Iliopsoas muscle to visceral fat ratio on CT predicts Cushing's syndrome in elderly females with adrenal tumors.

There is no computed tomography (CT)-based numerical index for predicting Cushing's syndrome (CS) in patients with adrenal incidentalomas. We tested the hypothesis that the iliopsoas muscle (Ip-M) to visceral fat (V-fat) ratio (IVR) on CT may predict CS in elderly female patients with adrenal tumors. We examined the V-fat area, subcutaneous fat (S-fat) area, Ip-M area, V-fat/S-fat ratio, and IVR at the third lumbar vertebra (L3) level using abdominal CT in female patients aged ≥50 years with cortisol-producing adrenal tumor diagnosed with CS or non-functioning adrenal tumor (NFT) in the derivation cohort. We performed receiver operating characteristic (ROC) analysis to evaluate the diagnostic value of the V-fat/S-fat ratio and IVR for predicting CS. We assessed the usefulness of the IVR in a separate validation cohort. In the derivation cohort, the IVR was significantly lower in the 9 patients with CS than in the 15 patients with NFT (p < 0.001). In ROC analysis with a cut-off value of 0.067, the IVR showed a sensitivity of 100%, specificity of 80.0%, positive likelihood ratio (PLR) of 5.000, and negative likelihood ratio (NLR) of 0.000. The area under the curve was significantly higher for the IVR than for the V-fat/S-fat ratio (0.933 vs. 0.704, respectively, p = 0.036). In 23 patients in the validation cohort, the IVR demonstrated a PLR of 5.714 and an NLR of 0.327. The novel IVR index, based on single-slice CT at the L3 level, predicted CS in elderly female patients with adrenal tumors.

GHS-R1a deficiency mitigates lipopolysaccharide-induced lung injury in mice via the downregulation of macrophage activity.

Acute respiratory distress syndrome (ARDS) is a critical illness syndrome characterized by dysregulated pulmonary inflammation. Currently, effective pharmacological treatments for ARDS are unavailable. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a), has a pivotal role in regulating energy metabolism and immunomodulation. The role of endogenous ghrelin in ARDS remains unresolved. Herein, we investigated the role of endogenous ghrelin signaling by using GHS-R1a-null (ghsr-/-) mice and lipopolysaccharide (LPS)-induced ARDS model. Ghsr-/- mice survived longer than controls after LPS-induced lung injury. Ghsr-/- mice showed lower levels of pro-inflammatory cytokines and higher oxygenation levels after lung injury. The peritoneal macrophages isolated from ghsr-/- mice exhibited lower levels of cytokines production and oxygen consumption rate after LPS stimulation. Our results indicated that endogenous ghrelin plays a pivotal role in initiation and continuation in acute inflammatory response in LPS-induced ARDS model by modulating macrophage activity, and highlighted endogenous GHS-R1a signaling in macrophage as a potential therapeutic target in this relentless disease.

Neuromedin U suppresses insulin secretion by triggering mitochondrial dysfunction and endoplasmic reticulum stress in pancreatic ß-cells.

Neuromedin U (NMU), a highly conserved peptide in mammals, is involved in a wide variety of physiological processes. NMU, which is synthesized in ß-cells and co-localizes with insulin, directly acts on ß-cells via NMU receptor 1 (NMUR1) to suppress glucose-stimulated insulin secretion (GSIS). The mechanism underlying this insulinostatic effect has yet to be elucidated. We observed that NMU caused mitochondrial dysfunction by impairing mitochondrial biogenesis, respiration, and mitochondrial Ca2+ uptake in ß-cell-derived MIN6-K8 cells. NMU administration induced the endoplasmic reticulum (ER) stress, as reflected by the activation of ER stress signaling pathways involving ATF6, XBP-1s, and PERK-ATF4-CHOP. Nmu knockdown in MIN6-K8 cells increased the number of insulin granules and improved mitochondrial biogenesis and function. NMU was upregulated in both the islets of db/db mice and palmitate-treated MIN6-K8 cells. Our results highlight the crucial role of NMU in the maintenance of ß-cell function and glucose metabolism through regulation of mitochondria dysfunction and ER stress. In pathological stages that develop into diabetes, upregulation of NMU could suppress the insulin secretion by inducing mitochondrial dysfunction and ER stress, which may contribute to subsequent ß-cell dysfunction.

Neuromedin U suppresses prolactin secretion via dopamine neurons of the arcuate nucleus.

Neuromedin U (NMU) has a precursor that contains one additional peptide consisting of 33 or 36 amino acid residues. Recently, we identified this second peptide from rat brain and designated it neuromedin U precursor-related peptide (NURP), showing it to stimulate prolactin release from the pituitary when injected via the intracerebroventricular (icv) route. Here, we examined whether NMU, like NURP, also stimulates prolactin release. Unlike NURP, icv injection of NMU significantly decreased the secretion of prolactin from the pituitary. This suppression of prolactin release by NMU was observed in hyper-prolactin states such as lactation, stress, pseudopregnancy, domperidone (dopamine antagonist) administration, and icv injection of NURP. Immunohistochemical analysis revealed that icv injection of NMU induced cFos expression in dopaminergic neurons of the arcuate nucleus, but not the substantia nigra. Mice with double knockout of NMU and neuromedin S (NMS), the latter also binding to NMU receptors, showed a significant increase of the plasma prolactin level after domperidone treatment relative to wild-type mice. These results suggest that NMU and NURP may play important reciprocal roles in physiological prolactin secretion.

Elevated levels of circulating fibroblast growth factor 23 with hypercalcemia following discontinuation of denosumab.

We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.

Elevated levels of periostin and TGF-ß1 in the bronchoalveolar lavage fluid of patients with idiopathic eosinophilic pneumonia.

BACKGROUND: Periostin is induced in bronchial epithelial cells and fibroblasts by various stimuli including interleukin (IL)13 and transforming growth factor (TGF)-ß1, and is involved in allergic diseases such as asthma and atopic dermatitis, playing an important role in tissue remodeling and fibrosis. The role of periostin in the pathogenesis of eosinophilic lung diseases, however, is unclear. OBJECTIVE: To examine the contribution of periostin to eosinophilic inflammation of the lung in humans, we evaluated periostin, IL-13, and TGF-ß1 levels in the bronchoalveolar lavage fluid (BALF) of patients with eosinophilic pneumonia (EP). METHODS: Periostin, IL-13, and TGF-ß1 concentrations in the BALF were measured by enzyme-linked immunosorbent assay in patients with acute EP, chronic EP, idiopathic pulmonary fibrosis (IPF), and sarcoidosis. Further, we analyzed the relationship between periostin, IL-13, and TGFß-1, levels and the number of inflammatory cells in the BALF. RESULTS: The absolute number of eosinophils, and the periostin, IL-13, and TGF-ß1 levels in the BALF were significantly higher in patients with EP than in patients with IPF and sarcoidosis. Concentrations of periostin significantly correlated with the concentrations of TGF-ß1, but not those of IL-13, in the BALF of patients with EP. Periostin levels also significantly correlated with the absolute number of eosinophils in the BALF of patients with IPF, but not EP. CONCLUSIONS: Our findings suggest that TGF-ß1 might increase the production of periostin in the lungs of patients with EP. Periostin might contribute the pathogenesis of not only EP, but also IPF.

Factors associated with pneumococcal vaccination in elderly people: a cross-sectional study among elderly club members in Miyakonojo City, Japan.

BACKGROUND: Pneumonia is the third leading cause of death in Japan. All elderly people aged 65 years or older are recommended to receive a pneumococcal vaccine. A subsidy for part of the cost of routine pneumococcal vaccination in this age group was introduced in 2014. Factors related to vaccination behavior among elderly adults have not been well reported. The purpose of this study was to investigate factors associated with vaccine uptake among elderly people in Japan. METHODS: We conducted a cross-sectional study, using a self-administered questionnaire among elderly club members aged 65 years or older in one city of Japan in April 2017. The participants were selected from among all elderly club members in the study area. Variables extracted from the questionnaire were analyzed using logistic regression analysis. RESULTS: A total of 208 elderly club members participated in the study. The mean age (± SD) was 77.2 (± 5.3) years. The pneumococcal vaccination rate was 53.2%. Logistic regression analysis revealed three variables that had a significant association with pneumococcal vaccination: a recommendation for vaccination from medical personnel (aOR 8.42, 95% CI 3.59-19.72, p <  0.001), receiving influenza vaccination in any of the previous three seasons (aOR 3.94, 95% CI 1.70-9.13, p = 0.001), and perception of the severity of pneumonia (aOR 1.23, 95% CI 1.03-1.48, p = 0.026). CONCLUSIONS: Although the pneumococcal vaccination rate in this study was increased compared with previous reports, almost half of study participants had not yet received vaccination. Our findings could be helpful for developing vaccination strategies to increase the vaccine coverage in the elderly population.

Clinical Symptoms, Neurological Signs, and Electrophysiological Findings in Surviving Residents with Probable Arsenic Exposure in Toroku, Japan.

Chronic arsenic intoxication is known to cause multisystem impairment and is still a major threat to public health in many countries. In Toroku, a small village in Japan, arsenic mines operated from 1920 to 1962, and residents suffered serious sequelae of arsenic intoxication. We have performed annual medical examinations of these residents since 1974, allowing us to characterize participants' long-term health following their last exposure to arsenic. The participants could not be described as having "chronic arsenic intoxication," because their blood arsenic levels were not measured. In this study, we defined them as having "probable arsenic intoxication." Symptoms frequently involved the sensory nervous system, skin, and upper respiratory system (89.1-97.8%). In an analysis of neurological findings, sensory neuropathy was common, and more than half of the participants complained of hearing impairment. Longitudinal assessment with neurological examinations and nerve conduction studies revealed that sensory dysfunction gradually worsened, even after exposure cessation. However, we could not conclude that arsenic caused the long-term decline of sensory function due to a lack of comparisons with age-matched healthy controls. This is the first study to characterize the longitudinal sequelae after probable arsenic exposure. Our study will be helpful to assess the prognosis of patients worldwide who still suffer from chronic arsenic intoxication.

Neuromedin U suppresses glucose-stimulated insulin secretion in pancreatic ß cells.

Neuromedin U (NMU), a highly conserved peptide in mammals, is implicated in energy homeostasis and glycemic control, and may also be involved in the regulation of adipoinsular axis function. However, the role of NMU in regulating insulin secretion has not been clearly established. In this study, we investigated the role of NMU in the regulation of insulin secretion both in vitro and in vivo. We found that NMU and NMU receptor (NMUR) 1 were expressed in mouse islets and ß cell-derived MIN6-K8 cells. In mice, NMU suppressed glucose-stimulated insulin secretion (GSIS) both in vitro and in vivo. Additionally, an NMUR1 agonist inhibited GSIS in both MIN6-K8 cells and mice islets. Moreover, NMU attenuated intracellular Ca2+ influx in MIN6-K8 cells, potentially causing a decrease in insulin secretion. siNmu-transfected MIN6-K8 cells showed elevated GSIS. Treatment with anti-NMU IgG increased GSIS in isolated mouse pancreatic islets. These results suggested that NMU can act directly on ß cells through NMUR1 in an autocrine or paracrine fashion to suppress insulin secretion. Collectively, our results highlight the crucial role of NMU in suppressing pancreatic insulin secretion, and may improve our understanding of glucose homeostasis.

NERP-2 regulates gastric acid secretion and gastric emptying via the orexin pathway.

Neuroendocrine regulatory peptide (NERP)-2 is derived from a distinct region of VGF, a neurosecretory protein originally identified as a product of a nerve growth factor-responsive gene in rat PC12 cells. Colocalization of NERP-2 with orexin-A in the lateral hypothalamus increases orexin-A-induced feeding and energy expenditure in both rats and mice. Orexigenic and anorectic peptides in the hypothalamus modulate gastric function. In this study, we investigated the effect of NERP-2 on gastric function in rats. Intracerebroventricular administration of NERP-2 to rats increased gastric acid secretion and gastric emptying, whereas peripheral administration did not affect gastric function. NERP-2-induced gastric acid secretion and gastric emptying were blocked by an orexin 1 receptor antagonist, SB334867. NERP-2 also induced Fos expression in the lateral hypothalamus and the dorsomotor nucleus of the vagus X, which are key sites in the central nervous system for regulation of gastric function. Atropine, a blocker of vagal efferent signal transduction, completely blocked NERP-2-induced gastric acid secretion. These results demonstrate that central administration of NERP-2 activates the orexin pathway, resulting in elevated gastric acid secretion and gastric emptying.

Possible Role of IL-25 in Eosinophilic Lung Inflammation in Patients with Chronic Eosinophilic Pneumonia.

PURPOSE: Interleukin (IL)-25 and IL-33 induce IL-5 production by various types of cells, such as type 2 helper T (Th2) cells and type 2 innate lymphoid cells. The number of Th2 cells and concentration of IL-5 in the bronchoalveolar lavage fluid (BALF) are increased in patients with eosinophilic pneumonia (EP). To examine the contribution of IL-25 and IL-33 to eosinophilic inflammation of the lung in humans, we evaluated IL-5, IL-25 and IL-33 levels in the BALF of patients with EP. METHODS: IL-5, IL-25, and IL-33 concentrations in the BALF were measured by enzyme-linked immunosorbent assay in patients with acute eosinophilic pneumonia (AEP), chronic eosinophilic pneumonia (CEP), idiopathic pulmonary fibrosis (IPF), and sarcoidosis. RESULTS: The absolute number of eosinophils, and IL-5 levels, but not IL-33 levels, in the BALF were significantly higher in patients with EP than in patients with IPF and sarcoidosis. IL-25 levels in the BALF were significantly higher in patients with CEP, but not in patients with AEP, than in patients with IPF and sarcoidosis. The absolute number of eosinophils was significantly correlated with the IL-5 concentration in the BALF of patients with EP. IL-5 concentrations were significantly correlated with IL-25 concentrations in the BALF of patients with CEP, but not in patients with AEP. IL-5 levels were not correlated with IL-33 levels in the BALF of patients with EP. CONCLUSIONS: Our findings suggest that IL-25 plays an important role via IL-5 in eosinophilic lung inflammation in patients with CEP.

Clinical application of ghrelin for chronic respiratory failure.

Chronic respiratory failure, which is often caused by chronic obstructive pulmonary disease, chronic lower respiratory tract infection, or interstitial pneumonia, often leads to cachexia with disease progression. Patients who have chronic respiratory failure with cachexia exhibit increased morbidity. Although cachectic status is an important clinical problem, there are no effective therapies for cachexia. Ghrelin has various effects, including increasing food intake, attenuating sympathetic nerve activity, inhibiting inflammation, increasing cardiac output, and controlling fat utilization. These effects of ghrelin are ideal targets for the treatment of severely wasting chronic respiratory disease. In a few clinical studies, including a small randomized controlled trial, ghrelin administration to cachectic patients with chronic respiratory failure improved exercise tolerance, dyspnea, and appetite. The patients in these studies gained muscle mass and weight. In another study of chronic lower respiratory tract infection with cachexia, ghrelin suppressed airway inflammation by decreasing neutrophil accumulation in the airway, resulting in improvements in oxygenation and exercise tolerance. Although further clinical investigations are needed to clarify its usefulness, ghrelin is expected to become a novel therapy for cachectic patients with chronic respiratory failure.

Ghrelin does not influence cancer progression in a lung adenocarcinoma cell line.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), is produced in the human stomach. Although ghrelin has therapeutic potential for cancer cachexia, ghrelin treatment may have a concern about accelerating cancer progression. Here, using the human lung adenocarcinoma cell line HLC-1, we investigated the effects of ghrelin on molecular mechanisms linked to cancer progression, including cell viability, proliferation, resistance to apoptosis, and mitochondrial activity. Both types of mouse alveolar epithelial cells (types I and II) expressed the GHSR, as did the human normal airway cell lines BEAS-2B and HLC-1. Treatment with ghrelin (10-2, 10-1, 1, 10 µM) did not affect cell viability or proliferation. Pretreatment of HLC-1 cells with ghrelin (10 µM) did not affect resistance to paclitaxel-induced apoptosis. The parameters of mitochondrial respiration, including basal respiration, proton leak, ATP production, maximal respiration, spare respiratory capacity, and non-mitochondrial respiration, of the HLC-1 cells pretreated with or without ghrelin were unchanged. Taken together, ghrelin does not influence cancer progression in lung adenocarcinoma cells.

Clinical application of ghrelin for diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, and its progression significantly worsens the patient's quality of life. Although several drugs are available for DPN, all of these provide only symptomatic relief. We investigated the therapeutic effects of ghrelin for DPN, based on its various physiological functions. Seven patients with type 2 diabetes with typical clinical signs and symptoms of DPN were hospitalized. Synthetic human ghrelin (1.0 µg/kg) was administered intravenously for 14 days. Motor nerve conduction velocity (MCV) of the posterior tibial nerve improved significantly after the treatment, compared to that at baseline (35.1 ± 1.8 to 38.6 ± 1.8 m/s, p < 0.0001), while the MCV in six untreated patients did not change throughout hospitalization. The subjective symptoms assessed based on the total symptom score also significantly improved (15.6 ± 3.1 to 11.1 ± 2.2, p = 0.047). Although sensory nerve conduction velocity (SCV) of the sural nerve could not be detected in three patients at baseline, it was detected in two of the three patients after 14 days of ghrelin administration. Overall, SCV did not change significantly. Plasma glucose, but not serum C peptide, levels during a liquid meal tolerance test significantly improved after treatment. These results suggest that ghrelin may be a novel therapeutic option for DPN; however, a double-blind, placebo-controlled trial is needed in the future.

The Impacts of Cellular Senescence in Elderly Pneumonia and in Age-Related Lung Diseases That Increase the Risk of Respiratory Infections.

Pneumonia generates considerable negative impacts on the elderly. Despite the widespread uses of vaccines and appropriate antibiotics, the morbidity and mortality of elderly pneumonia are significantly higher compared to the counterparts of young populations. The definitive mechanisms of high vulnerability in the elderly against pathogen threats are unclear. Age-associated, chronic low-grade inflammation augments the susceptibility and severity of pneumonia in the elderly. Cellular senescence, one of the hallmarks of aging, has its own characteristics, cell growth arrest and senescence-associated secretory phenotype (SASP). These properties are beneficial if the sequence of senescence-clearance-regeneration is transient in manner. However, persisting senescent cell accumulation and excessive SASP might induce sustained low-grade inflammation and disruption of normal tissue microenvironments in aged tissue. Emerging evidence indicates that cellular senescence is a key component in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are known to be age-related and increase the risk of pneumonia. In addition to their structural collapses, COPD and IPF might increase the vulnerability to pathogen insults through SASP. Here, we discuss the current advances in understanding of the impacts of cellular senescence in elderly pneumonia and in these chronic lung disorders that heighten the risk of respiratory infections.

Ghrelin administration suppresses inflammation-associated colorectal carcinogenesis in mice.

Ghrelin is a 28-amino-acid peptide that stimulates the release of pituitary growth hormone. Because of its orexigenic effects, ghrelin is being developed as a therapeutic option for postoperative support and treatment of anorexia-cachexia syndrome of cancer patients. However, ghrelin has a multiplicity of physiological functions, and it also affects cell proliferation. Therefore, the effects of ghrelin administration on carcinogenesis and cancer progression in patients susceptible to cancer should be clarified. In this study, we examined the effects of ghrelin on cancer promotion in vivo using murine intestinal carcinogenesis models. Intestinal tumorigenesis was examined to determine the effects of either exogenous ghrelin administration or ghrelin deficiency following deletion of the Ghrl gene. Two murine intestinal tumorigenesis models were used. The first was the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced inflammation-associated colon carcinogenesis model and the second was the Apc(Min/+) genetic cancer susceptibility model. In AOM/DSS-treated mice, administration of ghrelin significantly suppressed tumor formation in the colon. In contrast, ghrelin administration did not affect the number of intestinal tumors formed in Apc(Min/+) mice. The absence of endogenous ghrelin did not affect the incidence of intestinal tumors in either AOM/DSS-treated mice or Apc(Min/+) mice, though tumor size tended to be larger in Ghrl(-/-) colons in the AOM/DSS model. No tumor-promoting effect was observed by ghrelin administration in either tumorigenesis model. In summary, this study provides in vivo experimental evidence for the usefulness of ghrelin administration in the chemoprevention of inflammation-associated colorectal carcinogenesis and may suggest its safety in patients under colitis-associated cancer susceptibility conditions.

One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice.

A high-fat diet (HFD) induces inflammation in systemic organs including the hypothalamus, resulting in obesity and diabetes. The vagus nerve connects the visceral organs and central nervous system, and the gastric-derived orexigenic peptide ghrelin transmits its starvation signals to the hypothalamus via the vagal afferent nerve. Here we investigated the inflammatory response in vagal afferent neurons and the hypothalamus in mice following one day of HFD feeding. This treatment increased the number of macrophages/microglia in the nodose ganglion and hypothalamus. Furthermore, one-day HFD induced expression of Toll-like receptor 4 in the goblet cells of the colon and upregulated mRNA expressions of the proinflammatory biomarkers Emr1, Iba1, Il6, and Tnfα in the nodose ganglion and hypothalamus. Both subcutaneous administration of ghrelin and celiac vagotomy reduced HFD-induced inflammation in these tissues. HFD intake triggered inflammatory responses in the gut, nodose ganglion, and subsequently in the hypothalamus within 24 h. These findings suggest that the vagal afferent nerve may transfer gut-derived inflammatory signals to the hypothalamus via the nodose ganglion, and that ghrelin may protect against HFD-induced inflammation.

Chronic effects of neuroendocrine regulatory peptide (NERP-1 and -2) on insulin secretion and gene expression in pancreatic ß-cells.

Neuroendocrine regulatory peptides (NERP-1 and -2) are novel amidated peptides derived from VGF, a polypeptide secreted from neurons and endocrine cells through a regulated pathway. Dr. Nakazato Masamitsu reported that NERP-1 and -2 may have a local modulator function on the human endocrine system, and clearly showed expression of NERP-1 and -2 in human pancreas islets. Based on these data, we investigated the alteration of insulin secretion, insulin granule-related protein, and pancreas-specific transcription factors in response to NERPs expression. We confirmed the expression of NERP-1 and -2 in the pancreas of a human diabetes patient, in addition to diabetic animal models. When INS1 cells and primary rat islets were incubated with 10nM NERPs for 3 days, glucose-stimulated insulin secretion levels were blunted by NERP-1 and -2. The number of insulin granules released from the readily releasable pool, which is associated with the first phase of glucose-stimulated insulin release, was decreased by NERP-1 and -2. Insulin granule-related proteins and mRNAs were down-regulated by NERP-2 treatment. NERP-2 decreased the expression of BETA2/NeuroD and insulin and controlled the nucleo-cytoplasmic translocation of FOXO1 and Pdx-1. We observed that NERP-2 levels were dramatically increased in diabetic pancreas. In conclusion, NERP-2 may play an important role in insulin secretion through the regulation of insulin secretory granules and ß-cell transcription factors. In addition, NERP-2 expression is increased in diabetic conditions. Therefore, we suggest that NERPs may be potent endogenous suppressors of glucose-dependent insulin secretion.

Hypometabolism of watershed areas of the brain in HTLV-1-associated myelopathy/tropical spastic paraparesis.

In previous studies of human T-lymphotropic virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), areas of slow blood flow in the spinal cord were related to pathological changes. While the pathological changes in the brain are milder than those in the spinal cord, they are also more significant in sites with slow blood flow. In this study, we investigated brain glucose metabolism in slow blood flow areas using fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET). Clinical features and brain (18)F-FDG-PET parameters were analyzed in six patients with HAM/TSP. For comparison of PET data, eight healthy volunteers were enrolled as normal controls (NLs). Glucose metabolism in the watershed areas of the middle and posterior cerebral arteries, as compared with that in the occipital lobes as a control, was significantly lower in HAM/TSP patients than in NLs. This result confirmed the relationship between slow blood flow areas and hypometabolism in HAM/TSP, and is consistent with previous findings that pathological changes are accentuated in sites with slow blood flow.

Ghrelin administration for chronic respiratory failure: a randomized dose-comparison trial.

BACKGROUND: Repeated ghrelin administration leads to improvements in symptoms, muscle wasting and exercise tolerance in cachectic patients with pulmonary disease. We investigated the optimal ghrelin dose for underweight patients with chronic respiratory failure. METHODS: In this multicenter, randomized, dose-comparison exploratory study, 44 cachectic patients with chronic respiratory failure were randomly assigned pulmonary rehabilitation with intravenous twice-daily administration of 1 or 2 µg/kg ghrelin for 3 weeks. The primary endpoint was improvement in 6-min walking distance (6 MWD). The secondary endpoint was change in peak VO2. RESULTS: Twenty-one patients were assigned to the 1 µg/kg ghrelin group and 23 to the 2 µg/kg ghrelin group. Change from baseline 6 MWD after treatment was similar between groups(1 µg/kg: 53.9 m, 2 µg/kg: 53.9 m, p = 0.99). Mean change in peak VO2 was significantly greater in the 2 µg/kg group (63.1 ml/min) than in the 1 µg/kg group (-63.8 ml/min, p = 0.048). Food intake and lean body mass significantly increased in both groups, and the St. George Respiratory Questionnaire score, body weight, and body mass index were remarkably improved in only the 2 µg/kg group, although there was no significant difference between groups. No treatment-related serious events were reported for either group. CONCLUSION: Improvements in the oxygen uptake capacity were greater in patients receiving 2 µg/kg ghrelin twice daily for 3 weeks than in those receiving 1 µg/kg, although exercise tolerance was similar between groups at the end of the 3-week treatment period. Thus, a twice daily dose of 2 µg/kg ghrelin is recommended over 1 µg/kg ghrelin for patients with chronic respiratory failure and weight loss.