Norihiko Aoki

Two Germline Missense Mutations at Codons 804 and 806 of the RET Proto-oncogene in the Same Allele in a Patient with Multiple Endocrine Neoplasia Type 2B without Codon 918 Mutation

Multiple endocrine neoplasia (MEN) type 2B is a clinically distinct entity among the autosomal dominant MEN 2 syndromes. Most patients with MEN 2B carry a germline mutation (M918T) of the RET proto‐oncogene, while a few carry A883F. We examined a patient with MEN 2B, but without M918T or A883F, and her relatives. Here, we report the presence in this patient of 2 germline mutations, V804M and Y806C in the same allele. While the novel Y806C was inherited from her father, its carriers (her father and brother) was not affected by MEN 2. In contrast, V804M was a de novo mutation, that has been reported in patients with familial medullary thyroid carcinoma. Combinations of mutations of the RET proto‐oncogene may cause oncogenic activities different from those of single mutations.

Clinical features of multiple endocrine neoplasia type 1 (MEN1) phenocopy without germline MEN1 gene mutations : analysis of 20 Japanese sporadic cases with MEN1

OBJECTIVE Multiple endocrine neoplasia type 1 (MEN1) is a familial tumour syndrome of endocrine tumours involving parathyroids, anterior pituitary and enteropancreatic neuroendocrine tissues, and is inherited in an autosomal dominant manner with high penetrance. Recently, the gene responsible for this syndrome, MEN1, was positionally cloned from chromosome 11q13.

Comprehensive study of urinary cortisol metabolites in hyperthyroid and hypothyroid patients.

Objective  To further analyse the significance and mutual relationship of thyroid function‐linked alterations in cortisol metabolism that have been separately and variously reported.

Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity

Adrenergic receptors (ARs) are cell-surface G-protein-coupled receptors for catecholamines. They are essential components of the sympathetic nervous system, organized within the autonomic nervous system (ANS), which controls various physiological functions, including energy homeostasis and metabolism of glucose and lipids. An impairment of ANS function in metabolism is considered to be one of the pathological states associated with human obesity and related metabolic diseases; thus, alterations in AR function might be implicated in the pathophysiology of these diseases. Several studies have suggested an association between obesity phenotypes and some AR polymorphisms. In vitro and human clinical studies indicate that some of these polymorphisms have functional and pathophysiological significance, including the linkage to ANS function. This review summarizes present knowledge of AR polymorphisms related to human obesity, and their association with ANS function.

Hyperbaric exposure with high oxygen concentration inhibits growth-associated increase in the glucose level of diabetic Goto-Kakizaki rats

We have specially designed a hyperbaric chamber for animal experiments, which is an oxygen tank with an oxygen concentrator and an air compressor [1]. This hyperbaric chamber is designed to automatically maintain the elevated atmospheric pressure and oxygen concentration. Increased atmospheric pressure enhances the partial pressure of oxygen and causes more oxygen to dissolve into the blood and plasma. We postulated that the increased availability of oxygen induced by hyperbaric exposure with high oxygen concentration might have a beneficial impact on glucose metabolism. Therefore, we tested this hypothesis by exposing type 2 diabetic Goto-Kakizaki (GK) rats to hyperbaric exposure with high oxygen concentration. GK rats are non-obesemodels of type 2 diabetesmellitus, developed by selective breeding of an outbred colony of Wistar rats with high glucose levels asmeasured by the oral glucose tolerance test [2]. Ten 5-week-old male GK rats were randomly assigned to the control (n 1⁄4 5) or hyperbaric (n 1⁄4 5) group. All rats were individually housed in cages of the same size. Rats in the hyperbaric group were exposed to an atmospheric pressure of 1.25 atm with an oxygen concentration of 35.0% automatically maintained by a computer-assisted system. The chamber was 180 cm long and 70 cm in diameter, making it large enough to house a number of rats (up to 20 cages) simultaneously. The rats in the hyperbaric group were exposed to the hyperbaric environment for 6 h (10 : 00–16 : 00) daily for 4weeks. Food andwater were provided ad libitum for both groups. All ratswere kept in a controlled environmentwith fixed 12 : 12 h light : dark cycles (lights off from 19 : 00 to 07 : 00) and room temperature maintained at 22 2 C. After the rats were anaesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg/kg), blood was sampled. Plasma obtained by centrifugation was used for measurement of glucose level. Plasma glucose was determined by a glucose-oxidative method [3]. The glucose levels were significantly lower in the hyperbaric group at 7 and 9 weeks than in the control group (figure 1). Exercise is known to be effective for preventing and improving impaired glucose tolerance in type 2 diabetes mellitus. Previous studies demonstrated that voluntary running exercise is effective in preventing insulin resistance in streptozotocin-induceddiabetic (impaired insulin secretion model) [4] and Otsuka Long-Evans Tokushima Fatty (OLETF) (insulin resistant model) [5–7] rats. Previous studies observed that both non-obese GK [8] and obese OLETF [9] rats showed a growth-associated increase in the glucose level. Consistent with our hypothesis that the increased availability of oxygen induced by hyperbaric exposure with high oxygen concentration would have a beneficial impact on glucose metabolism, we observed that the growth-associated increase in the glucose level was completely inhibited by hyperbaric exposure with high oxygen concentration (figure 1). Hyperbaric exposure with high oxygen concentration might therefore provide a new approach to improve impaired glucose tolerance without exercise, food restriction, or drug, e.g. insulin treatment.

Mechanism of feminization in male patients with non-alcoholic liver cirrhosis: role of sex hormone-binding globulin.

SummaryWe measured serum sex hormone-binding globulin (SHBG) using a radioimmunoassay developed by us, testosterone (T), estradiol (E2), free T and free E2 in 50 male patients with non-alcoholic liver cirrhosis (compensated: 30, decompensated; 20) and age-matched healthy male subjects. SHBG was significantly increased in patients with liver cirrhosis compared with healthy subjects. The high serum SHBG level in male compensated cirrhotic patients tended to decrease with progression to the decompensated state. Serum cholinesterase showed a positive correlation with SHBG in liver cirrhosis. Serum free T and the T/ SHBG ratio decreased, while serum E2, free E2, and the E2/T and the free E2/free T ratios increased in liver cirrhosis, resulting in estrogen predominance and feminization of male patients. These changes were more marked in decompensated than compensated liver cirrhosis. An increased free E2/free T ratio was observed in patients with gynecomastia, palmar erythema or vascular spider. The T/SHBG ratio showed a positive correlation with serum free T, suggesting that it can be used as a free T index in liver cirrhosis. From these observations, it is suggested that serum SHBG plays an important role, by regulating the serum free T level in the occurrence of feminization in male patients with non-alcoholic liver cirrhosis.

Effects of running exercise on fibre-type distribution of soleus and plantaris muscles in diabetic Otsuka Long-Evans Tokushima fatty rats.

Aim:  Effect of running exercise on fibre‐type distributions of the slow soleus and fast plantaris muscles was investigated in male Otsuka Long‐Evans Tokushima fatty rats (OLETF) as an animal model of spontaneous type 2 diabetes mellitus.

T393C polymorphism of GNAS1 associated with the autonomic nervous system in young, healthy Japanese subjects

1. T393C polymorphism of the gene encoding the Gs‐protein α‐subunit (GNAS1) has been reported recently to be associated with hypertension in which dysfunctions of the autonomic nervous system (ANS) are closely involved. In the present study, the association of this polymorphism with ANS activity was investigated in young, healthy Japanese males.

MULTIPLE NONFUNCTIONAL PANCREATIC ISLET CELL TUMOR IN MULTIPLE ENDOCRINE NEOPLASIA TYPE I

A case of multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type I (MEN I) is reported. The patient was a 41‐year‐old woman who had a past history of thyroid cancer (papillary carcinoma) and hyperparathyroidism due to parathyroid adenoma. Later, a nonfunctional pituitary tumor and Ave nonfunctional pancreatic tumors were found simultaneously and the patient was finally diagnosed as having MEN I. Following surgical enucleation, the pancreatic tumors were histopathologlcally diagnosed as benign islet cell tumors. One of them (tumor 3) exhibited a solid nodular pattern while the others showed gyriform patterns. They were divided histochemlcally and immunohistochemically into three types: two (tumors 1 and 2) produced a single hormone (glucagon), one (tumor 3) produced five (Insulin, glucagon, somatostatin, gastrin and pancreatic polypeptide) and the remaining two (tumors 4 and 5) produced two (glucagon and pancreatic polypeptide). Electron microscopically, three types of endosecretory granules were found in the tumor cells of tumor 3 but only one type was found in tumor 4. However, in the tumor 4 extract, glucagon, pancreatic polypeptide, C‐peptlde, somatostatin, vasoactive intestinal peptide and growth hormone releasing factor were detected by radioimmunoassay. These findings suggest that these pancreatic tumors were both multicellular and multihormonal.

Indomethacin augments inhibitory effects of interferons on lymphoproliferative response

Lectin-induced lymphoproliferative response was enhanced by the addition of indomethacin to the culture and in contrast, suppressed by the addition of interferon. However, when indomethacin and interferon were concomitantly present in the lectin-driven cultures, the suppressive effect of interferon on the lymphocyte blastogenesis surpassed the enhancing effect of indomethacin on the response. Furthermore, and unexpectedly, the inhibitory effect on the response due to interferon was definitely augmented in the presence of indomethacin as compared with the response in the absence of indomethacin.