Rupture of the gastrocnemius muscle at its distal musculotendinous junction: conservative treatment and outcomes in 11 dogs.

CASE HISTORY: Medical records from three veterinary referral centres and a university veterinary teaching hospital in Australia and the USA were reviewed to identify dogs with a diagnosis of distal gastrocnemius musculotendinous junction rupture (DGMJR) that were treated without surgery between 2007 and 2020. CLINICAL AND IMAGING FINDINGS: All dogs (n = 11) presented with unilateral, pelvic limb lameness and bruising, swelling or pain on palpation at the distal musculotendinous junction. The diagnosis was confirmed with ultrasound or MRI in six dogs; radiographs were used to excluded stifle and tarsus pathology in four dogs; and five dogs were diagnosed on physical examination findings. TREATMENT AND OUTCOME: All dogs were managed conservatively, either with complete confinement alone (n = 10; median 9 weeks), external coaptation alone (n = 1), or a combination of both (n = 4). Sporting dogs (n = 7) were completely confined (median 22 weeks) for longer periods than companion dogs (n = 3; median 5 weeks).A good to excellent outcome was achieved for all cases in this cohort. The seven sporting dogs achieved an excellent outcome; returning to their previous level of sport, with complete resolution of lameness and recovery of a normal tibiotarsal stance. The four companion dogs achieved a good outcome; returning to their previous level of activity but with persistently increased tibiotarsal standing angle compared to the contralateral limb. CLINICAL RELEVANCE: Conservative treatment represents a viable treatment option for dogs with a rupture of the gastrocnemius muscle at its distal musculotendinous junction.

A compilation and characterisation of lithics in kimberlite and common maar-diatremes and tephra ring deposits.

Maar-diatreme volcanoes are the second-most common type on land, occurring in volcanic fields within all major tectonic environments. Their deposits typically contain an abundance of lithic fragments quarried from the substrate, and many contain large, deep-sourced lithic fragments that were erupted to the surface. Primary volcaniclastic deposits fill the diatreme structure formed during eruption. There is negligible inelastic deformation of diatreme-adjacent country rock, indicating that country rock is removed to create the diatreme structures, either by being shifting downward below observable levels, ejected upward to contribute to surficial deposits, or dissolved and hidden in magma erupted or intruded at depth. No previous study has systematically reviewed and analysed the reported lithic fragments of maar-diatreme systems. We present a comprehensive compilation from published work of lithic characteristics in maar ejecta rings and in diatreme deposits of both common and kimberlite maar-diatremes. For maar-diatremes and their tephra ring deposits, we find no correlations among lithic clast sizes, shapes, depositional sites, and excavation depths. This is difficult to reconcile with models involving systematic diatreme deepening coupled with tephra-ring growth, but consistent with those involving chaotic explosions and mixing. Larger amounts of data are needed to further examine how these types of volcanoes operate.

Inequality in access to hearing care for older adults in residential homes.

BACKGROUND: The population of older people in residential homes is projected to rise. There are unrecognized hearing difficulties among residents and prevalence of hearing loss in this population is underreported. This can result in an overestimation of levels of cognitive impairment. Untreated hearing loss is associated with social isolation, depression, disruptive behaviour and cognitive decline. This study aimed to explore the provision of hearing care (hearing assessment, rehabilitation and staff training) in Scottish care homes for older people. METHODS: A survey comprising 18 questions was distributed to the managers (or designated staff members) of 659 care homes across Scotland. RESULTS: Responses were obtained from 154 care homes. The results support existing evidence that hearing is not assessed in the majority of homes, resulting in under detection of hearing loss. Staff lack training in supporting residents' hearing needs. Access to hearing care in residential homes differs across health board areas. CONCLUSIONS: There is an urgent requirement for hearing assessment of older adults on admission to residential care. Care providers require this information to construct effective care plans and mitigate the effects of hearing loss. Those responsible for providing hearing rehabilitation services require information about service users to address any unmet need.

DendroScan: an open source tool to conduct comparative statistical tests and dendrogrammatic analyses on particle morphometry.

Quantitative shape analysis of juvenile pyroclasts is applied in volcanology to reconstruct the dynamics and styles of eruptions, and to explore the details of tephra transport, dispersal, and emplacement. Morphometric analyses often include comparison of multiple data sets with a set of dimensionless shape parameters. Here we present "DendroScan", an open source Matlab program that provides the user with all the multivariate statistical methods needed to produce such morphometric comparisons. Serving as a statistical "toolbox", DendroScan conducts Levene-, t-, and equivalence tests, presenting the results in ad hoc interpretable graphs. Furthermore, it is designed to conduct dendrogrammatic analyses of particle morphometry, a recently developed approach for the inter-comparison of multiple morphometric data sets. DendroScan produces tree diagrams, in which the analysed samples are sorted according to their morphometric dissimilarity, allowing the user to identify, e.g., samples that are statistically equivalent. To demonstrate DendroScan's potential, ten experimental samples are compared with volcanic ash samples generated by the Havre 2012 deep-sea eruption in the Kermadec arc (New Zealand). We show how, using DendroScan-based results, information on the eruptive mechanism can be inferred, and how the cooling history of the experimental melt is reflected in the dissimilarity of thermally granulated fragments.

The utility of screening diagnostic tests in identifying associative immune-mediated haemolytic anaemia in dogs.

The study aimed to (1) define the proportion of dogs with immune-mediated haemolytic anaemia (IMHA) that have associative and non-associative disease and (2) evaluate the utility of screening diagnostic tests in identifying potential triggers of associative IMHA. Medical records of 78 dogs diagnosed with IMHA at a specialist hospital in Sydney from July 2008 to August 2017 were reviewed. The original diagnosis was revised according to published guidelines (Garden et al., 2019) as either diagnostic, supportive or suspicious for IMHA. Associative IMHA was confirmed if immunosuppressive therapy was discontinued within six weeks of effective treatment of a potential trigger. Associative IMHA was considered possible when a potential trigger was identified but its significance could not be confirmed. Associative IMHA was confirmed (3) or suspected (7) in 10 dogs (13%, confidence interval [CI] 7.1%-22%), with 68 cases presumed to be non-associative. Associative IMHA was present in 3/29 (10.3%) of dogs with criteria diagnostic for IMHA, 4/42 (9.5%) of dogs with criteria supportive for IMHA and 3/7 (42.9%) of dogs with criteria suspicious for IMHA. Abdominal ultrasound was performed in 68 dogs and identified possible triggers in five (7.3%, CI 3.2% to 16%). Thoracic radiographs were performed in 70 dogs but did not identify any potential triggers (0%, CI 0% to 5.2%). Urine culture was performed in 22 dogs and was positive in three (14%, CI 4.7% to 33.3%). Routine screening tests, particularly thoracic radiographs, have a low yield in identifying potential triggers of associative IMHA, but are more likely to be useful in dogs fulfilling less stringent diagnostic criteria of IMHA.

Prolonged isolation stress accelerates the onset of Alzheimer's disease-related pathology in 5xFAD mice despite running wheels and environmental enrichment.

Research has demonstrated that stress can exacerbate AD pathology in transgenic mouse models of AD. The purpose of the present studies was to extend this work by determining whether a social stressor, isolation stress, would increase the number of Aß plaques in 5xFAD + transgenic mice in comparison to group-housed controls, and accelerate the onset of cognitive deficits in contextual fear-conditioning. Additionally, we aimed to determine whether the pathological impact of isolation stress could be prevented through exposure to exercise alone or to exercise and an enriched environment throughout the isolation period. Two-month-old 5xFAD + and 5xFAD- animals were isolated or group-housed for two and three months. An additional subset of 5xFAD + mice were housed in isolation, housed in isolation with an exercise wheel, or housed in isolation with an exercise wheel and an enriched environment. Both two and three months of isolation stress significantly increased the number of plaques in the hippocampus of 5xFAD + mice, and three months of isolation increased hippocampal BACE1 expression. Isolated animals also displayed a significant cognitive deficit in contextual fear-conditioning, independent of genotype. Furthermore, neither exercise nor an enriched environment were able to prevent these isolation-induced effects. Understanding how stress impacts the onset and progression of AD is critical, as many individuals endure significant stress over their lifespan, including prolonged social isolation, a societal trend likely to worsen with time.

Intraventricular murine Aß infusion elicits hippocampal inflammation and disrupts the consolidation, but not retrieval, of conditioned fear in C57BL6/J mice.

Although one of the defining characteristics of Alzheimer's disease is the presence of amyloid-beta (Aß) plaques, the early accumulation of soluble Aß oligomers (AßOs) may disrupt synaptic function and trigger cognitive impairments long before the appearance of plaques. Furthermore, murine models aimed at understanding how AßOs alter formation and retrieval of associative memories are conducted using human Aß species, which are more neurotoxic in the mouse brain than the native murine species. Unfortunately, there is currently a lack of attention in the literature as to what the murine version of the peptide (mAß) does to synaptic function and how it impacts the consolidation and retrieval of associative memories. In the current study, adult mice were infused with mAß 0, 2, 6, or 46 h after contextual-fear conditioning, and were tested 2-48 h later. Interestingly, only mAß infusions within 2 h of training reduced freezing behavior at test, indicating that mAß disrupted the consolidation, but not retrieval of fear memory. This consolidation deficit coincided with increased IL-1ß and reduced synaptophysin mRNA levels, without disrupting other synaptic signaling-related genes here examined. Despite differences between murine and human Aß, the deleterious functional outcomes of early-stage synaptic oligomer presence are similar. Thus, models utilizing or inducing the production of mAß in non-transgenic animals are useful in exploring the role of dysregulated synaptic plasticity and resultant learning deficits induced by Aß oligomers.

The α5-GABAAR inverse agonist MRK-016 upregulates hippocampal BDNF expression and prevents cognitive deficits in LPS-treated mice, despite elevations in hippocampal Aß.

Alzheimer's disease is marked by the presence of amyloid-beta (Aß) plaques, elevated central cytokine levels, dysregulation of BDNF-related gene expression, and cognitive decline. Previously, our laboratory has demonstrated that repeated administration of peripheral LPS is sufficient to significantly increase the presence of central Aß in the hippocampus, and that this upregulation corresponds with deficits in learning and memory. We have also previously demonstrated that the inverse benzodiazepine agonist MRK-016 (MRK) can protect against memory acquisition and consolidation errors in mice. To extend these findings, the current study explored the protective effects of MRK in the context of LPS-induced hippocampal Aß accumulation. Hippocampal Aß was significantly elevated, relative to saline-treated animals, following seven days of peripheral LPS injections. Animals were then trained in a contextual fear conditioning paradigm and were immediately treated with MRK or saline once training was complete. Behavioral testing occurred the day after training. Results from this study demonstrate that repeated injections of LPS significantly elevate hippocampal Aß, and inhibit acquisition of contextual fear. Post-training treatment with MRK restored behavioral expression of fear in LPS-treated animals, despite elevated hippocampal Aß, an effect that may be attributed to increased BDNF mRNA expression. Therefore, our data indicate that MRK can prevent LPS- induced cognitive deficits associated with elevated Aß, and restore hippocampal BDNF expression.

Comparison of bone healing, as assessed by computed tomography, following tibial tuberosity advancement in dogs with and without autogenous cancellous bone grafts.

AIMS: To objectively compare measures of bone healing, using computed tomography (CT) in dogs following bilateral tibial tuberosity advancement (TTA), between tibiae treated with and without autogenous cancellous bone grafts. METHODS: Ten dogs with bilateral cranial cruciate ligament disease requiring surgical stabilisation were prospectively recruited to undergo single-session bilateral TTA, with only one, randomly assigned, tibia receiving bone graft in the osteotomy deficit. Bone healing at the osteotomy site was assessed using CT performed 38-70 days post-operatively. CT images were evaluated using both objective measurements of osseous bridging and subjective evaluation by six radiologists. Repeated measures ANOVA was used to compare the objective outcomes between the grafted and non-grafted tibiae. RESULTS: The mean percentage of the osteotomy deficit bridged at the lateral cortex was greater in grafted (77.6, SD 35.2%) compared to non-grafted (63.0, SD 36.5%) tibiae (p=0.001), but did not differ at the medial cortex (p=0.1). The mean minimum callus width was greater in grafted (7.2, SD 3.3 mm) compared to non-grafted (3.6, SD 2.9 mm) tibiae (p<0.001). There was no difference in mean attenuation (measured in Hounsfield units) of the callus between grafted and non-grafted tibiae (p=0.5). The grafted tibia was deemed to have superior bone healing in 50/60 subjective assessments made by radiologists. CONCLUSIONS: Superior osseous bridging was detected by CT analysis following TTA using autogenous cancellous bone grafts compared with no graft. This was shown by greater bridging percentage at the lateral cortex and formation of a broader callus. Qualitative assessments made by six radiologists also supported the conclusion that bone healing was improved by use of autogenous cancellous bone graft. CT was a useful method for assessing evidence of bone healing following TTA. CLINICAL RELEVANCE: These findings justify the application of autogenous cancellous bone graft to augment healing following TTA in dogs.

Collapse of an iconic conifer: long-term changes in the demography of Widdringtonia cedarbergensis using repeat photography.

BACKGROUND: Conifer populations appear disproportionately threatened by global change. Most examples are, however, drawn from the northern hemisphere and long-term rates of population decline are not well documented as historical data are often lacking. We use a large and long-term (1931-2013) repeat photography dataset together with environmental data and fire records to account for the decline of the critically endangered Widdringtonia cedarbergensis. Eighty-seven historical and repeat photo-pairs were analysed to establish 20th century changes in W. cedarbergensis demography. A generalized linear mixed-effects model was fitted to determine the relative importance of environmental factors and fire-return interval on mortality for the species. RESULTS: From an initial total of 1313 live trees in historical photographs, 74% had died and only 44 (3.4%) had recruited in the repeat photographs, leaving 387 live individuals. Juveniles (mature adults) had decreased (increased) from 27% (73%) to 8% (92%) over the intervening period. Our model demonstrates that mortality is related to greater fire frequency, higher temperatures, lower elevations, less rocky habitats and aspect (i.e. east-facing slopes had the least mortality). CONCLUSIONS: Our results show that W. cedarbergensis populations have declined significantly over the recorded period, with a pronounced decline in the last 30 years. Individuals that established in open habitats at lower, hotter elevations and experienced a greater fire frequency appear to be more vulnerable to mortality than individuals growing within protected, rocky environments at higher, cooler locations with less frequent fires. Climate models predict increasing temperatures for our study area (and likely increases in wildfires). If these predictions are realised, further declines in the species can be expected. Urgent management interventions, including seedling out-planting in fire-protected high elevation sites, reducing fire frequency in higher elevation populations, and assisted migration, should be considered.

Subclinical Bacteriuria in Older Cats and its Association with Survival.

BACKGROUND: Bacterial urinary tract infections are uncommon in cats in general but the prevalence increases to 29% in older cats with comorbidities (Veterinary Clinical Pathology 2008, 37, 317; Journal of Feline Medicine & Surgery 2007, 9, 124; Veterinary Microbiology 2009, 136, 130). Frequently, the infections are subclinical. The clinical relevance of subclinical bacteriuria (SB) is uncertain, and the optimal treatment requires clarification. OBJECTIVE: Prospective, observational study to: (i) identify the prevalence and incidence count of SB in older (≥7 years), nonazotemic cats, (ii) evaluate specific risk factors for SB, and (iii) investigate the potential relationship between untreated SB and survival. ANIMALS: Sixty-seven, nonazotemic cats were tested on 5 occasions over 3 years. METHODS: Urine samples were obtained by cystocentesis for quantitative urine culture and blood samples for measurement of serum creatinine concentration. Episodes of SB were not treated. Serum creatinine concentration, body weight, urine specific gravity, sex, and age were evaluated as potential risk factors for a positive urine culture. The association between urine culture results and survival was evaluated with Cox's proportional hazard model. RESULTS: A total of 256 urine samples was obtained. The prevalence of SB varied between 10 and 13%, and incident infections were uncommon. Female cats were 21 times more likely to have a positive urine culture than were male cats (odds ratio [OR], 21.2; confidence interval [CI], 4.1-110; P = .00028). Subclinical bacteriuria was not significantly associated with survival. CONCLUSION AND CLINICAL IMPORTANCE: Subclinical bacteriuria is common in nonazotemic, older cats. Although antimicrobial treatment was withheld, the presence of SB was not adversely associated with survival.

Hippocampal Aß expression, but not phosphorylated tau, predicts cognitive deficits following repeated peripheral poly I:C administration.

Alzheimer's disease is marked by the accumulation of the amyloid-beta (Aß) peptide, and increases in phosphorylation of the microtubule associated protein, tau. Changes in these proteins are considered responsible, in part, for the progressive neuronal degeneration and cognitive deficits seen in AD. We examined the effect of repeated consecutive peripheral poly I:C injections on cognitive deficits, central Aß, and phosphorylated tau accumulation, following three treatment durations: 7, 14, and 21 days. Forty-eight hours after the final injection, animals were trained in a contextual fear-conditioning paradigm, and tested 24h later. Immediately after testing, the hippocampus was collected to quantify Aß and phosphorylated tau accumulation. Results showed that, although poly I:C-induced Aß was significantly elevated at all time points examined, poly I:C only disrupted cognition after 14 and 21 days of administration. Moreover, elevations in phosphorylated tau were not seen until the 14-day time point. Interestingly, phosphorylated tau expression then declined at the 21-day time point. Finally, we demonstrated that Aß levels are a stronger predictor of cognitive dysfunction, explaining 37% of the variance, whereas phosphorylated tau levels only accounted for 0.2%. Taken together, these results support the hypothesis that inflammation-induced elevation in Aß disrupts cognition, independently of phosphorylated tau, and suggest that long-term administration of poly I:C may provide a model to investigate the contribution of long-term inflammation toward the development of Alzheimer's-like pathology.

Imatinib methanesulfonate reduces hyperphosphorylation of tau following repeated peripheral exposure to lipopolysaccharide.

For years, the prevailing hypothesis for Alzheimer's Disease (AD) has proposed a mechanism by which deposition of amyloid-beta (Aß) in the brain is independent of tau-pathologies and cognitive decline. However, despite extensive research on the disease, the mechanisms underlying the etiology of tau-pathology remain unknown. Previous research in our lab has shown that imatinib methanesulfonate (IM) blocks the peripheral production of Aß in response to LPS, thereby preventing the buildup of Aß in the hippocampus, and rescuing the cognitive dysfunction that normally follows. The present study aimed to examine the link between Aß and tau following inflammation, and to expand our understanding of how IM affects AD pathology. Specifically, we hypothesized that the IM-mediated inhibition of Aß production following inflammation would successfully protect against the hyperphosphorylation of tau (ptau). Here we show that 7days of LPS treatment in male C57BL/6J mice, which normally produces elevations in peripheral and central Aß, also produces hyperphosphorylation of tau. However, just as pre-treatment and concurrent treatment with IM blocks Aß production, it also blocks the phosphorylation of tau. In addition, 7days of LPS-induced inflammation and Aß production also leads to elevated total tau protein expression. Our results may provide support for the hypothesis that enhanced expression of tau following LPS administration is a protective measure by hippocampal neurons to compensate for the loss of the microtubule-stabilizing protein due to phosphorylation. More importantly, our results support the hypothesis that blocking the production of Aß that follows inflammation also leads to reduced tau phosphorylation, lending credence to a model in which Aß initiates tau phosphorylation.

Pre-treatment of C57BL6/J mice with the TLR4 agonist monophosphoryl lipid A prevents LPS-induced sickness behaviors and elevations in dorsal hippocampus interleukin-1ß, independent of interleukin-4 expression.

Peripheral administration of lipopolysaccharide (LPS) elevates production of pro-inflammatory cytokines, and motivates the expression of sickness behaviors. In this study, we tested the ability of an LPS-derived adjuvant, monophosphoryl lipid A (MPLA), to prevent LPS-induced sickness behaviors in a burrowing paradigm. Testing occurred over a three-day period. Animals received a single injection of either MPLA or saline the first two days of testing. On day three, animals received either LPS or saline. Tissue from the dorsal hippocampus was collected for qRT-PCR to assess expression of IL-1ß and IL-4. Results indicate that, during the pre-treatment phase, administration of MPLA induces an immune response sufficient to trigger sickness behaviors. However, we observed that animals pre-treated with MPLA for two days were resistant to LPS-induced sickness behaviors on day three. Results from the qRT-PCR analysis indicated that LPS-treated animals pre-treated with MPLA expressed significantly less IL-1ß compared to LPS-treated animals pre-treated with saline. However, we did not observe a significant difference in IL-4 expression between groups. Therefore, results indicate that under the given parameters of the study, MPLA pre-treatment protects against LPS-induced sickness behaviors, at least in part, by decreasing expression of the pro-inflammatory cytokine IL-1ß.

Administration of the inverse benzodiazepine agonist MRK-016 rescues acquisition and memory consolidation following peripheral administration of bacterial endotoxin.

Recent evidence suggests that inflammation-induced decrements in cognitive function can be mitigated via manipulation of excitatory or inhibitory transmission. We tested the ability of the inverse benzodiazepine agonist, MRK-016 (MRK) to protect against LPS-induced deficits in memory acquisition and consolidation, using a contextual fear conditioning (CFC) paradigm. In Experiment One, mice received lipopolysaccharide (LPS) and/or MRK injections prior to CFC training, and were then tested 24h after training. In Experiment Two, animals received similar treatment injections immediately after training, and were tested 24h later. Additionally, hippocampal samples were collected 4h after LPS injections and immediately after testing, to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA expression. Results indicate that MRK can protect against LPS-induced learning/memory decrements in both paradigms. We also found, in both paradigms, that animals treated with LPS/Saline expressed significantly less BDNF mRNA when compared to Saline/Saline-treated animals 4h after LPS administration, but that MRK did not restore BDNF expression levels. Further, treatment administrations had no effect on IGF-1 mRNA expression at any collection time-point. In summary, MRK-016 can protect against LPS-induced deficits in memory acquisition and consolidation, in this hippocampus-dependent paradigm, though this protection occurs independently of recovery of BDNF expression.

A disintegrin and metalloprotease-12 is type I myofiber specific in Bos taurus and Bos indicus cattle.

A disintegrin and metalloproteinase-12 (ADAM12) is involved in the regulation of myogenesis and adipogenesis and is of interest as a potential target to manipulate skeletal muscle development and intramuscular fat (IMF) deposition in cattle to increase beef yield and improve meat quality. The longissimus thoracis muscle (LM) and semitendinosus muscle (STM) from 5 Bos taurus (Angus) and 5 Bos indicus (Brahman) cattle were collected for histological and ADAM12 gene and protein expression analysis. Myofiber typing was used to determine if ADAM12 expression patterns related to differences in muscling and IMF deposition, which are influenced by proportions of the different myofiber types. The STM was found to contain a higher proportion of glycolytic myofibers than the LM, which contained a greater proportion of oxidative myofibers (myofiber ratio of glycolytic to more oxidative types in LM and STM of 1.1 and 3.5, respectively; P < 0.05). ADAM12 gene expression, fluorescent immunohistochemical staining for ADAM12, and image analysis found ADAM12 to be greater in the LM (P < 0.05). Regression analysis found a strong, positive relationship for the distribution of ADAM12 against the proportion of type I myofibers (P < 0.05, r(2) = 0.86). These findings suggest ADAM12 is upregulated in muscles with more slow-oxidative myofibres, such as the LM, and is linked to type I myofibers in cattle. ADAM12 may be important in the regulation and maintenance slow myofibers in the LM muscle.

Myocardial gene delivery using molecular cardiac surgery with recombinant adeno-associated virus vectors in vivo.

We use a novel technique that allows for closed recirculation of vector genomes in the cardiac circulation using cardiopulmonary bypass, referred to here as molecular cardiac surgery with recirculating delivery (MCARD). We demonstrate that this platform technology is highly efficient in isolating the heart from the systemic circulation in vivo. Using MCARD, we compare the relative efficacy of single-stranded (ss) adeno-associated virus (AAV)6, ssAAV9 and self-complimentary (sc)AAV6-encoding enhanced green fluorescent protein, driven by the constitutive cytomegalovirus promoter to transduce the ovine myocardium in situ. MCARD allows for the unprecedented delivery of up to 48 green fluorescent protein genome copies per cell globally in the sheep left ventricular (LV) myocardium. We demonstrate that scAAV6-mediated MCARD delivery results in global, cardiac-specific LV gene expression in the ovine heart and provides for considerably more robust and cardiac-specific gene delivery than other available delivery techniques such as intramuscular injection or intracoronary injection; thus, representing a potential, clinically translatable platform for heart failure gene therapy.

Leukemia inhibitory factor-dependent increase in myoblast cell number is associated with phosphotidylinositol 3-kinase-mediated inhibition of apoptosis and not mitosis.

Leukemia inhibitory factor (LIF) is an important regulator of skeletal muscle regeneration and has been suggested to be mitogenic for myogenic cells because it has been shown to increase the quantity of myoblast cells grown in culture over extended periods of time. Using the established C2C12 murine myoblast cell line, we observed that LIF treatment did not significantly increase the rate at which myoblasts synthesise DNA under conditions which increased cell quantity by 73% above control, whilst the known mitogen fibroblast growth factor-2 significantly increased DNA synthesis under these conditions. Consequently, we examined the capacity of LIF to prevent apoptotic cell death. LIF treatment significantly reduced staurosporine-induced apoptotic DNA fragmentation by 37% compared to control and also reduced the proteolytic activation of caspase-3 by 40% compared to control. This effect of LIF was completely abolished by addition of the phosphatidylinositol 3-kinase inhibitor wortmannin, indicating that the phosphatidylinositol 3-kinase signalling pathway, previously shown to be linked to LIF-dependent increases in cell number, is necessary in mediating the anti-apoptotic effects of LIF. LIF treatment was also associated with increased levels of Bcl-xL and XIAP transcripts compared to control. Therefore, we suggest that the role of LIF in skeletal muscle regeneration and myogenesis is that of a survival factor rather than a mitogen.