Mitochondrial mutations alter endurance exercise response and determinants in mice.

Primary mitochondrial diseases (PMDs) are a heterogeneous group of metabolic disorders that can be caused by hundreds of mutations in both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes. Current therapeutic approaches are limited, although one approach has been exercise training. Endurance exercise is known to improve mitochondrial function in heathy subjects and reduce risk for secondary metabolic disorders such as diabetes or neurodegenerative disorders. However, in PMDs the benefit of endurance exercise is unclear, and exercise might be beneficial for some mitochondrial disorders but contraindicated in others. Here we investigate the effect of an endurance exercise regimen in mouse models for PMDs harboring distinct mitochondrial mutations. We show that while an mtDNA ND6 mutation in complex I demonstrated improvement in response to exercise, mice with a CO1 mutation affecting complex IV showed significantly fewer positive effects, and mice with an ND5 complex I mutation did not respond to exercise at all. For mice deficient in the nDNA adenine nucleotide translocase 1 (Ant1), endurance exercise actually worsened the dilated cardiomyopathy. Correlating the gene expression profile of skeletal muscle and heart with the physiologic exercise response identified oxidative phosphorylation, amino acid metabolism, matrisome (extracellular matrix [ECM]) structure, and cell cycle regulation as key pathways in the exercise response. This emphasizes the crucial role of mitochondria in determining the exercise capacity and exercise response. Consequently, the benefit of endurance exercise in PMDs strongly depends on the underlying mutation, although our results suggest a general beneficial effect.

Marine heatwave-driven mass mortality and microbial community reorganisation in an ecologically important temperate sponge.

Marine heatwaves (MHWs) are increasing in frequency, duration and intensity, disrupting global marine ecosystems. While most reported impacts have been in tropical areas, New Zealand experienced its strongest and longest MHW in 2022, profoundly affecting marine sponges. Sponges are vital to rocky benthic marine communities, with their abundance influencing ecosystem functioning. This study examines the impact of this MHW on the photosynthetic sponge Cymbastella lamellata in Fiordland, New Zealand. We describe the extent, physiological responses, mortality, microbial community changes and ecological impact of this MHW on C. lamellata. The Fiordland MHW reached a maximum temperature of 4.4°C above average, lasting for 259 days. Bleaching occurred in >90% of the C. lamellata Fiordland population. The population size exceeded 66 million from 5 to 25 m, making this the largest bleaching event of its kind ever recorded. We identified the photosynthetic symbiont as a diatom, and bleached sponges had reduced photosynthetic efficiency. Post-MHW surveys in 2023 found that over 50% of sponges at sampling sites had died but that the remaining sponges had mostly recovered from earlier bleaching. Using a simulated MHW experiment, we found that temperature stress was a driver of necrosis rather than bleaching, despite necrosis only rarely being observed in the field (<2% of sponges). This suggests that bleaching may not be the cause of the mortality directly. We also identified a microbial community shift in surviving sponges, which we propose represents a microbial-mediated adaptive response to MHWs. We also found that C. lamellata are key contributors of dissolved organic carbon to the water column, with their loss likely impacting ecosystem function. We demonstrate the potential for MHWs to disrupt key marine phyla in temperate regions, highlighting how susceptible temperate sponges globally might be to MHWs.

Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons.

Axon injury is a hallmark of many neurodegenerative diseases, often resulting in neuronal cell death and functional impairment. Dual leucine zipper kinase (DLK) has emerged as a key mediator of this process. However, while DLK inhibition is robustly protective in a wide range of neurodegenerative disease models, it also inhibits axonal regeneration. Indeed, there are no genetic perturbations that are known to both improve long-term survival and promote regeneration. To identify such a neuroprotective target, we conducted a set of complementary high-throughput screens using a protein kinase inhibitor library in human stem cell-derived retinal ganglion cells (hRGCs). Overlapping compounds that promoted both neuroprotection and neurite outgrowth were bioinformatically deconvoluted to identify specific kinases that regulated neuronal death and axon regeneration. This work identified the role of germinal cell kinase four (GCK-IV) kinases in cell death and additionally revealed their unexpected activity in suppressing axon regeneration. Using an adeno-associated virus (AAV) approach, coupled with genome editing, we validated that GCK-IV kinase knockout improves neuronal survival, comparable to that of DLK knockout, while simultaneously promoting axon regeneration. Finally, we also found that GCK-IV kinase inhibition also prevented the attrition of RGCs in developing retinal organoid cultures without compromising axon outgrowth, addressing a major issue in the field of stem cell-derived retinas. Together, these results demonstrate a role for the GCK-IV kinases in dissociating the cell death and axonal outgrowth in neurons and their druggability provides for therapeutic options for neurodegenerative diseases.

Understanding costs and benefits of thermal plasticity for pest management: insights from the integration of laboratory, semi-field and field assessments of Ceratitis capitata (Diptera: Tephritidae).

The relative costs and benefits of thermal acclimation for manipulating field performance of pest insects depend upon a number of factors including which traits are affected and how persistent any trait changes are in different environments. By assessing plastic trait responses of Ceratitis capitata (Mediterranean fruit fly) across three distinct operational environments (laboratory, semi-field, and field), we examined the influence of different thermal acclimation regimes (cool, intermediate [or handling control], and warm) on thermal tolerance traits (chill-coma recovery, heat-knockdown time, critical thermal minimum and critical thermal maximum) and flight performance (mark-release-recapture). Under laboratory conditions, thermal acclimation altered thermal limits in a relatively predictable manner and there was a generally positive effect across all traits assessed, although some traits responded more strongly. By contrast, dispersal-related performance yielded strongly contrasting results depending on the specific operational environment assessed. In semi-field conditions, warm- or cold-acclimated flies were recaptured more often than the control group at cooler ambient conditions suggesting an overall stimulatory influence of thermal variability on low-temperature dispersal. Under field conditions, a different pattern was identified: colder flies were recaptured more in warmer field conditions relative to other treatment groups. This study highlights the trait- and context-specific nature of how thermal acclimation influences traits of thermal performance and tolerance. Consequently, laboratory and semi-field assessments of dispersal may not provide results that extend into the field setting despite the apparent continuum of environmental complexity among them (laboratory < semi-field < field).

Physical Activity Among Urban Children with Asthma: Does Sleep Matter?

The present study examined associations between sleep and physical activity among a diverse sample of 97 urban children (ages 7-9) with persistent asthma. Differences in associations were evaluated by race/ethnicity and weight status. The extent to which sleep moderated the association between lung function and physical activity was also evaluated. Generalized linear models were utilized to examine associations. Findings indicated that, among the aggregate sample, more frequent nighttime awakenings were associated with less time spent engaging in moderate-to-vigorous physical activity (MVPA). Important differences in these associations were identified by both race/ethnicity and weight status. Better lung function was associated with, (a) higher levels of MVPA for children with better sleep efficiency and fewer nighttime awakenings, and (b) lower levels of MVPA for children with poorer sleep efficiency and more frequent nighttime awakenings. In short, sleep mattered with respect to children's physical activity levels in this sample.

Are oral rehydration solutions optimized for treating diarrhea?

BACKGROUND: A historical turning point occurred in the treatment of diarrhea when it was discovered that glucose could enhance intestinal sodium and water absorption. Adding glucose to salt water (oral rehydration solution, ORS) more efficiently replaced intestinal water and salt losses. AIM: Provide a novel hypothesis to explain why mainstream use of ORS has been strongly recommended, but weakly adopted. METHODS: Traditional (absorptive) and novel (secretory) physiological functions of glucose in an ORS were reviewed. RESULTS: Small amounts of glucose can stimulate both intestinal absorption and secretion. Glucose can exacerbate a net secretory state and may aggravate pathogen-induced diarrhea, particularly for pathogens that affect glucose transport. CONCLUSION: A hypothesis is made to explain why glucose-based ORS does not appreciably reduce diarrheal stool volume and why modern food science initiatives should focus on ORS formulations that replace water and electrolytes while also reducing stool volume and duration of diarrhea.

Effect of 8 days of exercise-heat acclimation on aerobic exercise performance of men in hypobaric hypoxia.

Exercise-heat acclimation (EHA) induces adaptations that improve tolerance to heat exposure. Whether adaptations from EHA can also alter responses to hypobaric hypoxia (HH) conditions remains unclear. This study assessed whether EHA can alter time-trial performance and/or incidence of acute mountain sickness (AMS) during HH exposure. Thirteen sea-level (SL) resident men [SL peak oxygen consumption (V̇o2peak) 3.19 ± 0.43 L/min] completed steady-state exercise, followed by a 15-min cycle time trial and assessment of AMS before (HH1; 3,500 m) and after (HH2) an 8-day EHA protocol [120 min; 5 km/h; 2% incline; 40°C and 40% relative humidity (RH)]. EHA induced lower heart rate (HR) and core temperature and plasma volume expansion. Time-trial performance was not different between HH1 and HH2 after 2 h (106.3 ± 23.8 vs. 101.4 ± 23.0 kJ, P = 0.71) or 24 h (107.3 ± 23.4 vs. 106.3 ± 20.8 kJ, P > 0.9). From HH1 to HH2, HR and oxygen saturation, at the end of steady-state exercise and time-trial tests at 2 h and 24 h, were not different (P > 0.05). Three of 13 volunteers developed AMS during HH1 but not during HH2, whereas a fourth volunteer only developed AMS during HH2. Heat shock protein 70 was not different from HH1 to HH2 at SL [1.9 ± 0.7 vs. 1.8 ± 0.6 normalized integrated intensities (NII), P = 0.97] or after 23 h (1.8 ± 0.4 vs. 1.7 ± 0.5 NII, P = 0.78) at HH. Our results indicate that this EHA protocol had little to no effect-neither beneficial nor detrimental-on exercise performance in HH. EHA may reduce AMS in those who initially developed AMS; however, studies at higher elevations, having higher incidence rates, are needed to confirm our findings.

Hard palate defect repair by using haired angularis oris axial pattern flaps in dogs.

OBJECTIVE: To describe the repair of large hard palate defects with a haired angularis oris axial pattern flap (HAOF) and to report the postoperative outcome. STUDY DESIGN: Anatomical cadaver study and short case series. ANIMALS: One cadaver and three dogs with neoplasia of the caudal hard palate. METHODS: Large caudal and central hard palate defects were reconstructed by using the HAOF. The flap, composed of full-thickness skin and buccal mucosa, was rotated at the base of the angularis oris artery. The haired surface of the skin flap was placed facing into the oral cavity. RESULTS: Reconstruction of defects extending as far rostral as the maxillary canine tooth were feasible on the cadaver. The flap in dog 1 healed without complication and was intact at day 649 after surgery. Two minor areas of dehiscence were noted in dog 2, without further evidence of complications at 1331 days after surgery. Dog 3 had upper respiratory obstructive noise due to swelling immediately after surgery. These signs resolved, but local recurrence of the tumor prompted euthanasia at day 86. CONCLUSION: Anatomical studies provide evidence that the HAOF can be used to reconstruct caudal and central hard palate defects extending to the maxillary canine teeth. Its clinical use led to successful closure of such defects in three dogs. CLINICAL SIGNIFICANCE: HAOF provides an alternative for reconstruction of large defects of the caudal and central hard palate.

Influences of hypobaric hypoxia on skin blood flow and sweating responses during exercise in neutral and hot environments.

Exposure to hot environments augments cutaneous vasodilation and sweating during exercise compared with these responses in cooler environments. The effects of hypobaric hypoxia on these responses are less clear, as are the effects of heat and simulated altitude combined. We evaluated the individual and potential additive effects of environmental heat and hypobaric hypoxia on skin blood flow and sweating responses during exercise. Thirteen volunteers (11 M, 2 F; age 25.3 ± 6.1 yr; height 177 ± 9 cm; weight 81.2 ± 16.8 kg) completed 30 min of steady-state (SS) exercise on a cycle ergometer at 50% V̇o2peak during four separate conditions: 1) sea level thermoneutral (SLTN; 250 m, 20°C, 30-50% RH), 2) sea level hot (SLH; 250 m, 35°C, 30% RH), 3) simulated altitude thermoneutral (ATN; 3,000 m, 20°C, 30-50% RH), and 4) simulated altitude hot (AH; 3,000 m, 35°C, 30% RH). Skin blood flow and local sweating rate (LSR) were recorded on the ventral forearm. During exercise, SS cutaneous vascular conductance in AH (63 ± 31% peak) and SLH (52 ± 19% peak) were significantly higher than both SLTN (20 ± 9% peak, P < 0.001) and ATN (25 ± 12% peak, P < 0.05) but were not different from each other (P > 0.05). SS LSR was similarly increased in the hot environments but unaffected by simulated altitude. We propose that multiple antagonistic mechanisms during exposure to 3,000-m simulated altitude result in no net effect on skin blood flow or sweating responses during exercise in thermoneutral or hot environments.

Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury.

Optic neuropathies such as glaucoma are characterized by the degeneration of retinal ganglion cells (RGCs) and the irreversible loss of vision. In these diseases, focal axon injury triggers a propagating axon degeneration and, eventually, cell death. Previous work by us and others identified dual leucine zipper kinase (DLK) and JUN N-terminal kinase (JNK) as key mediators of somal cell death signaling in RGCs following axonal injury. Moreover, others have shown that activation of the DLK/JNK pathway contributes to distal axonal degeneration in some neuronal subtypes and that this activation is dependent on the adaptor protein, sterile alpha and TIR motif containing 1 (SARM1). Given that SARM1 acts upstream of DLK/JNK signaling in axon degeneration, we tested whether SARM1 plays a similar role in RGC somal apoptosis in response to optic nerve injury. Using the mouse optic nerve crush (ONC) model, our results show that SARM1 is critical for RGC axonal degeneration and that axons rescued by SARM1 deficiency are electrophysiologically active. Genetic deletion of SARM1 did not, however, prevent DLK/JNK pathway activation in RGC somas nor did it prevent or delay RGC cell death. These results highlight the importance of SARM1 in RGC axon degeneration and suggest that somal activation of the DLK/JNK pathway is activated by an as-yet-unidentified SARM1-independent signal.

Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A.

Delayed revascularization of ischemic neural tissue is a major impediment to preservation of function in central nervous system (CNS) diseases including stroke and ischemic retinopathies. Therapeutic strategies allowing rapid revascularization are greatly needed to reduce ischemia-induced cellular damage and suppress harmful pathologic neovascularization. However, key mechanisms governing vascular recovery in ischemic CNS, including regulatory molecules governing the transition from tissue injury to tissue repair, are largely unknown. NF-E2-related factor 2 (Nrf2) is a major stress-response transcription factor well known for its cell-intrinsic cytoprotective function. However, its role in cell-cell crosstalk is less appreciated. Here we report that Nrf2 is highly activated in ischemic retina and promotes revascularization by modulating neurons in their paracrine regulation of endothelial cells. Global Nrf2 deficiency strongly suppresses retinal revascularization and increases pathologic neovascularization in a mouse model of ischemic retinopathy. Conditional knockout studies demonstrate a major role for neuronal Nrf2 in vascular regrowth into avascular retina. Deletion of neuronal Nrf2 results in semaphorin 6A (Sema6A) induction in hypoxic/ischemic retinal ganglion cells in a hypoxia-inducible factor-1 alpha (HIF-1α)-dependent fashion. Sema6A expression increases in avascular inner retina and colocalizes with Nrf2 in human fetal eyes. Extracellular Sema6A leads to dose-dependent suppression of the migratory phenotype of endothelial cells through activation of Notch signaling. Lentiviral-mediated delivery of Sema6A small hairpin RNA (shRNA) abrogates the defective retinal revascularization in Nrf2-deficient mice. Importantly, pharmacologic Nrf2 activation promotes reparative angiogenesis and suppresses pathologic neovascularization. Our findings reveal a unique function of Nrf2 in reprogramming ischemic tissue toward neurovascular repair via Sema6A regulation, providing a potential therapeutic strategy for ischemic retinal and CNS diseases.

Sympathetic neural and hemodynamic responses to head-up tilt during isoosmotic and hyperosmotic hypovolemia.

We hypothesized that muscle sympathetic nerve activity (MSNA) during head-up tilt (HUT) would be augmented during exercise-induced (hyperosmotic) dehydration but not isoosmotic dehydration via an oral diuretic. We studied 26 young healthy subjects (7 female, 19 male) divided into three groups: euhydrated (EUH, n = 7), previously exercised in 40°C while maintaining hydration; dehydrated (DEH, n = 10), previously exercised in 40°C during which ~3% of body weight was lost via sweat loss; and diuretic (DIUR, n = 9), a group that did not exercise but lost ~3% of body weight via diuresis (furosemide, 80 mg by mouth). We measured MSNA, heart rate (HR), and blood pressure (BP) during supine rest and 30° and 45° HUT. Plasma volume (PV) decreased similarly in DEH (-8.5 ± 3.3%) and DIUR (-11.4 ± 5.7%) (P > 0.05). Plasma osmolality was similar between DIUR and EUH (288 ± 4 vs. 284 ± 5 mmol/kg, respectively) but was significantly higher in DEH (299 ± 5 mmol/kg) (P < 0.05). Mixed-model ANOVA was used with repeated measures on position (HUT) and between-group analysis on condition. HR and MSNA increased in all subjects during HUT (main effect of position; P < 0.05). There was also a significant main effect of group, such that MSNA and HR were higher in DEH compared with DIUR (P < 0.05). Changes in HR with HUT were larger in both hypovolemic groups compared with EUH (P < 0.05). The differential HUT response "strategies" in each group suggest a greater role for hypovolemia per se in controlling HR responses during dehydration, and a stronger role for osmolality in control of SNA.NEW & NOTEWORTHY Interactions of volume regulation with control of vascular sympathetic nerve activity (SNA) have important implications for blood pressure regulation. Here, we demonstrate that SNA and heart rate (HR) during hyperosmotic hypovolemia (exercise-induced) were augmented during supine and tilt compared with isoosmotic hypovolemia (diuretic), which primarily augmented the HR response. Our data suggest that hypovolemia per se had a larger role in controlling HR responses, whereas osmolality had a stronger role in control of SNA.

The origin and loss of periodic patterning in the turtle shell.

The origin of the turtle shell over 200 million years ago greatly modified the amniote body plan, and the morphological plasticity of the shell has promoted the adaptive radiation of turtles. The shell, comprising a dorsal carapace and a ventral plastron, is a layered structure formed by basal endochondral axial skeletal elements (ribs, vertebrae) and plates of bone, which are overlain by keratinous ectodermal scutes. Studies of turtle development have mostly focused on the bones of the shell; however, the genetic regulation of the epidermal scutes has not been investigated. Here, we show that scutes develop from an array of patterned placodes and that these placodes are absent from a soft-shelled turtle in which scutes were lost secondarily. Experimentally inhibiting Shh, Bmp or Fgf signaling results in the disruption of the placodal pattern. Finally, a computational model is used to show how two coupled reaction-diffusion systems reproduce both natural and abnormal variation in turtle scutes. Taken together, these placodal signaling centers are likely to represent developmental modules that are responsible for the evolution of scutes in turtles, and the regulation of these centers has allowed for the diversification of the turtle shell.

Effects of nutrient and water restriction on thermal tolerance: A test of mechanisms and hypotheses.

Nutritional deprivation or desiccation can influence thermal tolerance by impacting the insects' ability to evaporatively cool, maintain cell membrane integrity and conduct protective or repair processes. Recovery from chilling is also linked to the re-establishment of iono- and osmo-regulatory homeostasis. Here, using Mediterranean fruit fly (Ceratitis capitata, Diptera: Tephritidae), we manipulated water and nutrient availability to test the mechanistic expectation that changes in whole organism lipid and water content can elicit variation in cold or heat tolerance (scored as chill coma recovery time and heat knockdown time). We measured body condition (body water and lipid content) as well as heat shock protein 70 gene (hsp70) and protein (HSP70) levels. A significant reduction in body water content with water restriction did not translate into differences in chill coma recovery. When nutrient restriction was coupled with water deprivation, this resulted in a significant reduction (-54%) of heat knockdown time in females but male flies were unaffected. There was no evidence for an hsp70 or HSP70 response under any of the stress treatments and therefore no correlation with heat or cold tolerance. Heat hardening decreased all hsp levels. Therefore, although body water and total body lipid content differed between the treatment groups, the contribution of these factors to thermal tolerance was inconsistent with mechanistic expectations in heat knockdown time and insignificant for chill coma recovery. These results therefore highlight that the effects of resource restriction on thermal limits in insects are mechanistically more complex than previous models of stress resistance have suggested.

Comparison of Circumference Measures and Height-Weight Tables With Dual-Energy X-Ray Absorptiometry Assessment of Body Composition in R.O.T.C. Cadets.

Mitchell, KM, Pritchett, RC, Gee, DL, and Pritchett, KL. Comparison of circumference measures and height-weight tables with dual-energy X-ray absorptiometry assessment of body composition in R.O.T.C. cadets. J Strength Cond Res 31(9): 2552-2556, 2017-Height-weight tables and circumference measures are used by the U.S. Army to predict body composition because they require little equipment or expertise. However, agreement between the Army's new 2002 circumference equation and an established laboratory technique has not been determined. The purpose of this study was to quantify agreement in body fat percentages between the Army's circumference measures (taping) and dual-energy X-ray absorptiometry (DXA); second to determine categorical agreement between height-weight tables and DXA. Male Reserve Officer Training Corps (R.O.T.C.) cadets (N = 23; 20.6 ± 1.6 years, 179.1 ± 6.6 cm; 81.4 ± 10.3 kg) were taped according to Army protocol to predict body fat. The % body fat prediction was compared with DXA through a Bland-Altman Plot with ±2-4% body fat established as a zone of agreement (ZOA). Thirteen out of 23 cadets fell outside the ZOA. No cadet was over the compliance threshold (20-22% fat) using the tape method, however, with DXA, 7 out of 23 cadets were noncompliant. Height-weight tables provided a moderate level of categorical agreement with DXA. The results depict poor agreement between taping and DXA, as taping generally underestimated % body fat. Compared with taping, height-weight tables were better able to identify excess fat weight.

Dispersal propensity, but not flight performance, explains variation in dispersal ability.

Enhanced dispersal ability may lead to accelerated range expansion and increased rates of population establishment, thereby affecting population genetic structure and evolutionary potential. Morphological, behavioural and physiological traits that characterize dispersive individuals from residents are poorly understood for many invertebrate systems, especially in non-polymorphic pterygote species. Here we examined phenotypic differences between dispersal-prone and philopatric individuals from repeated mark-release-recapture (MRR) experiments using an invasive agricultural pest, Ceratitis capitata Comprehensive morphometric assessment and subsequent minimal adequate modelling using an information theoretic approach identified thorax mass : body mass ratio as a key predictor of disperser flies under semi-natural conditions. Performance differences in flight ability were then examined under controlled laboratory conditions to assess whether greater thorax mass : body mass ratio was associated with enhanced flight ability. The larger thorax : body mass ratio was associated with measurable differences in mean flight duration, most predominantly in males, and also by their willingness to disperse, scored as the number and duration of voluntary flights. No other measures of whole-animal flight performance (e.g. mean and peak vertical force, total or maximum flight duration) differed. Variation in voluntary behaviour may result in significant alterations of movement behaviour and realized dispersal in nature. This phenomenon may help explain intraspecific variation in the dispersal ability of insects.

Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death.

Glaucoma, a major cause of blindness worldwide, is a neurodegenerative optic neuropathy in which vision loss is caused by loss of retinal ganglion cells (RGCs). To better define the pathways mediating RGC death and identify targets for the development of neuroprotective drugs, we developed a high-throughput RNA interference screen with primary RGCs and used it to screen the full mouse kinome. The screen identified dual leucine zipper kinase (DLK) as a key neuroprotective target in RGCs. In cultured RGCs, DLK signaling is both necessary and sufficient for cell death. DLK undergoes robust posttranscriptional up-regulation in response to axonal injury in vitro and in vivo. Using a conditional knockout approach, we confirmed that DLK is required for RGC JNK activation and cell death in a rodent model of optic neuropathy. In addition, tozasertib, a small molecule protein kinase inhibitor with activity against DLK, protects RGCs from cell death in rodent glaucoma and traumatic optic neuropathy models. Together, our results establish a previously undescribed drug/drug target combination in glaucoma, identify an early marker of RGC injury, and provide a starting point for the development of more specific neuroprotective DLK inhibitors for the treatment of glaucoma, nonglaucomatous forms of optic neuropathy, and perhaps other CNS neurodegenerations.

Outcomes of Limb-Sparing Surgery Using Two Generations of Metal Endoprosthesis in 45 Dogs With Distal Radial Osteosarcoma. A Veterinary Society of Surgical Oncology Retrospective Study.

OBJECTIVE: To report outcomes in dogs with distal radial osteosarcoma (OSA) treated with metal endoprosthesis limb-sparing surgery and compare outcomes between 2 generations of endoprosthesis. STUDY DESIGN: Multi-institutional retrospective case series. ANIMALS: Forty-five dogs with distal radial OSA treated with endoprosthesis and chemotherapy. METHODS: Data of dogs treated with either first-generation endoprosthesis (GEN1) or second-generation endoprosthesis (GEN2) were sourced from medical records and radiographs. Surgical outcomes included postoperative lameness assessment and the presence, severity, and time to onset of complications. Oncologic outcomes included presence of local recurrence or metastasis, time to onset of local recurrence, metastasis-free interval (MFI), and survival time. Results for surgical and oncologic outcomes were compared between GEN1 and GEN2. RESULTS: Twenty-eight dogs received GEN1 and 17 dogs received GEN2. There were 39 complications (96%, 14 minor, 29 major) including infection (78%), implant-related complication (36%), and local recurrence (24%). Metastatic frequency was 67% and median MFI was 188 days (95% confidence interval [CI]: 126-250 days). Survival time ranged from 34 days to 6.1 years with a median of 289 days (95% CI: 207-371 days). There was no significant difference in complication severity, frequency, time to complication, MFI, or survival time between dogs receiving GEN1 and GEN2. CONCLUSION: There was no significant difference in outcomes between dogs receiving GEN1 and GEN2 for limb-sparing surgery of the radius. Metastatic frequency and survival time for metal endoprosthesis were similar to that of amputation with curative intent chemotherapy.

Neuroprotective role of Nrf2 for retinal ganglion cells in ischemia-reperfusion.

Retinal ischemia plays a critical role in multiple vision-threatening diseases and leads to death of retinal neurons, particularly ganglion cells. Oxidative stress plays an important role in this ganglion cell loss. Nrf2 (NF-E2-related factor 2) is a major regulator of the antioxidant response, and its role in the retina is increasingly appreciated. We investigated the potential retinal neuroprotective function of Nrf2 after ischemia-reperfusion (I/R) injury. In an experimental model of retinal I/R, Nrf2 knockout mice exhibited much greater loss of neuronal cells in the ganglion cell layer than wild-type mice. Primary retinal ganglion cells isolated from Nrf2 knockout mice exhibited decreased cell viability compared to wild-type retinal ganglion cells, demonstrating the cell-intrinsic protective role of Nrf2. The retinal neuronal cell line 661W exhibited reduced cell viability following siRNA-mediated knockdown of Nrf2 under conditions of oxidative stress, and this was associated with exacerbation of increase in reactive oxygen species. The synthetic triterpenoid CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide), a potent Nrf2 activator, inhibited reactive oxygen species increase in cultured 661W under oxidative stress conditions and increased neuronal cell survival after I/R injury in wild-type, but not Nrf2 knockout mice. Our findings indicate that Nrf2 exhibits a retinal neuroprotective function in I/R and suggest that pharmacologic activation of Nrf2 could be a therapeutic strategy. Oxidative stress is thought to be an important mediator of retinal ganglion cell death in ischemia-reperfusion injury. We found that the transcription factor NF-E2-related factor 2 (Nrf2), a major regulator of oxidative stress, is an important endogenous neuroprotective molecule in retinal ganglion cells in ischemia-reperfusion, exerting a cell-autonomous protective effect.  The triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) reduces neurodegeneration following ischemia-reperfusion in an Nrf2-dependent fashion. This suggests that Nrf2-activating drugs including triterpenoids could be a therapeutic strategy for retinal neuroprotection.

Service utilisation and family support of people with dementia: a cohort study in England.

OBJECTIVES: This study aimed to compare costs of caring for people with dementia in domiciliary and residential settings, central England. METHODS: A cohort of people with dementia was recruited during a hospital stay 2008-2010. Data were collected by interview at baseline, and 6- and 12-month follow-up, covering living situation (own home with or without co-resident carer, care home); cognition, health status and functioning of person with dementia; carer stress; utilisation of health and social services; and informal (unpaid) caring input. Costs of formal services and informal caring (replacement cost method) were calculated. Costs of residential and domiciliary care packages were compared. RESULTS: Data for 109 people with dementia were collected at baseline; 95 (87.2%) entered hospital from their own homes. By 12 months, 40 (36.7%) had died and 85% of the survivors were living in care homes. Over one-half of people with dementia reported social care packages at baseline; those living alone had larger packages than those living with others. Median caring time for co-resident carers was 400 min/day and 10 h/week for non co-resident carers. Residential care was more costly than domiciliary social care for most people. When the value of informal caring was included, the total cost of domiciliary care was higher than residential care, but not significantly so. Carer stress reduced significantly after the person with dementia entered a care home. CONCLUSIONS: Caring for people with dementia at home may be more expensive, and more stressful for carers, than care in residential settings.