Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells.

Malignant mesothelioma is an aggressive tumor arising from the mesothelial cells of serous membranes and is associated with tumor angiogenesis, which is a prerequisite for tumor progression. Vascular endothelial growth factors (VEGFs) including VEGF-A have a crucial role in tumor angiogenesis. However, bevacizumab, a monoclonal antibody to VEGF-A, has recently been reported not to improve the progression-free survival of patients with malignant mesothelioma. Cell culture supernatant contains extracellular components such as serum, which can mask the existence of unknown cell-derived factors in the supernatant and make it difficult to detect the factors by subsequent protein analysis. We tried using serum-free culture for human mesothelioma cell lines, NCI-H28, NCI-H2452 and NCI-H2052, and only NCI-H2052 cells adapted to serum-free culture. We found that serum-free culture supernatant derived from NCI-H2052 cells induces the formation of capillary-like tube structures (tube formation) in three-dimensional culture, in which endothelial cells sandwiched between two layers of collagen or embedded in collagen are incubated with various angiogenic inducers. However, neither neutralization of VEGF-A nor RNA interference of VEGF receptor 2 (VEGFR2) suppressed the supernatant-induced tube formation. Using mass spectrometry, we identified a total of 399 proteins in the supernatant, among which interleukin-8 (IL-8), growth-regulated α-protein, midkine, IL-18, IL-6, hepatoma-derived growth factor, clusterin and granulin (GRN), also known as progranulin (PGRN), were included as a candidate protein inducing angiogenesis. Neutralizing assays and RNA interference showed that PGRN, but not the above seven candidate proteins, caused the supernatant-induced tube formation. We also found that NCI-H28 and NCI-H2452 cells express PGRN. Furthermore, we demonstrate that not only PGRN but also GRN-like protein have an important role in the supernatant-induced tube formation. Thus, mesothelioma-derived GRNs induce VEGF-independent angiogenesis.

Light-to-moderate alcohol intake reduces lipid accumulation product and attenuates its relation to hypertension.

Lipid accumulation product (LAP), an index calculated by using triglyceride level and waist circumference, has been shown to predict hypertension, diabetes and cardiovascular disease. Alcohol is known to influence blood pressure and blood lipids. The aim of this study was to clarify the relationships among alcohol intake, LAP and hypertension. The subjects, middle-aged Japanese men (n=21,572), were divided into non-, light (<22 g ethanol per day), moderate (⩾ 22 and<44 g ethanol per day) and heavy (⩾ 44 g ethanol per day) drinkers. The relationships between alcohol intake and LAP and between LAP and hypertension were investigated. There were U- and J-shaped relationships between alcohol intake and LAP in subjects with and without hypertension, respectively. The adjusted odds ratios with their 95% confidence intervals for hypertension in subjects with vs subjects without high LAP were 3.04 (2.69-3.43, P<0.01), 2.32 (1.92-2.81, P<0.01), 2.10 (1.89-2.33, P<0.01) and 2.11 (1.87-2.38, P<0.01) in non-, light, moderate and heavy drinkers, respectively. Thus, the positive association between LAP and hypertension is weaker in drinkers than in nondrinkers. The results suggest that light-to-moderate alcohol drinking reduces LAP level in patients with hypertension and attenuates the relation of LAP to hypertension.

Smoking and lipid-related indices in patients with diabetes mellitus.

AIMS: Lipid-related indices, including the ratio of LDL cholesterol to HDL cholesterol, the ratio of triglycerides to HDL cholesterol and lipid accumulation product, are known to be good discriminators for cardiovascular disease. The aim of this study was to clarify the relationships between smoking and the lipid indices in patients with diabetes. METHODS: Subjects were those who had been diagnosed as having diabetes mellitus at annual health check-ups at their places of work (n = 2563). The subjects were divided into three groups of non-smokers, light smokers (≤ 20 cigarettes/day) and heavy smokers (> 20 cigarettes/day). The relationships between smoking and the lipid indices were investigated. RESULTS: Both in all subjects and in the subjects without a habit of alcohol drinking, the LDL cholesterol:HDL cholesterol ratio and the log-transformed triglyerides:HDL cholesterol ratio tended to be higher with an increase in the amount of smoking, and the log-transformed lipid accumulation product was significantly higher in heavy smokers than in non-smokers. In the non-alcohol drinking subjects, the odds ratios of heavy smokers vs. non-smokers for high LDL cholesterol:HDL cholesterol ratio [2.32 (95% CI 1.40-3.84)], for high triglycerides:HDL cholesterol ratio [1.69 (95% CI 1.06-2.69)] and for high lipid accumulation product [1.65 (95% CI 1.02-2.67)] were significantly higher than a reference level of 1.00. The associations between smoking and the lipid indices were weaker in alcohol drinkers than in non-drinkers. CONCLUSIONS: In patients with diabetes, the levels of lipid-related indices were higher in smokers than in non-smokers, and cardiometabolic disorders, reflected by high lipid indices, are thought to be involved in the proneness of smokers to develop atherosclerotic cardiovascular disease.

Inhibition of CXCL10 release by monomeric C3bi and C4b.

Cellulose acetate (CA) beads are often used for leucocyte apheresis therapy against inflammatory bowel disease. In order to clarify the mechanism of the anti-inflammatory effects of CA, global analysis of the molecules generated in blood by the interaction with CA beads was performed in this study. An activated medium was collected from whole blood that had been preincubated with CA beads, and the effects of the CA-activated medium on leucocyte function were investigated. Fresh blood was stimulated with lipopolysaccharide (LPS) or interferon (IFN)-ß in the presence of the activated medium, and levels of chemokines and cytokines, including CXCL10 (IFN-inducible protein-10), and phosphorylated STAT1 (signal transducer and activator of transcription 1), which is known to be essential for CXCL10 production in leucocytes, were measured. IFN-ß- or LPS-induced CXCL10 production, expression of CXCL10 mRNA and phosphorylation of STAT1 were significantly reduced in the presence of the medium pretreated with CA beads compared with the control without the CA bead treatment. The factors inhibiting CXCL10 production were identified as the C3 and C4 fragments by mass spectrometry. The monomeric C3bi and C4b proteins were abundant in the medium pretreated with CA beads. Furthermore, purified C3bi and C4b were found to inhibit IFN-ß-induced CXCL10 production and STAT1 phosphorylation. Thus, STAT1-mediated CXCL10 production induced by stimulation with LPS or IFN was potently inhibited by monomeric C3bi and C4b generated by the interaction of blood with CA beads. These mechanisms mediated by monomeric C3bi and C4b may be involved in the anti-inflammatory effects of CA.

Associations of alcohol drinking and cigarette smoking with serum lipid levels in healthy middle-aged men.

AIMS: The aim of this study is to determine whether influences of drinking alcohol on serum lipid levels are different in smokers and non-smokers. METHODS: Subjects were 25,689 healthy male workers aged 40 to 59 years. Serum total and HDL cholesterol and triglyceride concentrations were measured and LDL cholesterol concentrations were estimated by using the Friedewald formula. The subjects were divided into three groups by average daily consumption of cigarettes (non-smokers; light smokers, less than 20 cigarettes per day; heavy smokers, 20 or more cigarettes per day) and by average daily alcohol consumption (non-drinkers; light drinkers, less than 30 g of ethanol per day; heavy drinkers, 30 g or more of ethanol per day). RESULTS: In overall subjects, serum HDL, LDL and total cholesterol were significantly lower and triglyceride was significantly higher in heavy smokers than in non-smokers. In the smoker groups, serum total cholesterol was significantly lower in heavy drinkers than in non-drinkers, while no difference in total cholesterol was observed in non- and heavy drinkers of the non-smoker group. Both in the smoker and non-smoker groups, HDL cholesterol was higher and LDL cholesterol was lower in drinkers than in non-drinkers. The difference in LDL cholesterol between non-drinkers and drinkers was more prominent in smokers than in non-smokers. The above associations were not altered after the adjustment for age, body weight and alcohol intake. CONCLUSIONS: The results suggest that smoking increases the lowering effect of alcohol drinking on LDL cholesterol, but does not affect the relationship of alcohol drinking with HDL cholesterol.

Influence of drinking alcohol on atherosclerotic risk in alcohol flushers and non-flushers of Oriental patients with type 2 diabetes mellitus.

AIMS: Facial flushing caused by alcohol drinking is a typical symptom of high sensitivity to alcohol in orientals. We investigated whether drinking alcohol influences atherosclerotic risk factors in alcohol flushers and non-flushers in patients with diabetes mellitus. METHODS: A cross-sectional study was performed using 225 subjects with type 2 diabetes. Sensitivity to alcohol was surveyed by a questionnaire on facial flushing. Subjects were divided into three groups by average amount of alcohol drinking (non-drinkers; light drinkers: <140 g/week; heavy drinkers: 140 g/week or more). RESULTS: Systolic blood pressure and blood HDL cholesterol were significantly higher in heavy drinkers than in non-drinkers. There were no significant differences in body mass index, blood pressure, blood total cholesterol, HDL cholesterol, uric acid, fibrinogen and sialic acid levels in flushers and non-flushers. In alcohol flushers, diastolic blood pressure and HDL cholesterol in heavy drinkers were significantly higher than those in non-drinkers, and systolic blood pressure was significantly higher in heavy drinkers than in non-drinkers and light drinkers. On the other hand, blood pressure and HDL cholesterol in non-flushers were not significantly different among non-, light and heavy drinkers. Serum total cholesterol was not significantly different among the three drinking groups both in flushers and non-flushers. CONCLUSIONS: Blood pressure and HDL cholesterol are more prone to be affected by drinking in flushers than in non-flushers, suggesting that alcohol sensitivity evaluated by flushing response due to drinking alcohol should be taken into account when the effects of alcohol drinking on atherosclerotic risk factors are considered in oriental patients with type 2 diabetes mellitus.

Isokinetic external rotation strength of shoulder : correlation with age and muscle size.

The purpose of this study was to determine the correlation between quantitative (cross sectional areas) evaluation of the posterior cuff muscles and mechanical strength in asymptomatic shoulders with special reference to aging. The cross-sectional area of the combined infraspinatus and teres minor muscles were measured, in the sagittal oblique magnetic resonance images, in eighty-one patients with a mean age of 44.06 years (range 19 - 74). These areas were correlated with the measured isokinetic strength in external rotation at angular velocities of 60 deg/s and 180 deg/s using Cybex 770 NORM. The results show that there was a gradual decrease in size of the muscles as the age of the individual increases. A strong correlation was found between aging and combined cross-sectional area and peak torque as well. The correlation between combined cross-sectional area and peak torques at both angular velocities were less strong. Further, the correlation between the peak torque/cross-sectional area ratio with aging was also less significant, which may imply that the decrease in the muscle strength was greater than the change in muscle area. Our results suggest that there may be other qualitative and biochemical factors that may determine the true strength of the muscles in the aged population.

New simple method for purification of class I alcohol dehydrogenase.

AIMS: The purpose of this study was to develop a new simple method for purification of rat class I alcohol dehydrogenase (ADH, EC 1.1.1.1). METHODS AND RESULTS: Immobilized p-hydroxyacetophenone was used as a ligand for affinity chromatography for the initial purification step after ammonium sulfate precipitation of the cytosolic fraction of rat liver. Then the eluant was separated by using ion-exchange chromatography, and homogenous class I ADH, as judged by the results of SDS-PAGE and confirmed by the results of the amino-acid sequence of peptides degraded from a 39 kDa protein, was obtained with a high yield (57%). The purified ADH showed kinetic constants of 1.3 mmol/l for Km and 62.4 per min for Kcat with ethanol as a substrate. ADH was also successfully purified from yeast by a similar method using p-hydroxyacetophenone affinity chromatography. CONCLUSIONS: This simple method involving only two chromatographic procedures may be very useful for purification of ADH.

Age-dependent relation of serum sialic acid concentration to aortic pulse wave velocity in type 2 diabetes.

OBJECTIVE: The purpose of this study was to determine whether age affects the significance of serum sialic acid concentration as a marker of atherosclerosis in patients with diabetes. METHODS: In this cross-sectional study, we investigated the relationship of serum sialic acid concentration to aortic pulse wave velocity (a-PWV) and the effects of age on this relationship in patients with type 2 diabetes. RESULTS: In the elderly (70 years or over) diabetic patients, a-PWV showed a significant positive correlation with serum sialic acid. This relationship was also significant after adjustment for age, duration of diabetes, body mass index, systolic blood pressure, LDL cholesterol, HDL cholesterol and fibrinogen levels. In elderly diabetic patients, a-PWV also showed a significant positive correlation with age and duration of diabetes and a significant negative correlation with serum HDL cholesterol level. On the other hand, in the younger (31-60 years) diabetic patients, there was no significant correlation between serum sialic acid level and a-PWV, while a-PWV showed significant positive correlations with age, duration of diabetes and plasma fibrinogen level. CONCLUSIONS: Serum sialic acid level reflects atherosclerosis in elderly diabetic patients but not in younger diabetic patients. This may explain recent controversial findings regarding the relationship between serum sialic acid level and incidence of coronary heart disease in diabetes.

Relation of serum sialic acid to blood coagulation activity in type 2 diabetes.

The level of serum sialic acid, which is known to reflect atherosclerotic progress and to be related to the incidence of cardiovascular diseases, is increased in patients with diabetes. To elucidate the mechanism of the relation of serum sialic acid to fibrinogen, the relationship between serum sialic acid and markers of blood coagulation activity was investigated in type 2 diabetic patients. The concentration of serum sialic acid showed significant positive correlations with blood platelet count and with plasma concentrations of fibrinogen, D-dimer, thrombin-antithrombin III complex and plasmin-alpha2 plasmin inhibitor complex. These relationships were still significant after adjustment for age, sex, smoking history, body mass index, hemoglobin A, mean arterial pressure and low-density lipoprotein cholesterol. The correlation coefficient of blood fibrinogen with serum sialic acid was still significant after adjustment for D-dimer, thrombin-antithrombin III complex or plasmin-alpha2 plasmin inhibitor complex. On the contrary, blood fibrinogen showed no significant correlation with D-dimer, thrombin-antithrombin III complex or plasmin-alpha2 plasmin inhibitor complex, although an increase in blood fibrinogen is known to be an atherosclerotic risk factor. These results suggest that the serum sialic acid level reflects blood coagulation activity in type 2 diabetic patients and is related to blood fibrinogen level independently of blood coagulation activity.

Diminished inibitory action of ethanol on the contraction of gallbladder isolated from chronically ethanol-fed Guinea pigs.

Ethanol is known to decrease the gallbladder contractility. The purpose of this study was to clarify the mechanism of tolerance to the inhibitory action of ethanol on the gallbladder contractility. Male guinea pigs were fed ethanol (3%) or calorie-matched sucrose in the drinking water for 4 weeks. Then, the gallbladder was isolated, and its isometric tension was measured. The contractile responses to KCl, BAY K8644, histamine, and phorbol 12,13-dibutyrate in the normal medium were not different between the gallbladder strips from ethanol-fed and control guinea pigs. Ethanol at 25 mmol/l in vitro did not affect the contractile responses to KCl and BAY K8644 in the gallbladder strips from both ethanol-fed and control guinea pigs. On the other hand, ethanol at 25 mmol/l in vitro significantly inhibited the contractile responses to histamine and phorbol 12,13-dibutyrate in the gallbladder strips from the control guinea pigs, but it did not affect the contractile response to histamine and significantly augmented that to phorbol 12,13-dibutyrate in the strips from the ethanol-fed guinea pigs. Diphenhydramine, a selective H(1) receptor antagonist, abolished the histamine contraction in gallbladder strips from both control and ethanol-fed guinea pigs, while cimetidine, a selective H(2) receptor antagonist, did not affect histamine contraction, implying that histamine-induced contraction of guinea pig gallbladders is mediated only by H(1) receptors. Verapamil (1 micromol/l) completely inhibited the phorbol 12,13-dibutyrate-induced contraction of the strips from both ethanol-fed and control guinea pigs. The histamine-induced contraction was partly inhibited in the absence of Ca(2+) in the medium. In the gallbladder strips from both ethanol-fed and control guinea pigs, ethanol at 25 mmol/ in vitro did not affect the histamine-induced contraction in the absence of extracellular Ca(2+). Tolerance to the inhibitory action of ethanol developed selectively on contractile responses to histamine and phorbol 12,13-dibutyrate. Chronic ethanol administration produces tolerance to in vitro gallbladder contractility mediated by the Ca(2+) entry through L-type Ca(2+) channels linked with protein kinase C activation.

Extracellular pH affects platelet aggregation associated with modulation of store-operated Ca(2+) entry.

The pH dependence of store-operated Ca(2+) influx (SOCI) into human platelets, as well as its physiological consequence, aggregation, was studied. In Ca(2+)-free medium, thapsigargin (1 microM) induced a small increase in intracellular free-Ca(2+) ([Ca(2+)](i)), which was not affected by changes in extracellular pH. The addition of Ca(2+) (0.5-3 mM) after Ca(2+) store depletion caused by thapsigargin resulted in concentration-dependent increases in [Ca(2+)](i) (SOCI), which were strongly inhibited by SKF-96365 (100 microM), an inhibitor of receptor-mediated Ca(2+) entry. SOCI was inhibited by acidosis (pH 6.9) and augmented by alkalosis (pH 7.9). The addition of Ca(2+) (0.5-3 mM) to platelets, which were kept in Ca(2+)-free medium, slightly but significantly increased [Ca(2+)](i). This Ca(2+) leak entry was also decreased and increased by extracellular acidosis (pH 6.9) and alkalosis (pH 7.9), respectively, but not affected by SKF-96365. Neither thapsigargin (1 microM) stimulation in Ca(2+)-free solution nor elevation of extracellular Ca(2+) alone was sufficient to induce platelet aggregation. In contrast, the addition of Ca(2+) (1 mM) to platelets activated by thapsigargin resulted in aggregation, which was markedly inhibited by SKF-96365 (100 microM). Platelet aggregation associated with SOCI was also inhibited by extracellular acidosis (pH 6.9) and augmented by extracellular alkalosis (pH 7.9). These results suggest that acidosis-induced inhibition, as well as alkalosis-induced promotion of platelet aggregation, involve pH effects on SOCI.

Acidosis inhibits gallbladder contraction mediated by protein kinase C activation.

The effects of extracellular acidosis on gallbladder contraction were investigated using gallbladder strips isolated from guinea pigs. In an acidic medium (pH 6.9), gallbladder contraction induced by histamine and prostaglandin E2 was significantly lower than that in a normal medium (pH 7.4). Acidosis affected neither gallbladder contraction induced by histamine in the absence of extracellular Ca2+ nor that induced by KCl. Acidosis significantly inhibited Ca2+-induced contraction in the presence of sodium fluoride and phorbol 12,13-dibutyrate but not that in the presence of KCl. Staurosporine (30 nM) significantly inhibited gallbladder contraction induced by histamine and prostaglandin E2, but not that by KCl. Histamine-induced contraction in the presence of staurosporine was not affected by acidosis. Acidosis significantly inhibited Ca2+-induced contraction in the presence of histamine but not that in the presence of both histamine and staurosporine. These results suggest that extracellular acidosis selectively inhibits gallbladder contraction mediated by protein kinase C activation.

Nitric oxide-dependent and -independent inhibition by lipopolysaccharide of phosphoinositide hydrolysis in vascular smooth muscle.

The present study was designed in order to clarify the mechanisms of diminished phosphoinositide (PI) hydrolysis by lipopolysaccharide (LPS) in blood vessels. In vitro pretreatment of rat aortic strips with LPS (1 microg/ml) for 10 or 24 hrs inhibited 5-hydroxytryptamine (5-HT, 100 microM)-induced inositol monophosphate accumulation in a time-dependent manner. Coincubation of the aortas with N(G)-monomethyl-L-arginine (LNMMA, 1 mM) completely prevented the early diminution of 5-HT-stimulated PI hydrolysis after 10-hr exposure to LPS but did not affect the delayed diminution after 24-hr exposure. Coincubation with cycloheximide (1 microM) did not prevent the delayed LPS-induced diminution of phosphoinositide hydrolysis. Tetraethylammonium (10 mM) did not restore the diminished phosphoinositide hydrolysis after 24-hr exposure to LPS, suggesting that the diminution is not due to K+ channel activation. Sodium fluoride (10 mM)-induced inositol monophosphate accumulation was also decreased in the aortic strips after LPS incubation for 24 hrs, and this decrease was not prevented by coincubation with LNMMA. LPS incubation time-dependently increased nitric oxide (NO) production in the aortas, which was completely inhibited by LNMMA or cycloheximide. These results suggest that NO is mainly involved in the inhibitory action of LPS on stimulated-PI hydrolysis in the early stage, while in the later stage, a factor(s) besides NO causes attenuation of the stimulated-PI hydrolysis.

Intracellular alkalinization augments alpha(1)-adrenoceptor-mediated vasoconstriction by promotion of Ca(2+) entry through the non-L-type Ca(2+) channels.

Modulation by intracellular pH of the vasoconstriction induced by alpha-adrenoceptor agonists was investigated in isolated guinea pig aorta. NH(4)Cl (15 mM) increased intracellular pH of aortic smooth muscle cells by about 0.2 pH unit and significantly augmented KCl-induced contraction of aortic strips, whereas simultaneous administration of NH(4)Cl (15 mM) plus Na(+) propionate (30 mM) failed to affect intracellular pH or contractility. NH(4)Cl (15 mM) potentiated contractions induced by alpha-adrenoceptor agonists, norepinephrine, phenylephrine and clonidine. Contraction induced by alpha(1)-selective adrenoceptor agonist, phenylephrine, but not that induced by norepinephrine or clonidine, was insensitive to inhibition by verapamil (1 microM). Phenylephrine-induced contraction was not affected by NH(4)Cl in Ca(2+)-free medium whereas extracellular Ca(2+)-induced contraction of phenylephrine-stimulated aorta was significantly augmented by NH(4)Cl. Consistently, 45Ca(2+)uptake into phenylephrine 1 microM)-stimulated aortic strips was increased by incubation with NH(4)Cl. The potentiating effects of NH(4)Cl on both phenylephrine-induced Ca(2+) entry and contraction were antagonized by Na(+) propionate. These results suggest that intracellular alkalinization facilitates alpha(1)-adrenoceptor-mediated vasoconstriction by facilitation of an agonist-induced Ca(2+) entry pathway that is independent of L-type Ca(2+) channels.

Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R), was originally purified from the rat stomach. Like the synthetic growth hormone secretagogues (GHSs), ghrelin specifically releases growth hormone (GH) after intravenous administration. Also consistent with the central actions of GHSs, ghrelin-immunoreactive cells were shown to be located in the hypothalamic arcuate nucleus as well as the stomach. Recently, we showed that a single central administration of ghrelin increased food intake and hypothalamic agouti-related protein (AGRP) gene expression in rodents, and the orexigenic effect of this peptide seems to be independent of its GH-releasing activity. However, the effect of chronic infusion of ghrelin on food consumption and body weight and their possible mechanisms have not been elucidated. In this study, we determined the effects of chronic intracerebroventricular treatment with ghrelin on metabolic factors and on neuropeptide genes that are expressed in hypothalamic neurons that have been previously shown to express the GHS-R and to regulate food consumption. Chronic central administration of rat ghrelin (1 microg/rat every 12 h for 72 h) significantly increased food intake and body weight. However, it did not affect plasma insulin, glucose, leptin, or GH concentrations. We also found that chronic central administration of ghrelin increased both neuropeptide Y (NPY) mRNA levels (151.0 +/- 10.1% of saline-treated controls; P < 0.05) and AGRP mRNA levels (160.0 +/- 22.5% of saline-treated controls; P < 0.05) in the arcuate nucleus. Thus, the primary hypothalamic targets of ghrelin are NPY/AGRP-containing neurons, and ghrelin is a newly discovered orexigenic peptide in the brain and stomach.

Daunorubicin inhibits gene expression of cyclooxygenase-2 in vascular smooth muscle cells.

Daunorubicin (0.1-1 microM) concentration-dependently inhibited prostacyclin production induced by interleukin-1beta (IL-1beta, 2.5 ng/ml) in cultured aortic smooth muscle cells isolated from rats. IL-1beta stimulation caused activation of nuclear factor-kappaB (NF-kappaB) and expression of cyclooxygenase-2 (COX-2) mRNA and protein, which were inhibited by daunorubicin. However, COX activity, evaluated by conversion of exogenous arachidonic acid to prostacyclin, was not affected by daunorubicin (0.1-1 microM). Protein expression of COX-1 and NF-kappaB was not affected by daunorubicin. Daunorubicin also inhibited nitric oxide (NO) production induced by IL-1beta. These results suggest that daunorubicin attenuated prostacyclin synthesis through inhibiting expression of COX-2 mRNA, which could be explained by perturbation of NF-kappaB activation.

Range of motion after Bankart repair. Vertical compared with horizontal capsulotomy.

We studied the range of shoulder motion of patients who underwent vertical as compared with horizontal capsulotomies during open Bankart repair for recurrent anterior dislocations of the shoulder. A vertical capsulotomy was used in 10 shoulders and a horizontal capsulotomy was used in 14 shoulders. Except for the method of capsulotomy, the surgical procedure and postoperative rehabilitation were the same. The range of motion was measured at 1.5, 2, 3, 4, 5, 6, 9, and 12 months after the surgery, and at the final follow-up (average, 49 months for the vertical and 26 months for the horizontal group). No dislocations recurred, and the anterior apprehension test was negative in all of the patients in both groups. External rotation in abduction was greater in the horizontal group than in the vertical group; the differences were significantly greater at 9 months and 12 months after surgery and at the final follow-up. External rotation in adduction, flexion, and internal rotation were not significantly different between the groups. We conclude that Bankart repair through a horizontal capsulotomy preserves a better range of external rotation in abduction than does a vertical approach.

Position of immobilization after dislocation of the glenohumeral joint. A study with use of magnetic resonance imaging.

BACKGROUND: Glenohumeral dislocations often recur, probably because a Bankart lesion does not heal sufficiently during the period of immobilization. Using magnetic resonance imaging, we assessed the position of the Bankart lesion, with the arm in internal and external rotation, in shoulders that had had a dislocation. METHODS: Coaptation of a Bankart lesion was examined with use of magnetic resonance imaging, with the arm held at the side of the trunk and positioned first in internal rotation (mean, 29 degrees) and then in external rotation (mean, 35 degrees), in nineteen shoulders. Six shoulders (six patients) had had an initial anterior dislocation, and thirteen shoulders (twelve patients) had had recurrent anterior dislocation. Fast-spin-echo T2-weighted axial images were made when the dislocation had occurred less than two weeks earlier, and spin-echo T1-weighted axial images after intra-articular injection of gadolinium-diethylenetriamine pentaacetic acid were made when the dislocation had occurred more than two weeks earlier. Separation and displacement of the anteroinferior portion of the labrum from the glenoid rim were measured on the axial images, and coaptation of the anterior part of the capsule to the glenoid neck was assessed by measurement of the detached area, opening angle, and detached length. RESULTS: Separation and displacement of the labrum were both significantly less (p = 0.0047 and p = 0.0017, respectively) when the arm was in external rotation than when it was in internal rotation. The detached area and the opening angle of the anteroinferior portion of the capsule were both significantly smaller (p = 0.0003 and p < 0.0001, respectively), and the detached length was significantly shorter (p < 0.0001) with the arm in external rotation. CONCLUSION: Immobilization of the arm in external rotation better approximates the Bankart lesion to the glenoid neck than does the conventional position of internal rotation.

[Effects of ethanol on the nervous and vascular systems: the mechanisms of alcohol-induced hypertension].

Many previous experimental and epidemiological studies have shown that alcohol consumption has a positive correlation with the incidence of hypertension. The effects of ethanol on the nervous and vascular systems in relation to the mechanisms of alcohol-induced hypertension proposed so far are reviewed here. Alcohol ingestion influences many pathophysiological functions which regulate blood pressure, as follows: 1) Sympathetic nervous activity is increased after drinking. 2) Ethanol acts directly on the contractility of vascular smooth muscle. Ethanol acutely contracts some arteries and increases their contractile responses to agonists, while it also displays inhibitory effects on vasocontractility in other arteries. Thus, ethanol has two opposite actions, both of which depend on the kinds of vessels and animal species used for the experiments. Intra- and extracellular Ca2+ mobilization and activation of the contractile apparatus have been suggested as mechanisms for ethanol's vasocontractile actions. 3) Chronic alcohol ingestion has been reported to induce a deficiency of blood and intracellular magnesium, which influences cellular Ca2+ homeostasis through attenuation of plasmalemmal ATPase activity. Direct alcohol effects on cardiovascular systems may not be involved in hypertension that develops after long-term habitual drinking. 4) Ethanol affects vascular endothelial functions, inhibiting endothelial NO- and EDHF-dependent vasorelaxations. 5) The serum levels of vasoactive substances such as cathecolamines, renin-aldosterone, prostacyclin, and endothelin have been reported to be affected by alcohol ingestion or ethanol in vitro. 6) In heavy drinkers, alcohol withdrawal results in an elevation of blood pressure due to sympathetic nervous stimulation. 7) Long-term heavy drinking often results in the development of insulin resistance and glucose intolerance, which in turn triggers hypertension. 8) The difference in the genetic polymorphism of acetaldehyde dehydrogenase among Japanese people may not be directly related to development of alcohol-induced hypertension. As mentioned above, alcohol shows multiple actions on various factors regulating blood pressure. More detailed and integrated mechanisms for alcohol-induced hypertension, which is not a homogeneous disease, remain to be clarified.