Effects of DSP-8658, a novel selective peroxisome proliferator-activated receptors a/γ modulator, on adipogenesis and glucose metabolism in diabetic obese mice.

AIMS/INTRODUCTION: Peroxisome proliferator-activated receptors (PPARs) play a key regulating role in homeostasis. In this study, we investigated the effects of DSP-8658, a novel selective PPARa/γ modulator, on adipogenesis and glucose metabolism in diabetic obese mice and compared these effects to those of pioglitazone, a PPARγ full agonist. MATERIALS AND METHODS: DSP-8658 functional activity was assessed by PPARγ-target genes expression in adipose 3T3-L1 cells and its anti-diabetic efficacy evaluated in db/db mice. The effects of DSP-8658 on adipogenesis were investigated diet induced obese (DIO) KK-A(y) mice. RESULTS: DSP-8658 reduced the expression of PPARγ-target gene 11 beta hydroxysteroid dehydrogenase type 1 with an EC50 value 2.1-fold that of pioglitazone and 28.4-fold that of rosiglitazone. On the other hand, DSP-8658 increased the expression of fatty acid binding protein 4 and glycerol kinase genes with EC50 values 33-fold and >15-fold those of pioglitazone and 163-fold and >38-fold those of rosiglitazone, respectively. In db/db mice, DSP-8658, like pioglitazone, decreased blood glucose, HbA1c, and plasma triglyceride levels and increased plasma insulin concentration and pancreatic insulin contents. In DIO KK-A(y) mice, DSP-8658, unlike pioglitazone, decreased subcutaneous adipose tissue weight and mean adipocyte size. However, both DSP-8658 and pioglitazone improved blood glucose and HbA1c levels with similar efficacy. Although DSP-8658 did not change the expression levels of fatty acid transport protein 1 and glycerol kinase genes in subcutaneous adipose tissue of KK-A(y) mice, pioglitazone increased these gene expression levels. CONCLUSION: Unlike PPARγ full agonists, DSP-8658 ameliorates blood glucose without increasing adipogenesis in diabetic obesity mice.

[Endobronchial brachytherapy for intra-luminal recurrence after lung cancer resection].

A 63-year-old man who had squamous cell carcinoma in left lung was received left lower lobectomy with lymph node dissection (pT3N0M0). Twenty months after surgery, the patient showed bloody sputum and bronchofiberscopy revealed intra-luminal recurrence on trachea. Endobronchial brachytherapy in combination with external beam radiotherapy was selected and complete remission was achieved. After the brachytherapy, bronchitis was observed and was healed 23 months after the therapy.

Trehalose-producing operon treYZ from Arthrobacter ramosus S34.

Arthrobacter ramosus S34, which produces trehalose from maltooligosaccharide, was isolated. A trehalose-producing operon, treYZ, was cloned from the genome. Expression experiments with treY and treZ confirmed that they coded malto-oligosyltrehalose synthase and malto-oligosyltrehalose trehalohydrolase, respectively. The amino acid sequence of TreY from A. ramosus S34 and that from Arthrobacter sp. Q36 did not show high identity, nor did those of TreZ.

The natural course of atraumatic shoulder instability.

Over the years, we have observed a shifting among loose shoulder, voluntary dislocation, habitual dislocation, and sustained subluxation, leading us to the conclusion that they are all varieties of the same condition: atraumatic shoulder instability. For this study, we followed the natural course of atraumatic shoulder instability in 341 patients (573 shoulders) for 3 years or more. There were 467 cases of loose shoulder, 49 cases of voluntary dislocation, 56 cases of habitual dislocation, and 1 case of sustained subluxation. The average follow-up period was 4 years and 6 months. Spontaneous recovery occurred in 50 cases. The average age of patients at the onset of atraumatic shoulder instability who exhibited a change in instability was 14.6 years. The average age of patients at the onset of atraumatic shoulder instability who exhibited no change in shoulder instability was 19.4 years. There was a significant difference of P < .01 in the age of onset between these two groups. The incidence of spontaneous recovery in the group that discontinued overhead sports was 8.7 times greater than in the group that continued to play overhead sports. The incidence of spontaneous recovery in the group that discontinued non-overhead sports was only 1.4 times greater than in the group that continued to play non-overhead sports. However, no instance of spontaneous recovery was observed among patients who changed from playing non-overhead sports to playing overhead sports. The spontaneous recovery of atraumatic shoulder instability encountered in this study shows that it is best to place priority on observing the course of atraumatic shoulder instability for several years and to avoid performing unnecessary surgery.

[A family of hereditary spastic paraplegia with dementia, ataxia, and dystonia].

We reported three siblings with complicated hereditary spastic paraplegia. The striking features in these patients were characterized by early onset of gait disturbance, mental deficiency, and dystonia. The most likely diagnosis was Mast syndrome. Patient 1: A 44 years-old woman. She first developed gait disturbances at age of 8. She was admitted in our hospital because of progressive spastic paraplegia. Neurological examination revealed mental deficiency, saccadic pursuit eye movement, speech disturbance of cerebellar type, ataxia, and spastic paraplegia. She showed also dystonia in the face, tongue, and trunk. MRI showed cerebellar atrophy. Patient 2: A 51 years-old brother of the patient 1. He had mentally retarded. Late teens he developed gait disturbance. Gradually he manifested spastic paraplegia, dysarthria, dysphasia, mental deficiency, and ataxia. He also showed incontinence of urine and feces. Then he became bedridden, apathetic, and showed forced crying. MRI showed diffuse brain atrophy. Patient 3: A 48 year-old woman. This woman, a sister of the patient 1, showed progressive gait disturbance and dysarthria. She also developed incontinence, apathy, and dystonia. She became bedridden, responding to simple questions with only occasional single-word answers. Her speech was slurred, and spastic paraplegia was noted. MRI showed diffuse brain atrophy including marked atrophy of the cerebellum.

When can complete regression of low-grade gastric lymphoma of mucosa-associated lymphoid tissue be predicted after helicobacter pylori eradication?

AIMS: Recent studies suggest that primary low-grade gastric lymphomas of mucosa-associated lymphoid tissue (MALT) are cured in many cases between 1 and 18 months after H. pylori eradication. The aim of this study is to elucidate when complete regression (CR) of MALT lymphoma can be histologically predicted after H. pylori eradication. METHODS AND RESULTS: Twenty-one patients with low-grade gastric MALT lymphoma were treated with triple therapy (amoxicillin, clarythromycin and proton pump inhibitor) for 14 days. Subsequently, they were followed up by sequential endoscopy and biopsy (number of biopsy specimens for each endoscopy is 3-8, with an average of 4) from 91 to 657 days (average: 309 +/- 165 days). Eradication of H. pylori infection was achieved in all patients. Nine patients were free of lymphoma at 1 to 2 months after eradication and remained in CR at 163-657 days. Twelve patients showed residual lymphoma at 1 to 2 months after eradication. Five out of 12 patients revealed only one or two small foci of lymphoma-cell aggregation and showed a high incidence (80%) of CR at the latest biopsy (135-434 days, average 276 +/- 115 days after eradication), while seven patients showed diffuse remains of lymphoma cells and indicated CR in only one case (14%) at 362 days, partial regression in five cases at 130-431 days (average 227 +/- 114 days), and no change in one case at 91 days after eradication. CONCLUSIONS: : These results suggest that CR of low-grade MALT lymphoma can be predicted at 1 to 2 months after eradication therapy by checking histological changes of MALT lymphoma cells.

The effects of physical exercise on body fat distribution and bone mineral density in postmenopausal women.

OBJECTIVE: The present cross-sectional study investigated the effects of physical exercise on body fat distribution and bone mineral density (BMD). METHODS: Subjects were 57 postmenopausal women (mean age, 60.5+/-6.4 years) who had exercised regularly for at least 2 years. Controls were 130 age-matched sedentary women. Age, years since menopause (YSM), height, weight, and body mass index (BMI, wt./ht.(2)) were recorded. Total fat mass, percentage of body fat, trunk fat mass, leg fat mass, the ratio of trunk fat mass to leg fat mass (trunk-leg fat ratio), total body lean mass, percentage of body lean, and lumbar spine BMD (L2-L4) were measured by dual-energy X-ray absorptiometry. RESULTS: Baseline characteristics and leg fat mass did not differ between the two groups. Total fat mass, percentage of body fat, trunk fat mass, and trunk-leg fat ratio were lower (P<0.05, P<0.01, P<0.01 and P<0.001, respectively), while total body lean mass, percentage of body lean mass, and lumbar spine BMD were higher in exercising women (P<0.05, P<0.05 and P<0.01, respectively). Performing physical exercise was inversely correlated with trunk-leg fat ratio (standardized regression coefficient=-0.178, P<0.01), but positively correlated with BMD (0. 203, P<0.01) irrespective of age, height, YSM, and total fat mass. CONCLUSION: Physical exercise has beneficial effects on body fat distribution and BMD in postmenopausal women. Reduction of upper body fat distribution with physical exercise may be more attributable to the decrease in trunk fat mass.

Relationship between body fat distribution and bone mineral density in premenopausal Japanese women.

OBJECTIVE: To investigate the relationship between body fat distribution and bone mineral density (BMD). METHODS: Subjects were 282 premenopausal women (mean age +/- standard deviation [SD], 38.8 +/- 8.5 years; range, 20-51 years) with regular menstrual cycles. Baseline characteristics included age, age at menarche, height, weight, body mass index ([BMI], weight/height(2)), and parity. Anthropometric characteristics including the ratio of trunk fat mass to leg fat mass (trunk-leg fat ratio), percentage of body fat, and total body lean mass were measured by whole-body scanning with dual-energy x-ray absorptiometry. Lumbar spine BMD (L2-4) was also measured by dual-energy x-ray absorptiometry. Correlations of BMD to baseline and anthropometric characteristics were investigated using univariate and multivariate analysis. RESULTS: Although height, trunk-leg fat ratio, and total body lean mass were positively correlated with lumbar spine BMD (r =.18, P <.01; r =.17, P <.01; and r =.25, P <.001; respectively), age at menarche was inversely correlated with BMD (r = -.19, P <.01). On multivariable analysis, trunk-leg fat ratio, height, age at menarche, and total body lean mass were still independently correlated with lumbar spine BMD (P <. 05). However, total fat mass was not correlated with BMD. CONCLUSION: Upper body fat distribution rather than overall adiposity is associated with lumbar spine BMD in premenopausal women. Humoral factors associated with body fat mass appear to influence lumbar spine BMD.

Difference in the effect of adiposity on bone density between pre- and postmenopausal women.

OBJECTIVES: Elevated bone mineral density (BMD) in obese women is partially attributable to the higher circulating estrogen levels derived from extraglandular aromatization in adipose tissue. However, it remains unclear whether there is an effect of overall adiposity on BMD in both pre- and postmenopausal women. The difference in the effect of overall adiposity on BMD between pre- and postmenopausal women was investigated. MATERIALS AND METHODS: Subjects were 296 premenopausal women with regular menstruation and 233 postmenopausal women. Age, age at menarche, years since menopause (YSM, in postmenopausal women), weight, height, and body mass index were recorded. Total fat mass amount, lean mass amount, and percentage of body fat were measured by whole body scanning with dual-energy X-ray absorptiometry (DEXA). Lumbar spine BMD (L2-L4) was measured by DEXA. In each group, significant determinants of BMD were investigated using univariate and stepwise multiple regression analysis. RESULTS: In postmenopausal women, YSM, lean mass amount, total fat mass amount, and height were significant determinants of BMD (R(2)=0.273, P<0.001). In premenopausal women, only two variables including lean mass amount and age at menarche were significant determinants of lumbar spine BMD (R(2)=0.110, P<0.001), but total fat mass amount and percentage of body fat were not significant determinants of BMD. CONCLUSION: The effect of overall adiposity on BMD is more prominent in postmenopausal women than in premenopausal women.

Cloning and nucleotide sequence of a gene encoding a glycogen debranching enzyme in the trehalose operon from Arthrobacter sp. Q36.

A gene located just upstream of the treYZ operon was isolated from Arthrobacter sp. strain Q36. The gene, designated treX, encoded an 823-amino acid protein. The amino acid sequence of the protein had 50% identity with the TreX protein (isoamylase) from Sulfolobus acidocaldarius ATCC 33909 which has a treZXY operon on the genome. We suggest that Arthrobacter treX is an isoamylase gene, and that it is a component of a treXYZ operon.

Association of upper arm circumference at muscle flexion with lumbar spine bone mineral density.

We investigated the association of upper arm circumference at muscle flexion with lumbar spine (L2-L4) bone mineral density (BMD) in 252 postmenopausal Japanese women (mean age, 62.0 +/- 7.6 years; range, 43-78 years) with right-side dominance. Age, age at menopause, years since menopause (YSM), weight, and height were recorded. Dominant upper arm circumference (cm) was measured at muscle flexion. Lumbar spine BMD was measured by dual-energy X-ray absorptiometry (DXA). Correlations between BMD and variables were determined using Pearson's correlation coefficient. Significant predictors of the lumbar spine BMD were determined using stepwise multiple regression analysis. Upper arm circumference, weight, and height were positively correlated with BMD (r = 0.397, 0.343, and 0.323, respectively), whereas YSM and age were inversely correlated with BMD (r = -0.415 and -0.392, respectively). On stepwise multiple regression analysis, YSM, upper arm circumference, and weight were significant predictors of BMD (R2 = 0.322, P < 0.0001). Predicted value of the lumbar spine BMD was calculated by the following formula: Predicted BMD = 0.249 - 0.0078 (YSM) + 0.016 (upper arm circumference) + 0.0046 (weight). Dominant upper arm circumference at muscle flexion in combination with YSM and weight is a useful predictor of lumbar spine BMD.

The contribution of menopause to changes in body-fat distribution.

OBJECTIVE: To investigate whether menopause contributes to changes in body-fat distribution, irrespective of aging or obesity. METHODS: The subjects were 545 premenopausal (aged 16-55 years; mean +/- standard deviation, 37.7 +/- 9.1 years) and 219 postmenopausal (aged 45-65 years, 58.0 +/- 5.0 years) women. Baseline characteristics included age, body mass index (BMI), and menopausal status (premenopause or postmenopause). The ratio of trunk fat to leg fat (trunk-leg ratio) was estimated by dual-energy X-ray absorptiometry. The trunk-leg ratio and baseline characteristics were compared between the 2 groups. In all subjects (n = 764), possible correlations between the trunk-leg ratio and the baseline characteristics were determined using univariate and multivariate analysis. In postmenopausal women, the relationship of the trunk-leg ratio to YSM or age after adjusting for BMI was investigated. RESULTS: The trunk-leg ratio and BMI were significantly higher in postmenopausal women than in premenopausal women. In all subjects, age and BMI were positively correlated with the trunk-leg ratio (r = 0.445 and 0.587, respectively, p < 0.0001). Menopause was also positively correlated with the trunk-leg ratio on univariate regression analysis (standardized regression coefficient = 0.369, p < 0.0001). On multiple regression analysis, age, BMI, and menopause were independently correlated with the trunk-leg ratio (p < 0.05). In postmenopausal women, age and YSM were positively correlated with the trunk-leg ratio, independent of the BMI (p < 0.01). CONCLUSIONS: Menopause contributes to a change in body-fat distribution, irrespective of aging or obesity.

Serum androgen levels and muscle mass in women with polycystic ovary syndrome.

OBJECTIVE: To relate serum androgen levels and muscle size in women with polycystic ovary syndrome (PCOS). METHODS: Forty-eight women with PCOS were studied. Baseline characteristics included age, height, weight, and hirsutism. Total-body lean mass was measured by wholebody scanning with dual-energy x-ray absorptiometry, and the lean mass index (total-body lean mass/height2, kg/m2) was calculated. Trunk-leg fat mass ratio (trunk-leg fat ratio) was assessed by dual-energy x-ray absorptiometry. Serum testosterone, dehydroepiandrosterone sulfate, and androstenedione levels were measured by radioimmunoassay. Subjects were arbitrarily divided into two groups according to lean mass index (lean mass index at least 14 kg/m2, n = 24; or less than 14 kg/m2, n = 24). Baseline characteristics and serum androgen levels were compared between the groups. In all subjects, lean mass index was correlated with age, height, trunk-leg fat ratio, and serum androgen levels. RESULTS: Although trunk-leg fat ratio, serum testosterone and androstenedione levels, and the prevalence of hirsutism were significantly higher in women with a lean mass index at least 14 kg/m2, age and height did not differ significantly between the groups. Trunk-leg fat ratio and serum testosterone and androstenedione levels correlated significantly with lean mass index (r = .68, .75, and .54, respectively). Hirsutism also correlated with lean mass index (standardized regression coefficient = .49; P<.05). CONCLUSION: Muscle size in women with PCOS correlated positively with serum androgen levels and upper body-fat distribution, independent of height.

Bone mineral density in postmenopausal women with endometrial cancer.

OBJECTIVE: The aim of the study was to investigate the relationship between endometrial cancer and bone mineral density (BMD). MATERIALS AND METHODS: A total of 55 postmenopausal Japanese women with well-differentiated adenocarcinoma and 284 age-matched healthy women were studied. Baseline characteristics including age, age at menopause, years since menopause (YSM), weight, height, body mass index (BMI), prior menstrual history, parity, and fertility were recorded for each subject. Lumbar spine BMD (L2-4), and body fat indices including body fat mass amount and percent body fat were measured by dual-energy X-ray absorptiometry. These variables were compared between the two groups. In all subjects (n = 339), correlations of BMD with the presence of endometrial cancer, baseline characteristics, and body fat indices were investigated, using univariate and multiple regression analyses. RESULTS: BMD, weight, BMI, body fat mass amount, and percent body fat were significantly higher in women with endometrial cancer. Other baseline characteristics did not differ between the two groups. Age at menopause, height, weight, BMI, percent body fat, and body fat mass amount were positively correlated with BMD, while age and YSM were inversely correlated with BMD. After adjusting for age, YSM, and height, the presence of endometrial cancer was still correlated with BMD (P < 0.05). However, after adding body fat mass amount to these three adjusted variables, there was no correlation between the presence of endometrial cancer and BMD. CONCLUSION: Women with endometrial cancer have a high BMD. This is attributable to high body fat mass amount in this disease.

Kynurenine concentration of serum was increased by exercise.

Kynurenine pathway of tryptophan makes a lot of physiological active substances, such as quinolinate, NAD and so on, suggesting that kynurenine itself may play a very important role physiologically. Therefore, we examined the influence of exercise on serum kynurenine concentration. At first, we assayed kynurenine concentration of students (n = 13) who took part in a rugby camp for three days. The mean value of kynurenine concentration of before and after training were 1.362 +/- 0.306 microM and 1.725 +/- 0.511 microM respectively. These data means that severe exercise rise the serum kynurenine concentration. Then we tried to examine the relationship between the level of exercise and serum kynurenine concentration. Serum kynurenine concentration had significantly increased immediately after the exercise from 1.869 +/- 0.285 microM to 2.138 +/- 0.248 microM of 24 hours later by loading of 65% heart rate max exercise for each subject. These results suggested that at least the severe exercise affect on the tryptophan metabolism. We will discuss the change of serum kynurenine concentration by another sports such as soccer game and 20 km run.

The effect of menopause on regional and total body lean mass.

OBJECTIVES: To investigate the effect of menopause on regional and total body lean mass. METHODS: Evaluation of 123 healthy premenopausal women (40.6 +/- 10.8 years) and 123 healthy postmenopausal women (61.8 +/- 7.5 years). All subjects were right side dominant. Regional (head, bilateral arms, trunk, and bilateral legs) and total body lean mass were measured using whole-body scanning by dual-energy X-ray absorptiometry. Baseline characteristics including age, height, weight, and menopausal state were recorded. These variables were compared between pre- and postmenopausal women. In all subjects, correlations between regional or total body lean mass and baseline characteristics were investigated using univariate and multiple regression analyses. RESULTS: Height, and lean mass of the trunk, bilateral legs and total body were significantly lower in postmenopausal women than in premenopausal women, while lean mass of the bilateral arms did not differ between the two groups. On univariate regression analysis, bilateral arms lean mass was positively correlated with height (P < 0.001). Trunk, bilateral legs, and total body lean mass were inversely correlated with age and menopausal state (P < 0.001), but were positively correlated with height (P < 0.001). After adjusting for age and height, trunk lean mass was still correlated with menopausal state (P < 0.01). CONCLUSIONS: Menopause induces lean mass loss, independent of aging and height. Trunk lean mass is more prone to decline with menopause than lean mass of other sites.

Entry and intracellular growth of Legionella dumoffii in alveolar epithelial cells.

We have found that Legionella dumoffii strain Tex-KL (ATCC 33343) invades into and proliferates in the human lung alveolar epithelial-cell line A549 in vitro. The organism associated with the A549 cells at a 10-fold greater magnitude than L. pneumophila Philadelphia-1 during in vitro coculture for 1 h. Thereafter, L. dumoffii Tex-KL invaded the cells at a significantly higher rate (100- to 1,000-fold) than did L. pneumophila Philadelphia-1. After internalization, however, both bacteria proliferated at the same rate. This in vitro finding led us to examine the bacterial localization in lungs in a fatal case of L. dumoffii pneumonia. Double immunostaining revealed the bacteria in surfactant apoprotein A-positive cells (i.e., type II alveolar epithelial cells). Next, we infected guinea pigs intratracheally with L. dumoffii Tex-KL. The animals became sick with a fever from 24 h to 48 h after infection with 10(4) to 10(9) cfu of L. dumoffii Tex-KL. The lung tissues were examined through electron microscopy at definite intervals. Many bacteria were found not only inside phagocytic cells in the alveolar space, but also in type I and type II alveolar epithelial cells. These findings strongly suggest that L. dumoffii has an ability to invade into and proliferate in human alveolar epithelial cells, which may explain the rapid and fulminant progress of pneumonia caused by L. dumoffii.