Adult-onset Still's Disease with Acute Kidney Injury Requiring Hemodialysis: A Case Report and Literature Review.

Adult-onset Still's disease (AOSD) is characterized by high spiking fever, evanescent rash, and arthritis. However, AOSD rarely presents with severe acute kidney injury (AKI). We herein present the case of a 56-year-old woman with new-onset AOSD who rapidly developed AKI. A physical examination and laboratory data revealed spiking fever, evanescent rash, thrombocytopenia, hyperferritinemia, and azotemia. The patient was diagnosed with AOSD complicated by AKI and macrophage activation syndrome. Treatment with high-dose steroids, hemodialysis, and plasma exchange successfully resolved her AKI. In this report, we review previously published reports on AOSD accompanied by AKI and discuss this rare complication in AOSD.

PDK1-Foxo1 in agouti-related peptide neurons regulates energy homeostasis by modulating food intake and energy expenditure.

Insulin and leptin intracellular signaling pathways converge and act synergistically on the hypothalamic phosphatidylinositol-3-OH kinase/3-phosphoinositide-dependent protein kinase 1 (PDK1). However, little is known about whether PDK1 in agouti-related peptide (AGRP) neurons contributes to energy homeostasis. We generated AGRP neuron-specific PDK1 knockout (AGRPPdk1(-/-)) mice and mice with selective expression of transactivation-defective Foxo1 (Δ256Foxo1(AGRP)Pdk1(-/-)). The AGRPPdk1(-/-) mice showed reductions in food intake, body length, and body weight. The Δ256Foxo1(AGRP)Pdk1(-/-) mice showed increased body weight, food intake, and reduced locomotor activity. After four weeks of calorie-restricted feeding, oxygen consumption and locomotor activity were elevated in AGRPPdk1(-/-) mice and reduced in Δ256Foxo1(AGRP)Pdk1(-/-) mice. In vitro, ghrelin-induced changes in [Ca(2+)](i) and inhibition of ghrelin by leptin were significantly attenuated in AGRPPdk1(-/-) neurons compared to control neurons. However, ghrelin-induced [Ca(2+)](i) changes and leptin inhibition were restored in Δ256Foxo1(AGRP)Pdk1(-/-) mice. These results suggested that PDK1 and Foxo1 signaling pathways play important roles in the control of energy homeostasis through AGRP-independent mechanisms.

Stressor-responsive central nesfatin-1 activates corticotropin-releasing hormone, noradrenaline and serotonin neurons and evokes hypothalamic-pituitary-adrenal axis.

A recently discovered satiety molecule, nesfatin-1, is localized in neurons of the hypothalamus and brain stem and colocalized with stress-related substances, corticotropin-releasing hormone (CRH), oxytocin, proopiomelanocortin, noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Intracerebroventricular (icv) administration of nesfatin-1 produces fear-related behaviors and potentiates stressor-induced increases in plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in rats. These findings suggest a link between nesfatin-1 and stress. In the present study, we aimed to further clarify the neuronal network by which nesfatin-1 could induce stress responses in rats. Restraint stress induced c-Fos expressions in nesfatin-1-immunoreactive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus, and in the nucleus of solitary tract (NTS), locus coeruleus (LC) and dorsal raphe nucleus (DR) in the brain stem, without altering plasma nesfatin-1 levels. Icv nesfatin-1 induced c-Fos expressions in the PVN, SON, NTS, LC, DR and median raphe nucleus, including PVN-CRH, NTS-NA, LC-NA and DR-5-HT neurons. Nesfatin-1 increased cytosolic Ca2+ concentration in the CRH-immunoreactive neurons isolated from PVN. Icv nesfatin-1 increased plasma ACTH and corticosterone levels. These results indicate that the central nesfatin-1 system is stimulated by stress and activates CRH, NA and 5-HT neurons and hypothalamic-pituitary-adrenal axis, evoking both central and peripheral stress responses.

PDK-1/FoxO1 pathway in POMC neurons regulates Pomc expression and food intake.

Both insulin and leptin signaling converge on phosphatidylinositol 3-OH kinase [PI(3)K]/3-phosphoinositide-dependent protein kinase-1 (PDK-1)/protein kinase B (PKB, also known as Akt) in proopiomelanocortin (POMC) neurons. Forkhead box-containing protein-O1 (FoxO1) is inactivated in a PI(3)K-dependent manner. However, the interrelationship between PI(3)K/PDK-1/Akt and FoxO1, and the chronic effects of the overexpression of FoxO1 in POMC neurons on energy homeostasis has not been elucidated. To determine the extent to which PDK-1 and FoxO1 signaling in POMC neurons was responsible for energy homeostasis, we generated POMC neuron-specific Pdk1 knockout mice (POMCPdk1(-/-)) and mice selectively expressing a constitutively nuclear (CN)FoxO1 or transactivation-defective (Delta256)FoxO1 in POMC neurons (CNFoxO1(POMC) or Delta256FoxO1(POMC)). POMCPdk1(-/-) mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1(POMC) mice exhibited mild obesity and hyperphagia compared with POMCPdk1(-/-) mice. Although expression of the CNFoxO1 made POMCPdk1(-/-) mice more obese due to excessive suppression of Pomc gene, overexpression of Delta256FoxO1 in POMC neurons had no effects on metabolic phenotypes and Pomc expression levels of POMCPdk1(-/-) mice. These data suggest a requirement for PDK-1 and FoxO1 in transcriptional regulation of Pomc and food intake.

Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway.

The hypothalamic paraventricular nucleus (PVN) functions as a center to integrate various neuronal activities for regulating feeding behavior. Nesfatin-1, a recently discovered anorectic molecule, is localized in the PVN. However, the anorectic neural pathway of nesfatin-1 remains unknown. Here we show that central injection of nesfatin-1 activates the PVN and brain stem nucleus tractus solitarius (NTS). In the PVN, nesfatin-1 targets both magnocellular and parvocellular oxytocin neurons and nesfatin-1 neurons themselves and stimulates oxytocin release. Immunoelectron micrographs reveal nesfatin-1 specifically in the secretory vesicles of PVN neurons, and immunoneutralization against endogenous nesfatin-1 suppresses oxytocin release in the PVN, suggesting paracrine/autocrine actions of nesfatin-1. Nesfatin-1-induced anorexia is abolished by an oxytocin receptor antagonist. Moreover, oxytocin terminals are closely associated with and oxytocin activates pro-opiomelanocortin neurons in the NTS. Oxytocin induces melanocortin-dependent anorexia in leptin-resistant Zucker-fatty rats. The present results reveal the nesfatin-1-operative oxytocinergic signaling in the PVN that triggers leptin-independent melanocortin-mediated anorexia.

[Anorexia nervosa with refeeding syndrome: prevention and treatment of RS].

Refeeding syndrome (RS), seen in the early stages of anorexia nervosa (AN) treatment, has not been paid sufficient attention regarding its strong association with poor outcomes. This report describes a case of AN restriction type (AN-R) with sequent RS appearance despite the introduction of progressive and careful low-calorie nutrition, and discusses RS treatment. The patient was a 16-year-old female. She was first diagnosed with AN at the age of 14 when she went on a diet, admitted into pediatrics, and recovered: however, AN recurred after she started high school, and her weight decreased to 31.8 kg. She was admitted to pediatrics again, refused to receive treatment, discharged from the hospital, and introduced to our department. Soon after she came to us, her weight went down to 29.6 kg, and continued to decrease to 26.8 kg. She was recommended to receive inpatient care, but she firmly refused. A few days later, her experience of loss of consciousness made her agree to receive inpatient care. At this time, she was already weakened and had difficulty performing voluntary body movements as well as excretion. She was treated carefully and placed on 125 kcal/day. On the 6th day of treatment, severe liver damage was observed, her serum phosphorus level went down to 2.0 mg/dL, and she was diagnosed with RS. The lowest concentration of serum phosphorus observed was 1.3 mg/dL with blood abnormality and delirium; however, our strict management with intravascular phosphorus administration supported her increased dietary intake, and the patient was able to leave the hospital on the 54th day after admission. Based on this experience, the pathogenesis of RS was overviewed, and RS prevention as well as treatment was discussed. It has been reported that low phosphorus levels are observed in approximately one quarter of AN patients, and, thus, immediate action and treatment of hypophosphatemia are necessary when considering RS occurrence. In this study, the observed serum phosphorus concentration was higher than the general reported values; however, it is critical to pay attention to any quick drop in the serum phosphorus level rather than the absolute value. Also, as a preventative method, it is important to start the treatment before the patient's situation becomes critical. Since eating disorders are classified as psychiatric disorders, treatments under involuntary hospital admission should be allowed to avoid the worst situation. The following are suggestions to justify protective hospital admissions for such cases and their minimal requirements. Such actions should be taken for patients who are significantly underweight or in a critical health condition due to sudden weight loss. It is easier for patients to adapt to the treatment when the condition is new-onset or short disorder duration cases before they become chronic problems. After the caregiver-patient medical care relationship has been forget and significant effort has been made to get the patient to agree to treatment, compulsory treatment should be implemented in cases in which patients do not agree to treatment to avoid life-threatening situations.

[Roles and functional interplay of the gut, brain stem, hypothalamus and limbic system in regulation of feeding].

The brain controls feeding via two components; homeostatic and accessory regulation. Homeostatic regulation is executed by the hypothalamic centers. Accessory regulation occurs in response to environmental conditions and stimuli such as memory, stress, emotion, reward and hedonic feeling, which are operated by the limbic system, particularly the hippocampus and amygdala. Nutrients and visceral hormones, representing peripheral metabolic states, regulate activity of these brain areas, which is performed by direct action after entering through blood-brain area and by sending information via the vagus nerve and brain stem. We here review how the hippocampus and amygdala as well as gut, brain stem and hypothalamus function and interact with each other to achieve integrative regulation of feeding.