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Background: TOF-Watch(®) monitors are designed to display train-of-four (TOF) count when neuromuscular block is intense, and to display TOF ratio when it is less intense. In dogs recovering from non-depolarizing neuromuscular block, when all four twitches are easily visible and apparently of similar magnitude, TOF-Watch(®) monitors often display TOF counts and not TOF ratios, as would be expected. We have never encountered this problem when the monitor was calibrated before neuromuscular blocking agent administration.Methods: Fourteen healthy female dogs undergoing ovariohysterectomy were investigated. Recovery from neuromuscular block was assessed with a calibrated TOF-Watch SX(®) monitor. When the TOF ratio returned to 90%, the TOF-Watch SX(®) was replaced with an uncalibrated TOF-Watch(®) monitor. The output obtained from the uncalibrated TOF-Watch(®) was compared with that of the calibrated device.Results: The median TOF ratio measured by the calibrated TOF-Watch SX(®) unit at recovery was 91 (86-100)% (n=14). The uncalibrated TOF-Watch(®) monitor displayed TOF counts in six dogs [2 (0, 4)] and TOF ratios in the remaining eight dogs [91 (79, 98)%], that is, the uncalibrated device failed to display appropriately >40% of the time.Conclusions: TOF-Watch(®) monitors must be calibrated before neuromuscular blocking agents are administered to dogs. When these devices are not so calibrated, they default to a reference value for twitch magnitude that was defined in healthy adult people. Even though neuromuscular transmission was restored in these dogs, we surmise that they did not achieve the default reference value, causing the monitor to display TOF counts rather than TOF ratios. [ABSTRACT FROM AUTHOR]

The intestinal extracellular matrix (ECM) helps maintain appropriate tissue barrier function and regulate host-microbial interactions. Chondroitin sulfate- and dermatan sulfate-glycosaminoglycans (CS/DS-GAGs) are integral components of the intestinal ECM, and alterations in CS/DS-GAGs have been shown to significantly influence biological functions. Although pathologic ECM remodeling is implicated in inflammatory bowel disease (IBD), it is unknown whether changes in the intestinal CS/DS-GAG composition are also linked to IBD in humans. Our aim was to characterize changes in the intestinal ECM CS/DS-GAG composition in intestinal biopsy samples from patients with IBD using mass spectrometry. We characterized intestinal CS/DS-GAGs in 69 pediatric and young adult patients (n = 13 control, n = 32 active IBD, n = 24 IBD in remission) and 6 adult patients. Here, we report that patients with active IBD exhibit a significant decrease in the relative abundance of CS/DS isomers associated with matrix stability (CS-A and DS) compared to controls, while isomers implicated in matrix instability and inflammation (CS-C and CS-E) were significantly increased. This imbalance of intestinal CS/DS isomers was restored among patients in clinical remission. Moreover, the abundance of pro-stabilizing CS/DS isomers negatively correlated with clinical disease activity scores, whereas both pro-inflammatory CS-C and CS-E content positively correlated with disease activity scores. Thus, pediatric patients with active IBD exhibited increased pro-inflammatory and decreased pro-stabilizing CS/DS isomer composition, and future studies are needed to determine whether changes in the CS/DS-GAG composition play a pathogenic role in IBD., (© 2024. The Author(s).)

In the context of aging and age-associated neurodegenerative disorders, the brain's extracellular matrix (ECM) serves as a critical regulator for neuronal health and cognitive function. Within the extracellular space, proteoglycans and their glycosaminoglycan attachments play essential roles in forming, stabilizing, and protecting neural circuits throughout neurodevelopment and adulthood. Recent studies in rodents reveal that chondroitin sulfate-glycosaminoglycan (CS-GAG) containing perineuronal nets (PNNs) exhibit both structural and compositional differences throughout the brain. While animal studies are illuminating, additional research is required to translate these interregional PNN/CS-GAG variations to human brain tissue. In this perspective article, we first investigate the translational potential for interregional CS-GAG variances across species as novel targets for region-specific therapeutic development. We specifically focus on the observation that alterations in brain PNN-associated CS-GAGs have been linked with the progression of Alzheimer's disease (AD) neuropathology in humans, but these changes have not been fully recapitulated in rodent models of this disease. A second highlight of this perspective article investigates whether AD-associated shifts in CS-GAGs in humans may be dependent on region-specific baseline differences in CS-GAG sulfation patterning. The current findings begin to disentangle the intricate relationships between the interregional differences in brain PNN/CS-GAG matrices across species, while emphasizing the need to better understand the close relationship between dementia and changes in brain CS-GAG sulfation patterns in patients with AD and related dementias., Competing Interests: DT is employed by Meta Reality Labs, however this study did not include any products or services related to the company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hendrickson, Francis, Kumar, Le, Scarlett, Keene, Tovar and Alonge.)

Objective: Preserving core body temperature across a wide range of ambient temperatures requires adaptive changes of thermogenesis that must be offset by corresponding changes of energy intake if body fat stores are also to be preserved. Among neurons implicated in the integration of thermoregulation with energy homeostasis are those that express both neuropeptide Y (NPY) and agouti-related protein (AgRP) (referred to herein as AgRP neurons). Specifically, cold-induced activation of AgRP neurons was recently shown to be required for cold exposure to increase food intake in mice. Here, we investigated how consuming a high-fat diet (HFD) impacts various adaptive responses to cold exposure as well as the responsiveness of AgRP neurons to cold., Methods: To test this, we used immunohistochemistry, in vivo fiber photometry and indirect calorimetry for continuous measures of core temperature, energy expenditure, and energy intake in both chow- and HFD-fed mice housed at different ambient temperatures., Results: We show that while both core temperature and the thermogenic response to cold are maintained normally in HFD-fed mice, the increase of energy intake needed to preserve body fat stores is blunted, resulting in weight loss. Using both immunohistochemistry and in vivo fiber photometry, we show that although cold-induced AgRP neuron activation is detected regardless of diet, the number of cold-responsive neurons appears to be blunted in HFD-fed mice., Conclusions: We conclude that HFD-feeding disrupts the integration of systems governing thermoregulation and energy homeostasis that protect body fat mass during cold exposure., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

To address the needs of the life sciences community and the pharmaceutical industry in pre-clinical drug development to both maintain and continuously assess tissue metabolism and function with simple and rapid systems, we improved on the initial BaroFuse to develop it into a fully functional, pumpless, scalable multi-channel fluidics instrument that continuously measures changes in oxygen consumption and other endpoints in response to test compounds. We and several other laboratories assessed it with a wide range of tissue types including retina, pancreatic islets, liver, and hypothalamus with both aqueous and gaseous test compounds. The setup time was less than an hour for all collaborating groups, and there was close agreement between data obtained from the different laboratories. This easy-to-use system reliably generates real-time metabolic and functional data from tissue and cells in response to test compounds that will address a critical need in basic and applied research., Competing Interests: Declaration of interests I.R.S., D.C., G.K., K.B., and M.K.G. have financial ties to EnTox Sciences, Inc. (Mercer Island, WA, USA), the manufacturer/distributor of the BaroFuse perifusion system used in this study. There is a patent pending on the BaroFuse, the rights to which would be granted to the University of Washington. T.J.W. has received equity and royalty from Ocutheia, LLC. S.A.S. has received grant funding from Ono Pharmaceutical Co., Ltd., and is a consultant for Novo Nordisk., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

A prospective study was designed to (a) investigate the rate of daily weight gain among kittens less than 9 weeks old presented to an animal shelter, (b) identify factors (e.g., sex, clinical signs of disease, diet, and medical treatment) that affect daily weight gain, and (c) investigate the mortality of study kittens. The study of 203 kittens was conducted at a managed admission, no-kill animal shelter in upstate New York, USA, from April 2014 through October 2014. Body weight was measured daily from day of intake to adoption or 12 weeks of age. Fecal score, clinical signs of disease, food type, and medical treatments were recorded daily. Lethargy and being female were significantly associated with lower daily weight gain. Despite the challenges of shelter and foster care, the average daily weight gain for study kitten was higher than that reported in other settings such as catteries and laboratories. Five study kittens (2.5%) died or were euthanized. Daily monitoring systems provide opportunities for interventions, increased live outcomes, and improved welfare for kittens in shelter and foster care.

Background: The increased prevalence of inflammatory bowel disease (IBD) among patients with obesity and type 2 diabetes suggests a causal link between these diseases, potentially involving the effect of hyperglycemia to disrupt intestinal barrier integrity., Aim: To investigate whether the deleterious impact of diabetes on the intestinal barrier is associated with increased IBD severity in a murine model of colitis in mice with and without diet-induced obesity., Methods: Mice were fed chow or a high-fat diet and subsequently received streptozotocin to induce diabetic-range hyperglycemia. Six weeks later, dextran sodium sulfate was given to induce colitis. In select experiments, a subset of diabetic mice was treated with the antidiabetic drug dapagliflozin prior to colitis onset. Endpoints included both clinical and histological measures of colitis activity as well as histochemical markers of colonic epithelial barrier integrity., Results: In mice given a high-fat diet, but not chow-fed animals, diabetes was associated with significantly increased clinical colitis activity and histopathologic markers of disease severity. Diabetes was also associated with a decrease in key components that regulate colonic epithelial barrier integrity (colonic mucin layer content and epithelial tight junction proteins) in diet-induced obese mice. Each of these effects of diabetes in diet-induced obese mice was ameliorated by restoring normoglycemia., Conclusion: In obese mice, diabetes worsened clinical and pathologic outcomes of colitis via mechanisms that are reversible with treatment of hyperglycemia. Hyperglycemia-induced intestinal barrier dysfunction offers a plausible mechanism linking diabetes to increased colitis severity. These findings suggest that effective diabetes management may decrease the clinical severity of IBD., Competing Interests: Conflict-of-interest statement: All authors have no conflicts of interest to declare., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

To investigate whether glucoregulatory neurons in the hypothalamus can sense and respond to physiological variation in the blood glucose (BG) level, we combined continuous arterial glucose monitoring with continuous measures of the activity of a specific subset of neurons located in the hypothalamic ventromedial nucleus that express pituitary adenylate cyclase activating peptide (VMNPACAP neurons) obtained using fiber photometry. Data were collected in conscious, free-living mice during a 1-h baseline monitoring period and a subsequent 2-h intervention period during which the BG level was raised either by consuming a chow or a high-sucrose meal or by intraperitoneal glucose injection. Cross-correlation analysis revealed that, following a 60- to 90-s delay, interventions that raise the BG level reliably associate with reduced VMNPACAP neuron activity (P < 0.01). In addition, a strong positive correlation between BG and spontaneous VMNPACAP neuron activity was observed under basal conditions but with a much longer (∼25 min) temporal offset, consistent with published evidence that VMNPACAP neuron activation raises the BG level. Together, these findings are suggestive of a closed-loop system whereby VMNPACAP neuron activation increases the BG level; detection of a rising BG level, in turn, feeds back to inhibit these neurons. To our knowledge, these findings constitute the first evidence of a role in glucose homeostasis for glucoregulatory neurocircuits that, like pancreatic β-cells, sense and respond to physiological variation in glycemia., Article Highlights: By combining continuous arterial glucose monitoring with fiber photometry, studies investigated whether neurons in the murine ventromedial nucleus that express pituitary adenylate cyclase activating peptide (VMNPACAP neurons) detect and respond to changes in glycemia in vivo. VMNPACAP neuron activity rapidly decreases (within <2 min) when the blood glucose level is raised by either food consumption or glucose administration. Spontaneous VMNPACAP neuron activity also correlates positively with glycemia, but with a longer temporal offset, consistent with reports that hyperglycemia is induced by experimental activation of these neurons. Like pancreatic β-cells, neurons in the hypothalamic ventromedial nucleus appear to sense and respond to physiological variation in glycemia., (© 2023 by the American Diabetes Association.)

When mammals are exposed to a warm environment, overheating is prevented by activation of "warm-responsive" neurons (WRNs) in the hypothalamic preoptic area (POA) that reduce thermogenesis while promoting heat dissipation. Heat exposure also impairs glucose tolerance, but whether this also results from activation of POA WRNs is unknown. To address this question, we sought in the current work to determine if glucose intolerance induced by heat exposure can be attributed to activation of a specific subset of WRNs that express pituitary adenylate cyclase-activating peptide (ie, POAPacap neurons). We report that when mice are exposed to an ambient temperature sufficiently warm to activate POAPacap neurons, the expected reduction of energy expenditure is associated with glucose intolerance, and that these responses are recapitulated by chemogenetic POAPacap neuron activation. Because heat-induced glucose intolerance was not blocked by chemogenetic inhibition of POAPacap neurons, we conclude that POAPacap neuron activation is sufficient, but not required, to explain the impairment of glucose tolerance elicited by heat exposure., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To examine the risk of developing an overweight or obese (O/O) body condition score (BCS) in gonadectomized versus intact dogs and, separately, the impact of age at gonadectomy on O/O outcomes among sterilized dogs., Animals: Dogs were patients of Banfield Pet Hospital in the US from 2013 to 2019. After exclusion criteria were applied, the final sample consisted of 155,199 dogs., Procedures: In this retrospective cohort study, Cox proportional hazards models evaluated associations between O/O and gonadectomy status, sex, age at gonadectomy, and breed size. Models were used to estimate the risk of becoming O/O in gonadectomized versus intact dogs and, separately, to estimate risk of O/O BCS according to age at surgery among gonadectomized dogs., Results: Gonadectomy increased O/O risk for most dogs compared to intact dogs. Unlike most prior findings, O/O hazard ratios among gonadectomized versus intact dogs were larger for males than females. O/O risk varied according to breed size but not linearly. Sterilizing at 1 year old tended to yield a lower O/O risk compared to doing so later. Comparative O/O risk among dogs gonadectomized at 6 months versus 1 year varied by breed size. Overall patterns for obesity related to size were similar to patterns in the O/O analysis., Clinical Relevance: Veterinarians are uniquely positioned to help prevent O/O in their patients. Results extend understanding of risk factors for O/O development in dogs. In combination with information about other benefits and risks associated with gonadectomy, these data can help tailor recommendations regarding gonadectomy in individual dogs.

In rodent models of type 2 diabetes (T2D), central administration of FGF1 normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons and, if so, whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here, we show that FGF1 inhibited ARC NPY/AgRP neuron activity, both after intracerebroventricular injection in vivo and when applied ex vivo in a slice preparation; we also showed that the underlying mechanism involved increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons was also highly durable, lasting for at least 2 weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by intracerebroventricular FGF1 injection in rodent models of T2D.

Perineuronal nets (PNNs) are chondroitin-sulfate glycosaminoglycan (CS-GAG) containing extracellular matrix structures that assemble around neurons involved in learning, memory, and cognition. Owing to the unique patterning of negative charges stemming from sulfate modifications to the attached CS-GAGs, these matrices play key roles in mediating glycan-protein binding, signaling interactions, and charged ion buffering of the underlying circuitry. Histochemical loss of PNN matrices has been reported for a range of neurocognitive and neurodegenerative diseases, implying that PNNs might be a key player in the pathogenesis of neurological disorders. In this hypothesis and theory article, we begin by highlighting PNN changes observed in human postmortem brain tissue associated with Alzheimer's disease (AD) and corresponding changes reported in rodent models of AD neuropathology. We then discuss the technical limitations surrounding traditional methods for PNN analyses and propose alternative explanations to these historical findings. Lastly, we embark on a global re-evaluation of the interpretations for PNN changes across brain regions, across species, and in relation to other neurocognitive disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Scarlett, Hu and Alonge.)

The extracellular matrix (ECM) of the brain comprises unique glycan "sulfation codes" that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate-glycosaminoglycan (CS-GAG) containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), we show that patients with a clinical diagnosis of AD-related dementia undergo a re-coding of their PNN-associated CS-GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p-tau) accumulation, and cognitive impairment. As these CS-GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology., (© 2021 the Alzheimer's Association.)

Intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) elicits remission of diabetic hyperglycemia in rodent models of type 2 diabetes. Here, we present an optimized protocol to study the intracellular signaling pathways underlying the FGF1-induced sustained glucose lowering in the mouse brain. This protocol combines icv injection of FGF1 and osmotic mini-pump infusion of U0126, an inhibitor of MAPK/ERK signaling. We describe the surgical procedure and verification of U0126 inhibition of FGF1-stimulated hypothalamic MAPK/ERK signaling via western blot. For complete details on the use and execution of this protocol, please refer to Brown et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that following icv FGF1 injection, hypothalamic signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family, is induced for at least 24 h. Further, we show that this prolonged response is required for the sustained antidiabetic action of FGF1 since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, fails to mimic the sustained glucose lowering induced by FGF1. These data identify sustained activation of hypothalamic MAPK/ERK signaling as playing an essential role in the mechanism underlying diabetes remission induced by icv FGF1 administration., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

To maintain energy homeostasis during cold exposure, the increased energy demands of thermogenesis must be counterbalanced by increased energy intake. To investigate the neurobiological mechanisms underlying this cold-induced hyperphagia, we asked whether agouti-related peptide (AgRP) neurons are activated when animals are placed in a cold environment and, if so, whether this response is required for the associated hyperphagia. We report that AgRP neuron activation occurs rapidly upon acute cold exposure, as do increases of both energy expenditure and energy intake, suggesting the mere perception of cold is sufficient to engage each of these responses. We further report that silencing of AgRP neurons selectively blocks the effect of cold exposure to increase food intake but has no effect on energy expenditure. Together, these findings establish a physiologically important role for AgRP neurons in the hyperphagic response to cold exposure., Competing Interests: JD, CF, CP, BP, SL, KO, JN, VD, MT, RP, KK, JS, MB, MS, GM No competing interests declared, (© 2020, Deem et al.)

We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH) 1 , but whether these PNNs play a role in either the pathogenesis of type 2 diabetes (T2D) or its treatment remains unclear. Here we show that PNN abundance within the Arc is markedly reduced in the Zucker diabetic fatty (ZDF) rat model of T2D, compared with normoglycaemic rats, correlating with altered PNN-associated sulfation patterns of chondroitin sulfate glycosaminoglycans in the MBH. Each of these PNN-associated changes is reversed following a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) at a dose that induces sustained diabetes remission in male ZDF rats. Combined with previous work localizing this FGF1 effect to the Arc area 2-4 , our finding that enzymatic digestion of Arc PNNs markedly shortens the duration of diabetes remission following icv FGF1 injection in these animals identifies these extracellular matrix structures as previously unrecognized participants in the mechanism underlying diabetes remission induced by the central action of FGF1.

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lep ob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.

Objectives: The aims of this descriptive study were to identify risk factors for feline Microsporum canis infection at shelter intake, to describe screening test accuracy, and to refine confirmatory testing time frames., Methods: Database records for the general feline population and intake data, medical records and fungal culture logs for cats diagnosed with M canis at a limited admissions shelter were accessed retrospectively for a period of 2 years., Results: The feline population at the study shelter had a prevalence of M canis of 1.8% (95% confidence interval [CI] 1.6-2.0%). Kittens were eight (95% CI 4.8-13.5) times more likely to present with dermatophytosis than adults. Although more cats presented with M canis during summer and autumn, season was not significant when the model was controlled for age. Owner-surrendered cats were half as likely (95% CI 0.41-0.77) as transported cats to be diagnosed with M canis . Wood's lamp examinations had a sensitivity of 66.8% (95% CI 60.2-73.4) and a specificity of 74.8% (95% CI 64.2-85.1) compared with dermatophyte test medium (DTM) culture. In 78.8% (95% CI 61-91) of littermate or household groups with mixed Wood's lamp results, all cats were DTM culture positive. Under consistent incubation conditions, 202/202 diagnostic DTM plates for M canis -infected cats showed recognizable colony growth before 7 days (median 4 days), and 19/19 fomite carrier cat cultures showed growth before 12 days (median 5 days)., Conclusions and Relevance: Applying the results of this study to shelter protocols could optimize diagnostic approaches and shorten the length of stay for shelter cats and kittens, resulting in streamlined shelter operations and improved feline welfare.

Central activation of fibroblast growth factor (FGF) receptors regulates peripheral glucose homeostasis and reduces food intake in preclinical models of obesity and diabetes. The current work was undertaken to advance our understanding of the receptor expression, as sites of ligand action by FGF19, FGF21, and FGF1 in the mammalian brain remains unresolved. Recent advances in automated RNAscope in situ hybridization and droplet digital PCR (ddPCR) technology allowed us to interrogate central FGFR/beta klotho (Klb) system at the cellular level in the mouse, with relevant comparisons to nonhuman primate and human brain. FGFR1-3 gene expression was broadly distributed throughout the CNS in Mus musculus, with FGFR1 exhibiting the greatest heterogeneity. FGFR4 expression localized only in the medial habenula and subcommissural organ of mice. Likewise, Klb mRNA was restricted to the suprachiasmatic nucleus (SCh) and select midbrain and hindbrain nuclei. ddPCR in the rodent hypothalamus confirmed that, although expression levels are indeed low for Klb, there is nonetheless a bonafide subpopulation of Klb+ cells in the hypothalamus. In NHP and human midbrain and hindbrain, Klb + cells are quite rare, as is expression of FGFR4. Collectively, these data provide the most robust central map of the FGFR/Klb system to date and highlight central regions that may be of critical importance to assess central ligand effects with pharmacological dosing, such as the putative interactions between the endocrine FGFs and FGFR1/Klb, or FGF19 with FGFR4., (© 2019 Wiley Periodicals, Inc.)

In rodent models of type 2 diabetes (T2D), sustained remission of diabetic hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1). To identify the brain areas responsible for this effect, we first used immunohistochemistry to map the hypothalamic distribution of phosphorylated extracellular signal-related kinase 1/2 (pERK1/2), a marker of mitogen-activated protein kinase-ERK signal transduction downstream of FGF receptor activation. Twenty minutes after icv FGF1 injection in adult male Wistar rats, pERK1/2 staining was detected primarily in two hypothalamic areas: the arcuate nucleus-median eminence (ARC-ME) and the paraventricular nucleus (PVN). To determine whether an action of FGF1 localized to either the ARC-ME or the PVN is capable of mimicking the sustained antidiabetic effect elicited by icv FGF1, we microinjected either saline vehicle or a low dose of FGF1 (0.3 µg/side) bilaterally into either the ARC-ME area or PVN of Zucker Diabetic Fatty rats, a model of T2D, and monitored daily food intake, body weight, and blood glucose levels over a 3-week period. Whereas bilateral intra-arcuate microinjection of saline vehicle was without effect, remission of hyperglycemia lasting >3 weeks was observed following bilateral microinjection of FGF1 into the ARC-ME. This antidiabetic effect cannot be attributed to leakage of FGF1 into cerebrospinal fluid and subsequent action on other brain areas, since icv injection of the same total dose was without effect. Combined with our finding that bilateral microinjection of the same dose of FGF1 into the PVN was without effect on glycemia or other parameters, we conclude that the ARC-ME area (but not the PVN) is a target for sustained remission of diabetic hyperglycemia induced by FGF1., (© 2019 by the American Diabetes Association.)

Background: Current nutritional intervention strategies have not proven effective in improving childhood ponderal and linear growth in underweight and stunted children. Novel markers are needed to classify children who are likely to respond to available interventions and to identify those requiring additional interventions. Fibroblast Growth Factor 21 (FGF21), an endocrine hormone that regulates metabolism and growth during periods of reduced protein intake, may be useful in this context., Objectives: We aimed to determine the associations between plasma FGF21 concentrations and subsequent growth, and the association between change in FGF21 concentrations and concurrent growth, in children receiving nutritional supplementation., Methods: A total of 120 children between ages 6 and 13 mo with weight-for-age z score (WAZ) between -3 and -2 were enrolled from an urban slum in Dhaka, Bangladesh. Children received 376-kcal feeding supplements daily for 5 mo and were followed for 5 additional mo. FGF21 was measured in plasma collected at enrollment and month 5. FGF21 values that fell above the 90th percentile of baseline concentrations (1056.5 pg/mL) were considered high. Linear regression was used to examine the association between baseline FGF21 status and 5-mo change in WAZ and length-for-age z score (LAZ), and the association between 5-mo change in FGF21 and concurrent WAZ and LAZ change., Results: The median baseline FGF21 concentration was 241.4 pg/mL (IQR: 111.7, 451.3 pg/mL). On average, children with high baseline FGF21 gained 0.58 WAZ (95% CI: 0.28, 0.88) and 0.54 LAZ (95% CI: 0.23, 0.84) more during supplementation than those with low values. Change in FGF21 concentration during supplementation was negatively associated with change in WAZ (-0.48; 95% CI: -0.67, -0.29) and LAZ (-0.31; 95% CI: -0.52, -0.11)., Conclusions: FGF21 may be a useful marker of growth faltering and may allow identification of children who are more or less likely to respond to nutritional supplementation. This trial was registered at clinicaltrials.gov as NCT02441426.

We recently reported that in rodent models of type 2 diabetes (T2D), a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces remission of hyperglycemia that is sustained for weeks. To clarify the peripheral mechanisms underlying this effect, we used the Zucker diabetic fatty fa / fa rat model of T2D, which, like human T2D, is characterized by progressive deterioration of pancreatic β-cell function after hyperglycemia onset. We report that although icv FGF1 injection delays the onset of β-cell dysfunction in these animals, it has no effect on either glucose-induced insulin secretion or insulin sensitivity. These observations suggest that FGF1 acts in the brain to stimulate insulin-independent glucose clearance. On the basis of our finding that icv FGF1 treatment increases hepatic glucokinase gene expression, we considered the possibility that increased hepatic glucose uptake (HGU) contributes to the insulin-independent glucose-lowering effect of icv FGF1. Consistent with this possibility, we report that icv FGF1 injection increases liver glucokinase activity by approximately twofold. We conclude that sustained remission of hyperglycemia induced by the central action of FGF1 involves both preservation of β-cell function and stimulation of HGU through increased hepatic glucokinase activity., (© 2018 by the American Diabetes Association.)

In leptin-deficient ob/ob mice, obesity and diabetes are associated with abnormal development of neurocircuits in the hypothalamic arcuate nucleus (ARC) 1 , a critical brain area for energy and glucose homeostasis 2,3 . As this developmental defect can be remedied by systemic leptin administration, but only if given before postnatal day 28, a critical period (CP) for leptin-dependent development of ARC neurocircuits has been proposed 4 . In other brain areas, CP closure coincides with the appearance of perineuronal nets (PNNs), extracellular matrix specializations that restrict the plasticity of neurons that they enmesh 5 . Here we report that in humans as well as rodents, subsets of neurons in the mediobasal aspect of the ARC are enmeshed by PNN-like structures. In mice, these neurons are densely-packed into a continuous ring that encircles the junction of the ARC and median eminence, which facilitates exposure of ARC neurons to the circulation. Most of the enmeshed neurons are both GABAergic and leptin receptor-positive, including a majority of Agrp neurons. Postnatal formation of the PNN-like structures coincides precisely with closure of the CP for Agrp neuron maturation and is dependent on input from circulating leptin, as postnatal ob/ob mice have reduced ARC PNN-like material that is restored by leptin administration during the CP. We conclude that neurons crucial to metabolic homeostasis are enmeshed by PNN-like structures and organized into a densely packed cluster situated circumferentially at the ARC-ME junction, where metabolically-relevant humoral signals are sensed., Competing Interests: Competing Interests Statement The authors declare no competing financial or non-financial interests in relation to the work described here.

OBJECTIVE To characterize the clients served by and the cats and dogs admitted to nonprofit spay-neuter clinics. DESIGN Cross-sectional survey. SAMPLE 2,154 dogs and 1,902 cats that were owned by 3,768 survey respondents and admitted to 22 nonprofit spay-neuter clinics across the United States between April 29, 2013, and January 24, 2014. PROCEDURES Participating clinics distributed surveys to clients during each of 4 quarterly study weeks. The survey collected descriptive information about clients' pets and households as well as their decision-making regarding sterilization of their pets. For each of the study weeks, clinics reported the total number of surgeries, including those involving shelter animals, feral cats, and other owned animals. RESULTS Respondents indicated that 49% of dogs and 77% of cats had not been examined previously by a veterinarian, except during vaccine clinics. Among animals ≥ 4 months of age, 1,144 of 1,416 (81%) cats and 572 of 1,794 (32%) dogs had not received a rabies vaccination. Previous litters were reported for 204 of 716 (28%) queens and 153 of 904 (17%) bitches. Most clients' (53%) household income was < $30,000 annually. Common reasons for clinic choice included cost; friend, neighbor, or family recommendation; and good reputation. CONCLUSIONS AND CLINICAL RELEVANCE Nonprofit spay-neuter clinics predominantly served low-income clients and animals lacking regular veterinary care, in addition to animals from shelters and community cats. These clinics increase access to services needed for animal population control and public health.

Growing evidence implicates neurons that project from the lateral parabrachial nucleus (LPBN) to the hypothalamic ventromedial nucleus (VMN) in a neurocircuit that drives counterregulatory responses to hypoglycemia, including increased glucagon secretion. Among LPBN neurons in this circuit is a subset that expresses cholecystokinin (LPBNCCK neurons) and is tonically inhibited by leptin. Because uncontrolled diabetes is associated with both leptin deficiency and hyperglucagonemia, and because intracerebroventricular (ICV) leptin administration reverses both hyperglycemia and hyperglucagonemia in this setting, we hypothesized that deficient leptin inhibition of LPBNCCK neurons drives activation of this LPBN→VMN circuit and thereby results in hyperglucagonemia. Here, we report that although bilateral microinjection of leptin into the LPBN does not ameliorate hyperglycemia in rats with streptozotocin-induced diabetes mellitus (STZ-DM), it does attenuate the associated hyperglucagonemia and ketosis. To determine if LPBN leptin signaling is required for the antidiabetic effect of ICV leptin in STZ-DM, we studied mice in which the leptin receptor was selectively deleted from LPBNCCK neurons. Our findings show that although leptin signaling in these neurons is not required for the potent antidiabetic effect of ICV leptin, it is required for leptin-mediated suppression of diabetic hyperglucagonemia. Taken together, these findings suggest that leptin-mediated effects in animals with uncontrolled diabetes occur through actions involving multiple brain areas, including the LPBN, where leptin acts specifically to inhibit glucagon secretion and associated ketosis.

Background: Equine odontoclastic tooth resorption and hypercementosis (EOTRH) is a frequently diagnosed condition in adult horses. The underlying etiology is still unknown. Hematologic, biochemical, and endocrine values have not been reported in EOTRH-affected horses., Objectives: The main objective of the study was to describe the hematologic, biochemical, and endocrine parameters in horses with EOTRH., Study Design: Descriptive cross-sectional study of client-owned animals with EOTRH., Methods: A complete blood count, biochemistry panel, and endocrine profile were performed in horses diagnosed with EOTRH. Diagnosis was based on oral and radiographic examination findings and confirmed with histopathology., Results: Eighteen horses with EOTRH aged 10 to 32 years from various regions of the United States were sampled. The only consistent abnormality on the complete blood cell count and chemistry panel was hypoalbuminemia (88%). Endocrine parameters demonstrated no major abnormalities in the functioning of the thyroid and pituitary pars intermedia. The parathyroid hormone concentration was increased in 7 (47%) of 15 horses with an elevated 25-hydroxy vitamin D in 3 (17%) of 17 horses. Main Limitations: The main limitations of this study are the small sample size and lack of age-matched and management-matched control horses., Conclusions: The relevance of elevated parathyroid hormone in this study cannot be determined due to the lack of age-based controls and large population studies. With the small population evaluated in this study, there are no obvious hematological, biochemical, and endocrine changes evident. Further evaluation with signalment-matched controls will be necessary to evaluate some trends noted in the laboratory values.

Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that central nervous system (CNS) action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacological inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high-fat diet (HFD) feeding. Similarly, selective deletion of the aPKC isoform Pkc-λ in proopiomelanocortin (POMC) neurons disrupts leptin action, reduces melanocortin content in the paraventricular nucleus, and markedly increases susceptibility to obesity, glucose intolerance, and insulin resistance specifically in HFD-fed male mice. These data implicate aPKC as a novel regulator of energy and glucose homeostasis downstream of the leptin-PI3K pathway in POMC neurons., (© 2017 by the American Diabetes Association.)

Dynamic adjustment of insulin secretion to compensate for changes of insulin sensitivity that result from alteration of nutritional or metabolic status is a fundamental aspect of glucose homeostasis. To investigate the role of the brain in this coupling process, we used cold exposure as an experimental paradigm because the sympathetic nervous system (SNS) helps to coordinate the major shifts of tissue glucose utilization needed to ensure that increased thermogenic needs are met. We found that glucose-induced insulin secretion declined by 50% in rats housed at 5°C for 28 h, and yet, glucose tolerance did not change, owing to a doubling of insulin sensitivity. These potent effects on insulin secretion and sensitivity were fully reversed by returning animals to room temperature (22°C) for 4 h or by intravenous infusion of the α-adrenergic receptor antagonist phentolamine for only 30 min. By comparison, insulin clearance was not affected by cold exposure or phentolamine infusion. These findings offer direct evidence of a key role for the brain, acting via the SNS, in the rapid, highly coordinated, and reciprocal changes of insulin secretion and insulin sensitivity that preserve glucose homeostasis in the setting of cold exposure., (© 2017 by the American Diabetes Association.)

Background: Radioiodine ( 131 I) is effective treatment for hyperthyroidism in cats, but optimal dose to restore euthyroidism without inducing hypothyroidism is unclear. Treatment-induced hypothyroidism can lead to azotemia and reduced duration of survival., Objective: To compare efficacy and short-term outcomes of low-dose 131 I versus higher, standard-dose 131 I as treatment for hyperthyroidism., Animals: A total of 189 client-owned cats undergoing 131 I treatment for mild-to-moderate hyperthyroidism (serum T 4 ≥ 4.0 μg/dL and <13.0 μg/dL)., Methods: Prospective, nonrandomized, cohort study comparing treatment with either low-dose (2 mCi, n = 150) or standard-dose (4 mCi, n = 39) 131 I. Serum T 4 , thyroid-stimulating hormone (TSH), and creatinine concentrations were measured after 1, 3, and 6 months to determine persistent hyperthyroidism, overt hypothyroidism (low T 4 , high TSH), subclinical hypothyroidism (normal T 4 , high TSH), and azotemia., Results: There was no significant difference in prevalence of cats with persistent hyperthyroidism between standard- and low-dose treatment groups at 3 (0% versus 5.3%; P = .34) and 6 (0% versus 3.3%; P = .51) months. Overt (18% versus 1%; P = .0005) or subclinical (46% versus 21%; P = .004) hypothyroidism was more common in cats at 6 months after standard-dose 131 I. No difference in incidence of azotemia existed between groups, but cats treated with standard-dose 131 I had higher creatinine concentrations (P < .05) and higher percent rises in creatinine (P < .0001)., Conclusions and Clinical Importance: Low-dose 131 I is safe and effective for cats with mild-to-moderate hyperthyroidism, as evidenced by a cure rate of >95% with reduced frequency of iatrogenic hypothyroidism and azotemia., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Type 2 diabetes (T2D) is among the most common and costly disorders worldwide. The goal of current medical management for T2D is to transiently ameliorate hyperglycemia through daily dosing of one or more antidiabetic drugs. Hypoglycemia and weight gain are common side effects of therapy, and sustained disease remission is not obtainable with nonsurgical approaches. On the basis of the potent glucose-lowering response elicited by activation of brain fibroblast growth factor (FGF) receptors, we explored the antidiabetic efficacy of centrally administered FGF1, which, unlike other FGF peptides, activates all FGF receptor subtypes. We report that a single intracerebroventricular injection of FGF1 at a dose one-tenth of that needed for antidiabetic efficacy following peripheral injection induces sustained diabetes remission in both mouse and rat models of T2D. This antidiabetic effect is not secondary to weight loss, does not increase the risk of hypoglycemia, and involves a novel and incompletely understood mechanism for increasing glucose clearance from the bloodstream. We conclude that the brain has an inherent potential to induce diabetes remission and that brain FGF receptors are potential pharmacological targets for achieving this goal.

Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMN(SF1) neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMN(SF1) neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMN(SF1) fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMN(SF1) neurons. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMN(SF1) neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMN(SF1) neurons and suggest that these neurons are part of an ascending glucoregulatory LPBN→VMN(SF1)→aBNST neurocircuit.

Objective: To determine if concentrations of free thyroxine (FT4) measured by semi-automated chemiluminescent immunoassay (CLIA) correspond to FT4 determined by equilibrium dialysis (ED) in hypothyroid dogs positive for thyroglobulin antibody (TGA)., Animals: Thirteen TGA-positive dogs classified as hypothyroid based on subnormal FT4 concentrations by ED., Methods: Qualitative assessment of canine TGA was performed using an enzyme-linked immunosorbent assay. Serum total thyroxine and total triiodothyronine concentrations were measured by radioimmunoassay. Serum FT4 concentration was determined by ED, and also by semi-automated CLIA for human FT4 (FT4h) and veterinary FT4 (FT4v). Canine thyroid stimulating hormone concentration was measured by semi-automated CLIA., Results: Each dog's comprehensive thyroid profile supported a diagnosis of hypothyroidism. For detection of hypothyroidism, sensitivities of CLIA for FT4h and FT4v were 62% (95% CI, 32-85%) and 75% (95% CI, 36-96%), respectively, compared to FT4 by ED. Five of 13 (38%) dogs had FT4h and 2 of 8 (25%) dogs had FT4v concentrations by CLIA that were increased or within the reference range. Percentage of false-negative test results for FT4 by CLIA compared to ED was significantly (P < .0001 for FT4h and P < .001for FT4v) higher than the hypothesized false-negative rate of 0%., Conclusions and Clinical Importance: Caution should be exercised in screening dogs for hypothyroidism using FT4 measured by CLIA alone. Some (25-38%) TGA-positive hypothyroid dogs had FT4 concentrations determined by CLIA that did not support a diagnosis of hypothyroidism., (Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Our current understanding of glucose homeostasis is centered on glucose-induced secretion of insulin from pancreatic islets and insulin action on glucose metabolism in peripheral tissues. In addition, however, recent evidence suggests that neurocircuits located within a brain-centered glucoregulatory system work cooperatively with pancreatic islets to promote glucose homeostasis. Among key observations is evidence that, in addition to insulin-dependent mechanisms, the brain has the capacity to potently lower blood glucose levels via mechanisms that are insulin-independent, some of which are activated by signals emanating from the gastrointestinal tract. This review highlights evidence supporting a key role for a "gut-brain-liver axis" in control of glucose homeostasis by the brain-centered glucoregulatory system and the implications of this regulatory system for diabetes pathogenesis and treatment.

While the overall trend in euthanasia has been decreasing nationally, large dogs are at a higher risk of euthanasia than other sized dogs in most animal shelters in the United States. We hypothesized one way to increase the lives saved with respect to these large dogs is to keep them home when possible. In order to develop solutions to decrease relinquishment, a survey was developed to learn more about the reasons owners relinquish large dogs. The survey was administered to owners relinquishing their dogs at two large municipal facilities, one in New York City and one in Washington, D.C. There were 157 responses between the two facilities. We found both significant similarities and differences between respondents and their dogs from the two cities. We identified opportunities to potentially support future relinquishers and found that targets for interventions are likely different in each community.

Objective: To determine the prevalence of various lesion types detected by histologic evaluation of uterine biopsy samples collected from subfertile bitches., Design: Retrospective case series., Animals: 399 sexually intact bitches., Procedures: Results of histologic evaluation of canine uterine biopsy samples submitted by a single veterinary practice and clinical histories of dogs from which samples were obtained were reviewed. Clinical data including age, reason for biopsy, and histopathologic findings were recorded. The prevalence of specific lesions was determined, categorized by severity and age, and statistically analyzed., Results: Endometritis (170/399 [42.6%] cases) and cystic endometrial changes, including cystic endometrial hyperplasia (133/399 [33.3%]) were the most prevalent lesions in the study population. Eighty-nine of 170 (52.4%) cases of endometritis were characterized as chronic with predominantly lymphocytic or lymphoplasmacytic inflammatory infiltrates, 51 (30.0%) included mixed inflammatory reactions, and 30 (17.6%) were characterized as having acute inflammation with neutrophils, eosinophils, or both. Fibrosis was common (101/399 [25.3%] cases). Eosinophilic endometritis was significantly associated with a history of fetal loss during the same breeding cycle. No significant difference was found in prevalence of lesions among age groups., Conclusions and Clinical Relevance: The high prevalence of endometritis in this population of dogs suggested that acute and chronic endometritis may be related to subfertility in bitches. The association of eosinophilic endometrial infiltrates with a history of fetal loss may be an important diagnostic finding in dogs with endometritis.

A retrospective study using a geographic information system (GIS) was conducted to capture, map, and analyze intake data of caregiver (owner)-surrendered kittens (aged 0-6 months) to the Society for the Prevention of Cruelty to Animals (SPCA) of Tompkins County, NY, from 2009 to 2011. Addresses of caregiver-surrendered kittens during the study period were mapped (n = 1,017). Mapping and analysis of the resultant data set revealed that the distribution of kittens was nonrandom. Seventeen statistically significant (p = .001) clusters were identified, 1 of which was the SPCA of Tompkins County (due to anonymously surrendered nonhuman animals). The remaining 16 clusters were composed of 52 homes; 27.5% (280/1,017) of the kittens in the data set originated from these 52 homes. The majority of kittens within clusters were surrendered from high-density residential and manufactured residential home parks. Analyzing such clusters using GIS is a novel approach for targeting spay/neuter and educational programs to areas contributing disproportionately to shelter populations. This method may prove useful to help shelters more effectively allocate their limited resources, but further evaluation of this and other targeted approaches is needed to assess the long-term efficacy of such programs.

Objective: To estimate the prevalence of canine parvovirus (CPV) strains among dogs with enteritis admitted to a referral hospital in the southwestern United States during an 11-month period and to compare diagnostic test results, disease severity, and patient outcome among CPV strains., Design: Prospective observational study., Animals: 72 dogs with histories and clinical signs of parvoviral enteritis., Procedures: For each dog, a fecal sample or rectal swab specimen was evaluated for CPV antigen via an ELISA. Subsequently, fecal samples (n = 42 dogs) and pharyngeal swab specimens (16) were obtained and tested for CPV antigen via an ELISA and CPV DNA via a PCR assay. For specimens with CPV-positive results via PCR assay, genetic sequencing was performed to identify the CPV strain., Results: 56 dogs tested positive for CPV via ELISA or PCR assay. For 42 fecal samples tested via both ELISA and PCR assay, 27 had positive results via both assays, whereas 6 had positive PCR assay results only. Ten pharyngeal swab specimens yielded positive PCR assay results. Genetic sequencing was performed on 34 fecal or pharyngeal swab specimens that had CPV-positive PCR assay results; 25 (73.5%) were identified as containing CPV type-2c, and 9 (26.5%) were identified as containing CPV type-2b. No association was found between CPV strain and disease severity or clinical outcome., Conclusions and Clinical Relevance: CPV type-2b and CPV type-2c posed similar health risks for dogs; therefore, genetic sequencing of CPV does not appear necessary for clinical management of infected patients. The diagnostic tests used could detect CPV type-2c.

Anti-Müllerian hormone (AMH), or Müllerian inhibitory substance, is a hormone that is best known for its production by fetal testes in mammals and as the inhibitor of Müllerian (paramesonephric) duct development in males. However, following the development of the Müllerian ducts into the oviduct, uterus, and upper vagina in female mammals, the ovaries produce AMH, which can be found in measureable amounts within the peripheral circulation, especially in adults. The ovaries appear to be the sole source of AMH in the circulation; therefore, it may be a useful marker in clinically relevant situations when an assessment of the presence or absence of ovaries or ovarian remnants in dogs and cats is important. To that end, a commercially available, human-based assay was evaluated for the measurement of AMH in dogs and cats. A preliminary assessment involved a single test on a set of serum samples from dogs that were submitted to a diagnostic endocrinology laboratory for other tests. Favorable preliminary results led to a more formal assessment of the assay using serum samples from dogs and cats with the presence or absence of the ovaries known by surgical confirmation. Overall, a single measurement of serum AMH concentration was highly effective at distinguishing ovariohysterectomized from intact adult animals. In addition, the assay also accurately identified several cases of ovarian remnant syndrome., (© 2011 The Author(s))

Canine influenza virus (CIV) emerged around 2000 when an equine influenza virus (EIV) was transmitted to dogs in Florida. After 2003, the canine virus was carried by infected greyhounds to various parts of the United States and then became established in several large animal shelters, where it has continued to circulate. To better understand the evolution of CIV since its emergence, and particularly its microevolution in spatially restricted populations, we examined multiple gene segments of CIV from dogs resident in two large animal shelters in New York City during the period 2006 to 2009. In particular, we focused on viruses circulating in the two shelters in 2008 and 2009, which we found shared a common ancestor. While viruses in each shelter were generally monophyletic, we observed some gene flow between them. These shelter sequences were compared to earlier CIV isolates. The shelter viruses differed in 1 to 6 amino acids in each gene segment compared to viruses isolated in Florida between 2003 and 2005 and in Colorado in 2006 and 2008. A comparison of the sequences of equine and canine viruses revealed amino acid replacements that distinguished the viruses from the two hosts, but no clear evidence of positive selection indicative of host adaptation was detected, suggesting that any host range adaptation in CIV occurred early in the emergence of this virus or even before it transferred to dogs.

The role of nutrition and balanced metabolism in normal growth, development, and health maintenance is well known. Patients affected with either acute or chronic diseases often show disorders of nutrient balance. In some cases, a devastating state of malnutrition known as cachexia arises, brought about by a synergistic combination of a dramatic decrease in appetite and an increase in metabolism of fat and lean body mass. Other common features that are not required for the diagnosis include decreases in voluntary movement, insulin resistance, and anhedonia. This combination is found in a number of disorders including cancer, cystic fibrosis, AIDS, rheumatoid arthritis, renal failure, and Alzheimer's disease. The severity of cachexia in these illnesses is often the primary determining factor in both quality of life, and in eventual mortality. Indeed, body mass retention in AIDS patients has a stronger association with survival than any other current measure of the disease. This has led to intense investigation of cachexia and the proposal of numerous hypotheses regarding its etiology. Most authors suggest that cytokines released during inflammation and malignancy act on the central nervous system to alter the release and function of a number of neurotransmitters, thereby altering both appetite and metabolic rate. This review will discuss the salient features of cachexia in human diseases, and review the mechanisms whereby inflammation alters the function of key brain regions to produce stereotypical illness behavior. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009., (2010 Elsevier Inc. All rights reserved.)

The central melanocortin system plays a key role in the regulation of food intake and energy homeostasis. We investigated whether genetic or pharmacologic blockade of central melanocortin signaling attenuates cardiac cachexia in mice and rats with heart failure. Permanent ligation of the left coronary artery (myocardial infarction (MI)) or sham operation was performed in wild-type (WT) or melanocortin-4 receptor (MC4R) knockout mice. Eight weeks after surgery, WT-Sham mice had significant increases in lean body mass (LBM; P<0.05) and fat mass (P<0.05), whereas WT-MI did not gain significant amounts of LBM or fat mass. Resting basal metabolic rate (BMR) was significantly lower in WT-Sham mice compared to WT-MI mice (P<0.001). In contrast, both MC4-Sham and MC4-MI mice gained significant amounts of LBM (P<0.05) and fat mass (P<0.05) over the study period. There was no significant difference in the BMR between MC4-Sham and MC4-MI mice. In the second experiment, rats received aortic bands or sham operations, and after recovery received i.c.v. injections of either artificial cerebrospinal fluid (aCSF) or the melanocortin antagonist agouti-related protein (AGRP) for 2 weeks. Banded rats receiving AGRP gained significant amount of LBM (P<0.05) and fat mass (P<0.05) over the treatment period, whereas banded rats receiving aCSF did not gain significant amounts of LBM or fat mass. These results demonstrated that genetic and pharmacologic blockade of melanocortin signaling attenuated the metabolic manifestations of cardiac cachexia in murine and rat models of heart failure.

The proinflammatory cytokine leukemia inhibitory factor (LIF) is induced in disease states and is known to inhibit food intake when administered centrally. However, the neural pathways underlying this effect are not well understood. We demonstrate that LIF acutely inhibits food intake by directly activating pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. We show that arcuate POMC neurons express the LIF-R, and that LIF stimulates the release of the anorexigenic peptide, alpha-MSH from ex vivo hypothalami. Transgenic mice lacking gp130, the signal transducing subunit of the LIF-R complex, specifically in POMC neurons fail to respond to LIF. Furthermore, LIF does not stimulate the release of alpha-MSH from the transgenic hypothalamic explants. These findings indicate that POMC neurons mediate the acute anorectic actions of central LIF administration and provide a mechanistic link between inflammation and food intake.