Three-year denosumab treatment in postmenopausal Japanese women and men with osteoporosis: results from a 1-year open-label extension of the Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT).

SUMMARY: A 12-month extension phase of DIRECT in Japanese subjects with osteoporosis showed that total 3 years of denosumab treatment in Japanese postmenopausal women and men with osteoporosis was associated with low fracture rates, persistent bone turnover marker (BTM) reductions, continuous bone mineral density (BMD) increases, and a favorable overall benefit/risk profile. INTRODUCTION: The DIRECT trial demonstrated that 2 years of treatment with denosumab 60 mg subcutaneously every 6 months significantly reduced the incidence of vertebral fracture compared to placebo in Japanese postmenopausal women and men with osteoporosis. The purpose of this study is to evaluate the efficacy and safety of denosumab treatment for up to 3 years. METHODS: This study includes a 2-year randomized, double-blind, placebo-controlled phase and a 1-year open-label extension phase in which all subjects received denosumab. The data correspond to 3 years of denosumab treatment in subjects who received denosumab (long-term group) and 1 year of denosumab treatment in subjects who received placebo (cross-over group) in the double-blind phase. RESULTS: Eight hundred and ten subjects who completed the double-blind phase enrolled into the extension phase, and 775 subjects completed the study. All subjects received denosumab with daily supplements of calcium and vitamin D. The cumulative 36-month incidences of new or worsening vertebral fractures and new vertebral fractures were 3.8 and 2.5 %, respectively, in the long-term group. In this group, the BMD continued to increase, and the reduction in BTMs was maintained. In the cross-over group, comparable BMD increases and BTMs reductions to those of in their first year of the long-term group were confirmed. Adverse events did not show a notable increase with long-term denosumab administration. One event of osteonecrosis of the jaw occurred in the cross-over group. CONCLUSIONS: Three-year denosumab treatment in Japanese subjects with osteoporosis showed a favorable benefit/risk profile.

The pharmacokinetic profile of crocetin in healthy adult human volunteers after a single oral administration.

Crocetin, a unique carotenoid with a short carbon chain length, is an active compound of saffron and Gardenia jasminoides Ellis used as traditional herbal medicine. The present study was undertaken to investigate the pharmacokinetic profiles of crocetin in healthy adult subjects. The study was conducted as an open-label, single dose escalation with 10 Filipino volunteers (5 men and 5 women). The subjects received a single dose of crocetin at three doses (7.5, 15 and 22.5 mg) in one week interval. Blood samples were collected from the brachial vein before and at 1, 2, 4, 6, 8, 10 and 24 h after administration. Plasma concentrations of crocetin were determined by high-performance liquid chromatography (HPLC). Crocetin was rapidly absorbed and detected within an hour of administration with a mean time to reach maximum concentration (T(max)) of crocetin ranging from 4.0 to 4.8 h. The mean values of C(max) and AUC(0-24h) ranged from 100.9 to 279.7 ng/ml and 556.5 to 1720.8 ng. h/ml respectively. C(max) and AUC values increased with dose proportional manner. Crocetin was eliminated from human plasma with a mean elimination half life (T(½) of 6.1 to 7.5 h. In summary, there were no serious adverse events up to 22.5 mg dose of crocetin while crocetin was found to be absorbed more quickly than the other carotenoids such as ß-carotene, lutein and lycopene.

Effect of crocetin from Gardenia jasminoides Ellis on sleep: a pilot study.

Crocetin is a pharmacologically active carotenoid compound of Gardenia jasminoides Ellis used as a traditional herbal medicine and natural colorant. The present pilot study investigated the effect of crocetin on sleep. The clinical trial comprised a double-blind, placebo-controlled, crossover trial of 21 healthy adult men with a mild sleep complaint. It included two intervention periods of 2 weeks each, separated by a 2-week washout period. We measured objective sleep quality using an actigraph, and assessed the subjective symptoms using St Mary's Hospital Sleep Questionnaire. Actigraph data showed that after administration of crocetin, the number of wakening episodes was reduced compared to that of the placebo (p=0.025). Subjective data from St Mary's Hospital Sleep Questionnaire showed that crocetin tended to improve the quality of sleep compared to sleep before its intake. Additionally, no side effects from crocetin intake were observed. The results suggest that crocetin may contribute to improving the quality of sleep.

Isotopic investigations for the origin of relic from the Matsusaki site, Japan.

We measured the environmental radioactivity and isotope ratio, (87)Sr/(86)Sr ratio, (234)U/(238)U, delta(13)C, and (228)Ra/(226)Ra activity ratio, of adhesion that adhered to a wooden tubing vessel obtained from the Matsusaki site, one of the salt-production sites where Moshio is manufactured, in Aichi Prefecture, Japan. The environmental radioactivity and isotope ratio verified that the adhesion originated from the seaweed and/or sea grass.

Effect of daily oral minodronate on vertebral fractures in Japanese postmenopausal women with established osteoporosis: a randomized placebo-controlled double-blind study.

UNLABELLED: SUMMARY; A randomized placebo-controlled trial was conducted to examine the effect of daily oral 1 mg minodronate on vertebral fractures in 704 postmenopausal women with established osteoporosis for 24 months. Minodronate treatment reduced vertebral fractures by 59% without serious adverse events. Minodronate is a safe and effective bisphosphonate for osteoporosis treatment. INTRODUCTION: Minodronate increases bone mineral density (BMD) in postmenopausal osteoporotic patients. However, its efficacy in reducing osteoporotic fractures has not been tested. METHODS: To examine anti-fracture efficacy and safety of daily oral minodronate in postmenopausal women with established osteoporosis, a randomized, double-blind, placebo-controlled trial was conducted in 704 postmenopausal women (55 to 80 years) with one to five vertebral fractures and low BMD. Subjects were randomly assigned to receive daily oral 1 mg minodronate (n = 359) or placebo (n = 345) for 24 months, with daily supplements of 600 mg calcium and 200 IU vitamin D(3). RESULTS: Daily 1 mg minodronate for 24 months reduced the risk of vertebral fractures by 59% (95% CI, 36.6-73.3%). Furthermore, when fractures during the first 6 months were eliminated, the risk of vertebral fractures from 6 to 24 months was reduced by 74% in minodronate-treated group. Minodronate treatment also reduced height loss. Bone turnover markers were suppressed by about 50% after 6 months of minodronate treatment and remained suppressed thereafter. The overall safety profile including gastrointestinal safety was similar between the two groups. CONCLUSIONS: Daily oral minodronate is safe, well-tolerated, and is effective in reducing vertebral fracture risk in postmenopausal women with established osteoporosis.

Autologous blood transfusion for kidney transplant recipients.

Autologous blood transfusion (ABT) is rarely employed in patients with end-stage renal disease (ESRD); these patients are usually anemic. Since 1998, we have attempted ABT for ESRD patients undergoing living-related kidney transplantation. Among 20 patients enrolled in this study the preoperative hemoglobin and hematocrit levels were 10.0 +/- 1.2 mg/dL (range, 8.1-11.7) and 30.0 +/- 3.7% (range, 24.7-34.3), respectively. Blood volume collected on each occasion was 235.7 +/- 57.7 mL (range, 200-400), and the number of blood collections was 2.45 +/- 0.9 (range, 1-4). Total collected volume was 567.5 +/- 157.5 mL (range, 400-800). Symptomatic hypotension was seen in two patients, but vital signs recovered spontaneously. No other problems related to blood collection were observed. Allogeneic transfusion was need in only one patient (5%). ABT was safe and efficacious in ESRD patients scheduled for living-related kidney transplantation.

Neuroendoscopic surgery for intracerebral haemorrhage--comparison with traditional therapies.

Endoscopy is a new therapeutic option for hypertensive intracerebral haemorrhage. Although it has the advantages of being less invasive than craniotomy and more effective than conservative treatment, not all patients are candidates for it. Since it is important to clarify which characteristics of patients are indications for this operation, we retrospectively evaluated the role of endoscopic surgery in comparison with traditional treatments for hypertensive intracerebral haemorrhage. Seven patients were treated with endoscopic surgery in our institution between January 2000 and November 2001. Two had thalamic haemorrhage, 4 putaminal haemorrhage, and 1 intracerebral haemorrhage. The average age of patients was 55 years. Endoscopic operation was mainly selected for haematomas more than 20 ml and less than 40 ml in volume. Generally, endoscopy yielded good outcomes with GR in 50 % of patients. Adequate indications for endoscopic operation may be the following; 1) Putaminal haematoma of small-intermediate size, 2) Haematoma situated deep in the brain, e. g., thalamic haemorrhage, 3) Intraventricular haematoma, 4) High-risk patients who cannot tolerate general anaesthesia.

Hyperbaric oxygen for anorexia nervosa.

Hyperbaric oxygen was given to a patient with anorexia nervosa who had developed postoperative ileus, resulting in not only improvement in ileus, but also enhancement of intestinal movement, inducing the feeling of hunger, and thereby increasing food ingestion. Hyperbaric oxygen may be effective as an initial treatment for anorectic patients showing severe bloating and resistance to food ingestion.

Systemic effects of hyperthermic isolated lower limb perfusion with carboplatin and interferon-beta.

The changes in systemic circulation during hyperthermic isolated lower limb perfusion with carboplatin and interferon-beta were investigated in 19 patients with malignant melanoma. The cardiac output (CO) increased significantly (p < 0.01) from 3.81 +/- 0.22 L/min before the procedure to 5.30 +/- 0.49 L/min 1 h after hyperthermic perfusion. The double product (mean arterial pressure x heart rate) also increased significantly (p < 0.01) from 5,145 +/- 372 mm Hg/min to 6,760 +/- 486 mm Hg/min. In some patients, it increased to more than twice the control value. These changes were accompanied by an increase in body temperature, presumably caused by the systemic leakage of both warmed blood and interferon-beta. Blood chemistry data demonstrated no significant changes in the liver or renal function. However, the serum CPK level increased markedly on the first postoperative day, and persisted for 1 week, thus suggesting that some muscle damage occurred during the procedure. There was no operative death or severe complications. From these data, we concluded that hyperthermic isolated limb perfusion with interferon-beta is a relatively safe therapeutic method for malignant melanoma of the extremities. However, care should be taken in patients with ischemic heart disease who may suffer a heart attack due to the rapid increase in cardiac work during the procedure.

Effect of segmental transcatheter arterial chemoembolization on branched chain amino acids and tyrosine ratio in patients with hepatocellular carcinoma.

The effect of segmental transcatheter arterial chemoembolization (TAE) on serum amino acid levels and liver function were studied in 23 patients with HCC associated with hepatitis virus C (22 patients) or alcoholism (1 patient), with compensated liver cirrhosis (Child A 18 patients, Child B 5 patients). Serum levels of branched-chain amino acids (BCAA), tyrosine, branched-chain amino acids to tyrosine ratio (BTR), ammonia, total bilirubin and albumin, and prothrombin times were measured before and after TAE (24 h, 7 and 14 days). The BTR was increased significantly 24 h after TAE (p<0.001) and gradually decreased to pre-TAE levels. Serum tyrosine levels decreased at 24 h after TAE (p<0.005) and later increased. Serum BCAA levels increased slightly at 7days after TAE and were decreased at 14 days after TAE. This results indicated that the increased BTR was due primarily to the decreased tyrosine level at 24 h after TAE. Serum ammonia levels gradually decreased after TAE and the prothrombin time and serum levels of total bilirubin and albumin were not significantly changed. In this study, segmental TAE had little influence on liver function, and the BTR unexpectedly increased at 24 h after TAE. These results suggest that segmental TAE has minimal side effects and may have a beneficial effect on amino acid metabolism.

Adxanthromycins A and B, new inhibitors of ICAM-1/LFA-1 mediated cell adhesion molecule from Streptomyces sp. NA-148. II. Physico-chemical properties and structure elucidation.

Adxanthromycins A and B are new inhibitors of ICAM-1/LFA-1 mediated cell adhesion molecule isolated from the fermentation broth of Streptomyces sp. NA-148. The molecular formula of adxanthromycins A and B were determined as C42H40O17 and C48H50O22, respectively by FAB-MS and NMR spectral analyses, and the structures of both compounds were elucidated to be a dimeric anthrone peroxide skeleton containing alpha-D-galactose by various NMR spectral analyses and chemical degradation.

Effect of short duration morning bright light in elderly men: sleep structure.

Sleep structure was measured in five healthy elderly men in their homes. The subjects were exposed to bright light (6000 lx) for 30 min in the morning or instructed to sit in front of a desktop lighting device without light. Relative to the control conditions, bright light exposure significantly decreased time in bed and the number of awakenings. Rapid eye movement sleep was significantly fragmented by stage 1 sleep in the control condition compared with the bright light condition. These findings indicate that a short duration of morning bright light changes sleep structure and is effective in maintaining sleep.

Isoforms of the small non-catalytic subunit of smooth muscle myosin light chain phosphatase.

Chicken gizzard smooth muscle myosin light chain phosphatase is composed of a approximately 37 kDa catalytic subunit, a approximately 110 kDa myosin binding or targeting subunit and a approximately 20 kDa subunit (MPs) whose function is as yet undefined. It was reported previously that a cloned chicken gizzard MPs cDNA encodes a protein of 186 amino acids (aa) [Y.H. Chen, M.X. Chen, D.R. Alessi, D.G. Gampbell, C. Shanahan, P. Cohen, P.T.W. Cohen, FEBS Lett. 356 (1994) 51-55]. More recently, we obtained by PCR amplification another MPs cDNA that encodes a protein of only 161 aa [Y. Zhang, K. Mabuchi, T. Tao, Biochim. Biophys. Acta 1343 (1997) 51-58]. In this work we obtained cDNAs corresponding to both sequences using a different set of PCR primers, indicating that the two sequences correspond to isoforms that most likely arose from alternative splicing of the same gene. Using two polyclonal antibodies, one raised against the recombinant 161 aa isoform of chicken gizzard MPs and the other against a C-terminal polypeptide that is present only in the 186 aa isoform, we found that while the 161 aa isoform is the predominant one in chicken gizzard, in chicken aorta it is the 186 aa one; in chicken stomach both isoforms are present, and in mammalian tissues such as ferret and rat only the 186 aa isoform is detected. Furthermore, we purified the MPs associated with the chicken gizzard myosin light chain phosphatase holoenzyme and determined its molecular weight, amino acid composition and six residues of its C-terminal sequence. The results from these analyses showed conclusively that the predominant isoform in chicken gizzard is the 161 aa one.

Bright light treatment for sleep-wake disturbances in aged individuals with dementia.

Treatment using bright light exposure was carried out on six aged subjects with dementia in two nursing homes. Sleep logs were recorded by the staff. Bright light treatment was applied in the late morning every day. The %sleep in the lights-out period and/or the %wake in daytime increased in three subjects. In the other three subjects, sleep onset time was advanced. In all subjects abnormal behavior episodes around the lights-out time tended to be reduced. These results suggest that bright light treatment is effective in improving the sleep-wake disturbances of aged individuals with dementia.

Effects of moderately bright light on subjective evaluations in healthy elderly women.

Eight healthy elderly women aged 56-72 years (mean age: 67.4 years) participated in this study. They were exposed to moderately bright light (1000 lux) for 1h in the morning every 6 days in their homes. Moderately bright light improved self evaluations for alertness, mood, motivation, happiness, refreshment, concentration and appetite after the second exposure to the light. Sleep maintenance, anxiety and integrated sleep feeling also improved after the fourth exposure to the light. The phase of rectal temperature rhythm did not change in a moderately bright light condition. These results suggest that bright light influences sleep quality and self evaluations without changing the biological rhythm phase.

Sleep improvement by light in a demented aged individual.

We administered daily morning bright light exposure in two separate periods to a demented aged subject in a nursing home and analyzed the sleep pattern changes from the sleep diary over 6 months. In the first light exposure period, the ratio of sleep time in night hours increased and maintained a higher value throughout the period than the previous baseline. After stopping the light exposure, the sleep pattern of the subject deteriorated. Resuming the light exposure reproduced similar sleep pattern changes. These results suggest that morning bright light exposure provides a better environment for aged persons to maintain a regular sleep-wake pattern.

Effects of short duration morning bright light in healthy elderly subjects. I: subjective feeling and ophthalmological examinations.

Seven aged subjects aged 61-78 years were exposed to 6000 lx bright light for 30 min during morning hours at their homes for 1 week. Visual analog scale was recorded before bedtime and after rising to assess subjective feelings. Ophthalmological examinations were made before and after light exposure, to exclude pre-existing ocular disorders and to detect ocular damage. Furthermore, ocular fatigue was self-evaluated immediately before and after exposure. Visual analog scale results indicated that alertness reduced significantly before bedtime. Ophthalmological abnormalities were not found after exposure. These findings suggest that short duration morning bright light exposure reduces night-time vigilance.

Evaluation of altered myocardial high energy phosphate metabolism in patients on maintenance dialysis using phosphorus-31 magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES: Assessment of left ventricular metabolism and function is important in patients on maintenance dialysis because congestive heart failure occurs quite frequently and has a poor prognosis. The purpose of this study was to evaluate the changes of myocardial high energy metabolism in dialysis patients by using phosphorus-31 (31P) magnetic resonance (MR) spectroscopy. METHODS: Phosphorus-31 spectra were obtained from anteroseptal wall of the heart in six normal subjects (mean age, 24 +/- 1 years) and 14 dialysis patients (mean age, 52 +/- 11 years), using a 1.5-tesla clinical MR system. Four patients had previous history of heart failure. Echocardiography was performed in all patients to evaluate left ventricular (LV) hypertrophy and LV function. RESULTS: The averaged ratio of phosphocreatine (PCr)/beta-adenosine triphosphate (beta-ATP) in dialysis patients (1.15 +/- 0.25 mean +/- standard deviation), was significantly lower than that in healthy subjects (1.63 +/- 0.21; P < 0.01). There was no significant difference in PCr/beta-ATP ratios between the non-LV hypertrophy group (1.21 +/- 0.24; n = 7) and the LV hypertrophy group (1.09 +/- 0.24; n = 7). The averaged PCr/beta-ATP ratio in four patients with history of heart failure (0.96 +/- 0.18) was significantly lower than that of the 10 patients without history of heart failure (1.22 +/- 0.23; P < 0.05). CONCLUSIONS: These results indicate that patients on maintenance dialysis have decreased PCr/beta-ATP ratio and 31P MR spectroscopy can provide noninvasive assessment of altered high energy phosphate metabolism.

Expression profile of receptor-type protein tyrosine kinase genes in the human thyroid.

Protein tyrosine kinases (PTKs) play a role in regulating the growth and differentiated functions of thyroid cells and are probably involved in tumorigenesis of papillary-type thyroid carcinoma. To better understand the roles of PTKs in the physiology and pathophysiology of the thyroid, we analyzed the expression profile of receptor-type PTKs in normal human thyroid tissues. Highly conserved regions in the catalytic domains of receptor-type PTKs were amplified by RT-PCR using degenerate oligonucleotide primers. Nucleotide sequencing of about 100 clones identified 21 PTKs, including 16 receptor type and 5 nonreceptor type; no novel PTK was identified. Insulin-like growth factor I receptor, platelet-derived growth factor receptor (PDGFR), TrkE, Axl, epidermal growth factor receptor, etc., appear to be the most abundant receptor-type PTKs in the thyroid; many of which (PDGFR, TrkE, Axl, etc.) have never previously been demonstrated to be expressed in the thyroid. The expression of messenger RNAs (mRNAs) for PDGFR, axl, and trkE in normal thyroid cells was confirmed by Northern blot analysis, and interestingly, the expression levels of PDGFR and trkE mRNAs were decreased in all three thyroid carcinoma cell lines examined (FRO, WRO, and NPA), whereas axl mRNA and protein were overexpressed in 2 of 3 thyroid carcinoma cell lines (FRO and WRO) compared with that in normal tissue. The axl gene was, however, neither amplified nor rearranged. The biological activity of the ligand for Axl, the product of growth arrest-specific gene 6 (Gas6), was then evaluated, demonstrating modest mitogenic activity in thyroid carcinoma cells overexpressing Axl. Furthermore, gas6 mRNA was expressed in FRO cells. Thus, we here identify a variety of PTKs expressed in the thyroid gland, many of which may participate in the regulation of thyroid cell function. Variable expression levels of some PTKs in normal and cancerous cells suggest that there may be an imbalance and disarray of phosphorylation events in thyroid carcinoma cells. Furthermore, Gas6 is identified as a novel growth factor for thyroid carcinoma cells overexpressing Axl receptor tyrosine kinase.

[Changes in hemodynamic state and autonomic nerve function from sleeping to awaking with suggestion on the treatment of cardiovascular diseases].

Effects of sleeping and awaking on blood pressure, heart rate and heart rate variability were shown in normal and a diabetic patient using an ambulatory blood pressure monitor (ABPM), Holter recorder and an accelerometer indicating body motion and posture. From the circadian variation of blood pressure and autonomic nerve function, optimal treatments to protect cardio-vascular accidents were discussed. For the assessments of medication and selection of drugs, ABPM and Holter recording with simultaneous measurement of physical activity are useful.