Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats.

AIMS/HYPOTHESIS: Ghrelin, a stomach-derived hormone, functions in multiple biological processes, including glucose metabolism and cellular differentiation and proliferation. In this study, we examined whether early treatment with ghrelin can regenerate beta cells of the pancreas in an animal model of diabetes mellitus, the n0-STZ model, in which neonatal rats are injected with streptozotocin (STZ) at birth. METHODS: Following administration of ghrelin to n0-STZ rats from postnatal days 2 to 8, we examined beta cell mass, mRNA expression levels of insulin and of pancreatic and duodenal homeobox 1 (Pdx1) gene, and pancreatic morphology on days 21 and 70. In addition, we investigated the effects of ghrelin on beta cell replication. RESULTS: By day 21, ghrelin treatment increased pancreatic expression of insulin and Pdx1 mRNA in n0-STZ rats. The number of replicating cells was also significantly increased in the ghrelin-treated n0-STZ model. At day 70, n0-STZ rats exhibited hyperglycaemia, despite slight increases in plasma insulin levels. Ghrelin treatment resulted in the improvement of plasma glucose levels, which were associated with normal plasma insulin levels. Pancreatic insulin mRNA and protein levels were significantly increased in ghrelin-treated n0-STZ model animals. CONCLUSIONS/INTERPRETATION: These findings suggest that ghrelin promotes regeneration of beta cells in STZ-treated newborn rats. Thus, early administration of ghrelin may help prevent the development of diabetes in disease-prone subjects after beta cell destruction.

Expression of the gene for a membrane-bound fatty acid receptor in the pancreas and islet cell tumours in humans: evidence for GPR40 expression in pancreatic beta cells and implications for insulin secretion.

AIMS/HYPOTHESIS: G protein-coupled receptor 40 (GPR40) is abundantly expressed in pancreatic beta cells in rodents, where it facilitates glucose-induced insulin secretion in response to mid- to long-chain fatty acids in vitro. However, GPR40 gene expression in humans has not been fully investigated, and little is known about the physiological and pathophysiological roles of GPR40 in humans. The aim of this study, therefore, was to examine GPR40 expression and its clinical implications in humans. METHODS: GPR40 mRNA expression in the human pancreas, pancreatic islets and islet cell tumours was analysed using TaqMan PCR. RESULTS: GPR40 mRNA was detected in all human pancreases collected intraoperatively. It was enriched approximately 20-fold in isolated islets freshly prepared from the pancreases of the same individuals. The estimated mRNA copy number for the GPR40 gene in pancreatic islets was comparable to those for genes encoding sulfonylurea receptor 1, glucagon-like peptide 1 receptor and somatostatin receptors, all of which are known to be expressed abundantly in the human pancreatic islet. A large amount of GPR40 mRNA was detected in insulinoma tissues, whereas mRNA expression was undetectable in glucagonoma or gastrinoma. The GPR40 mRNA level in the pancreas correlated with the insulinogenic index, which reflects beta cell function (r=0.82, p=0.044), but not with glucose levels during the OGTT, the insulin area under the OGTT curve or the index for the homeostasis model assessment of insulin resistance (HOMA-IR). CONCLUSIONS/INTERPRETATION: The present study provides evidence for GPR40 gene expression in pancreatic beta cells and implicates GPR40 in insulin secretion in humans.

Plasma ghrelin levels in healthy elderly volunteers: the levels of acylated ghrelin in elderly females correlate positively with serum IGF-I levels and bowel movement frequency and negatively with systolic blood pressure.

Aging is associated with a decrease in growth hormone (GH) secretion, appetite and energy intake. As ghrelin stimulates both GH secretion and appetite, reductions in ghrelin levels may be involved in the reductions in GH secretion and appetite observed in the elderly. However, only preliminary studies have been performed on the role of ghrelin in elderly subjects. In this study, we sought to clarify the physiologic implications of the age-related alterations in ghrelin secretion by determining plasma ghrelin levels and other clinical parameters in healthy elderly subjects. Subjects were > or = 65 years old, corresponding to the SENIEUR protocol, had not had a resection of the upper gastrointestinal tract and had not been treated with hormones. One hundred and five volunteers (49 men and 56 women) were admitted to this study (73.4 +/- 6.3 years old). Plasma levels of acylated ghrelin in elderly female subjects positively correlated with serum IGF-I levels and bowel movement frequency and negatively with systolic blood pressure. In elderly men, desacyl ghrelin levels correlated only weakly with bowel movement frequency. These findings suggest that the plasma levels of the acylated form of ghrelin may influence the age-related alterations in GH/IGF-I regulation, blood pressure and bowel motility. These observational associations warrant further experimental studies to clarify the physiologic significance of these effects.

Up-regulation of uncoupling protein 3 gene expression by fatty acids and agonists for PPARs in L6 myotubes.

Uncoupling protein 3 (UCP3), which uncouples electron transport from ATP synthesis, is expressed at high levels in the skeletal muscle, an important organ in glucose and lipid metabolism. Because several reports proposed that fatty acids induced UCP3 gene expression in skeletal muscle in vivo, in the present study we examined the regulation of UCP3 gene expression by various fatty acids using L6 myotubes. UCP3 gene expression was increased in L6 myotubes by various fatty acids or by alpha-bromopalmitate, a nonmetabolized derivative of palmitic acid. Because fatty acids are also known as agonists for PPARs, we examined the involvement of PPARs in the regulation of the UCP3 gene expression. L-165041, a PPAR delta agonist, increased UCP3 gene expression in L6 myotubes, whereas neither Wy 14,643, a PPAR alpha agonist, nor Pioglitazone, a PPAR gamma agonist, increased it. Therefore, we conclude that UCP3 gene expression is increased by the activation of PPAR delta in L6 myotubes and postulate that PPAR delta mediates at least some part of the increased UCP3 gene expression by fatty acids in skeletal muscle in vivo.

Successful allogeneic stem cell transplantation from an unrelated donor for aggressive Epstein-Barr virus-associated clonal T-cell proliferation with hemophagocytosis.

We present here a case of aggressive Epstein-Barr virus (EBV)-associated clonal T-cell proliferation with hemophagocytosis that was successfully treated by allogeneic stem cell transplantation using an unrelated donor. A 17-year-old woman was admitted into the hospital with a high fever and liver dysfunction. Laboratory data including bone marrow aspiration revealed hemophagocytic syndrome with proliferation of immature T-lymphoid cells. The clonal proliferation of EBV-infected T cells was confirmed by Southern blot analysis using a terminal-repeat probe from the EBV genome and also by demonstrating T cell-receptor beta gene rearrangement. Intensive immunochemotherapy consisting of cyclosporin A, vincristine, etoposide, and high-dose methylprednisolone did not control the disease and relapse occurred repeatedly. Therefore, during remission after chemotherapy according to the CHOP-E regimen, the patient underwent allogeneic bone marrow transplantation (BMT) from an HLA-matched, unrelated donor. Donor selection was performed with help from the Japanese Association for Marrow Donor Program (JMDP). The patient has remained in good condition without recurrence of disease for 18 months after BMT. Allogeneic BMT is the treatment of choice for aggressive EBV-associated hemophagocytic lymphohistiocytosis even in the case where an HLA-matched sibling donor is not available, especially when the patient is refractory to intensive chemotherapy and/or there is a ready recurrence of disease after conventional therapy.

Ghrelin strongly stimulates growth hormone release in humans.

Ghrelin is a recently identified endogenous ligand for the GH secretagogue receptor and is involved in a novel system for regulating GH release. However, little is known about its GH-releasing activity and other endocrine effects in humans. To address this issue, we studied the GH, ACTH, cortisol, PRL, LH, FSH, and TSH responses to synthetic human ghrelin. In four normal male adults (28-37 yr), iv ghrelin administration released GH in a dose-dependent manner and 0.2, 1.0, and 5.0 microg/kg ghrelin produced 43.3 +/- 6.0, 81.5 +/- 12.7, and 107.0 +/- 10.7 ng/mL of the GH peak values at 30 min, respectively. ACTH, cortisol, and PRL levels were also elevated after ghrelin injection, while the lowest dose (0.2 microg/kg) resulted in only minimum peak values of these hormones (22.8 +/- 3.0 pg/mL, 9.4 +/- 1.9 microg/dL, and 4.6 +/- 0.6 ng/mL, respectively). There were no significant changes in LH, FSH, or TSH levels. This is the first study showing evidence that ghrelin strongly stimulates GH release in humans.

[A malpositioned CVP catheter].

A 2-year-old boy was scheduled for patch closures of ASD and VSD. After anesthesia induction, infection of a double lumen central venous catheter (5 Fr, Arrow) was tried into the superior vena cava through the right jugular vein by Seldinger's method. We confirmed the placement of the catheter by drawing a small amount of blood. After the operation, chest X-ray examination in ICU revealed the misplacement of the catheter into his right intrapleural space. The catheter was left overnight to be used as a drainage route of a possible bleeding. Next morning, no abnormal finding in his chest X-ray and stable circulatory and respiratory conditions were found and we proceeded to extubate his endotracheal tube and take away the catheter. Two hours after the removal of the catheter, the boy showed forced respiration. He became cyanotic rapidly and then he needed emergency intubation. Following chest X-ray examination and an aspiration of intrapleural space revealed a severe hemothorax of the right side, where catheter had been inserted. The boy recovered without any disorders. This case suggests the importance to confirm the placement of CVP catheter, and to prevent the possible complications due to the malpositioned catheter.

[The difficulties in communication through RS-232C interface between monitor devices and a personal computer--the difference of data output format and transmit mode].

We investigated data output format and transmit mode of communication through RS-232C interface between monitor devices and a personal computer. The baud rate, start bit, data bits, parity bit and stop bits are listed with transmit mode of six companies' monitor devices which are now widely sold in Japan. Each monitor device has its own data output format and transmit mode, which are quite different from the others and make it somewhat difficult to import data from different monitor devices to a personal computer. We suggest that, because two or three different monitor devices are commonly used during anesthesia, some general standard should be established to make an easy communication between monitor devices and a personal computer for ordinary users.

[Anesthetic management of a patient with abdominal aortic aneurysm (AAA) with giant bulla].

We report a case of abdominal aortic aneurysm with giant bulla in a 58-year-old man who had an elective abdominal aortic reconstruction surgery. Preoperative chest x-ray showed a giant bulla in the right lung and small bullae in the left. General anesthesia was induced with midazolam 0.5 mg, fentanyl 0.2 mg and succinylcholine chloride 80 mg. After tracheal intubation, anesthesia was maintained under spontaneous breathing with halothane 0.5-1% in a mixture of air and oxygen (FIO2 0.4-1.0) supplemented with continuous epidural mepivacaine from the catheter inserted the day before surgery. Since satisfactory analgesia and muscle relaxation were achieved by epidural mepivacaine, no analgesics and muscle relaxants were administered during the operation. Postoperatively, no complications occurred and the patient was extubated and transferred to the intensive care unit. We emphasize that combined epidural and light general anesthesia with spontaneous respiration might be ideal for the safe anesthetic management of a patient with a giant bulla.

Differences in the assessment of postoperative pain when evaluated by patients and doctors.

This study was undertaken to compare the assessment of pain intensity by 59 patients and by their doctors according to a visual analogue scale (VAS) at rest and when coughing at 5 and 20 hr after major abdominal surgery. The rating given by the patients, who received epidural analgesia to relieve postoperative pain, was significantly above, and moreover, significantly correlated with that given by the doctors at any time or under any condition of the assessment. However, the correlation between the ratings given by patients and doctors at rest at 5 hr after surgery was low (r = 0.39, rs = 0.38) and significantly different from that when coughing at 20 hr after the operation (r = 0.79, rs = 0.80). Our findings indicate that the assessment of postoperative pain may be associated with some unreliability, especially during early periods, when using the subjective or objective-rated VAS at rest separately, and thus requires the combined use or the concomitant use of the VAS when coughing. Substitutional use of the objective-rated VAS for the subjective-rated VAS is not advised.

Portable limb-load monitor utilizing a thin capacitive transducer.

We describe a self contained electronic device for controlling the limb loads exerted by patients having one affected foot and using a walking aid. The device measures the limb load with a thin capacitative transducer attached to the sole of the patient's shoe, and operates in two basic modes. In the first mode the device compares the load with two preset thresholds and emits audible feedback tones to guide the patient in maintaining the required load on his affected foot; a low frequency tone when the load falls between the two thresholds, and a high frequency tone when the load exceeds the upper threshold. Experimental results demonstrate the effectiveness of the device in controlling the limb load in the first mode. In the second mode, only one threshold is preset. When the load exceeds that threshold and is maintained above this level for a period longer than a selected stance-duration time, a low-frequency tone is generated.

Motion analysis in the movements of standing up from and sitting down on a chair. A comparison of normal and hemiparetic subjects and the differences of sex and age among the normals.

With regard to the motions of standing up from and sitting down on a chair, and standing quietly for thirty seconds, forty normal adults (ten young males, ten young females, ten elderly males and ten elderly females) and ten hemiparetics were compared by use of a force plate and an electrogoniometer. The hemiparetics had the following characteristics: (1) A long time was required for stabilization of sway at the center of force (C.O.F.) when standing up. (2) The C. O. F. was located to the back and deviated primarily to the sound leg, and the grade of sway was greatest during quiet standing. (3) Vertical 8 Hz fluctuation in quiet standing was seen in all cases, while in sitting down 3-4 Hz were recorded. (4) The motion time in standing up and sitting down was prolonged. (5) Long periods of initial knee flexion existed just before the knee extension in standing. (6) A broad lateral sway of C. O. F. was recorded in the standing movement. Among the normal groups, the following characteristics were noted: (1) The young stand up more rapidly. (2) The elderly needed more time to stabilize the antero-posterior sway in the standing up motion. (3) The C. O. F. of males was located more anteriorly than that of females. (4) The grade of sway in quiet standing was greater in females than in males. (5) In young males, the standing up time was shorter than the sitting down time, while in young females the situation was reversed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Systolic time intervals and echocardiographic parameters in Hegglin syndrome (author's transl)].

The cardiac function in Hegglin syndrome (HS; prolonged QT interval and shortened QS2) remains unclear. In order to estimate cardiac function of HS, left ventricular echocardiographic parameters and systolic time intervals (STI) were analyzed, and compared with those of normal subjects (N) (n = 20). Forty-six patients (pts) of HS are constituted of 23 pts with chronic renal failure, 7 with cardiomyopathy, 5 with ischemic heart disease, 5 with essential hypertension, 4 with acquired valvular disease, 1 with effusive pericarditis and 1 with Romano-Ward syndrome. Corrected preejection period (PEPc) and PEP/ET were significantly larger (0.15 +/- 0.02 vs 0.13 +/- 0.01, p less than 0.001; 0.48 +/- 0.13 vs 0.35 +/- 0.04, p less than 0.001, respectively) in HS. Corrected ejection time (ETc) was significantly smaller (0.37 +/- 0.02 vs 0.41 +/- 0.01, p less than 0.001) in HS. Mitral EF slope (DDR), ejection fraction (EF), and mean ventricular circumferential fiber shortening (mVCF) were significantly decreased (58 +/- 29 vs 92 +/- 25, p less than 0.001; 0.52 +/- 0.15 vs 0.62 +/- 0.07; p less than 0.005; 0.98 +/- 0.33 vs 1.18 +/- 0.20; p less than 0.05, respectively) in HS, but cardiac index (C.I.) did not differ. Thus, patients with Hegglin syndrome showed heart failure pattern in STI and hypodynamic cardiac function in echocardiographic parameters, and our data suggest that hypodynamic cardiac function of HS is caused by both lowered pump function and decreased myocardial contractility.

Locomotion of the hemipelvectomy amputee.

A locomotion study was performed on a hemipelvectomy amputee wearing a prosthesis. The experimental arrangement described in this paper, combining joint motion developed during walking, a computer analysis of the force pattern between the foot and ground and plotting of pressure point on the foot print, has enabled detailed investigation with demonstration of several abnormal features in the prosthetic gait of a hemipelvectomy amputee.