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The aim was to investigate the effect of three water levels (umbilical, 4th rib, and clavicular) on the respiratory function and respiratory muscle strength among elderly. Spirometry and respiratory strength were measured on land as baseline data. Next, water depth conditions were determined randomly, and spirometry and respiratory muscle strength were measured at each water level. The Vital Capacity and Expiratory reserve volume in the clavicular level were significantly lower than those in the land and umbilical trials. No significant difference was observed in other respiratory functions. Chest circumference and respiratory muscle strength were not significantly different among all conditions.

Introduction:This study aimed to investigate the cough strength and respiratory function as well as the factors affecting the cough strength of independent elderly people. Methods and Results: A total of 36 elderly people participated in this experiment, and two subjects with hypertension were excluded. All subjects were evaluated for vital capacity (VC), cough peak flow (CPF), and respiratory muscle strength by determination of the maximum inspiratory and expiratory pressure (PImax and PEmax, respectively) in a sitting position. Each measurement consisted of three trials, and the maximum values were adopted for the analysis. The average value of CPF was 291.5 ± 100.5 L/min. Moreover, 17 out of the 34 subjects had CPF P —0.64, P —0.40, P Conclusion: Elderly people who independently perform their activities of daily living do not always have high coughing ability and may have reduced VC associated with reduced coughing ability.

This study aimed to compare respiratory muscle strength in individuals performing continuous and noncontinuous walking exercises in water after the 6-week program. Twenty-nine healthy men were randomly divided into a continuous group (CG, n=14) and a noncontinuous group (NG, n=15). Firstly, both groups executed the 6-week program which set them to walk for 30 min, 4 times per week, over 6 weeks in a pool with the adjusted intensity that their walking speed increased the heart rate to 60% of the predicted maximum. After the 6-week program, participants in the CG continued the water-walking program for 4 weeks while those in the NG discontinued the water-walking program. In both groups, respiratory muscle strength evaluated by maximum inspiratory pressure (PImax) and maximum expiratory pressure (PEmax) increased significantly after the 6-week program compared with pre-exercise value. Compared to the value after the 6-week program, PEmax increased significantly in the CG after 10 weeks (P

Cerebral blood flow (CBF) would be impaired with dual stresses of heat and orthostatic changes, even if those stresses are mild, in the elderly with declined cardio- and cerebrovascular functions with aging. To test the hypothesis, we compared the response of blood flow in the internal carotid artery (ICA) and vertebral artery (VA) to dual stresses of heat and orthostatic changes between the elderly and young individuals. Nine elderly and eight young healthy men (71.3 ± 3.0 and 23.3 ± 3.1 years, mean ± SD, respectively) underwent measurements of blood flow in the ICA, VA and external carotid artery (ECA) via ultrasonography. The measurements were obtained in sitting and supine positions under normothermic (NT) and mildly hyperthermic (HT) conditions (ambient temperature 28 °C). Esophageal temperatures increased from NT (36.4 ± 0.2 °C, mean ± SE) to HT (37.4 ± 0.2 °C) with lower legs immersion in 42 °C water. With heat stress, ECA blood flow increased in both postures in both age groups (effect of heat, p

Fragrance inhalation of essential oils is widely used in aromatherapy, and it is known to affect blood pressure (BP) and heart rate (HR) via autonomic control of circulation. In this study, we aimed to test the hypothesis that the changes in hemodynamics with fragrance inhalation were observed along with changes in muscle sympathetic nerve activity (MSNA). In study 1, thirteen healthy men were exposed to fragrance stimulation of grapefruit essential oil for 10 min, and BP, HR, and MSNA were continuously measured. In study 2, another nine healthy men were exposed to the same fragrance stimulation; responses in BP and HR were continuously measured, and plasma noradrenaline and cortisol concentrations were determined. We found that diastolic BP increased significantly during fragrance inhalation, while the other variables remained unchanged in both studies. Although MSNA burst frequency, burst incidence, and total activity remained unchanged during fragrance inhalation, we found a significant linear correlation between changes in diastolic BP in the last 5 min of fragrance inhalation and changes in MSNA burst frequency. The plasma cortisol concentration decreased significantly at 10 min of fragrance inhalation, though the noradrenaline concentration remained unchanged. These results suggest, for the first time, that changes in BP with fragrance inhalation of essential oil are associated with changes in MSNA even with decreased stress hormone.

健常男性9名(平均23.2歳)を対象に、背臥位で安静呼気時および咳嗽時の外腹斜筋、内腹斜筋および腹横筋の超音波画像10秒間を3回記録した。OsiriXを用いた画像解析により安静呼気時および咳嗽時の最大筋肥厚時の静止画像を抽出し筋厚を1mm単位で測定した。3回の筋厚計測から平均値を求めた。その結果、安静呼気時と比べて咳嗽時の内腹斜筋および腹横筋の筋厚は有意に増大し、外腹斜筋の筋厚には有意な変化がみられなかった。以上より、咳嗽時には深部の筋活動が大きいと考えられた。

8週間の水中または陸上での吸息筋トレーニング(IMT)が呼吸筋力に及ぼす影響を比較した。健康男性29名を対象とし、15名(平均23.2±2.7歳)を水中群、14名(平均23.2±0.2歳)を陸上群に無作為に割り付けた。IMT開始前に、両群で口腔内の最大呼気圧(PImax)および最大吸気圧(PEmax)を測定した。水中群では、鎖骨の位置まで水に入り、座位にてIMTを実施した。陸上群では、陸上で座位にてIMTを行った。両群とも、IMT開始から6週後と8週後にベースラインと比較して吸息筋力が有意に増強したことが示された。IMT開始8週後の吸息筋力の変化率に有意差は認められなかった。さらに、8週後の呼吸筋力において両群で有意差は示されなかった。水中および陸上でのIMTは吸息筋力を向上させることが示されたが、水上および陸上においてIMT前後における呼気筋力変化率に有意差は認められなかった。

This study examined the effect of an exercise intervention on the composition of the intestinal microbiota in healthy elderly women. Thirty-two sedentary women that were aged 65 years and older participated in a 12-week, non-randomized comparative trial. The subjects were allocated to two groups receiving different exercise interventions, trunk muscle training (TM), or aerobic exercise training (AE). AE included brisk walking, i.e., at an intensity of &ge, 3 metabolic equivalents (METs). The composition of the intestinal microbiota in fecal samples was determined before and after the training period. We also assessed the daily physical activity using an accelerometer, trunk muscle strength by the modified Kraus&ndash, Weber (K-W) test, and cardiorespiratory fitness by a 6-min. walk test (6MWT). K-W test scores and distance achieved during the 6MWT (6MWD) improved in both groups. The relative abundance of intestinal Bacteroides only significantly increased in the AE group, particularly in subjects showing increases in the time spent in brisk walking. Overall, the increases in intestinal Bacteroides following the exercise intervention were associated with increases in 6MWD. In conclusion, aerobic exercise training that targets an increase of the time spent in brisk walking may increase intestinal Bacteroides in association with improved cardiorespiratory fitness in healthy elderly women.

Endurance training at a level (FATmax) that raises the maximal fat oxidation rate (max FOR) may contribute to body weight loss in obese individuals. However, max FOR and FATmax are reduced in subjects with obesity and/or with insulin resistance compared with those without. On the other hand, in humans, intranasal insulin administration increases the concentration of insulin in cerebrospinal fluid when peripheral effects are absent, resulting in reduced food intake and body weight. However, it remains unclear whether insulin delivery to the brain affects fat oxidation during exercise. In this study, we examined the effects of nasal insulin administration on max FOR during exercise in 11 normal-weight (N group) and seven overweight (O group) young individuals. On two separate days, either 40 IU regular insulin (INS) or normal saline, as placebo (PL), was randomly administered intranasally after overnight fasting, and then each participant underwent a graded exercise test. Indirect calorimetry was used to assess max FOR during exercise and FATmax. Blood insulin and glucose levels did not change after insulin administration. In the N group, max FOR tended to decrease in the INS trial (p = 0.050); FATmax and the total amount of fat oxidation during exercise were significantly smaller in the INS trial than in the PL trial. Max FOR was significantly smaller in the O group than in the N group (p = 0.021) and was not influenced by insulin administration. Blood adrenaline levels increased by exercise tended to be reduced by insulin administration in the N group only. In conclusion, intranasal insulin administration reduces fat oxidation during exercise without increasing peripheral insulin levels, possibly via the suppression of sympathetic nerve activity. The inhibitory effects of intranasal insulin administration on fat oxidation during exercise are diminished in overweight subjects, suggesting cerebral insulin effects are attenuated in this population. Disclosure H. Yokoyama: None. R. Takeda: None. E. Kawai: None. A. Ota: None. E. Morita: None. D. Imai: None. Y. Suzuki: None. T. Morioka: Consultant; Self; Ono Pharmaceutical Co., Ltd.. Research Support; Self; Novartis Pharma K.K., MSD K.K., Eli Lilly and Company, Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Takeda Pharmaceuticals U.S.A., Inc., Novo Nordisk Inc., Kowa Pharmaceuticals America, Inc., Astellas Pharma US, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd. M. Emoto: Speaker's Bureau; Self; Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Astellas Pharma Inc, Ono Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Company Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation. M. Inaba: None. K. Okazaki: None.

We aimed to examine the effect of 2-year cognitive–motor dual-task (DT) training on cognitive functions and motor ability of healthy elderly people without marked cognitive impairment. From the 25 participants of our 12-week DT trial conducted in 2014, we recruited 8 subjects who voluntarily participated in a new DT training program once a week for 2 years (exercise (EX) group). Their cognitive functions were evaluated by the Modified Mini-Mental State (3MS) examination and the Trail Making Test, and results were compared with those of the 11 subjects who discontinued the training and did not perform any types of exercise for 2 years (non-exercise (NO) group). Subjects in the NO group showed deterioration in the 3MS examination results, especially in the cognitive domain of attention. Meanwhile, participation in DT training maintained the scores in almost all domains of cognitive function, as well as the total 3MS scores. However, both groups had impaired quadriceps muscle strength and motor ability after the 2-year observation period. These results suggest that participating in exercise program comprising DT training for 2 years may be beneficial for maintaining the broad domains of cognitive function in healthy elderly people, although further verification is needed.

It remains unknown whether the high insulin (INS) levels in the brain affect fat oxidation during exercise. We examined the effects of the intranasal administration of INS, which increases the INS concentration in the cerebrospinal fluid when peripheral effects are lacking, on the maximum fat oxidation rate (maxFOR) and its intensity (FATmax) during exercise in 15 young normal-weight (N group) and eight young overweight (O group) individuals. On two separate days, either INS or placebo (PL) was randomly administered intranasally before a graded exercise test. Indirect calorimetry was used to assess maxFOR and FATmax during exercise. Blood INS and glucose levels did not change after INS administration. In the N group, maxFOR and FATmax were significantly smaller in the INS trial than in the PL trial. MaxFOR was significantly smaller in the O group than in the N group and was not influenced by INS administration. Exercise-induced elevation in blood epinephrine levels tended to be reduced by INS administration only in the N group. Intranasal INS administration reduces fat oxidation during exercise without any peripheral effects, possibly by suppressing sympathetic nerve activity. This inhibitory effect is diminished in overweight subjects, suggesting that cerebral insulin effects are attenuated in this population.

OBJECTIVE—We assessed the effects of a 2-day in-hospital diabetes educational program in preventing or delaying progression of impaired glucose tolerance (IGT) to type 2 diabetes, including analysis of changes in serum lipids, body weight, and blood pressure after the program. RESEARCH DESIGN AND METHODS—A total of 426 subjects (51 ± 9 years, BMI 24.6 ± 3.9 kg/m2) with newly diagnosed IGT were randomly assigned to three groups, 143 as the short-term hospitalization with diabetes education and support (STH) group, 141 as the nonhospitalization but diabetes education and support (DES) group, and 142 as the neither hospitalization nor education (control) group. RESULTS—The average follow-up was 3.1 years. The incidence of diabetes was 8.0, 10.7, and 13.2 cases per 100 person-years for STH, DES, and control groups, respectively. The incidence of diabetes was 42% lower (95% CI 33–51%) in the STH group and 27% lower (15–37%) in the DES group than in the control group. The incidence of diabetes was 21% lower (10–31%) in the STH group than in the DES group. CONCLUSIONS—The 2-day in-hospital program with diabetes education and support every 3 months was more effective in preventing or delaying the progression from IGT to diabetes than only diabetes education and support every 3 months.

We report a 52-year-old woman who was noted to have elevated alkaline phosphatase (ALP), hypercalcemia (Ca: 11.7 mg/dL), and intact parathyroid hormone (intact PTH: 643.1 pg/mL), and then referred to our hospital with suspected hyperparathyroidism. Ultrasound examination of the neck and magnetic resonance imaging showed a mass region in the posterior aspect of the left lobe of the thyroid, and Tl-Tc subtraction scintigraphy showed Tl uptake at the same location. Based on laboratory and imaging studies, she was diagnosed with primary hyperparathyroidism. The excised parathyroid was a large mass measuring 6.8 x 2.8 x 1.9 cm in diameter and weighing 15.4 g. It was soft, covered with a thin capsule, did not infiltrate the thyroid parenchyma, and showed no evidence of malignant process. Histopathological examination showed that it was clear cell adenoma. There was no evidence of metastasis from the parathyroid tumor in other organs. The post-operative course was excellent, and serum PTH, Ca, and ALP levels returned to normal. Among parathyroid tumors, large adenomas are commonly considered to be more likely malignant, but in this case it was benign despite measuring more than 6 cm in diameter. The histopathological type of the adenoma was clear cell adenoma, a very rare type. We report a clear cell adenoma of the parathyroid gland, which has not been described previously in Japan.

Graves' ophthalmopathy in hypothyroid state is called Hypothyroid Graves' Disease, which is a comparatively rare disease. We experienced a case of a 57 year old man with severe exophthalmos and diplopia, which are typical symptoms of Graves' opthalmopathy, and with an extremely high thyroid-stimulating antibody(TSAb) level. He also had a firm diffuse goiter and hypothyroidism with positive anti-thyroglobulin and anti-thyroid microsomal antigen. These findings suggested Hashimoto's thyroiditis. Severity of ophthalmopathy and TSAb level were improved during replacement therapy with T4. Although a thyroid stimulation-blocking antibody was also detected in this patient, we thought that hypothyroidism in this case was based on destructive change in the thyroid with Hashimoto's thyroiditis. Therefore, we should be aware of the fact that there are cases of hypothyroidism with Graves' ophthalmopathy and a high level of TSAb.

We report a rare case of virilizing adrenocortical adenoma complicated with Cushing's syndrome, thyroid papillary carcinoma and hypergastrinemia. A 45-year-old woman had a history of amenorrhea for 10 years, hypertension for 8 years, and diabetes mellitus for 3 years. Physical examination showed a masculinized woman with severe hirsutism, male-like baldness, deep voice, acne in the precordia, and clitorism. Plasma testosterone, DHEA-S and urinary 17-KS were high, and plasma cortisol level was it at the upper limit of the normal range, but it did not show a diurnal rhythm nor was suppressed by 2 and 8 mg of dexamethasone. Abdominal CT scan showed a left adrenal tumor (4.5 cm in size). Adrenal scintigram revealed uptake of the tracer on the left side, and plasma cortisol concentration was high in a blood sample from the left adrenal vein. Left adrenalectomy was performed. Histopathological features of resected adrenal tumor were consistent with those of adrenocortical adenoma, consisting of tumor cells with eosinophilic compact cytoplasm. Immunohistochemical staining for steroidogenic enzymes showed reactivity for P450sec, 3 beta-HSD, P450c17, P450c21 and P450c11. Plasma testosterone and cortisol levels decreased to the normal range postoperatively. The patient was also found to have a papillary thyroid carcinoma and hypergastrinemia. Our patient is a rare case of virilizing adrenocortical adenoma associated with Cushing's syndrome, thyroid papillary carcinoma, and hypergastrinemia.

When we commonly evaluate the thyroid function, we measure TSH, free T3 and free T4. However, there are some cases that are difficult to diagnose because of the existence of thyroid hormone autoantibodies. We experienced a case of a 14-year-old girl with diffuse struma whose TSH, free T3 and free T4 were elevated by detected with Amerlex M free T3 and free T4 kits, although she did not have any symptoms. As the free T4 level was low by the equilibrium dialysis method, we diagnosed this case as hypothyroidism due to chronic thyroiditis. Because we found thyroid hormone antibodies in her serum, we thought that this case presented pseudoelevations of free T3 and free T4 by the analogue method.

Starvation induces a decrease in circulating leptin levels and activation of the hypothalamus-pituitary-adrenal (HPA) axis. Leptin inhibits the HPA axis in unfed rodents or genetically leptin-deficient ob/ob mice, whereas it stimulates corticotropin-releasing hormone (CRH) gene expression in the paraventricular nucleus (PVN). However, the interactions between leptin, CRH and the HPA axis are poorly understood and are likely to be complex. We recently demonstrated that central leptin administration caused increases in plasma arginine-vasopressin (AVP) and AVP gene expression of the PVN in nonstressful rats. AVP stimulates the release of adrenocorticotropic hormone (ACTH), but it also potentiates the action of CRH on ACTH release. In this study, we investigated the effects of leptin on plasma ACTH and corticosterone levels, CRH mRNA of the PVN and proopiomelanocortin (POMC) mRNA of the pituitary in nonstrained rats. Intracerebroventricularly administered leptin caused increases in plasma ACTH and corticosterone levels in dose-dependent manners. In Northern blot analyses, the leptin injection induced significant increases in the expression of CRH mRNA in the PVN and POMC mRNA in the pituitary. The increased plasma ACTH and corticosterone levels by leptin were attenuated with intracerebroventricular pretreatment of a V1a receptor antagonist (OPC-21268) or a V1a/V1b receptor antagonist (dP[Tyr(Me)2]AVP), but not with that of a V2 receptor antagonist (OPC-31260). The leptin-induced CRH mRNA expression in the PVN and POMC mRNA expression in the pituitary were also reduced by the pretreatment with OPC-21268 and dP[Tyr(Me)2]AVP. These results suggest that intracerebroventricular leptin administration activates the HPA axis by AVP receptor activation through V1a receptors in the PVN which in turn activates CRH neurons to drive ACTH and corticosterone secretion in concert with AVP in nonstrained rats.

Renal hemodynamic features in obese non-insulin-dependent diabetic rats remain unknown. We investigated renal hemodynamic and morphologic changes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats at the age of 5 and 10 months compared with age-matched lean nondiabetic control rats (LETO). OLETF rats showed obesity compared with age-matched LETO rats. Hyperglycemia was mild in 5-month-old OLETF rats and moderate in 10-month-old OLETF rats. The absolute value for glomerular filtration rate (GFR) was significantly higher in OLETF rats than in age-matched LETO rats at the age of 5 and 10 months. Ten-month-old OLETF rats had significantly higher absolute values for renal plasma flow (RPF) than age-matched LETO rats but not 5-month-old OLETF rats. Stepwise multiple regression analysis revealed that body weight was a powerful determinant of GFR and RPF. When factored for body weight, no difference in GFR was demonstrated between 5-month-old OLETF and LETO rats, whereas 10-month-old OLETF rats still had significantly higher GFR and RPF than age-matched LETO rats. Renal hypertrophy was demonstrated in both 5- and 10-month-old OLETF rats even when factored for body weight. Glomerular volume was significantly increased in 10-month-old OLETF rats, but the ratio of glomerular volume to body weight was not different among the groups. Both absolute value for glomerular capillary length free from mesangial area and the value factored for glomerular area were significantly longer in OLETF rats than in age-matched LETO rats. Mesangial matrix expansion was remarkable in 10-month-old OLETF rats, and the glomerular sclerosis index was significantly higher in 10-month-old OLETF rats than in age-matched LETO rats. Stepwise multiple regression analysis revealed that body weight, hemoglobin A1c, and hypertriglyceridemia were powerful determinants for kidney weight and glomerular volume. These data suggest that renal hyperfiltration and hypertrophy observed in 10-month-old OLETF rats are related to diabetic metabolic disorders and that obesity-related conditions may be involved in the renal hemodynamic and morphologic features in OLETF rats. (J Lab Clin Med 1999;134:483-91)

The product of the ob gene protein, leptin, has been suggested to function as an endogenous mediator of the cardiovascular system via sympathetic nerve activity. Moreover, extensive distribution of leptin receptor-like immunoreactivity has been demonstrated in the choroid plexus, cerebral cortex, hippocampus, thalamus and hypothalamus, especially in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). In this study, we have investigated the in vivo effects of leptin on plasma arginine-vasopressin (AVP) secretion and the level of AVP messenger ribonucleotic acid (AVP mRNA) in the SON of conscious rats. Intracerebroventricularly administered leptin increased plasma AVP concentration in a dose-dependent manner (0–400 pmol/rat). The maximal effect was obtained at 15 min after the administration of leptin. Furthermore, in Northern blot analyses, the levels of AVP mRNa in the SON increased approximately 2-fold from the basal level after the administration of leptin. AVP mRNA expression in the PVN was also increased by leptin. However, leptin had no effects on plasma oxytocin (OXT) secretion and OXT gene expression in the SON. In conclusion, leptin is involved in AVP secretion via the central nervous system, however, its physiological role is unknown.

To assess the direct effect of androgen on the development of atherosclerosis, we investigated the effect of androgen and its receptor expression in rat vascular smooth muscle cells (VSMC) isolated from rat aorta. We detected the androgen receptor mRNA in VSMC by reverse transcription of the total RNA coupled with amplification of the resulting cDNA by polymerase chain reaction. Binding studies revealed the presence of a single class of binding sites for testosterone (Kd 7.37 nM, Bmax 10.59 fmol/mg protein) and dihydrotestosterone (DHT; Kd 4.89 nM, Bmax 11.37 fmol/mg protein) in VSMC. Measurement of 5α-reductase activity suggested that testosterone is converted to DHT in VSMC (Km 0.36 μM, Vmax 623 fmol/mg protein/h). Moreover, in the present study, DHT significantly stimulated DNA synthesis of VSMC (120–160% of control). The mitogenic activity of testosterone is much less potent than that of DHT. Considering these results, we concluded that androgen may directly accelerate atherosclerosis by stimulating the proliferation of VSMC.

Using newborn, suckling, weanling and adult rats, we studied the effect of age on the intestinal absorption of tobramycin, which is poorly absorbed in adult humans. The mean (±S.D.) bioavailability ( F ) values after administering tobramycin (30 mg/kg) orally to newborn, suckling and weanling rats were 39.4 ± 5.8, 19.9 ± 4.6, and 2.8 ± 0.9%, respectively (significant differences). A marked difference was observed between suckling and weanling rats. After duodenal administration of tobramycin (30 mg/kg) to suckling rats, absorption occurred more readily than in adult rats ( F = 104.0 ± 33.6 vs 27.2 ± 5.7%), and the mean F values for both ages were significantly higher than those in the respective oral sham experiments. Therefore, a high concentration of tobramycin in the intestine promotes intestinal absorption. When the cumulative amounts of tobramycin transferred from the mucosal to serosal side were determined in suckling, weanling and adult rats by an everted sac method, the amount was highest for suckling rats, with an abrupt change being found between suckling and weanling rats. The permeation of tobramycin from the mucosal to serosal side was not a saturable process in rats of all ages. An aminoglycoside (AMG), neomycin (10 mM), and a polyamine, spermine (10 mM), significantly increased the permeating of tobramycin in the jejunum and ileum of suckling rats and the jejunum of adult rats. Choline chloride (10 mM), tetraethylammonium (10 mM) and 2,4-dinitrophenol (0.5 mM) did not affect the permeation of tobramycin in any small intestinal regions (jejunum and ileum) of either suckling or adult rats. The following conclusions were drawn: (1) tobramycin absorption occurs readily from the small intestine of suckling rats, but markedly decreases during the weaning period; (2) tobramycin is transferred predominantly via passive diffusion in the immature small intestine of suckling rats; and (3) the intestinal absorption of tobramycin can be enhanced by direct delivery of a high drug concentration exposed to the small intestine, and this absorption is further facilitated with other AMGs or polyamines in the small intestine, particularly in suckling rats.

Gastrointestinal absorption of cefazolin, which is poorly absorbed in adults, and of cephradine, which is well absorbed in adults, was studied in rats during their development. Significantly higher concentrations of cefazolin in plasma after oral administration were observed in 1- and 2-week-old rats compared with 3-week-old and adult rats. A marked difference in the absorption of cefazolin by 2- and 3-week-old rats (at weaning period) was observed. No such marked difference in the absorption of cephradine by rats of various age groups was found. With cefazolin, a similar pattern of developmental change in jejunal uptake was observed. Cortisone, which causes early maturation of the intestinal membrane, was given as a preweaning injection to 2-week-old rats. This treatment decreased concentrations of cefazolin in plasma and jejunal uptake of cefazolin. Thus, the absorption of cefazolin in 1- and 2-week-old rats seems to depend on the permeability of the immature intestinal membrane before weaning. Cephradine absorption from the intestine of 1-week-old rats became saturated and inhibited by carnosine and glycylglycine when studied by the in situ loop method. Cefazolin absorption was proportional to luminally administered doses and was not affected by carnosine and glycylglycine. A nonsaturable process for cefazolin and a saturable process for cephradine were also observed in an in vitro uptake experiment.

Drug elimination from the body after intravenous administration of acyclovir (20 mg kg−1) was delayed in 1-week-old rats but the pharmacokinetic data for 2–5-week-old rats were the same as those for 8-week-old rats. The areas under the plasma concentration-time curves at 0–∞ h (AUC) after oral administration of acyclovir (20 mg kg−1) decreased with increasing age. The absolute bioavailabilities for 1-, 2·5-, 3- and 8-week-old rats were 77·59, 51·52, 14·61 and 7·30%, respectively. The gastrointestinal absorption of poorly absorbed acyclovir was good for rats younger than 2·5 weeks but dropped abruptly between 2·5 and 3 weeks of age. The intestinal membrane permeability of acyclovir was studied using the everted sac method. The rate of transfer of an initial concentration of 10 μm acyclovir from the mucosal to the serosal side was constant until 60 min in rats of different ages while the rate in 2–5-week-old rats was significantly greater than that in 3-, 4- and 8-week-old rats. Abrupt in-vivo and in-vitro changes were observed in the experimental results between 2·5- and 3-week-old rats; this period coincided with the weaning period of the rat. The membrane transport mechanism of acyclovir in 2·5- and 8-week-old rats was also studied. Cumulative transferred amounts of acyclovir were linear (r = 0·99) over the range 5 μm–1 min and dose-independent. The influence of metabolic inhibitors (sodium azide, 2,4-dinitrophenol, ouabain), purine and pyrimidine analogues (2-deoxyguanosine, guanine, adenine, uridine) and temperature on the permeation of acyclovir was studied. The permeation of acyclovir was inhibited only by 2-deoxyguanosine and guanine in 2·5-week-old rats. These results suggest that throughout the maturation period, the gastrointestinal absorption mechanism of acyclovir is predominantly via passive diffusion with little or no active or facilitated transport. The abrupt change that occurs during the weaning period is attributable not to facilitated transport but to a change in the factors regarding passive transport.

OBJECTIVE—We assessed the effects of a 2-day in-hospital diabetes educational program in preventing or delaying progression of impaired glucose tolerance (IGT) to type 2 diabetes, including analysis of changes in serum lipids, body weight, and blood pressure after the program. RESEARCH DESIGN AND METHODS—A total of 426 subjects (51 ± 9 years, BMI 24.6 ± 3.9 kg/m2) with newly diagnosed IGT were randomly assigned to three groups, 143 as the short-term hospitalization with diabetes education and support (STH) group, 141 as the nonhospitalization but diabetes education and support (DES) group, and 142 as the neither hospitalization nor education (control) group. RESULTS—The average follow-up was 3.1 years. The incidence of diabetes was 8.0, 10.7, and 13.2 cases per 100 person-years for STH, DES, and control groups, respectively. The incidence of diabetes was 42% lower (95% CI 33–51%) in the STH group and 27% lower (15–37%) in the DES group than in the control group. The incidence of diabetes was 21% lower (10–31%) in the STH group than in the DES group. CONCLUSIONS—The 2-day in-hospital program with diabetes education and support every 3 months was more effective in preventing or delaying the progression from IGT to diabetes than only diabetes education and support every 3 months.

The aim of this study was to clarify the clinical significance of urinary enzyme activity in patients with diabetes mellitus. Patients were divided into two groups: group A - 102 outpatients, group B-23 inpatients. Spot urine samples before breakfast from group A and aliquots of 24-hours urine collections at 4 degrees C from group B were used. Urinary enzyme activities (N-acetyl- beta-D-glucosaminidase: NAG, alkaline phosphatase: ALP, leucine aminopeptidase: LAP, gamma-glutamyl transpeptidase: gamma-GTP) were determined by spectrophotometric assay, rate assay, Tuppy method and Orlowski method, respectively. 1) In group A, the percentage of the cases which showed higher than the normal range (NAG: 1.3-8.7, ALP: 4.2-17.7, LAP: 0-22.9 U/g. cer.) was 42.2% in NAG, 21.6% in ALP, and 8.8% in LAP. In a multiple regression analysis, the predictor variables which contributed to NAG were HbA1c, age, urinary protein and the one that contributed to ALP, LAP, gamma-GTP was urinary beta 2-microglobulin. 2) In group B, 87% of NAG was above the normal range (Mean +/- 2 SD; 4.8 +/- 3.9 U/day). There was no difference in the NAG activity between patients with and without nephropathy. The percent of high activities of ALP, LAP and gamma-GTP were 17%, 17%, 4%, respectively. Most of them were patients with nephropathy. There were correlations among ALP, LAP and gamma-GTP, though no correlation existed between NAG and the other three enzymes. These results suggested: 1) NAG reflects lysosomal dysfunction of both glomerular and proximal tubular epithelial cells which may be caused by poor glycemic control.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of beta-lactam antibiotics in adult and neonatal rats were compared after their intravenous or oral administration. The distribution volumes of cefazolin, cefamandole and cefmetazole were larger for the neonatal than the adult rats, whereas the distribution volumes of cephradine and cephalexin were smaller for the neonates. Neonatal rats showed lower clearances than adults for all antibiotics tested. The maximum plasma concentrations (Cmax) after oral administration of cefazolin, cefamandole and cefmetazole were significantly higher (3-15 times) for neonatal than for adult rats. However, in the case of cephradine and cephalexin, the increase of Cmax for neonatal rats was small. The absolute bioavailabilities for cefazolin, cefamandole and cefmetazole were significantly larger in the neonates. Thus, cefazolin, cefamandole and cefmetazole, which were poorly absorbed by adults, were found to be easily absorbed by the intestines of neonatal rats.

A 46-year-old man was diagnosed as having benign symmetric lipomatosis (BSL) based on the grotesque physical examination findings and subcutaneous fat tissue biopsy. Although markedly overweight, the glucose tolerance was normal and insulin levels indicated no remarkable insulin resistance on the 75 g oral glucose tolerance test. Furthermore his visceral fat tissue was very slight and the circulating adiponectin concentration was high those which suggesting a high insulin sensitivity. In addition, the relevance of alcohol in the onset of BSL is strongly suggested based on alcoholic hepatopathy and the history of the development of grotesque physical appearance associated with increased alcohol consumption.

Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability, and is considered to be mainly the result of a hypothalamic defect. PWS is characterized by hyperphagia, obesity, mental retardation and hypogonadism from a young age. Hyperphagia is one of the most serious problems, which is organic in origin, inducing morbid obesity and leading to respiratory failure. Most studies attempting to control obesity in children with PWS by dietary management reported limited success due to difficulty in controlling foraging and food stealing. Here we report 16- and 20-year-old female patients with PWS who showed marked weight loss and improvement of respiratory failure by behavior modification and improvement of the environment.

The authors conducted a survey in July 2001 to examine the present state and forthcoming problems facing occupational health physicians (OHPs). The establishments investigated were those which employed 1,000 or more workers and had consulted us for the employment of OHPs. The number of establishments chosen was 1,658. A questionnaire was sent to the division chiefs responsible for the health management of the establishments, and those who supervised the OHPs engaged in the establishments were asked to complete the questionnaire. The questionnaire included items about the attributes of the perspective establishments, the work of OHPs and the personnel management system for the OHPs. Four hundred and forty-seven establishments (27.0%) out a total of 1,658 returned eligible responses for further analysis, and the major results were as follows: First, 79.2% of the manufacturing establishments which responded comprised those which employed 1,000 or more workers, even though the percentage of companies which employ 1,000 or more workers throughout Japan is 62.5%. The percentage of the establishments which employed full time OHPs was 64.2% in secondary industries (mining, constructing and manufacturing), and higher than the 40.8% in tertiary industries (other than farming, forestry, fishing and secondary industries). Second, although OHPs properly coped with the obligatory issues regulated by the related laws, the OHPs who routinely consulted with workers about their work-related health problems were few (36.7%). Third, despite the low percentage of the establishments (23.5%) which had recognized OHPs' work to be part of enterprise management, the budget of the health care section was kept unchanged (55.0%). And, in 49.0% of the establishments, the nomination of OHPs was recognized to be necessary irrespective of the presence of the related laws, and OHPs were expected to cope with the work-related health problems of workers (62.9%). On the other hand, the personnel management system for OHPs was insufficient, and the performance rating for OHPs' activity was prepared for only 50.3% of the establishments. In addition, when the subjects were confined to regular OHPs, they were allowed to attend internal training courses for regular employees in only 25.0% of the establishments. Taking the above into account, the activity of OHPs has to be developed more in tertiary industries. OHPs may also be asked to positively cope with workers' work-related health problems. Simultaneously, the personnel management system for OHPs has to be arranged properly.

When we commonly evaluate the thyroid function, we measure TSH, free T3 and free T4. However, there are some cases that are difficult to diagnose because of the existence of thyroid hormone autoantibodies. We experienced a case of a 14-year-old girl with diffuse struma whose TSH, free T3 and free T4 were elevated by detected with Amerlex M free T3 and free T4 kits, although she did not have any symptoms. As the free T4 level was low by the equilibrium dialysis method, we diagnosed this case as hypothyroidism due to chronic thyroiditis. Because we found thyroid hormone antibodies in her serum, we thought that this case presented pseudoelevations of free T3 and free T4 by the analogue method.

This study was designed to investigate the effects of environmental stress on metabolic derangements and the expression of diabetes phenotype in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of human type 2 diabetes (NIDDM). Acute environmental stress, i.e., exposure to water with immobilization for 1 h, caused a transient increase in blood glucose with decreased insulin secretion, and the stress-induced hyperglycemia augmented with age. The increased glycemia was associated with increased plasma levels of catecholamines and corticosterone. Short-term stress, the same stress of 1 h/day for 10 days, caused a significant decrease of food intake, which led to weight reduction in OLETF rats, aged 50 weeks. Blood glucose and insulin responses in OGTT showed no change before or after the short-term stress, despite the weight reduction. In chronic stress experiments, i.e., exposure to the same kind of stress for 6 days/week from 8 to 75 weeks of age, stressed rats did not gain weight, compared to control rats. Blood HbA1c levels and the index of insulin resistance after a 4-h unfed period were significantly lower in stressed rats than in controls from 35 and 45 weeks of age on, respectively. The occurrence of diabetes, diagnosed by OGTT, was also significantly lower in the rats subjected to chronic stress than in controls. These results suggest that chronic stress from 8 weeks of age inhibited weight gain, probably due to changes in eating behavior, preventing the deterioration of insulin resistance in OLETF rats. Plasma leptin levels were not modulated by stress, and correlated with body weight in the rats under chronic stress and in controls. These results suggest that in type 2 diabetes, blood glucose derangement due to stress is presumably associated not only with changes in counterregulatory hormones involved in glucose metabolism, but also with stress-induced changes in eating behavior.