mergers with intense star formation can form the most massive elliptical galaxies by z ≈ 1.5.

Unilateral synostosis of the zygo-maticotemporal suture associated with mandibular coronoid process impingement in a dog.

A 13-month-old dog was investigated for the complaint of open-mouth locked jaw. There were not any previous episodes of trauma witnessed. Computed tomographic evaluation revealed unilateral zygomatico-temporal synostosis and associated craniofacial asymmetry, with impingement of the mandibular coronoid process resulting in unilateral temporomandibular joint subluxation. Closed reduction of the subluxation was not maintained. Partial zygomatico-temporal suturectomy resulted in resolution of the clinical signs. To the author's knowledge, isolated zygomaticotemporal syno-stosis with associated temporomandibular subluxation has not been reported in the dog.

A dust-obscured massive maximum-starburst galaxy at a redshift of 6.34.

Massive present-day early-type (elliptical and lenticular) galaxies probably gained the bulk of their stellar mass and heavy elements through intense, dust-enshrouded starbursts--that is, increased rates of star formation--in the most massive dark-matter haloes at early epochs. However, it remains unknown how soon after the Big Bang massive starburst progenitors exist. The measured redshift (z) distribution of dusty, massive starbursts has long been suspected to be biased low in z owing to selection effects, as confirmed by recent findings of systems with redshifts as high as ~5 (refs 2-4). Here we report the identification of a massive starburst galaxy at z = 6.34 through a submillimetre colour-selection technique. We unambiguously determined the redshift from a suite of molecular and atomic fine-structure cooling lines. These measurements reveal a hundred billion solar masses of highly excited, chemically evolved interstellar medium in this galaxy, which constitutes at least 40 per cent of the baryonic mass. A 'maximum starburst' converts the gas into stars at a rate more than 2,000 times that of the Milky Way, a rate among the highest observed at any epoch. Despite the overall downturn in cosmic star formation towards the highest redshifts, it seems that environments mature enough to form the most massive, intense starbursts existed at least as early as 880 million years after the Big Bang.

CCR3 induced-p42/44 MAPK activation protects against staurosporine induced-DNA fragmentation but not apoptosis in airway smooth muscle cells.

BACKGROUND: Chemokine receptors (CCRs) are expressed on airway smooth muscle (ASM) cells. As their ligands are present in the airways in asthma, we hypothesized that ASM CCR activation could promote the increase in ASM mass seen in patients with chronic asthma. OBJECTIVE: To determine which CCRs are expressed by ASM cells and their potential functional relevance to the chronic airway changes seen in asthma. METHODS: CCR expression in primary ASM cell cultures and airway biopsies from patients with and without asthma was examined by RT-PCR, fluorescence-activated cell sorting and immunohistochemistry. ASM p42/44 MAPK activity, proliferation, migration and apoptosis were examined by western blotting, thymidine incorporation, transwell assay and TUNEL assay respectively. RESULTS: CCR3 was the most frequently expressed CCR protein and was present on 79 ± 14% of cells. CX3CR1 and CXCR6 were present on 6% and 11% of cells respectively. CCR3 ligands CCL11 and CCL24 caused rapid activation of p42/44 MAPK but not Akt. CCR3 activation did not affect ASM proliferation, migration or VEGF secretion. DNA fragmentation detected by TUNEL staining could be induced by staurosporine and Fas activation although only Fas activation resulted in caspase 3 cleavage. CCL11 and CCL24 protected ASM cells against DNA fragmentation dependent upon p42/44 MAPK activity only via caspase 3 independent pathways. CCR3 was expressed in the smooth muscle and epithelium in the airways of patients with and without asthma. Smooth muscle cell DNA fragmentation in the airways of patients with stable asthma and controls was very uncommon. CONCLUSIONS AND CLINICAL RELEVANCE: CCR3 is strongly expressed by ASM cells in vitro and in vivo. Protection against cell death by CCR3 activation is dependent on p42/44 MAPK but does not affect caspase 3 mediated apoptosis.

The suppression of star formation by powerful active galactic nuclei.

The old, red stars that constitute the bulges of galaxies, and the massive black holes at their centres, are the relics of a period in cosmic history when galaxies formed stars at remarkable rates and active galactic nuclei (AGN) shone brightly as a result of accretion onto black holes. It is widely suspected, but unproved, that the tight correlation between the mass of the black hole and the mass of the stellar bulge results from the AGN quenching the surrounding star formation as it approaches its peak luminosity. X-rays trace emission from AGN unambiguously, whereas powerful star-forming galaxies are usually dust-obscured and are brightest at infrared and submillimetre wavelengths. Here we report submillimetre and X-ray observations that show that rapid star formation was common in the host galaxies of AGN when the Universe was 2-6 billion years old, but that the most vigorous star formation is not observed around black holes above an X-ray luminosity of 10(44) ergs per second. This suppression of star formation in the host galaxy of a powerful AGN is a key prediction of models in which the AGN drives an outflow, expelling the interstellar medium of its host and transforming the galaxy's properties in a brief period of cosmic time.