Comprehensive safety management and assessment at rugby football competitions.

The present study aims to improve medical systems by designing objective safety assessment criteria for rugby competitions. We evaluated 195 competitions between 2002 and 2011 using an original safety scale comprising the following sections: 1) competence of staff such as referees, medical attendants and match day doctor; 2) environment such as weather, wet bulb globe temperature and field conditions; and 3) emergency medical care systems at the competitions. Each section was subdivided into groups A, B and C according to good, normal or fair degrees of safety determined by combinations of the results.Overall safety was assessed as A, B and C for 110, 78 and 7 competitions, respectively. The assessments of individual major factors were mostly favorable for staff, but the environment and medical care systems were assessed as C in 25 and 70, respectively, of the 195 competitions. Medical management involves not having a match day doctor, but also comprehensive management including preventive factors and responses from the staff, environment and medical-care systems. 6 cases of severe injuries and accidents occurred between 2002 and 2011, which were observed in Grade A competition. These cases revealed better prognosis without obvious impairment, thus confirming the value of the present assessment scale.

Impact of diabetes and glycaemic control on peripheral artery disease in Japanese patients with end-stage renal disease: long-term follow-up study from the beginning of haemodialysis.

AIMS/HYPOTHESIS: End-stage renal disease (ESRD) patients with diabetes have been regarded as being at the highest risk of cardiovascular disease. We therefore investigated the relationship between diabetes and the incidence of peripheral artery disease (PAD) in new haemodialysis patients. METHODS: We enrolled 1,513 ESRD patients who had just begun haemodialysis therapy. They were divided into two groups: those with (n = 739) and those without diabetes (n = 774). The endpoint was the development of PAD, defined as ankle brachial pressure index ≤ 0.9 or toe brachial pressure index <0.7 in patients with an ankle brachial pressure index >0.9. RESULTS: According to the Kaplan-Meier method, the 10 year event-free rate for development of PAD and lower limb amputation was significantly lower in the diabetes group than in the non-diabetes group (60.3% vs 82.8%, HR 2.99, 95% CI 2.27, 3.92, p<0.0001 and 93.9% vs 98.9%, HR 5.59, 95% CI 2.14, 14.7, p = .0005 for PAD and lower limb amputation, respectively). In patients with diabetes, quartile analysis of HbA1c levels showed that the highest quartile group (≥ 6.8% [51 mmol/mol]) had significant development of PAD and lower limb amputation compared with lower quartile groups (PAD HR 1.63, 95% CI 1.17, 2.28, p = .0038; lower limb amputation HR 2.99, 95% CI 1.17, 7.70, p = .023). CONCLUSIONS/INTERPRETATION: Diabetes was a strong predictor of PAD after initiation of haemodialysis therapy in patients with ESRD. In addition, higher HbA1c levels were associated with increased risk of developing PAD and requiring limb amputation in such diabetic populations.

Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CC) is a highly malignant carcinoma. We attempted to clarify the prognostic significance of c-Met overexpression and its association with clinicopathological factors in patients with CC. PATIENTS AND METHODS: One hundred and eleven patients with intrahepatic CC (IHCC) and 136 patients with extrahepatic CC (EHCC) who had undergone curative surgery were divided immunohistologically into c-Met(high) and c-Met(low) groups. Clinicopathological factors and outcomes were compared between the groups. c-Met and epidermal growth factor receptor (EGFR) expression was also examined in 10 CC cell lines. RESULTS: The positivity of c-Met was 45.0% in IHCC and 68.4% in EHCC; c-Met(high) expression was demonstrated in 11.7% of IHCC and 16.2% of EHCC. c-Met(high) expression was significantly correlated with the 5-year survival rate for CC overall (P=0.0046) and for IHCC (P=0.0013), histopathological classification in EHCC, and for EGFR overexpression in both IHCC and EHCC. Coexpression and coactivation of c-Met and EGFR were also observed in CC cell lines. Multivariate analysis revealed that c-Met(high) expression was an independent predictor of poor overall and disease-free survival in patients with IHCC. CONCLUSIONS: c-Met overexpression is associated with EGFR expression and is a poor prognostic factor in CC.

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma.

Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses > or = 12.5 mg kg(-1) day(-1) (P<0.05), but higher doses (50 mg kg(-1) day(-1), P<0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg(-1) day(-1)) also significantly (P=0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.

The effects of isoflurane on adrenomedullin-induced haemodynamic responses in pithed rats.

BACKGROUND AND OBJECTIVES: Adrenomedullin is a potent vasodilatory peptide. The mechanisms of adrenomedullin-induced responses are via guanine nucleotide guanosine 5'-triphosphate-binding protein (G-protein)-coupled receptor activation and are similar to those of calcitonin gene-related peptide (CGRP). Previously, we reported that sevoflurane and isoflurane inhibit CGRP-induced haemodynamic responses. The effects of volatile anaesthetics on adrenomedullin-induced haemodynamic responses, however, are unclear. We hypothesized that the volatile anaesthetic isoflurane inhibits adrenomedullin-induced haemodynamic responses. We studied the effects of isoflurane on adrenomedullin-induced haemodynamic responses in pithed rats, which enables us to evaluate the direct cardiovascular effects of drugs without interference from centrally mediated circulatory reflexes. METHODS: Male Wistar rats were pithed by inserting a stainless-steel rod into the spinal cord. Following median sternotomy, a flow probe was placed around the ascending aorta to measure aortic blood flow. Mean arterial pressure and cardiac output were maintained at approximately 100 mmHg and 50 mL min-1, respectively, with continuous infusion of norepinephrine. After 30 min inhalation of isoflurane (1%, or 2%) in oxygen, or only oxygen, adrenomedullin (1, 3, 10 or 30 microg kg-1) was administered intravenously. RESULTS: Adrenomedullin administration induced a transient increase followed by a persistent decrease in mean arterial pressure and cardiac output. Isoflurane (2%) significantly inhibited the initial increase in mean arterial pressure and the later decrease in mean arterial pressure and systemic vascular resistance. CONCLUSION: Isoflurane inhibits adrenomedullin-induced vasodilation and positive inotropic effect in pithed rats. Isoflurane might inhibit the adrenomedullin receptor-mediated response, which is a common pathway for both actions.

Female-specific neuroprotection against transient brain ischemia observed in mice devoid of prion protein is abolished by ectopic expression of prion protein-like protein.

This study was designed to examine the function of cellular prion protein and prion protein-like protein/Doppel, in transient ischemia-related neuronal death in the hippocampus. Two different lines of mice devoid of cellular prion protein, Zrch I Prnp(0/0) and Ngsk Prnp(0/0), were used. The former lacks cellular prion protein whereas the latter ectopically expresses prion protein-like protein/Doppel in the brain in the absence of cellular prion protein. Mice were subjected to 10 min-occlusion of the bilateral common carotid arteries with recovery for 14 days. Less than 10% of the pyramidal neurons in the CA1 subfield were degenerated in male and female wild-type mice. In contrast, more than half of the neurons were lost in male Zrch I Prnp(0/0) and Ngsk Prnp(0/0) mice. Such severe neuronal loss was also observed in female Ngsk Prnp(0/0) mice. However, female Zrch I Prnp(0/0) mice showed mild neuronal loss similar to wild-type mice. Flunarizine, a T- and L-type Ca(2+)-channel antagonist, significantly reduced the neuronal loss in female but not in male Ngsk Prnp(0/0) mice. These results indicate that loss of cellular prion protein renders hippocampal neurons susceptible to ischemic insult specifically in male but not female mice and the ectopic expression of prion protein-like protein/Doppel aggravates the ischemic neuronal death in female prion protein-null mice probably via overloading of Ca(2+)-dependent signaling.

Balloon pump-induced pulsatile perfusion during cardiopulmonary bypass does not improve brain oxygenation.

BACKGROUND: Whether pulsatile flow offers substantial advantages for brain protection during cardiopulmonary bypass is controversial. The purpose of this study is to determine whether differences exist between pulsatile and nonpulsatile bypass concerning the effects on internal jugular venous saturation and on the state of regional cerebral oxygenation during normothermia. METHODS: Twenty-two patients undergoing elective coronary artery bypass grafting were randomly divided into 2 groups: group 1 (n = 11) received nonpulsatile perfusion during cardiopulmonary bypass and group 2 (n = 11) received pulsatile perfusion during bypass. We used an intra-aortic balloon pump to generate pulsatility. A spectrophotometric probe (INVOS 3100R, Somanetics, Troy, Mich) was used to assess the state of regional cerebral oxygenation. A 4F fiberoptic oximetry oxygen saturation catheter was inserted into the right jugular bulb to monitor jugular venous oxygen saturation. Hemodynamic variables, arterial and jugular venous blood gases, and regional cerebral oxygenation were measured at 7 times points. RESULTS: In both groups, jugular venous oxygen saturation decreased at the early stage of the cardiopulmonary bypass (P =.03). Five patients in group 1 and 6 in group 2 had a jugular venous oxygen saturation of less than 50%. In both groups, the regional cerebral oxygenation value decreased during cardiopulmonary bypass (P =.04). CONCLUSIONS: The present results showed that pulsatility generated through the use of intra-aortic balloon pumping did not produce any beneficial effects on jugular venous oxygen saturation and regional cerebral oxygenation at normothermia.

Purification and properties of a new cathepsin from rat liver.

1) A lysosomal protease, a new cathepsin that inactivates glucose-6-phosphate dehydrogenase [EC 1.1.1.49] and some other enzymes and differs from cathepsin B [EC 3.4.22.1] was purified about 2,200-fold from crude extracts of rat liver by cell-fractionation, freezing and thawing, acetone treatment, gel filtration, and DEAE Sephadex and CM-Sephadex column chromatographies. 2) The new cathepsin was markedly activated by the thiol-reagent, 2-mercaptoethanol and inhibited by monoiodoacetate. 3) The molecular weight of the new cathepsin was found by Sephadex G-75 column chromatography to be 22,000, which is smaller than that of cathepsin B. 4) The optimum pH of the enzyme for inactivation of glucose-6-phosphate dehydrogenase was pH 5.0--5.5. The enzyme was unstable in alkali and on heat treatment. 5) The rates of inactivation of glucose-6-phosphate dehydrogenase, apo-ornithine aminotransferase [EC 2.6.1.13], apo-tyrosine aminotransferase [EC 2.6.1.5], apo-cystathionase [EC 4.4.1.1], glucokinase [EC 2.7.1.2], glyceraldehyde-3-phosphate dehydrogenase [EC 1.2.1.12], and malate dehydrogenase [EC 1.1.1.37] by the new cathepsin were higher than those by cathepsin B. However aldolase [EC 4.1.2.13] was inactivated more rapidly by cathepsin B than by the new cathepsin. Lactate dehydrogenase [EC 1.1.1.27], glutamate dehydrogenase [EC 1.4.1.2] and alcohol dehydrogenase [EC 1.1.1.1] were not inactivated by either cathepsin. Unlike cathepsin B, the new cathepsin scarcely hydrolyzes N-substituted derivatives of arginine.

Influence of constant sustained positive airway pressure on right ventricular performance.

OBJECTIVE: The detrimental effect of positive airway pressure on right ventricular (RV) performance is controversial and the aim of this study was to determine the effects of constant positive airway pressure without ventilatory fluctuation on RV performance with the aid of a pulmonary arterial catheter equipped with a rapid response thermistor for measuring RV ejection fraction (RVEF) and RV end-diastolic volume index (RVEDVI). DESIGN: A prospective, clinical study. SETTING: The central operating theatre of a university hospital. PATIENTS: Nine patients who had major surgery and required right heart catheterization for normal clinical management. MEASUREMENTS AND RESULTS: Cold indicator was injected into the RV 4 or 5 times for each airway pressure (0, 10 or 20 cmH2O) which was maintained manually stable for 15 s, and 9 paired data were analyzed by repeated-measures analysis of variance. They are separated into two groups; RVEF at zero airway pressure greater (A group) or less (B group) than 0.4. In A group (7 patients), increasing airway pressures (0 vs 10 vs 20 cmH2O) did not affect RVEF (0.55 +/- 0.05 vs 0.54 +/- 0.06 vs 0.56 +/- 0.04), RVEDVI (69 +/- 36 vs 73 +/- 29 vs 58 +/- 20 ml.m-2), or stroke volume index (SVI: 38 +/- 18 vs 40 +/- 17 vs 33 +/- 13 ml.beat-1.m-2); however, in B (2 patients), RVEF (0.35 and 0.38 vs 0.31 and 0.28 vs 0.19 and 0.17) and SVI (35 and 28 vs 32 and 27 vs 27 and 23) decreased, while RVEDVI increased (99 and 73 vs 103 and 97 vs 146 and 132). CONCLUSIONS: In most patients, the changes in RVEF, SVI, and RVEDVI did not occur under constant positive airway pressure, therefore the changes reported in mechanically ventilated patients may not attributable to the extent of positive airway pressure but rather to abrupt increases in airway pressure. These appears, however, to be patients whose RV function is so disturbed that they cannot cope with increased afterloads.

The cerebral hemodynamic response to electrically induced seizures in man.

The hemodynamic response to seizure has long been a topic for discussion in association with the neuronal damage resulting from convulsion. Electroconvulsive therapy (ECT) is an appropriate clinical model for the investigation of the cerebral physiology of seizure. In this study, we monitored the oxygenation state of brain tissue using near infrared (NIR) spectrophotometry, and flow velocity at the middle cerebral artery (MCA) using transcranial Doppler ultrasonography (tc-Doppler) in ninety cases where flow velocity at the middle cerebral artery (MCA) using transcranial Doppler ultrasonography (tc-Doppler) in ninety cases where ECT was prescribed to patients suffering from endogenous depression. Under general anesthesia with thiopental and succinyl choline, an electrical current was applied bilaterally at the minimal energy level. Throughout the therapy, end-tidal CO2 tension was maintained at 30-35 mmHg, and the SpO2 value was maintained above 98% by manual ventilation assistance. The total- and oxy-hemoglobin contents in the brain were reduced during the electrical shock, and then recovered to the pre-shock value (total-hemoglobin; 44.13 +/- 12.88 s after the shock, oxy-hemoglobin; 88.62 +/- 11.69 s after the shock). Subsequently, these values further increased beyond the preshock value. On the other hand, the deoxy-hemoglobin content increased for 90.73 +/- 15.88 s during and after the electrical shock, and decreased afterward. Reduction of cytochrome aa3 began 3.04 +/- 0.51 s after the electrical shock, and this was reoxygenated at 171.88 +/- 12.95 s after the shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet-activating factor-induced loss of vascular responsiveness to noradrenaline in pithed rats: involvement of nitric oxide.

The role of nitric oxide and cyclo-oxygenase products in the platelet-activating factor (PAF)-induced hyporesponsiveness to noradrenaline was investigated in pithed rats. Infusion of PAF (30 ng/kg/min) for 60 min reduced the mean arterial blood pressure and impaired the pressor responses to noradrenaline (10 ng/kg, 100 ng/kg, 1 microgram/kg). Administration of NG-monomethyl-L-arginine (L-NMMA, 30 mg/kg) restored the reduced MABP and the impaired responses to their original levels. Indomethacin (5 mg/kg) had no significant effect on the PAF-induced hyporesponsiveness. Administration of 30 mg/kg L-NMMA caused hypertension in the PAF vehicle-treated animals and reduced the pressor response to 1 microgram/kg noradrenaline. Administration of 3 mg/kg L-NMMA had no significant effect on the responsiveness to noradrenaline. These results suggest that nitric oxide contributes to the PAF-induced hyporesponsiveness to noradrenaline and that cyclo-oxygenase products do not play a major role in this hyporesponsiveness.

Platelet-activating factor receptor antagonist attenuates endotoxin-induced vascular hyporeactivity in the pithed rat.

The role of platelet activating factor (PAF) and nitric oxide (NO) in the endotoxin-induced hyporeactivity to noradrenaline was studied in the pithed rat. Pressor dose-response curves to noradrenaline (0.01-10 microg/kg, i.v.) were made starting 1 h after the administration of endotoxin (0.5 mg/kg, i.v.) to the rats. Saline was administered to the control rats. The PAF receptor antagonist, TCV-309 (3-bromo-5-[N-phenyl-N-[2-[[2-(1,2,3,4-tetrahydro-2-isoquinolylcarbon yloxy)ethyl]carbamoyl]ethy]carbamoyl]-1-propylpyridinium nitrate, 100 microg/kg, i.v.), or the NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA, 30 mg/kg, i.v.), was administered to the endotoxin-treated rats 20 or 10 min before the noradrenaline challenge. L-NMMA reversed endotoxin-induced hyporeactivity completely. TCV-309 produced a significant, but partial attenuation of the hyporeactivity to noradrenaline (P < 0.01). There was still significant hyporeactivity when compared with the control rats (P < 0.01) and the L-NMMA-treated endotoxin-administered rats (P < 0.05). These data suggest that endogenous PAF contributes to the vascular hyporeactivity to noradrenaline induced by endotoxin and that NO plays a major role in the endotoxin-induced hyporeactivity.

Flexure modulus of orthodontic stainless steel wires.

The flexure modulus of elasticity of standard stainless steel orthodontic wires was determined by the use of an iterative finite element technique to be 25.4 x 10(6) psi (175 x 10(3) MN/m2). This technique accounts for the configurational changes in the test specimens due to the relatively large deflection during the cantilever test. Under these conditions, the elementary strength of materials relationships does not accurately describe the flexure characteristics of the wires.

On the dermal absorption of cocaine.

A 5-mg dose of cocaine free base applied to the volar forearm skin surface of a volunteer resulted in a maximal urinary benzoylecgonine concentration of 55 ng/mL at 48 h, using discrete urine specimens. A total of 58 micrograms of benzoylecgonine, representing 1.2% of the dose, was excreted in the 96-h urine. An identical trial using 5 mg of cocaine hydrochloride resulted in a maximal urinary benzoylecgonine concentration of 15 ng/mL at 24 h. We conclude that dermal absorption of cocaine represents a minor, but significant route of exposure to this drug that needs to be considered when interpreting low-level urine drug testing results.

CT evaluation of primary benign retroperitoneal tumor.

We studied CT patterns in 21 cases of primary benign retroperitoneal tumor including teratoma in nine cases, schwannoma in six, leiomyoma in three, lipoma in one, lymphangioma in one, and neurofibroma in one. The tumors were analyzed for size, internal homogeneity, CT density, calcification, border with neighboring organs, and contrast enhancement (CE). The mean diameter of the tumors was 10.2 (+/- 4.8) cm. Internal homogeneous distribution was observed in 33%, calcification in 43%, and well-defined border in 86%. The CT density and calcification were compared according to histology, and the results were as follows: teratoma showed fat density in 78%, water density in 100%, and calcification in 89%; schwannoma showed water density in 100% and septal CE in 33%; leiomyoma showed soft tissue density in 100%, CE in 100%, and water density in 33%; lipoma showed fat density and calcification; and lymphangioma and neurofibroma showed water density. Internal homogeneity, fat density, cyst formation, and calcification are considered to be important predictors of primary benign retroperitoneal tumor on CT.

Asymptomatic adult Wilm's tumor (nephroblastoma) incidentally detected by CT.

Wilms' tumor (nephroblastoma), the most common renal neoplasm in children, is rarely found in adults. A 73-year-old woman with asymptomatic adult Wilms' tumor, incidentally detected by CT, is reported. CT and MRI showed a small mass with homogeneous enhancement after the administration of contrast medium. Ultrasonography demonstrated a well-defined echogenic mass with a halo-like, peripheral hypoechoic area. Selective angiography showed no tumor vessels. Although renal cell carcinoma should be considered in the differential diagnosis, it is still difficult to distinguish from small Wilms' tumor like this case.

Improved long-term stability of blood cocaine in evacuated collection tubes.

A study was undertaken to determine if a relatively minor modification of our existing specimen collection tubes could enhance the long-term stability of blood cocaine. We added cocaine, benzoylecgonine (BE) and ethanol to whole sheep blood in glass tubes that were prepared to contain one of several combinations of preservatives and anticoagulant. On day 1 and at intervals of up to one year, the drugs were measured by gas chromatography-mass spectrometry (cocaine and BE) or headspace gas chromatography (ethanol). Storage of blood containing 200 ng/mL cocaine at 4 degrees C for one year resulted in 100% loss of the drug using our normal 10 mL specimen collection tubes containing 100 mg sodium fluoride and 20 mg potassium oxalate. The substitution of oxalic acid for potassium oxalate reduced this loss to 76% without any significant effect on the benzoylecgonine or ethanol concentrations. Further addition of 10 mg echothiophate iodide, a quaternary ammonium compound, brought the cocaine loss down to 60% of the original concentration by one year. Further work will be required to determine if oxalic acid and/or echothiophate iodide could be used in blood collection vials intended for forensic toxicological purposes without any detrimental effect on other assays.

Biomechanical principles of tooth movement.

The major mechanical signals or stimuli in orthodontic therapy are the stress and the resultant strain or deformation in the periodontal supporting tissues. These signals are translated into biologic cellular activities by some yet unclear mechanisms. Direct action by the stresses and strains upon the cells as well as by secondary effects produced by stresses and strains (such as very low piezoelectric voltage) may occur. The relationship between stress and the rate of tooth movement is not a simple one and is dependent on the stage of tooth movement; there appears to be a monotonically increasing relationship between stress and rate of tooth movement at least for low stress values. Having presented this overview of our present knowledge of biomechanics, fundamentals of cellular dynamics can be developed on the one hand and therapeutic strategies expanded on the other hand by the subsequent articles.

Fundamentals of appliance design.

The fundamentals of appliance design include working knowledge of material properties, wire deflection characteristics as well as understanding of equilibrium concepts. This information must be used together with biomechanical principles of tooth movement ao design efficient appliances that will lead to predictable treatment results.

[The role of gallium-67 citrate scintigraphy in Crohn's disease].

We investigated the usefulness of gallium scintigraphy and its importance in the choice of a treatment method for Crohn's disease. The subjects for the study were 30 patients diagnosed as Crohn's disease. After intravenous injections of 67Ga-citrate 111 MBq, planar and SPECT images were taken at 48 and 72 hrs. The overall positive rate was 42.1%, and among the positive cases, 78.6% required surgical treatment. On the other hand, surgical treatment was only performed in 18.8% of the negative cases, which was significantly low percentage. However, since 75% of the cases, in whom surgical treatment was performed, showed preoperative positive 67Ga results, positive cases detected by 67Ga scintigraphy were considered to be high-risk cases requiring surgical treatment.