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GDF15 regulates energy balance and glucose homeostasis in rodents by activating its receptor GFRAL, expressed in the area postrema of the brain. However, whether GDF15-GFRAL signaling in the area postrema regulates glucose tolerance independent of changes in food intake and weight and contributes to the glucose-lowering effect of metformin remain unknown. Herein, we report that direct, acute GDF15 infusion into the area postrema of rats fed a high-fat diet increased intravenous glucose tolerance and insulin sensitivity to lower hepatic glucose production independent of changes in food intake, weight, and plasma insulin levels under conscious, unrestrained, and nonstressed conditions. In parallel, metformin infusion concurrently increased plasma GDF15 levels and glucose tolerance. Finally, a knockdown of GFRAL expression in the area postrema negated administration of GDF15, as well as metformin, to increase glucose tolerance independent of changes in food intake, weight, and plasma insulin levels. In summary, activation of GFRAL in the area postrema contributes to glucose regulation of GDF15 and metformin in vivo.

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Metformin, the most widely prescribed medication for obesity-associated type 2 diabetes (T2D), lowers plasma glucose levels, food intake, and body weight in rodents and humans, but the mechanistic site(s) of action remain elusive. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels to regulate energy balance, while GDF15 administration activates GDNF family receptor α-like (GFRAL) that is highly expressed in the area postrema (AP) and the nucleus of the solitary tract (NTS) of the hindbrain to lower food intake and body weight. However, the tissue-specific contribution of plasma GDF15 levels after metformin treatment is still under debate. Here, we found that metformin increased plasma GDF15 levels in high-fat (HF) fed male rats through the upregulation of GDF15 synthesis in the kidney. Importantly, the kidney-specific knockdown of GDF15 expression as well as the AP-specific knockdown of GFRAL expression negated the ability of metformin to lower food intake and body weight gain. Taken together, we unveil the kidney as a target of metformin to regulate energy homeostasis through a kidney GDF15-dependent AP axis.

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The area postrema (AP) of the brain is exposed to circulating metabolites and hormones. However, whether AP detects glucose changes to exert biological responses remains unknown. Its neighboring nuclei, the nucleus tractus solitarius (NTS), responds to acute glucose infusion by inhibiting hepatic glucose production, but the mechanism also remains elusive. Herein, we characterized AP and NTS glucose-sensing mechanisms. Infusion of glucose into the AP, like the NTS, of chow rats suppressed glucose production during the pancreatic (basal insulin)-euglycemic clamps. Glucose transporter 1 or pyruvate kinase lentiviral-mediated knockdown in the AP negated AP glucose infusion to lower glucose production, while the glucoregulatory effect of NTS glucose infusion was also negated by knocking down glucose transporter 1 or pyruvate kinase in the NTS. Furthermore, we determined that high-fat (HF) feeding disrupts glucose infusion to lower glucose production in association with a modest reduction in the expression of glucose transporter 1, but not pyruvate kinase, in the AP and NTS. However, pyruvate dehydrogenase activator dichloroacetate infusion into the AP or NTS that enhanced downstream pyruvate metabolism and recapitulated the glucoregulatory effect of glucose in chow rats still failed to lower glucose production in HF rats. We discovered that a glucose transporter 1- and pyruvate kinase-dependent glucose-sensing mechanism in the AP (as well as the NTS) lowers glucose production in chow rats and that HF disrupts the glucose-sensing mechanism that is downstream of pyruvate metabolism in the AP and NTS. These findings highlight the role of AP and NTS in mediating glucose to regulate hepatic glucose production.

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BACKGROUND: Given that visual impairment is bi-directionally associated with depression, we examined whether transcorneal electrical stimulation (TES), a non-invasive treatment for visual disorders, can ameliorate depressive symptoms. OBJECTIVE: The putative antidepressant-like effects of TES and the underlying mechanisms were investigated in an S334ter-line-3 rat model of retinal degeneration and a rat model of chronic unpredictable stress (CUS). METHODS: TES was administered daily for 1 week in S334ter-line-3 and CUS rats. The effects of TES on behavioral parameters, plasma corticosterone levels, and different aspects of neuroplasticity, including neurogenesis, synaptic plasticity, and apoptosis, were examined. RESULTS: In S334ter-line-3 rats, TES induced anxiolytic and antidepressant-like behaviors in the cylinder, open field, home cage emergence, and forced swim tests. In the CUS rat model, TES induced hedonic-like behavior and decreased behavioral despair, which were accompanied by reduced plasma corticosterone levels and upregulated expression of neurogenesis-related genes. Treatment with the neurogenesis blocker temozolomide only inhibited the hedonic-like effect of TES, suggesting the antidepressant-like effects of TES were mediated through both neurogenesis-dependent and -independent mechanisms. Furthermore, TES was found to normalize the protein expression of synaptic markers and apoptotic Bcl-2-associated X protein in the hippocampus and amygdala in the CUS rat model. The improvements in neuroplasticity may involve protein kinase B (AKT) and protein kinase A (PKA) signaling pathways in the hippocampus and amygdala, respectively, as demonstrated by the altered pAKT/AKT and pPKA/PKA ratios. CONCLUSION: The overall findings suggest a possible neuroplasticity mechanism of the antidepressant-like effects of TES.

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RATIONALE: The chronic mild stress (CMS) paradigm was first described almost 40 years ago and has become a widely used model in the search for antidepressant drugs for major depression disorder (MDD). It has resulted in the publication of almost 1700 studies in rats alone. Under the original CMS procedure, the expression of an anhedonic response, a key symptom of depression, was seen as an essential feature of both the model and a depressive state. The prolonged exposure of rodents to unpredictable/uncontrollable mild stressors leads to a reduction in the intake of palatable liquids, behavioral despair, locomotor inhibition, anxiety-like changes, and vegetative (somatic) abnormalities. Many of the CMS studies do not report these patterns of behaviors, and they often fail to include consistent molecular, neuroanatomical, and physiological phenotypes of CMS-exposed animals. OBJECTIVES: To critically review the CMS studies in rats so that conceptual and methodological flaws can be avoided in future studies. RESULTS: Analysis of the literature supports the validity of the CMS model and its impact on the field. However, further improvements could be achieved by (i) the stratification of animals into 'resilient' and 'susceptible' cohorts within the CMS animals, (ii) the use of more refined protocols in the sucrose test to mitigate physiological and physical artifacts, and (iii) the systematic evaluation of the non-specific effects of CMS and implementation of appropriate adjustments within the behavioral tests. CONCLUSIONS: We propose methodological revisions and the use of more advanced behavioral tests to refine the rat CMS paradigm, which offers a valuable tool for developing new antidepressant medications.

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The yellowtail rockfish, Sebastes flavidus, is a widespread and abundant mesopredator in the California Current Large Marine Ecosystem. We utilized stomach content and stable isotope analyses to investigate the trophic ecology of this species at three sites off central California just before (August-October 2013) and during (August and October 2014) a marine heat wave. Sebastes flavidus largely consumed pelagic prey (zooplankton and micronekton). Diets were dominated by tunicates (salps and pyrosomes), pelagic crustaceans (euphausiids, hyperid amphipods, larval decapods), and fishes, with the relative contribution of these prey taxa varying spatially (sample location, longitude, depth) and temporally (year, month), based on complementary multivariate analyses. Prey-specific indices demonstrated that individual S. flavidus diet composition typically was dominated by one of these prey groups, and that prey switching occurred based on the relative availability of prey and their energetic importance. Stable isotope analysis of δ15N indicated that the S. flavidus populations sampled in 2014 had been feeding at an elevated trophic position and more variable prey spectrum relative to 2013, probably as a consequence of greater piscivory and the incorporation of temporal changes in diet composition. Because its opportunistic feeding behavior reflects the dynamism and heterogeneity of the pelagic forage preyscape, S. flavidus may be an important ecosystem indicator species. For example, the novel incorporation of pyrosomes as a large portion of the diet of S. flavidus during 2013-2014 directly related to the massive increase in pyrosome abundance in the California Current during the 2014 marine heat wave.

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Recent marine spatial planning efforts, including the management and monitoring of marine protected areas (MPAs), increasingly focus on the importance of stakeholder engagement. For nearly 15 years, the California Collaborative Fisheries Research Program (CCFRP) has partnered volunteer anglers with researchers, the fishing industry, and resource managers to monitor groundfishes in California's network of MPAs. While the program has succeeded in generating sustained biological observations, we know little about volunteer angler demography or the impact of participation on their perceptions and opinions on fisheries data or MPAs. In this study we surveyed CCFRP volunteers to learn about (a) volunteer angler demographics and attitudes toward groundfish management and stock health, (b) volunteer angler motivations for joining and staying in the program, and (c) whether participation in the program influenced volunteer angler opinions on the quality of fisheries data used in resource management and the establishment of MPAs in California. CCFRP volunteers were older and had higher fishing avidity than average within the California recreational angling community. Many self-identified as more conservation-minded than their peers in the recreational fishing community and had positive views of California groundfish management and stock health. Participation in science and giving back to fisheries resources were major motivating factors in their decision to become and remain CCFRP volunteers. Angler opinions toward MPAs were more positive after volunteering with CCFRP. Those who had volunteered for seven or more years with CCFRP were more likely than not to gain a positive opinion of MPAs. Our survey results provide evidence that long-term engagement of stakeholders in collaborative research positively influences stakeholder opinions regarding marine resource management, and highlights CCFRP's success in engaging citizen science stakeholders in collaborative fisheries research.

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OBJECTIVES: To assess the association of a clinical decision support (CDS) algorithm for hospital discharge disposition with spending, readmissions, and postdischarge emergency department (ED) use. STUDY DESIGN: A retrospective study in a cohort of fee-for-service Medicare patients 65 years or older linked to a database of patients receiving CDS. METHODS: We evaluated (1) patients whose discharge disposition was concordant with the CDS recommendation versus those whose disposition was not and (2) patients receiving CDS for discharge disposition versus those not receiving CDS, regardless of concordance. Outcomes were spending over a 90-day episode, 90-day readmissions, and postdischarge ED utilization not associated with a readmission. RESULTS: Analysis of concordant versus discordant cases showed decreased spending for concordant cases ($860 savings; 95% CI, $162-$1558; P = .016), a decrease in readmissions (adjusted odds ratio [OR], 0.920; 95% CI, 0.850-0.995; P = .038), and no change in rate of postdischarge ED use (adjusted OR, 0.990; 95% CI, 0.882-1.110; P = .858). Analysis of patients receiving CDS versus not receiving CDS showed no significant difference in spending ($221 savings; 95% CI, -$115 to $557; P = .198), ED use (adjusted OR, 0.959; 95% CI, 0.908-1.012; P = .128), or readmission rate (adjusted OR, 1.004; 95% CI, 0.966-1.043; P = .840). CONCLUSIONS: Following the recommendation of a CDS algorithm for hospital discharge disposition was associated with lower spending, fewer readmissions, and no change in ED use over a 90-day episode of care.

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Meta-analyses of field studies have shown that biomass, density, species richness, and size of organisms protected by no-take marine reserves generally increase over time. The magnitude and timing of changes in these response variables, however, vary greatly and depend upon the taxonomic groups protected, size and type of reserve, oceanographic regime, and time since the reserve was implemented. We conducted collaborative, fishery-independent surveys of fishes for seven years in and near newly created marine protected areas (MPAs) in central California, USA. Results showed that initially most MPAs contained more and larger fishes than associated reference sites, likely due to differences in habitat quality. The differences between MPAs and reference sites did not greatly change over the seven years of our study, indicating that reserve benefits will be slow to accumulate in California's temperate eastern boundary current. Fishes in an older reserve that has been closed to fishing since 1973, however, were significantly more abundant and larger than those in associated reference sites. This indicates that reserve benefits are likely to accrue in the California Current ecosystem, but that 20 years or more may be needed to detect significant changes in response variables that are due to MPA implementation. Because of the high spatial and temporal variability of fish recruitment patterns, long-term monitoring is needed to identify positive responses of fishes to protection in the diverse set of habitats in a dynamic eastern boundary current. Qualitative estimates of response variables, such as would be obtained from an expert opinion process, are unlikely to provide an accurate description of MPA performance. Similarly, using one species or one MPA as an indicator is unlikely to provide sufficient resolution to accurately describe the performance of multiple MPAs.

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A 44-year-old woman with progressive cervical myelopathy and central cord syndrome was noted to have an extensive cervical intramedullary contrast-enhancing lesion on magnetic resonance imaging (MRI). The lesion resembled a spinal astrocytoma or ependymoma that required surgical intervention. She was subsequently diagnosed to have neuromyelitis optica (NMO), a rare idiopathic inflammatory demyelinating disorder, when the clinical examination revealed left optic atrophy. This was confirmed by a test showing seropositivity for NMO-immunoglobulin (IgG). Disease control was achieved with corticosteroids and immunosuppressive therapy. We report a rare case of a patient with NMO who had MRI features that could have easily led to the condition being misdiagnosed as a spinal cord tumor. The importance of careful history taking, awareness of typical radiological findings and the usefulness of serum NMO-IgG as a diagnostic tool are emphasized.

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PURPOSE: To determine the availability and accuracy of information provided by hospitals, imaging centers, and manufacturers regarding gluten in barium sulfate suspensions. METHODS: A total of 105 facilities were contacted via telephone to determine the gluten content of the contrast media used in those facilities. Manufacturers were contacted and their Web sites reviewed to determine the gluten content of their barium products. RESULTS: Thirty-nine percent of the hospitals and 52% of the imaging centers were not aware of the gluten content of the contrast media they used. Twenty-nine-and-a-half percent of the respondents provided the correct gluten content. The manufacturers noted that 5 products were tested and confirmed gluten free, 1 product was not tested but described as gluten free, 1 product's gluten content depended upon its flavor, and 1 product was reported to contain gluten. DISCUSSION: Clinicians caring for patients with celiac disease or patients who choose to restrict their gluten consumption must ensure that the barium sulfate suspension ingested is gluten free. CONCLUSION: It can be difficult to determine the gluten content of barium sulfate, as a majority of radiology departments and imaging centers did not know whether the product they use is gluten free. Educating staff members and improving product labeling would benefit the quality of care provided to patients with celiac disease.

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