Direct observation of long-lived isomers in 212Bi.

Long-lived isomers in (212)Bi have been studied following (238)U projectile fragmentation at 670 MeV per nucleon. The fragmentation products were injected as highly charged ions into a storage ring, giving access to masses and half-lives. While the excitation energy of the first isomer of (212)Bi was confirmed, the second isomer was observed at 1478(30) keV, in contrast to the previously accepted value of >1910 keV. It was also found to have an extended Lorentz-corrected in-ring half-life >30 min, compared to 7.0(3) min for the neutral atom. Both the energy and half-life differences can be understood as being due a substantial, though previously unrecognized, internal decay branch for neutral atoms. Earlier shell-model calculations are now found to give good agreement with the isomer excitation energy. Furthermore, these and new calculations predict the existence of states at slightly higher energy that could facilitate isomer deexcitation studies.

Improvement of tardive dyskinesia and dystonia associated with aripiprazole following a switch to quetiapine: case report and review of the literature.

WHAT IS KNOWN AND OBJECTIVE: Aripiprazole has a low risk of extrapyramidal symptoms. Switching to aripiprazole has been reported to improve tardive dyskinesia caused by other medications. The authors report a case and review previous reports of dystonia and dyskinesia associated with aripiprazole. CASE SUMMARY: We present a case of a 22-year-old man with schizophrenia who experienced dyskinesia and dystonia associated with aripiprazole. Switching from olanzapine to aripiprazole resulted in worsening dyskinesia and new onset of dystonia. The patient's dyskinesia and dystonia improved after switching from aripiprazole to quetiapine therapy. WHAT IS NEW AND CONCLUSION: There were several previous case reports on dyskinesia and dystonia associated with aripiprazole medication. The risk factors for tardive dyskinesia include older age and female sex. However, our case was a male patient who was younger compared with the previous cases and so should have been less at risk for dyskinesia in comparison with the previous cases. The effects of aripiprazole can include tardive movement disorders. Dyskinesia, dystonia and psychotic symptoms were improved with relatively small dose of quetiapine in this case. Whether some second-generation antipsychotics are more effective than others in the treatment of tardive dyskinesia remains unclear.

Regulation of muscle genes by moderate exercise.

Moderate-intensity exercise at the lactate threshold (LT) is considered to be a safe and effective training regimen for improving metabolic syndrome. The aim of the current study was to investigate the effects of moderate exercise performed at the LT on skeletal muscle gene expression. 6 healthy men participated in cycle ergometer training at LT, 60 min/d, 5 d/wk for 12 wks. Muscle samples were collected after 5 d of training, and then 2 d after training at wks 6 and 12. Quantitative real-time PCR analysis revealed that the expression of peroxisome proliferator activated receptor co-activated 1alpha was significantly increased at 1 h after the training session on day 5. Moreover, using serial analysis gene expression, we found that moderate training for 6 and 12 wks simultaneously induced the expression of a number of metabolic genes involved in the TCA cycle, beta-oxidation, and electron transport. Furthermore, several genes encoding antioxidant enzymes and contractile apparatus were induced. The expression levels of 233 novel transcripts were also altered in response to moderate exercise. Thus, moderate training at the LT is a sufficient stimulus to induce the expression of numerous genes implicated in the development of metabolic syndrome, transcripts involved in the contractile apparatus, and novel transcripts.

Anatomic study for pubic medullary screw insertion.

PURPOSE: To study the anatomy of the pubic ramus and adjacent structures in 160 Japanese to establish a safer pubic screw fixation technique. METHODS: 80 male and 80 female Japanese aged 16 to 89 (mean, 50) years (10 persons in each decade of age) underwent 3-dimensional computed tomographic scanning of their pelvises. The angle at which the screw should be targeted, the appropriate length of the screw, the size of the canal for screw insertion, and the proximity to the bladder, iliac artery, and iliac vein were determined. Correlations between the canal diameters (of the acetabular, base, and parasymphyseal areas) and body features (age, height, and weight) were analysed. RESULTS: In men and women respectively, the appropriate mean screw length was 124.6 and 123.8 mm; the guide wire should be targeted at a mean of 66 degrees and 67 degrees cephalad and 54.1 degrees and 55.9 degrees laterally for insertion of a retrograde pubic screw; the minimum distances from the pubis to the bladder/iliac artery/ iliac vein were 0 and 0 mm/4.9 and 4.6 mm/0.8 and 0.2 mm. In both men and women, the canal diameters at the base were positively correlated to weight. In women, the canal diameters at the parasymphyseal area were correlated to height and weight. Canal diameters at the acetabulum were not correlated to height and weight. CONCLUSION: Pubic screw fixation may be potentially disastrous (owing to joint penetration and iliac vein injury) and should be performed with caution. When the canal diameter at the acetabulum is extremely narrow, plate fixation, computer-assisted surgery, or changing to a smaller-diameter screw is recommended.

Detection of replicative intermediates of hepatitis C viral RNA in liver and serum of patients with chronic hepatitis C.

The hepatitis C virus is a positive stranded hepatotropic RNA virus. We describe a method of detecting positive and negative strands of hepatitis C viral RNA using the polymerase chain reaction. We tested serum and liver tissue from nine patients with chronic hepatitis C. The positive RNA strand of HCV was detected in the sera and livers of all nine, the negative strand was detected in the livers of eight (89%), and in the sera of five (55%). Titers of both strands of HCV RNA were determined by serial endpoint dilutions. The amount of the negative strand in the serum and liver was usually 10-100 times less than the positive strand. Predigestion of serum with ribonucleases did not alter the detection of the negative strand. This suggests that the negative strand found in the serum may be protected from digestion by being associated with virions.

Adenoviral-mediated gene transfer of ectodysplasin-A2 results in induction of apoptosis and cell-cycle arrest in osteosarcoma cell lines.

The extremely poor prognosis of patients with metastatic osteosarcoma indicates the need for novel therapeutic approaches. Ectodysplasin-A2 (EDA-A2) is a recently isolated member of the tumor necrosis factor superfamily that binds to X-linked ectodermal dysplasia receptor (XEDAR). In this report, we have analyzed the biological activity of EDA-A2 against osteosarcoma-derived cell lines. We report that XEDAR is expressed in cell lines derived from osteosarcoma and adenoviral-mediated expression of EDA-A2 in these cells results in the induction of apoptosis via caspase activation and cell-cycle arrest in the G(0)/G(1) phase. Treatment with EDA-A2 also upregulates the expression of alkaline phosphatase, a marker of osteogenic differentiation, in a caspase-dependent fashion. Collectively, our results suggest that EDA-A2 may be a promising agent for the gene therapy of osteosarcoma.

Suppression of tumor growth by intra-muscular transfer of naked DNA encoding adrenomedullin antagonist.

We have recently reported that the intra-tumoral injection of adrenomedullin (AM) antagonist (AMA; AM (22-52)) peptides significantly reduced the in vivo growth of a pancreatic cancer cell line in severely combined immunodeficient (SCID) mice. In the present study, we examined the effects of intra-tumoral and intra-muscular transfers of naked DNA encoding AMA on the in vivo growth of cancer cell lines. We demonstrate that these treatments induce the regression of a pancreatic cancer cell line and a breast cancer cell line inoculated in SCID mice. Furthermore, CD31-positive cells disappear completely from tumor tissues, following treatment, indicating that neo-vascularization is entirely inhibited. These results suggest that the intra-tumoral or intra-muscular transfer of naked DNA encoding AMA might be a promising alternative modality for treating human cancers.

Primary reattachment of avulsed skin flaps with negative pressure wound therapy in degloving injuries of the lower extremity.

Large avulsed skin flaps of the lower extremity caused by degloving injuries eventually develop skin necrosis in most cases. The current treatment option involves excision of the degloved skin and reapplication as a full- or split-thickness skin graft. We considered that reattachment of avulsed skin flaps without excision would be theoretically beneficial, since some circulation may remain around the connected pedicle and thus facilitate graft take. Furthermore, securing the skin to the original anatomic position is much easier using retained landmarks. We treated a total of 12 patients (13 cases) with degloving injuries of the lower extremity. In all cases, the avulsed skin flap was defatted and sewn back to the original position, then negative-pressure wound therapy was applied over those grafts as a bolster for approximately 7 days. Most of the avulsed skin flap took excellently, particularly close to the connected pedicle. Nine cases did not need any additional surgical procedures. Four cases required secondary skin graft for a small area of open wound due to partial necrosis of the defatted skin, as well as the raw surface left by the primary skin defect in the initial operation. Primary reattachment of the avulsed skin flaps without excision is convenient and efficient to cover the open wound over the exposed fascia and periosteum in degloving injuries. This would potentially offer a better alternative to definitive wound closure.

Characterization of phosphopeptide derived from bovine beta-casein: an inhibitor to intra-intestinal precipitation of calcium phosphate.

Casein phosphopeptide (CPP), a highly phosphorylated peptide fragment which inhibits the formation of hydroxyapatite crystal was isolated from pooled ileal contents of rats fed a semi-synthetic diet containing bovine beta-casein. The estimated amino acid sequence of the CPP was shorter than that of the trypsin-digested beta-casein but the core region consisting of consecutive bindings of phosphoserine was fully conserved. A moderate and exchangeable binding to Ca2+ of the CPP molecule well substantiates the high absorbability of calcium from milk and dairy products.

Effect of mild exercise training on glucose effectiveness in healthy men.

OBJECTIVE: To detect whether mild exercise training improves glucose effectiveness (S(G)), which is the ability of hyperglycemia to promote glucose disposal at basal insulin, in healthy men. RESEARCH DESIGN AND METHODS: Eight healthy men (18-25 years of age) underwent ergometer training at lactate threshold (LT) intensity for 60 min/day for 5 days/week for 6 weeks. An insulin-modified intravenous glucose tolerance test was performed before as well as at 16 h and 1 week after the last training session. S(G) and insulin sensitivity (S(I)) were estimated using a minimal-model approach. RESULTS: After the exercise training, VO(2max) and VO(2) at LT increased by 5 and 34%, respectively (P < 0.05). The mild exercise training improves S(G) measured 16 h after the last training session, from 0.018 +/- 0.002 to 0.024 +/- 0.001 min(-1) (P < 0.05). The elevated S(G) after exercise training tends to be maintained regardless of detraining for 1 week (0.023 +/- 0.002 min(-1), P = 0.09). S(I) measured at 16 h after the last training session significantly increased (pre-exercise training, 13.9 +/- 2.2; 16 h, 18.3 +/- 2.4, x10(-5). min(-1). pmol/l(-1), P < 0.05) and still remained elevated 1 week after stopping the training regimen (18.6 +/- 2.2, x10(-5). min(-1). pmol/l(-1), P < 0.05). CONCLUSIONS: Mild exercise training at LT improves S(G) in healthy men with no change in the body composition. Improving not only S(I) but also S(G) through mild exercise training is thus considered to be an effective method for preventing glucose intolerance.

A novel synthetic triazolotriazepine derivative JTT-606 inhibits bone resorption by down-regulation of action and production of bone resorptive factors.

In the search for a new class of bone-sparing agents, we have conducted random screening of the domestic chemical library using 45Ca release assay from prelabeled cultured neonatal mouse calvariae and identified a novel synthetic triazolotriazepine JTT-606 as a candidate for a potent inhibitor of bone resorption. JTT-606 inhibited 45Ca release dose dependently not only in the control calvarial culture but also in the stimulated cultures by interleukin-1alpha (IL-1alpha), fibroblast growth factor 2 (FGF-2), and parathyroid hormone (PTH). JTT-606 also inhibited both basal and stimulated osteoclast-like (OCL) cell formation in the coculture of mouse osteoblastic cells and bone marrow cells dose dependently, indicating its inhibitory effect on osteoclast differentiation. Ex vivo OCL cell formation by cultured bone marrow cells collected from ovariectomized (OVX) mice also was decreased dose dependently by in vivo application of JTT-606 to a level similar to that from sham-operated mice. Furthermore, JTT-606 inhibited resorbed pit formation by isolated mature osteoclasts as well as by unfractionated bone cells derived from rabbit long bones in the control and FGF-2-stimulated cultures dose dependently, indicating both the direct and the indirect actions of JTT-606 on mature osteoclast function. In addition, JTT-606 reduced production of IL-1alpha, tumor necrosis factor alpha (TNF-alpha), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the human peripheral blood mononuclear cell culture. In vivo analyses of mature OVX rats revealed that the application of JTT-606 for 12 weeks increased the BMD of the lumbar spine and decreased the levels of serum osteocalcin and urine deoxypyridinoline to levels similar to those of 17beta-estradiol-treated OVX rats. We propose that JTT-606 may inhibit both osteoclast differentiation and function by down-regulating both the action and the production of bone resorptive factors. It is speculated that JTT-606 could be a potent agent for the treatment of osteopenic disorders with elevated osteoclastic bone resorption.

Blood pressure and hormonal responses to aerobic exercise.

Twelve patients with essential hypertension (WHO stages I-II) were subjected to mild aerobic exercise for 10 to 20 weeks. The time course of changes in the resting blood pressure and multiple hormonal responses (plasma catecholamines, prostaglandin E, renin-angiotensin system, kallikrein-bradykinin system) were monitored. Depressor response of both systolic and diastolic pressures was seen, and after 5 weeks of exercise blood pressure stabilized at a significantly lower level. Adjustment of work load in response to increased physical fitness at the 10th week produced further reduction of blood pressure especially in diastole. After exercise therapy we found significant reductions in plasma catecholamine levels, and increases in levels of plasma prostaglandin E and the urinary excretion of sodium. A reduction in systolic/diastolic (mean) pressures by more than 20/10 (13) mm Hg was seen in 50% of patients after 10 weeks and in 78% after 20 weeks of exercise. Those who achieved effective blood pressure fall after 10 weeks of training (n = 6) were compared with the rest (n = 6). This analysis revealed that the initial value of plasma renin activity of the former was significantly lower than that of the latter. Significant negative correlations (r = -0.78) also were observed between the blood pressure reduction and corresponding initial value of plasma renin activity. These results indicate that exercise therapy is a potent nonpharmacological tool for the treatment of essential hypertension, especially of the low renin type. Both diminished sympathoadrenergic activity and enhancement of prostaglandin mechanisms might be responsible for the falls in arterial pressure.

Antihypertensive and volume-depleting effects of mild exercise on essential hypertension.

After a general clinical observation period of over 4 weeks, 20 essential hypertensive subjects (Japanese) were randomly divided into two groups. One group (n = 10; 4 men and 6 women; 51.4 +/- 2.8 years of age) agreed to physical training using bicycle ergometer exercise with the intensity at blood lactate threshold for 60 minutes three times a week for 10 weeks, while the other group (n = 10; 4 men and 6 women; 51.0 +/- 2.9 years of age) did no particular physical training and was followed once a week as the control. Changes in blood pressure, hemodynamics, and humoral factors of the exercised group were compared with values in the controls. The following significant changes were found only in the exercised group. Blood pressure was significantly (p less than 0.01) reduced. Whole blood and plasma volume indices were significantly reduced (p less than 0.05, p less than 0.01, respectively). The change in ratio of serum sodium to potassium positively correlated with the change in systolic blood pressure (r = 0.76, p less than 0.02). Plasma norepinephrine concentrations both at rest and at the workload of blood lactate threshold during graded exercise tests were significantly reduced (p less than 0.05, p less than 0.02 respectively) after 10 weeks of exercise training. The change in the resting level of plasma norepinephrine positively correlated with that in the mean blood pressure. No such changes were observed in the control group. In both groups, body weight and urinary sodium excretion showed no statistically significant changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Mild exercise decreases plasma endogenous digitalislike substance in hypertensive individuals.

Changes in a plasma endogenous digitalislike substance were investigated in relation to the antihypertensive mechanism of mild exercise. Fifteen women with mild essential hypertension and seven normotensive female volunteers were divided into exercised hypertensive (n = 10), nonexercised hypertensive (n = 5), and nonexercised normotensive (n = 7) groups. A 4-week general clinical observation period preceded the study period of 10 weeks. The exercised hypertensive individuals were treated with a lactate threshold exercise that corresponded to approximately 50% of the maximum oxygen consumption three times a week, whereas the nonexercised groups were observed at the outpatient clinic as control groups. In the exercised group, systolic blood pressure fell by 7 mm Hg (p = 0.05), diastolic by 6 mm Hg (p less than 0.01), and mean blood pressure by 7 mm Hg (p less than 0.01) after 10 weeks. The reduction in the plasma endogenous digitalislike substance was significant after 7 (-1.02 ng/ml, p less than 0.05) and 10 (-1.04 ng/ml, p less than 0.05) weeks in this group. It positively correlated with the reduction in diastolic (r = 0.70, p less than 0.05) or mean (r = 0.66, p less than 0.05) blood pressure and with changes in plasma norepinephrine (r = 0.76, p less than 0.05). The mean corpuscular volume of erythrocytes decreased (-1.7 fl, p less than 0.01) after 10 weeks of exercise, and the plasma volume index tended to decrease (-108 ml/m2, p = 0.28). In the control groups, significant changes in blood pressure and plasma endogenous digitalislike substance were not observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Osteogenesis by bone marrow stromal cells maintained on type I collagen matrix gels in vivo.

In this study, we demonstrated that bone marrow stromal cells maintained on type I collagen matrix induced bone in vivo. The formed bone contained bone marrow, and the process of bone formation occurred without cartilage formation. Bone marrow stromal cells differentiated into osteoblasts on type I collagen matrix in vitro, but types II, III, and V collagens did not possess this activity. These findings imply that type I collagen matrix offers a suitable environment for the induction of osteoblastic differentiation in vitro and osteogenesis in vivo.

Relationship of cigarette smoking to blood pressure and serum lipids.

The relationship between cigarette smoking and blood pressure and serum lipids was studied in 1775 men aged 20-59 years, in non-drinkers and drinkers separately, controlling for body mass index and physical fitness (VO2max). While systolic blood pressure was not associated with cigarette smoking, diastolic blood pressure decreased with increasing levels of cigarette smoking in non-drinkers but not in drinkers. Total cholesterol was inversely associated with smoking cigarettes in drinkers and was not associated in non-drinkers. High density lipoprotein (HDL)-cholesterol decreased with an increasing degree of cigarette consumption in non-drinkers but not in drinkers. An increase in total cholesterol/HDL-cholesterol ratio and triglyceride levels was positively associated with smoking cigarettes regardless of drinking habit. The present study suggests that cigarette smoking is a cardiovascular risk factor, partly due to its effect of increasing the atherogenic index, but it remains to be consolidated whether chronic smoking has an effect of lowering diastolic blood pressure.

A polymorphism upstream from the human paraoxonase (PON1) gene and its association with PON1 expression.

Human serum paraoxonase (PON1) is an esterase that has been shown to decrease the susceptibility of lipoproteins to lipid peroxidation. We found a polymorphism of cytosine/thymidine (-108C/T, the number is from the ATG codon) in the upstream region of the PON1 gene. The luciferase activity was lower in the -108T allele than in the -108C allele. The serum PON1 concentrations in 132 normal subjects were as follows: -108CC>-108CT and>-108TT genotypes. The polymorphism upstream from the PON1 gene is associated with transcription of the PON1 gene and the serum PON1 concentration.

Angiotensin II formation by an alternative pathway during exercise in humans.

OBJECTIVE: We postulated a 'kinin-tensin system' in which angiotensin II (Ang II) is cleaved by one or more serine protease independent of renin or angiotensin converting enzyme (ACE). The aim was to determine whether this alternative Ang II-forming pathway by serine proteases participates in the rise in plasma levels of Ang II during exercise in humans. DESIGN AND METHODS: The study consisted of two double-blind crossover experiments. in experiment 1 six healthy volunteers who had been taking either placebo (group P) or the ACE inhibitor captopril (150 mg/day for 3 days; group C) performed a cycle ergometer graded exercise test at four different exercise intensities: stage 1, half of the intensity at the blood lactate threshold (WLT); stage 2, the intensity at WLT; stage 3, the intensity at 4 mmol/l blood lactate; and stage 4, an intensity between stage 3 and maximum intensity. In experiment 2 the same volunteers took captopril (150 mg/day for 3 days) and performed exercise at an intensity corresponding to 90% of the 4 mmol/l blood lactate intensity for 30 min during intravenous drip injection of a serine protease inhibitor, nafamostat [NAF; 0.2 mg/kg per h; NAF(+) group] or saline [NAF(-) group]. RESULTS: In experiment 1 plasma Ang II levels increased from at rest to after exercise in both groups P and C. Although there was a significant treatment effect, captopril did not significantly alter the exercise-induced changes in Ang II level. In experiment 2 the increase in Ang II level after 30 min exercise in the NAF(+) group was significantly lower than in the NAF(-) group. CONCLUSIONS: These results suggest the presence of an alternative Ang II-forming pathway independent of ACE, and that one or more NAF-sensitive serine protease is responsible, at least partly, for generating Ang II during exercise.

Urinary kallikrein activity is increased during the first few weeks of exercise training in essential hypertension.

OBJECTIVE: To determine whether the renal kallikrein-kinin and dopamine systems participate in lowering blood pressure during mild exercise in hypertensives. DESIGN: After a general clinical observation period of 4 weeks, 27 essential hypertensives were divided into two groups. The exercise group underwent blood lactate threshold exercise, using a cycle ergometer for 60 min three times a week for 10 weeks. The non-exercise group was observed at the outpatient clinic. Blood pressure and humoral parameters were measured at weeks 0, 1, 2, 4 and 10 in both groups. METHODS: Blood pressure was measured indirectly with an automatic blood pressure recorder. Twenty-four-hour urinary kallikrein activity (by kininogenase assay), total or free dopamine and total noradrenaline (by high-performance liquid chromatography) were also measured. RESULTS: In the non-exercise group blood pressure and humoral parameters did not change. In the exercise group the change in resting blood pressure between weeks 0 and 10 was statistically significant. The change in 24-h urinary kallikrein activity of the exercise group was significantly greater than that of the non-exercise group between weeks 0 and 1 and weeks 0 and 2. Moreover, the change in systolic blood pressure (SBP) between weeks 0 and 2 was negatively correlated with the change in urinary kallikrein activity between weeks 0 and 2, the change in total dopamine between weeks 0 and 2 was negatively correlated with the change in diastolic blood pressure in the same period, and the change in SBP between weeks 0 and 10 was positively correlated with the change in total noradrenaline in the same period in the exercise group. Subjects with a relatively high baseline urinary kallikrein activity had a significantly greater change in SBP between weeks 0 and 10 than subjects with a relatively low baseline activity. CONCLUSIONS: The renal kallikrein-kinin and dopamine systems may participate in lowering blood pressure during the first few weeks of exercise training. The subsequent reduction of sympathetic activity may be involved in maintaining the lowered blood pressure. Mild exercise is more effective in reducing blood pressure in hypertensives who have a relatively high basal renal kallikrein-kinin system activity.

Identification of the anaerobic threshold using double product in patients with coronary artery disease.

This study compared the ventilatory threshold with the double-product break point in 104 patients with cardiovascular disease during ramp treadmill testing. The high correlation (r = 0.81) between the double-product break point and the ventilatory threshold, even in patients taking beta blockers, suggests the former method is a viable noninvasive alternative for identifying the anaerobic threshold in patients with cardiovascular disease, particularly when expired gas analysis is not appropriate or available.