Endocrine, inflammatory and immune responses and individual differences in acute hypobaric hypoxia in lowlanders.

When lowlanders are exposed to environments inducing hypobaric hypoxia (HH) such as high mountains, hemodynamic changes occur to maintain oxygen levels in the body. However, changes to other physiological functions under such conditions have yet to be clarified. This study investigated changes in endocrine, inflammatory and immune parameters and individual differences during acute HH exposure using a climatic chamber (75 min of exposure to conditions mimicking 3500 m) in healthy lowlanders. Aldosterone and cortisol were significantly decreased and interleukin (IL)-6, IL-8 and white blood cell (WBC) counts were significantly increased after HH. Lower peripheral oxygen saturation (SpO2) was associated with higher IL-6 and WBC counts, and higher IL-8 was associated with higher cortisol. These findings suggest that endocrine, inflammatory and immune responses are evoked even with a short 75-min exposure to HH and individuals with lower SpO2 seemed to show more pronounced responses. Our results provide basic data for understanding the physiological responses and interactions of homeostatic systems during acute HH.

Risk Factors of Hypoglycemic Encephalopathy and Prolonged Hypoglycemia in Patients With Severe Hypoglycemia.

BACKGROUND: The aim of the study was to investigate risk factors of hypoglycemic encephalopathy (HE) in patients with severe hypoglycemia. METHODS: We retrospectively enrolled patients with severe hypoglycemia who were transported to the emergency department in an ambulance. We defined severe hypoglycemia as plasma glucose level < 60 mg/dL (or capillary levels < 50 mg/dL). HE was defined as severe hypoglycemia with altered level of consciousness (Glasgow coma scale < 12) and prolonged HE as coma or stupor lasting > 24 h after glucose administration. We compared several parameters between patients with and without HE and between prolonged and recovered patients. RESULTS: Included were 173 patients with severe hypoglycemia; of them, 94 were diagnosed with HE, with 12 of them prolonged HE. Glucose level in HE patients was lower than that in those without HE (P < 0.001). Moreover, we noted a significant difference in glucose levels between the prolonged and recovered groups. Furthermore, body temperature was higher in prolonged versus recovered patients (P = 0.0017). CONCLUSION: Blood glucose level may be correlated with severity of altered level of consciousness. In addition, body temperature may be related to coma or prolonged stupor.

Therapeutic Efficacy of Twin-Block and Fixed Oral Appliances in Patients with Obstructive Sleep Apnea Syndrome.

PURPOSE: To compare the efficacy of twin-block (i.e., allows mouth opening) and fixed (i.e., maintains mouth closure) mandibular advancement splints (MASs) for the treatment of obstructive sleep apnea-hypopnea syndrome (OSA). MATERIALS AND METHODS: From 2011 to 2013, 23 patients with OSA in the twin-block group, and from 2013 to 2015, 29 patients in the fixed MAS group were included. All patients underwent polysomnography before and after 3 months of treatment. The two sets of polysomnographic and cephalometric variables were compared. RESULTS: A significant difference (p < 0.001) was observed in the apnea-hypopnea index before and after MAS treatment in both groups (twin-block group: 20.6 ± 11.5 vs. 14.7 ± 9.4; fixed group: 21.4 ± 15.2 vs. 11.2 ± 9.7). In the twin-block group, 5 patients (21.7%) were complete responders, 9 (39.1%) were fair responders, and 9 (39.1%) were nonresponders; the corresponding figures for the fixed group were 14 (48.3%), 9 (31.0%), and 6 (20.7%) patients. A significant between-group difference was observed in the distribution of responders (p = 0.046). The fixed group showed a significant improvement in the snoring index (p = 0.003), arousal index (p = 0.036), and desaturation rate (p = 0.012). Finally, the change in incisal overjet was larger in the fixed group than in the twin-block group (p < 0.001). CONCLUSIONS: These results suggest that fixed oral appliances are superior in treating OSA, based on their ability to prevent mouth opening and reduce incisal overjet.

Hypothalamic type of hypopituitarism and central diabetes insipidus probably linked to Rathke's cleft cyst.

A 73-year-old woman was admitted due to weight loss and generalized malaise. The basal levels of all the anterior pituitary hormones, except for prolactin, were reduced. However, they were all elevated in response to exogenous hypothalamic hormones. After starting hydrocortisone replacement, the patient had polyuria of >5,000 mL/day. T1-weighted MRI depicted a low signal of an oval mass in the sella turcica and an iso-intense signal of another mass at the pituitary stalk. These findings indicate a hypothalamic type of hypopituitarism and masked central diabetes insipidus which possibly derived from the atypical occupation of Rathke's cleft cyst at the pituitary stalk.

Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes.

There is evidence that betatrophin, a hormone derived from adipose tissue and liver, affects the proliferation of pancreatic beta cells in mice. The aim of this study was to examine circulating betatrophin concentrations in Japanese healthy controls and patients with type 1 and type 2 diabetes. A total of 76 subjects (12 healthy controls, 34 type 1 diabetes, 30 type 2 diabetes) were enrolled in the study. Circulating betatrophin was measured with an ELISA kit and clinical parameters related to betatrophin were analyzed statistically. Circulating betatrophin (Log transformed) was significantly increased in patients with diabetes compared with healthy subjects (healthy controls, 2.29 ± 0.51; type 1 diabetes, 2.94 ± 0.44; type 2 diabetes, 3.17 ± 0.18; p<0.001, 4.1 to 5.4 times in pg/mL order). Age, HbA1c, fasting plasma glucose and Log triglyceride were strongly associated with Log betatrophin in all subjects (n=76) in correlation analysis. In type 1 diabetes, there was a correlation between Log betatrophin and Log CPR. These results provide the first evidence that circulating betatrophin is significantly elevated in Japanese patients with diabetes. The findings of this pilot study also suggest a possibility of association between the level of betatrophin and the levels of glucose and triglycerides.

Central diabetes insipidus and hypothalamic type of hypopituitarism associated with atypical location of Rathke's cleft cyst.

A 68-year-old woman was admitted to determine the pathogenesis of weight loss and polyuria. Physical findings on admission showed BMI of 20.9, blood pressure of 147/69 mmHg, and that she had ciliac, axillar and pubic hair loss. Laboratory findings showed that plasma adrenocorticotropic hormone (ACTH) was 4.6 pg/mL with serum cortisol of 1.2 µg/dL. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were markedly reduced. Serum growth hormone (GH) and insulin growth factor (IGF)-1 were 0.054 ng/mL and 25 ng/mL, respectively. Serum prolactin was as high as 85.6 ng/mL. The levels of all the pituitary hormones were elevated in response to a mixture of exogenous corticotrophin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and growth hormone-releasing hormone (GRH). However, there was no response of ACTH and GH release to insulin-induced hypoglycemia and no response of LH and FSH release to clomiphene. Urine volume was more than 4,000 mL, with low urine osmolality of 134 mmol/kg. Plasma arginine vasopressin (AVP) was 0.8 pg/mL. There was no increase in urine osmolality and plasma AVP in response to 5% hypertonic saline load. Magnetic resonance imaging revealed Rathke's cleft cyst at the pituitary stalk level, but there was no abnormal finding in the hypothalamus. These findings indicate central diabetes insipidus and hypothalamic type of hypopituitarism, resulting from the atypical location of Rathke's cleft cyst.

Ectopic ACTH syndrome associated with large cell neuroendocrine carcinoma of the thymus.

A 38-year-old man was admitted for evaluation of Cushing's syndrome. Physical findings showed swelling of the face, and hypertension, but not Cushingoid stigmata. Laboratory data revealed serum cortisol level of 34.1 µg/dL and plasma ACTH of 140 pg/mL. Overnight administration of 1 and 8 mg dexamethasone did not suppress plasma ACTH or serum cortisol. Chest X-ray showed a mass at the upper-anterior quadrant of the mediastinum, and chest CT scan revealed a heterogenous tumor of approximately 60 mm in diameter, which infiltrated into the superior vena cava and ascending aorta, and caused superior vena cava syndrome. The tumor was resected. Histological examination indicated large cell neuroendocrine carcinoma of the thymus and positive immunoreactivity for ACTH. Ten days after the operation, the plasma ACTH decreased as low as 13.7 pg/mL. The present study indicates that large cell neuroendocrine carcinoma of the thymus can cause superior vena cava syndrome and ectopic ACTH syndrome.

Bilateral aldosteronoma associated with secondary aldosteronism in a chronic hemodialysis subject.

We demonstrated a rare case of bilateral aldosteronoma accompanied by secondary aldosteronism in a 37-year-old man with chronic renal failure on hemodialysis. He initially developed immunoglobulin A nephropathy at 11 years old, and had been treated with hemodialysis since the age of 17 years. His blood pressure was 110/68 mmHg, and no other abnormal findings were detected. Laboratory findings revealed that serum potassium was 3.9 mmol/L; plasma renin activity, 4.8 ng/ml/h and plasma aldosterone, 19,000 pg/mL. Abdominal computed tomography revealed bilateral adrenocortical tumors, measuring 34 and 40 mm in diameter in right and left tumors, respectively. (131)I-Adosterol scintigram showed bilateral accumulation. Left adrenalectomy was performed under laparoscopy. The tumor was encapsulated and well-circumscribed. The majority of the tumor was composed of a dark-brown portion admixed with sporadic foci of golden-yellow portions. Hyaline degeneration was detected in its central portion. The tumor was composed of clear cortical cells in viable portions. Tumor cells demonstrated immunoreactivity for the cholesterol side-chain cleavage enzyme, 3beta-hydroxysteroid dehydrogenase (3beta-HSD II) and 21-hydroxylase, but not 17 alpha-hydroxylase. In the adjacent non-neoplastic adrenals, 3 beta-HSD II was markedly present in the hyperplastic glomerulosa zone. These findings suggest that the presence of secondary aldosteronism, which is closely related to the conditions of chronic renal failure on hemodialysis, eventually promoted the development of bilateral aldosteronoma from the zona glomerulosa hyperplasia.

[A case of hospital-acquired pneumonia caused by intermediately susceptible carbapenem Acinetobacter baumannii].

The incidence of Acinetobacter baumannii pneumonia in hospital-acquired pneumonia in Japan is rare. We report a case of ventilator-associated A. baumanii pneumonia. A 69-year-old man admitted for fever was diagnosed with Streptococcus pneumoniae pneumonia based on chest radiography, urine antigen, and sputum examination. Despite appropriate antibiotics, the pneumonia progressed, necessitating intensive respiratory management. Ten days there after, he suffered sudden septic shock and superimposed pneumonia despite both carbapenem and fluoroquinolone administration. A. baumanii was detected from blood and sputum. Piperacilline/tazobactam, amikacin, and intensive care saved his life.

Acute myocardial infarction due to malignant neoplastic coronary embolus.

A 54-year old man was diagnosed with right lung carcinoma (squamous cell carcinoma, SCC), stage IIIB (c-T2N3M0). Transthoracic echocardiography (TTE) showed a huge 8.9 cm × 1.3 cm tumor in the left atrium (LA) that was invaded by a pulmonary vein, and the tumor moved under the mitral valve at LA systole. After 3 months, he was diagnosed with acute myocardial infarction (AMI) and emergency coronary angiography (CAG) was performed. CAG showed that the distal segment of the right coronary artery was totally occluded. TTE showed that the shape of the mass tip became sharp. He was discharged on hospital day 15. He died 4 months after discharge because of right lung carcinoma with respiratory failure. An autopsy showed that the cause of AMI was tumor embolism. SCC clearly occupied a blood vessel lumen in the distal segment. This is a rare case of AMI due to embolism of lung carcinoma during progression of the disease with direct invasion to the LA. TTE is useful for assessing lung carcinoma invasion.

Incomplete deficiency of hypothalamic hormones in hypothalamic hypopituitarism associated with an old traumatic brain injury.

A 62 year-old man was admitted to determine the pathogenesis of his hypoglycemia. He was unconscious and his plasma glucose level was 26 mg/dL. When he was 31 years old, he had a traffic accident and was unconscious for several days. Physical findings on admittance showed that the patient's BMI was 17.8 and blood pressure, 114/70 mmHg. He was alert. He had a hypogonadal face with a lack of beard, and he had an atrophic testis with a volume of 1 to 2 ml. Laboratory findings showed that his fasting plasma glucose was 73 mg/dL; serum sodium, 133 mmol/l; potassium, 4.1 mmol/l; serum insulin, less than 1.0 muU/ml.; plasma ACTH, 45.8 pg/ml; serum cortisol, 5.2 microg/dL; and free cortisol urinary excretion, less than 4.5 microg/day; serum LH, 0.8 mIU/ml; serum testosterone, less than 0.05 ng/ml; serum TSH, 2.0 uIU/ml; free T(4), 0.7 ng/dL; free T(3), 1.5 pg/ml; and serum prolactin, 29.0 ng/ml. The levels of all the pituitary hormones were elevated in response to a mixture of exogenous corticotrophin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and growth hormone-releasing hormone (GRH). However, there was no increased secretion of adrenocorticotropic hormone (ACTH) in response to hypoglycemia (induced by the administration of insulin) and there was no increased secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in response to the administration of clomiphene. Magnetic resonance imaging revealed an atrophied pituitary gland with an empty sella, but there were no abnormal findings of the hypothalamus. Hydrocortisone replacement at a dosage of 20 mg/day increased the patient's plasma glucose from 73 to 100 mg/dL and his serum sodium from 133 to 138 mmol/l. These findings therefore indicate a partial impairment in hypothalamic hormone release, resulting from a traumatic brain injury that the patient had received 31 years ago.

Regulation of voltage-gated K+ channels by glucose metabolism in pancreatic beta-cells.

Regulation of delayed rectifier-type K(+) channels (Kv-channels) by glucose was studied in rat pancreatic beta-cells. The Kv-channel current was increased in amplitudes by increasing glucose concentration from 2.8 to 16.6mM, while it was decreased by 2.8mM glucose in a reversible manner (down-regulation) in both perforated and conventional whole-cell modes. The current was decreased by FCCP, intrapipette 0mM ATP or AMPPNP. Glyceraldehyde, pyruvic acid, 2-ketoisocaproic acid, and 10mM MgATP prevented the down-regulation induced by 2.8mM or less glucose. The residual current after treatment with Kv2.1-specific blocker, guangxitoxin-1E, was unchanged by lowering or increasing glucose concentration. We conclude that glucose metabolism regulates Kv2.1 channels in rats beta-cells via altering MgATP levels.

SPARC is a major secretory gene expressed and involved in the development of proliferative diabetic retinopathy.

AIM: Neovascularization is an important event in proliferative diabetic retinopathy (PDR), where various secretory proteins including multiple growth factors are considered to be involved in this process. We searched for secretory proteins expressed in a surgical specimen obtained from the eyes of patients with PDR. METHODS: We developed the oligo-cap signal sequence trap (SST) strategy which enables us to screen for secretory or membrane proteins from a minimal starting material. Using this method, we were able to screen a cDNA library constructed from a surgical specimen obtained from the eyes of the patients with PDR. RESULTS: Majority of the cloned cDNAs turned out to encode secreted protein acidic and rich in cystein (SPARC), strongly suggesting that SPARC is highly expressed in PDR. Analysis of vitreous fluid from various patients has shown that the concentration of SPARC protein is increased in patients with PDR. Furthermore, subretinal injection of recombinant SPARC adenovirus induced PDR-like changes in the rat eye. CONCLUSIONS: Our results strongly suggested that SPARC is involved in the development of diabetic retinopathy (DR).

An increase in serum retinol-binding protein 4 in the type 2 diabetic subjects with nephropathy.

UNLABELLED: The present study was undertaken to determine retinol-binding protein 4 (RBP4) levels in subjects with diabetic nephropathy. A total of 149 type 2 diabetic subjects and 19 control subjects were enrolled. Serum levels of RBP4 were measured by a method of ELISA. Serum RBP4 levels were significantly greater in the subjects with type 2 diabetes mellitus than the controls (70.5 +/- 35.3 vs. 40.1 +/- 13.0 microg/ml, mean +/- SD, p<0.01). Serum RBP4 levels were gradually increased according to the progression of diabetic nephropathy (p value in trend test: <0.001). Its elevation was significantly greater in the diabetic subjects with stages 1, 3B and 4 than the control subjects (Stage 1: 64.6 +/- 29.7, Stage 3B: 123.3 +/- 71.8, Stage 4: 91.4 +/- 33.8 vs. CONTROL: 40.1 +/- 13.0 microg/ml, p<0.01). Similar results were obtained in the subjects based on the amount of albuminuria (Normo-: 64.6 +/- 29.7, Micro-: 63.7 +/- 29.4, and Marcoalbuminuria: 90.3 +/- 44.6 microg/ml, p <0.001). Serum RBP4 levels had a positive correlation with serum creatinine levels(r = 0.377, p<0.001), and a negative correlation with 1/creatinine (r = -0.420, p<0.001). Also, there was a negative correlation between serum RBP4 and the estimated glomerular filtration rate(r = -0.436, p<0.001). Multiple regression analysis showed that estimated glomerular filtration rate was an independent determinant for increased serum RBP4 levels. There was no difference in serum RBP4 levels between the advanced nephropathy with and without macrovascular diseases. These results indicate an increase in serum RBP4 levels in the type 2 diabetic subjects, particularly complicated with advanced renal impairment.

Cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is involved in adipocyte differentiation and hypertrophy, linking to obesity, and insulin resistance.

Both adipocyte hyperplasia and hypertrophy are determinant factors for adipocyte differentiation during the development of obesity. p21(WAF1/CIP1), a cyclin-dependent kinase inhibitor, is induced during adipocyte differentiation; however, its precise contribution to this process is unknown. Using both in vitro and in vivo systems, we show that p21 is crucial for maintaining adipocyte hypertrophy and obesity-induced insulin resistance. The absence of p21 in 3T3-L1 fibroblasts by RNA-mediated interference knockdown or in embryonic fibroblasts from p21(-/-) mice impaired adipocyte differentiation, resulting in smaller adipocytes. Despite normal adipose tissue mass on a normal diet, p21(-/-) mice fed high energy diets had reduced adipose tissue mass and adipocyte size accompanied by a marked improvement in insulin sensitivity. Knockdown of p21 in enlarged epididymal fat of diet-induced obese mice and also in fully differentiated 3T3-L1 adipocytes caused vigorous apoptosis by activating p53. Thus, p21 is involved in both adipocyte differentiation and in protecting hypertrophied adipocytes against apoptosis. Via both of these mechanisms, p21 promotes adipose tissue expansion during high fat diet feeding, leading to increased downstream pathophysiological consequences such as insulin resistance.

[A case of multidrug-resistant squamous cell lung carcinoma responding to S-1 plus CPT-11 combination chemotherapy].

The patient was a 63-year-old man who consulted our hospital with complaints of a cough and breathing difficulties. His chest CT revealed a 25-mm mass in his right S1 hilar area with spiculation, disseminated nodule in right lung, and pericardial effusions. Also, bronchoscope and TBLB revealed squamous cell carcinoma. This patient was diagnosed as lung cancer (cT4N3M1, stage IV), and chemotherapy was initiated. The chemotherapy was given in the order of CBDCA (AUC3) +GEM (1,000 mg/m(2)), DOC (60 mg/m(2)), and VNR (25 mg/m(2)), and the tumor response was PD. S- 1 (120 mg/body/day, continuous administration for 2 weeks followed by 1 week of rest) was chosen as fourth-line treatment, and a breast CT detected tumor size reduction following completion of the first course. However, after completion of three courses, the breast CT found tumor-enlargement again. Then the chemotherapy was changed to amrubicin (35 mg/m(2)), but the treatment was discontinued due to skin rash. We once experienced a size reduction with S-1, so S-1 (100 mg/body/day, day 1-14) plus CPT-11 (60 mg/m(2), day 1, 7, 14) combination chemotherapy was conducted at 4-week intervals. After two courses were completed, tumor size reduction was observed by breast XP and CT. The response rate was 40.0%. Currently, seven courses were completed, and we will continue this treatment due to the tumor response of SD. The S-1 single treatment and S-1+CPT-11 combination chemotherapy showed efficacy for this difficult case of NSCLC with refractoriness to multiple cancer drug chemotherapy. This combination treatment should be investigated further for its therapeutic benefit.

Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance.

Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.

Identification of ISG12b as a putative interferon-inducible adipocytokine which is highly expressed in white adipose tissue.

AIM: A number of adipocytokines have been suggested to be involved in the disruption of glucose metabolism, and also in the development of various diabetic complications. We attempted to identify and analyze additional adipocytokines, to better understanding the roles of adipocytes and adipocytokines. METHODS: An oligo-capping signal sequence trap, developed in our laboratory for screening the cDNAs of secretory proteins, was used to sreen cDNAs expressed in mouse white adipose tissue. Profiles of the genes identified in mice and cultured cells were further investigated by northern blotting and luciferase assay. RESULTS: A cDNA fragment of interferon-stimulated gene 12b (ISG12b) was obtained in the search. A northern blot analysis revealed ISG12b to be highly expressed in white adipose tissue. Interferon alpha (IFNalpha) was shown to induce ISG12b expression in the adipose tissue of BL6 mice in vivo, and also in a 3T3-L1 preadipocyte cell line in vitro. The level of ISG12b was higher in mature adipocytes than in preadipocytes. A promoter analysis demonstrated that the 369bp upstream from the transcription initiation site of ISG12b mRNA contain strong promoter activity, and the interferon-stimulated response elements (ISREs) were not present within the 5593bp upstream region. CONCLUSION: ISG12b is an additional candidate for a adipocytokine induced to express in adipose tissue by interferon.

A transcription factor of lipid synthesis, sterol regulatory element-binding protein (SREBP)-1a causes G(1) cell-cycle arrest after accumulation of cyclin-dependent kinase (cdk) inhibitors.

Sterol regulatory element-binding protein (SREBP)-1a is a unique membrane-bound transcription factor highly expressed in actively growing cells and involved in the biosynthesis of cholesterol, fatty acids, and phospholipids. Because mammalian cells need to synthesize membrane lipids for cell replication, the functional relevance of SREBP-1a in cell proliferation has been considered a biological adaptation. However, the effect of this potent lipid-synthesis activator on cell growth has never been explored. Here, we show that induction of nuclear SREBP-1a, but not SREBP-2, completely inhibited cell growth in inducible Chinese hamster ovary (CHO) cell lines. Growth inhibition occurred through G(1) cell-cycle arrest, which is observed in various cell types with transient expression of nuclear SREBP-1a. SREBP-1a caused the accumulation of cyclin-dependent kinase (cdk) inhibitors such as p27, p21, and p16, leading to reduced cdk2 and cdk4 activities and hypophosphorylation of Rb protein. In contrast to transactivation of p21, SREBP-1a activated p27 by enhancing stabilization of the protein through inhibition of SKP2 and KPC1. In vivo, SREBP-1a-expressing livers of transgenic mice exhibited impaired regeneration after partial hepatectomy. SREBP-1-null mouse embryonic fibroblasts had a higher cell proliferation rate than wild-type cells. The unexpected cell growth-inhibitory role of SREBP-1a provides a new paradigm to link lipid synthesis and cell growth.