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Summary Objective The purpose of this study was to pilot a "hybrid" style journal club and determine whether measurable effects could be detected over 8-weeks' time on evidence-based practice ability, desire, behaviors, use, and barriers. Background Journal clubs have been suggested as a method to increase nurses' confidence with using research evidence to guide practice. However, it is yet unknown how nurse educators can best implement effective programs for clinicians with varying schedules, education levels, and research skills. Setting and participants Thirty-six participants from one large urban United States hospital (72% registered nurses) were invited to access bi-weekly interdisciplinary journal club activities. Nurse educators created curriculum focused on clinical problem solving that was offered via in-person sessions or a social media site. Methods A pretest–posttest no control group design was used to measure impacts of those engaged in journal club activities. Data were collected using a combination of validated evidence-based practice instruments and program participation records. Findings A two-tailed paired t test showed significant increases over 8weeks' time in evidence-based practice use ( p =.002) and behaviors ( p =.007). Slight preference for in-person sessions was reported, although greater participation was reflected in online activities. Mean satisfaction ratings were high; however, attrition rates suggest that more is needed to maximize clinician engagement. Conclusion A hybrid method using online and in-person sessions was feasible and adaptive for varying learning styles and work schedules. Positive changes in measurements were detected among journal club participants. Instruments were identified that may be useful for trialing similar programs intended to increase evidence-based practice self-efficacy, use, behaviors, and ability.

Objectives Bordetella pertussis continues to cause outbreaks worldwide. To assess the role of children and adolescent in transmission of pertussis in Asia, we performed a multinational serosurveillance study. Methods From July 2013 to June 2016, individuals aged 10 to 18 years who had not received any pertussis-containing vaccine within the prior year were recruited in 10 centres in Asia. Serum anti–pertussis toxin (PT) IgG was measured by ELISA. Demographic data and medical histories were obtained. In the absence of pertussis immunization, anti-PT IgG ≥62.5 IU/mL was interpreted as B. pertussis infection within 12 months prior, among them levels ≥125 IU/mL were further identified as infection within 6 months. Results A total of 1802 individuals were enrolled. Anti-PT IgG geometric mean concentration was 4.5, and 87 (4.8%) individuals had levels ≥62.5 IU/mL; among them, 73 (83.9%) had received three or more doses of pertussis vaccine before age 6 years. Of 30 participants with persistent cough during the past 6 months, one (3.3%) had level ≥125 IU/mL. There was no significant difference in proportions with anti-PT IgG ≥62.5 IU/mL among age groups (13–15 vs. 10–12 years, 16–18 vs. 10–12 years), between types of diphtheria, pertussis and tetanus (DTP; whole cell vs. acellular), number of doses before age 6 years within the DTP whole-cell pertussis vaccine (five vs. four doses) or acellular pertussis vaccine (five vs. four doses) and history of persistent cough during the past 6 months (yes vs. no). Conclusions There is significant circulation of B. pertussis amongst Asian children and adolescents, with one in 20 having serologic evidence of recent infection regardless of vaccination background.

The epidemiology of needlestick and sharps injuries (NSIs) was investigated among a complete cross-section of 1,162 nurses from a large hospital in southern Japan (response rate 74.0%). Forty-six percent had experienced an NSI in the previous year. Most were caused by ampoules or vials, which injured 32.3% of all nurses and accounted for 42.9% of all NSI events. Twenty-two percent of all NSIs involved a device that had been used on a patient prior to the NSI (contaminated device), while the usage status of a further 2.8% of devices was unknown. Logistic regression indicated that nurses younger than 25 years of age were 2.18 times more likely to have sustained a single NSI in the past 12 months [odds ratio (OR) 2.18, 95% confidence intervals (CI) 1.15-4.17] and 2.39 times more likely to have sustained multiple NSIs (OR 2.39, 95% CI 1.08-5.34). Working mixed shifts (rotating day and night, as opposed to day shifts alone) was associated with a 1.67-fold increased risk of sustaining any NSI (OR 1.67, 95% CI 1.01-2.85) and a 2.72 times greater risk of sustaining an NSI from a contaminated device (OR 2.72, 95% CI 1.71-4.44). Nurses who reported significant fatigue after work were 1.87 times more likely to sustain multiple NSIs (OR 1.87, 95% CI 1.13-3.13) and 1.94 times more likely not to report their NSIs (OR 1.94, 95% CI 1.03-3.71). Perceived high mental pressure was associated with a 1.75-fold increased risk of sustaining an NSI from a contaminated device (OR 1.75, 95% CI 1.07-2.88). Nurses who reported suboptimal staffing levels in their wards were 2.21 times more likely not to report any NSIs they sustained in the previous year (OR 2.21, 95% CI 1.06-4.89). Overall, this study suggests that NSIs represent a complex and multi-faceted problem for Japanese nurses. Intervention strategies should consider the emerging complicity of psychosocial factors on NSI among hospital staff in Japan, as elsewhere.

summary Vertical mandibular position is considered to have an effect on the patency of the upper airway, because mouth opening is associated with a backward and downward displacement of the mandible and tongue. This study was conducted to investigate the nature of mandibular displacement at rest and to determine whether or not different respiration modes and body postures influence the mandibular position. The mandibular position was measured by use of a newly developed system with magnets and magnetic sensors placed on the upper and lower first molars, respectively. Vertical mandibular position was significantly affected by the degree of nasal airway obstruction. The proportion of the duration of mouth opening from 0 to 2.5 mm was about 80% in the sitting and lateral recumbent positions and 55% in the supine position. The amount and duration of vertical mandibular displacement were thus significantly increased by experimentally induced nasal respiratory obstruction. Furthermore, it was demonstrated that the amount and duration of mouth opening were significantly greater in the supine posture than in the sitting and lateral recumbent positions. It is thus shown that nasal respiratory disturbance may be a key determinant for mouth opening and breathing and the resultant vertical mandibular displacement.

The purpose of this study was to investigate masticatory muscle activity with and without the use of an activator during daytime and sleep, and further to focus on the changes in muscle activity produced by the daytime use. The subjects in this study were 10 healthy males (mean age: 27.6 years). A portable electromyogram (EMG) recording device was used to record the activity from the right temporal, masseter and digastric muscles. After recording, the integrated EMG values (microV s) were measured. The muscle activity was lower during sleep than during daytime, irrespective of the use of the activator. In sleep-time, temporal and digastric muscle activity was significantly decreased, although masseter muscle activity presented no significant differences. With the activator in use, the digastric muscle activity tended to increase in comparison with the elevator muscles during daytime and sleep. Although the activity of both elevator muscles was diminished by use of the activator during sleep in all subjects, some subjects showed an increase during daytime. These results suggested that the activator should be used, if possible, not only during sleep, but also during daytime and clenched on consciously to obtain the adaptation and development of the masticatory muscles for the 're-training of the muscles' at a new favourable mandibular position.

Antihypertensive activities derived from porcine skeletal muscle proteins were investigated. Thermolysin hydrolysates of porcine muscle water-insoluble proteins demonstrated antihypertensive activities in spontaneously hypertensive rats when administrated in single oral doses. Hydrolysates of porcine myosin and peptides (Met-Asn-Pro-Pro-Lys, Ile-Thr-Thr-Asn-Pro, Met-Asn-Pro, Pro-Pro-Lys) with parts of the sequence of myosin showed antihypertensive activities. This is the first report of antihypertensive activities of peptides derived from muscle proteins of domestic animals. The hydrolysates of porcine muscle protein and their corresponding bioactive peptides might be utilized for physiologically functional foods. Le produit de l'hydrolyse par la thermolysine des proteines insolubles dans l'eau du muscle porcin possede des proprietes antihypertensives lorsqu'elles sont administrees au rat par voie orale, en dose unique. Les hydrolysats de myosine et les fragments peptidiques synthetiques correspondants possedent la meme activite in vivo. C'est la premiere fois que l'on decouvre une activite antihypertensive dans des peptides provenant du muscle d'animal domestique. Ils pourraient etre utilises dans des aliments fonctionnels.

Objective - To investigate the relationship between oxidative stress and apoE phenotype in dementia of Alzheimer type (DAT). Material and methods - Hydroxyl radical content in blood, superoxide dismutase (SOD) activity in red blood cells (RBC) and plasma, Cu,Zn-SOD protein content in RBC, and apoE phenotype were determined in 24 DAT patients and 25 controls. Results - DAT patients with the apoE4 phenotype showed higher hydroxyl radical levels than DAT patients without the apoE4 phenotype or controls. SOD activities and Cu,Zn-SOD protein levels in RBC of DAT patients with and without the apoE4 phenotype showed no significant differences, but values in both patient groups were lower than in controls. The apoE4 phenotype was more prevalent in DAT patients than in controls. DAT patients with the apoE4 phenotype were younger at disease onset than DAT patients without the apoE4 phenotype. Conclusion - Our findings suggest that apoE4 and SOD individually influence oxidative stress in DAT.

The density of striatal dopamine D2 receptors has been shown to vary considerably among healthy subjects. This variability might be due to genetic or environmental factors. In the present analysis we searched for relationships between dopamine D2 receptor gene (DRD2) polymorphisms and striatal dopamine D2 receptor density in vivo, as measured by positron emission tomography and [11C]raclopride in 56 healthy subjects. There was a significant association between presence of a putative functional DRD2 promoter allele (-141C Del) and high striatal dopamine receptor density (t= 2.32, P= 0.02). In agreement with some previous studies the presence of the DRD2 TaqIA1 allele was associated with measures of low dopamine receptor density (t=2.58, P=0.01). Also the DRD2 TaqIB1 allele was associated with low dopamine receptor density (t= 2.58, P= 0.01) wheras there was no significant relationship between another common silent intronic DRD2 short tandem repeat polymorphism (STRP) and striatal dopamine D2 receptor density. The results suggest that DRD2 genotypes may participate differentially in the regulation of striatal dopamine D2 receptor density in healthy human subjects. The results should be interpreted with caution because of the limited sample size.

BACKGROUND Hepatocellular carcinoma (HCC) is generally considered a hypervascular tumor when visualized by angiography. However, small HCCs are not always found to be hypervascular. METHODS To evaluate this, 50 HCCs < or =3 cm in diameter were studied. The 50 tumors consisted of 16 well-differentiated HCCs, 25 moderately differentiated HCCs, and 9 that were each a mixture of well- and moderately differentiated HCC. RESULTS The mean number of portal tracts in the well-differentiated HCCs was 34% of the number in the surrounding nontumorous liver, and few intratumoral arterioles were seen. In contrast, the mean number of portal tracts in the moderately differentiated HCCs was 0.6% of the number in the surrounding nontumorous liver, and abundant intratumoral arterioles were seen. For HCCs that contained both well-differentiated and moderately differentiated tumor, the distribution of portal tracts and intratumoral arterioles in each portion was similar to that seen in well-differentiated or moderately differentiated HCC alone, respectively. HCCs that were larger than 1.5 cm in diameter had fewer portal tracts and more intratumoral arterioles than HCCs whose diameters were < or =1.5 cm. CONCLUSIONS As small HCCs increase in size and become increasingly dedifferentiated, the number of portal tracts apparently decreases and intratumoral arterioles develop. These findings may reflect changes in the hemodynamics as the HCC develops.

Objectives: To investigate the function of the muscarinic cholinergic receptor (mAchR) in narcolepsy and the effects of pharmacotherapy on mAchRs. Background: Muscarinic neural transmission serves as the main executive system in REM sleep. Studies in canine narcolepsy reported an increase in mAchRs in the pons. Methods: The mAchRs of 11 drug naive/free patients with narcolepsy and 21 normal controls were investigated using PET with [ 11 C] N -methyl-4-piperidylbenzilate ([ 11 C]NMPB). Measurements were done in the pons, thalamus, striatum, and cerebral cortex. Seven of the 11 patients also underwent additional PET scans after the alleviation of symptoms by pharmacotherapy. Results: There were no differences in [ 11 C]NMPB binding between the control and drug naive/free patients in all areas analyzed. At the time of on-medication PET scan, [ 11 C]NMPB binding in the thalamus was decreased, but only to a small degree compared with that by anticholinergic drugs. Conclusion: The present results do not support the notion that the mAchR is the main site of action of pharmacotherapy in the marked clinical improvement of human cataplexy.

Two patients with hepatocellular carcinoma (HCC) were identified who had substantial deletions within the hepatitis B virus (HBV) X gene from HCC tissues. In one patient, the deletion was found at nt. 382-389 (codons 128-130) of the X gene, followed by two nucleotide substitutions, a frame shift, and formation of a new stop codon. In the second patient, the deletion was found at nt. 389-396 (codons 130-132) of the X gene, followed by one nucleotide substitution, a frame shift, and formation of a new stop codon. The resulting X proteins in both cases would be truncated at the 3′ end and would be 20 amino acids shorter than the full length X protein. These patients had been identified during a study of 25 HCC patients from Qidong, China in whom a 228-base region of the X gene was sequenced. No deletions were found within this X gene sequence in HCC tissues from the other 23 patients or in the 20 adjacent noncancerous liver samples available from these patients. However, the fact that these deletions encompassed codons 130 and 131, two adjacent codons where point mutations were found in 21 of the remaining 23 patients, suggests that this region may play an important role in hepatocarcinogenesis.

In order to study the mechanisms by which p53 function is regulated, human wild-type p53 cDNA was cloned into a vaccinia virus vector and the expressed p53 protein was used to investigate binding of the p53 by cellular proteins from a cDNA expression library from human liver. One protein that bound wild-type p53 had >99% homology with DNA topoisomerase IIb. p53 protein was coimmunoprecipitated from topoisomerase II-rich cell lysates (but not from topoisomerase II-deficient cell lysates) by an antibody to topoisomerase IIa and IIb. This binding was shown to occur without a dsDNA intermediary. Hepatocellular carcinomas (HCCs) and adjacent nontumorous liver tissues from ten patients were studied to determine the level of expression of topoisomerase II and p53. Overexpressed topoisomerase II proteins were detected by western blot in six of ten HCCs (60%), including several in which presumed wild-type p53 was detected by immunohistochemistry. No topoisomerase II expression was detectable in the ten nontumorous liver tissues from the same patients or in a sample of normal human liver.

Spinal cord compression is an extremely serious complication of hereditary multiple exostoses (HME). A case of HME with compression of the cervical spinal cord is reported. Complete recovery following surgery was achieved. A review of the relevant literature revealed 51 previous cases of HME with cord/cauda equina compression. Most patients were under 30 years of age with more men affected than women. The family history was positive in 60%. The cervical and thoracic areas were predominantly affected, with the symptoms usually developing slowly. Recovery following surgery is to be expected in the majority of cases. In patients with HME and suffering from neurological symptoms, the possibility of spinal cord compression should be considered. Prompt diagnosis and surgical excision provide the best prognosis.

The optical limit of the Glauber theory with zero-range approximation, which is successfully used at high energies to connect the nucleon density distribution with reaction cross-sections (σR), gives somewhat smaller values of σR by 10–20% at intermediate energies. We have precisely measured the σR for 12C on Be, C, and Al at 30A–200A MeV, and for 9Be on Be at 70A–100A MeV to investigate the enhancement of σR compared to the optical-limit calculation. From the enhancements, we deduced the nucleon-nucleon range as a function of energies. We deduced the density distribution of 8B analyzing the known experimental σR for 8B with an enhancement correction or with the finite range effect as a test.

We evaluated the effects of systolic anterior motion systolic anterior motion of the mitral valve on cardiac haemodynamics. Seven adult mongrel dogs in which systolic anterior motion-septal contact was observed after dobutamine administration were used. To exclude the effects of left ventricular function and morphology, a stone removal basket catheter was placed in the left ventricular outflow tract, and haemodynamics were compared with the basket closed and opened. The basket was opened five times in three dogs not showing systolic anterior motion-septal contact, but the basket itself did not effect the haemodynamics. In the seven dogs that showed systolic anterior motion-septal contact without left ventricular hypertrophy, the basket was opened a total of 33 times in the presence of various degrees of systolic anterior motion-septal contact. After opening the basket, systolic anterior motion was reduced echocardiographically, and sign ( P

In this study, positron emission tomography (PET) was used to evaluate cortical control of saccades. Regional cerebral blood flow (rCBF) patterns demonstrated by 15 O water PET during saccadic task performance were tested in 13 normal volunteers and 20 ICD-9 schizo phrenics (10 unmedicated and 10 medicated). The following 3 saccadic tasks, which were controlled for sensory input and oculomotor output, were applied: (1) reflexive saccade = visually guided saccade, (2) volitional saccade = visually guided saccade with distracting stimuli, and (3) memory guided saccade. Schizophrenics lacked the frontal eye field (FEF) activation during every saccadic task. The left dorsolateral prefrontal cortex (DLPFC) was activated during volitional saccade only in normal controls. The rCBF of posterior parietal cortex increased in pararell with that in the DLPFC. These findings suggest functional hypofrontality in schizophrenia and the left DLPFC-PPC's crucial role in saccade against distracting stimuli and its dysfunction in the disease.

Plasminogen activator (PA) is a serine protease existing in two forms known as tissue-type (t-PA) and urokinase-type (u-PA). To examine whether PA is related to the postoperative clinical course of human breast cancer, total PA activity, t-PA activity, u-PA activity, and immunoreactive t-PA were determined in tissue extracts from 144 breast cancer specimens. The patients were initially divided into four groups according to the postoperative clinical course: Group I (83 patients who are disease-free), Group II (20 patients whose first metastases were found only in bone), Group III (19 patients whose first metastases were found in both bone and lung), and Group IV (22 patients whose first metastases were found only in lung). Total PA activity was significantly lower in Groups, II, III and IV than in Group I. Both t-PA activity and t-PA antigen levels were also significantly lower in Groups II, III and IV than in Group I, while no significant difference was found in u-PA activity among these groups, indicating that low activity of total PA in Groups II, III and IV was due to a decrease in t-PA but not in u-PA. In the multivariate analyses, t-PA activity was found to be an independent prognostic factor for relapse-free survival. When four groups of patients were further analysed in terms of nodal status, both t-PA activity and antigen levels were markedly decreased in the node-negative Group II compared with the node-negative Groups III and IV or with the node-positive Groups II, III and IV. Of additional interest, u-PA activity was significantly higher in node-positive patients than in node-negative patients with any group. The clinico-pathologic analyses of the patients in this series showed that node involvement and lymphatic invasion were more frequently positive in Groups III and IV than in Groups I and II. When 144 breast cancers were categorised in terms of combinations of oestrogen receptor (ER) and progesterone receptor (PgR) status, breast cancers which were positive for both receptors were found to contain the highest t-PA activity and antigen. This study provides provocative evidence suggesting a possible differential significance of t-PA and u-PA expression in human breast cancer.

Semi-purified diets supplemented with either a high linoleate (n-6) (safflower) oil or a high alpha-linolenate (n-3) (perilla) oil were fed to mouse mothers and their offspring through 6 weeks of age. The proportions of n-3 and n-6 highly unsaturated fatty acids in brain phospholipids reflected the n-3/n-6 balance of the diets while no difference was found in phospholipid compositions or cholesterol/phospholipid ratios. In the elevated plus maze task, the total number of entries into the open- and enclosed-arms was smaller and the time spent in the dark enclosed arms tended to be longer in the perilla group than the safflower group. The time required to reach a safe platform in Morris's water maze test was less in the perilla group, but no significant difference was observed in the entries into the arms darkened with a movable cover in Y-maze dark-preference task. The safflower group was more sensitive to pentobarbital; the anesthesia onset time was less and the anesthetic time was longer than in the perilla group. Increased locomotion induced by scopolamine injection was less in the safflower group as compared with the perilla group. These results indicate that in mice the dietary alpha-linolenate/linoleate balance affects the n-3/n-6 ratio of brain phospholipid acyl chains and that this is accompanied by general behavioral changes as well as changes in sensitivities to drugs known to affect behavior.

Plasminogen activator (PA) is a serine protease which exists in two forms: tissue-type (t-PA) and urokinase-type (u-PA). The total PA activity was measured in tumour extracts of 235 breast cancer patients who were followed for a median of 8.5 years after surgery. Patients were initially divided into three groups with low (< 60 units mg-1 protein), intermediate (60-300 unit mg-1 protein), or high (> 300 unit mg-1 protein) total PA activity in tumour extracts. The PA activity was not significantly associated with the recognised prognostic factors of age, menstrual status, tumour size, lymph node involvement, histologic type, grade of anaplasia, and/or vessel involvement. A significant association was found between total PA activity and the oestrogen receptor (ER) or progesterone receptor (PgR) status. Among receptor-positive tumours, a significantly greater proportion of patients had high PA activity in their tumour extracts. Breast cancer patients with low total PA activity had a significantly shorter disease-free and overall survival rate when compared to those with intermediate or high PA activity. In univariate and multivariate analyses, total PA activity (< 60 unit mg-1 vs > or = 60 unit mg-1 protein) was found to be a significant prognostic factor for disease-free and overall survival of about the same import as lymph node involvement. Furthermore, the combination of total PA activity and nodal status could be even more precise in predicting survival times and probabilities in individual patients. This retrospective study demonstrates the total PA activity is a valuable prognostic factor in determining prognosis in human breast cancer.

Hormonal regulation of plasminogen activator expression in 7,12-dimethylbenz[a]anthracene (DMBA)--induced rat mammary carcinomas was studied both in vivo and in vitro and was compared to that in DMBA-mammary dysplasia induced in neonatally androgenised rats. The plasminogen activator activity in DMBA-mammary carcinomas, but not in DMBA-mammary dysplasia, was regulated by oestrogen. This suggests that expression of this enzyme is hormonally regulated in carcinoma cells. Furthermore, in two of six DMBA-mammary carcinoma groups classified in terms of hormonal treatment, plasminogen activator activity was not under the control of oestrogen. Thus, the present results suggest that at the time of carcinogenesis, the hormonal milieu determines the hormone sensitivities of the malignant cells.

Apoptosis-inducing factor (AIF) is a phylogenetically conserved redox-active flavoprotein that contributes to cell death and oxidative phosphorylation in Saccharomyces cerevisiae, Caenorhabditis elegans, mouse and humans. AIF has been characterized as a caspase-independent death effector that is activated by its translocation from mitochondria to the cytosol and nucleus. Here, we report the molecular characterization of AIF in Drosophila melanogaster, a species in which most cell deaths occur in a caspase-dependent manner. Interestingly, knockout of zygotic D. melanogaster AIF (DmAIF) expression using gene targeting resulted in decreased embryonic cell death and the persistence of differentiated neuronal cells at late embryonic stages. Although knockout embryos hatch, they undergo growth arrest at early larval stages, accompanied by mitochondrial respiratory dysfunction. Transgenic expression of DmAIF misdirected to the extramitochondrial compartment (DeltaN-DmAIF), but not wild-type DmAIF, triggered ectopic caspase activation and cell death. DeltaN-DmAIF-induced death was not blocked by removal of caspase activator Dark or transgenic expression of baculoviral caspase inhibitor p35, but was partially inhibited by Diap1 overexpression. Knockdown studies revealed that DeltaN-DmAIF interacts genetically with the redox protein thioredoxin-2. In conclusion, we show that Drosophila AIF is a mitochondrial effector of cell death that plays roles in developmentally regulated cell death and normal mitochondrial function.

This paper presents a novel microfluidic device for controlling axonal elongation dynamically by releasing nerve growth factor (NGF) onto a nerve cell. The presented device consists of nano-holes for NGF release and a micro valve for its release control. The amount of NGF that stimulate cells can be controlled very precisely by opening and closing the microvalve. Experiments using a fluorescent solution showed that constant chemical release through the nano-holes was successfully controlled by opening and closing the microvalve at about 2 Hz. This result indicates that the switching control of the microvalve will generate desired concentration of chemicals released from the nano-holes. Moreover, axonal guidance was tested on the fabricated device. We succeeded in guiding an axon of the cell in the direction of the nano-hole array along the NGF concentration gradient.

Summary. This study was conducted to evaluate reports that hepatitis B virus (HBV) DNA sequences can be found in the serum and/or tumour tissue from some hepatocellular carcinoma (HCC) patients who have no detectable hepatitis B surface antigen (HBsAg) in their sera. Such HBV infections would be highly atypical, because prospective studies have shown a clear succession of specific serologic markers during and after most HBV infections. As most HBsAg-negative HCC patients in Japan have hepatitis C virus (HCV) infections, the present study was conducted to determine whether some of these patients actually have unrecognized HBV infections. Thirty newly diagnosed HCC patients from Kurume, Japan, with antibody to the hepatitis C virus (anti-HCV) were studied. None of the 30 had HBsAg detectable in their serum. Of 22 for whom test results for antibodies to the hepatitis B core antigen (anti-HBc) and antibodies to HBsAg (anti-HBs) were available, 14 (64%) had anti-HBc and anti-HBs, four (18%) had anti-HBc alone, and four (18%) had no HBV markers. Nested polymerase chain reaction was used to detect the HBV surface (S), core (C), polymerase (P) and core promoter gene sequences in the HCC tissues and in the adjacent nontumorous liver tissues. HBV DNA was detected in HCC and/or adjacent nontumorous liver in 22 of 30 (73%) patients [detected in both HCC and nontumorous liver in 19/30 patients (63%)]. Among the 22 patients with detectable HBV DNA, more than one HBV gene was detected in 10 (46%). Among the four patients whose sera were negative for all HBV markers, three had HBV DNA in either HCC and nontumorous liver (two cases) or only in the nontumorous liver (one case); HBV DNA could not be detected in tissues from the fourth patient. In 18 of 21 (86%) patients with detectable HBV core promoter sequences, mutations at both nucleotides 1762 (A–GT) and 1764 (G–A) in the core promoter region were found. No deletions were detected in the core promoter gene region of the type reported to be associated with some cases of HBsAg-negative HBV infection. Thus, HBV DNA was detectable in 22 (73%) HBsAg-negative, anti-HCV-positive HCCs, including three (10%) who were also negative for anti-HBc and anti-HBs. HBV mutations at both nucleotides 1762 (A–GT) and 1764 (G–A) in the core promoter region were found in the majority of cases, mutations that have previously been reported in HBV that is integrated in HCC DNA. In serologic surveys to determine etiologic associations of HCC, patients such as those in this study would have been incorrectly designated as having ‘HCV-associated HCC,’ whereas the data in this study suggest that HBV could have played a role in the development of their HCCs.

Integration of hepatitis B virus is thought to be an essential step in hepatitis B virus associated hepatocarcinogenesis. Mutations at nucleotides 1762 and 1764 in the hepatitis B virus, within a sequence encoding both the core promoter gene and the X gene, have been found frequently in patients with hepatocellular carcinoma. However, integration of these mutant sequences has not been reported to date. Methods. A 228-base pair segment of the hepatitis B virus core promoter gene was amplified from hepatocellular carcinomas and adjacent non-tumourous liver tissue by nested PCR and sequenced. Integration of hepatitis B virus into human genomic DNA was investigated using the ‘genome walking’ method. Results. Point mutations were found in both hepatitis B virus nucleotides 1762 and 1764 in 8 of 14 hepatocellular carcinoma tissues (57%) and in 11 of 14 adjacent non-tumourous liver tissues (79%). Three patients were evaluated using the ‘genome walking’ method; all were found to have hepatitis B virus DNA integrated in their hepatocellular carcinoma (two patients) and/or in their non-tumourous liver tissue (three patients). Integration occurred in all tissues near host genomic sites that are prone to integration. Hepatitis B virus was integrated at or near the hepatitis B virus DR1 site in all samples, and all contained truncated X gene sequences that have been reported to be capable of producing fusion transcripts with transactivation potential. Conclusions. Integrated hepatitis B virus DNA containing core promoter mutations at nucleotides 1762 and 1764 was found in hepatocellular carcinoma and/or adjacent non-tumourous liver tissue of three patients. These findings leave open the possibility that insertional mutagenesis or transactivation by fusion transcripts resulting from hepatitis B virus integration could play a role in hepatocarcinogenesis in some patients.

Objective: To establish a rat preeclampsia model with fetoplacental growth restriction caused by bestatin via induction of placental apoptosis. Study design: 200 mg/kg/day of bestatin or saline as a control were infused intraperitoneally into pregnant Wistar rats from 15 days' gestation. In the first experiment, maternal blood pressure and proteinuria were examined during the pre- and postpartum periods. In the second experiment, cesarean sections were performed at 20 days' gestation and the weights of pups and placentas, and levels of proteinuria and placental apoptosis were examined. Results: Physiological decrease of blood pressure in late pregnancy was not detected in the bestatin group but proteinuria level at 20 days' gestation was elevated. The weights of pups and placentas in the bestatin group were significantly lower than those in the controls, bestatin strongly inducing apoptosis in the placenta. Conclusion: Bestatin may cause a preeclampsia-like condition through induction of placental apoptosis.

The objectives of this study were to make a men-women comparison as to the effects of job stress and sex-role orientation on mental health and to determine if marital status modifies effects of job stress and sex-role orientation on mental health in women. Subjects were 644 men and 301 women who were working at two private companies and one national agency. Job contents, sex-role orientation and mental health were measured by the Job Content Questionnaire, the Bem Sex-Role Inventory and the 30-item General Health Questionnaire, respectively. High job demands and femininity in men, masculinity in women predicted poor mental health. The best predictor of poor mental health was consciousness of being a woman in unmarried women, and stress outside the job in married women.

Whole cell currents were recorded in single myocytes dissociated from guinea-pig ventricles, and caged compounds were loaded intracellularly through the patch electrodes. Flash photolysis of caged cyclic GMP (cGMP) increased the amplitudes of both catecholamine-induced Cl- (ICl) and Ca2+ currents (ICa) which were pre-activated by submaximum doses of isoprenaline. Transient activation of ICl by photo-release of cyclic AMP (cAMP) showed a half decay time (t1/2) of 16.7 +/- 1.4 sec (mean +/- S.E.M., n = 14). This decay was markedly delayed by inhibiting phosphodiesterases using 3-isobutyl-1-methyl-xanthine (IBMX). The intracellular application of cGMP (10-50 microM) also prolonged the decay of the ICl response to caged cAMP (t1/2 = 38.0 +/- 7.1 sec, n = 12). These findings strongly support the hypothesis that cGMP facilitates the beta-adrenergic response of ionic currents through the inhibition of phosphodiesterase in mammalian cardiac myocytes.

Metastasis to the breast from extramammary malignancies is rare. This is the third case report of metastatic breast cancer from esophageal cancer. We report the clinical, radiographic, and pathologic findings of a 57-year-old woman who underwent esophagectomy for esophageal cancer and developed metastatic cancer 2 years later. Pathologic examination of a resected specimen of the breast revealed squamous cell carcinoma invading the mammary glands. Estrogen receptor and axillary lymph node metastasis were negative with immunostaining. She is alive 6 months after the modified radical mastectomy.

Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive molecule. The susceptibility of tumors to fluoropyrimidines is reported to correlate with tumor levels of these enzymes. To obtain some insight into the tumor types susceptible to fluoropyrimidine therapy, we measured expression levels of these two enzymes in various types of human cancer tissues (241 tissue samples) by the ELISA methods. DPD exists in all the cancer types studied, such as bladder, breast, cervical, colorectal, esophageal, gastric, hepatic, pancreatic, prostate, and renal cancers. Among them, the cervical, hepatic, pancreatic, esophageal, and breast cancer tissues expressed high levels of DPD (median >70 U/mg protein), while high concentrations of the dThdPase were expressed in esophageal, cervical, breast, and pancreatic cancers and hepatoma (median >150 U/mg protein). The dThdPase/DPD ratio, which was reported to correlate with the susceptibility of human cancer xenografts to capecitabine, was high in esophageal, renal, breast, colorectal, and gastric cancers (median ratio of >1.5). In any of these three parameters, the inter-patient DPD variability for each cancer type was much larger than the DPD variability among cancer types; highest/lowest ratios for dThdPase, DPD, and dThdPase/DPD were 10-321, 7-513, and 2-293, respectively. These results indicate that measurements of the three parameters, DPD, dThdPase and dThdPase/DPD, would be useful criteria for selecting cancer patients suitable for fluoropyrimidine therapy rather than for selecting cancer types.

Inhibitors of angiotensin I-converting enzyme (ACE) have been shown to have antihypertensive effects and have been utilized for pharmaceuticals and physiologically functional foods. In the present study, efforts were directed to find ACE inhibitory activities derived from muscle proteins. Porcine skeletal muscle proteins were hydrolyzed by eight proteases, and the inhibitory activities of the hydrolysates toward ACE were measured. Among the digests of the water-insoluble protein fraction prepared from muscle, thermolysin digest demonstrated the highest activity. Also, among hydrolysates of porcine myosin produced by the same enzymes, thermolysin digest showed the most potent inhibitory activity. Two ACE inhibitory peptides were purified from thermolysin digest of myosin. The sequences of these inhibitory peptides, named myopentapeptides A and B, were Met-Asn-Pro-Pro-Lys and Ile-Thr-Thr-Asn-Pro. These sequences were found in the primary structure of the myosin heavy chain. The concentrations of the peptides showing 50% inhibition values (IC50) of ACE were 945.5 and 549.0 μM, respectively. Also, six tripeptides, Met-Asn-Pro, Asn-Pro-Pro, Pro-Pro-Lys, Ile-Thr-Thr, Thr-Thr-Asn, and Thr-Asn-Pro, which have parts of the sequences of the myopentapeptides, demonstrated activity. Their IC50 values were 66.6, 290.5, >1000, 678.2, 672.7, and 207.4 μM, respectively.

Mutations of the p53 tumor suppressor gene are common in hepatocellular carcinomas (HCCs). Detection of mutations by sequencing provides more information than immunohistochemical staining, but the equipment needed and the time required make it less practical for use in large-scale studies or in studies in developing countries. The degree of correlation between results obtained with these two methods has been studied in various tumors but has not been well-established in human HCCs. Paraffin sections of HCCs of 28 patients from Qidong, China were immunohistochemically stained using monoclonal antibody to p53. In addition, exons 5-8 of the p53 gene were sequenced in these HCCs. Of the 28 HCCs, nine had 0-9% of nuclei stained for p53, and 19 had 50-95% stained. Mutations in p53 exons 5-8 were found in 17/28 (61%) HCCs, including 15 at codon 249 (exon 7), one at codon 198 (exon 6), and one at codon 175 (exon 5). Among these 17 cases with p53 mutations, 16 cases (94%) had 50-95% of nuclei stained. Among 11 HCCs with no mutations by sequencing, 8 were also negative by immunohistochemistry (0-9% of nuclei stained) (73%) (the five HCCs with no staining whatsoever all had wild-type p53). Immunohistochemical staining to detect p53 mutations in human HCCs detected most mutations that were detected by sequencing (94% sensitivity, 73% specificity), and this method is therefore suitable when sequencing cannot be performed.

We measured hydroxyl radical (.OH) levels in blood, superoxide dismutase (SOD) activity in red blood cells (RBC) relative to both total protein (RBC-SOD/P) and Cu,Zn-SOD protein (RBC-SOD/SOD), SOD activity in plasma (plasma-SOD), and Cu,Zn-SOD protein relative to total RBC protein (Cu,Zn-SOD/P) in 22 patients with probable dementia of the Alzheimer type (DAT group, mean age 74.8+/-9.4 years), 16 with probable vascular dementia (VAD group, mean age 76.9+/-6.7 years) and 19 non-demented controls (control group, mean age 73.5+/-6.2 years). Levels of .OH in the DAT and VAD groups were significantly (P

There is evidence to suggest that a focus of less-differentiated hepatocellular carcinoma (HCC) may arise within a pre-existing well-differentiated HCC, eventually replacing it. In the present study, the p53 tumor suppressor gene was analyzed by immunohistochemistry in 31 hepato-cellular carcinomas (HCCs) containing two or more regions in the same nodule with different histologic grades. p53 was overexpressed in the nucleus in 13 of 31 HCCs (42%), in seven of which p53 overexpression was seen only in the less-differentiated area of the tumor. This suggests that overexpression of presumed mutant p53 may have contributed to dedifferentiation during the development of HCC.

The clinical pharmacokinetics of the cognitive enhancer, aniracetam (200 mg), was studied in elderly patients with cerebrovascular disease (CVD) and compared with those of young healthy volunteers. Six female hospitalized patients (mean age 84.5 years) were used in this study. The serum level of anisic acid and p-methoxyhippuric acid, major metabolites of aniracetam, reached a peak at 2h after oral administration, and returned to basal level by 6 h. Mean creatinine clearance was 20-30ml/min. The t 1/2 of metabolites was increased by 4- to 7-fold in the elderly patients compared with young volunteers. This study showed that t max t 1/2 and AUC were enlarged in the elderly; however, no clinical side effects were observed.

Background. Although elevation of blood pressure is considered to be the main adverse effect under rHuEpo therapy in haemodialysis patients, the precise mechanism remains obscure. The direct effect of rHuEpo on endothelial cells (EC) has been suggested as one of contributing factors of rHuEpo-induced hypertension. Methods. EC were incubated with various concentrations of rHuEpo (0, 1000, 5000, 10 000 mU/ml) for up to 7 days, and cell numbers, DNA and protein synthesis by EC and supernatant concentrations of immunoreactive endothelin-1 (ET) were determined by haemocytometer, 3 H-thymidine and 3 H-leucine incorporation, and RIA, respectively. The effect of rHuEpo on EC proliferation was confirmed by anti-rHuEpo rabbit antiserum. The effect of cycloheximide or actinomycin D was also examined on the increase in ET production by rHuEpo. Results. rHuEpo dose-dependently stimulated the proliferation of cultured EC, and this proliferative effect was inhibited by anti-rHuEpo rabbit antiserum. DNA and protein syntheses by EC were also increased by rHuEpo. The supernatant concentrations of ET cultured with rHuEpo at 5000 mU/ml or more showed significantly greater values than those without rHuEpo and the increase in ET in the supernatants of media containing 5000 mU/ml rHuEpo was inhibited by incubation with 0.2 μg/ml actinomycin D or 10 μg/ml cycloheximide. Further, rHuEpo increased DNA synthesis by EC which had been cultured in E-BM medium containing 0.5 or 2% FBS for 3h and which were recultured in E-BM medium containing 5% FBS for 15 h. Conclusions. rHuEpo directly stimulates EC proliferation as a competence factor, and it also accelerates endothelin-1 production in association with stimulation of DNA and protein syntheses by EC.

Ocular toxoplasmosis may be remarkably atypical in situations of evident immunosuppression such as acquired immunodeficiency syndrome, malignancy, and use of chronic immunosuppressive drug therapy.1 Aggressive forms in immunocompetent hosts are very rare.2,3 We present a case of severe, bilateral necrotising retinitis by Toxoplasma gondii initially misdiagnosed as an acute retinal necrosis (ARN) syndrome, in a patient with systemic lupus erythematosus (SLE) and diabetes mellitus type 2, who was taking medium dose prednisone. A 47 year old woman reported a 3 month history of rapid visual loss in the right eye followed by a decrease in her left eye vision 2 months later. Twenty days before the onset of ocular symptoms the patient had a seizure. Her medical history showed a SLE,4 with an active lupus central nervous system disease controlled with prednisone (0.5 mg/kg/day), and type 2 diabetes mellitus. At her first visit to our service, visual acuity was hand movements in both eyes. Slit lamp examination showed 3+ aqueous cells and flare, and 2+ anterior vitreous cells in both eyes. The fundus showed a 2+ vitreous haze and almost 360° creamy white necrotising retinitis extending from the ora serrata to the posterior pole, including the macula in both eyes (Fig 1A and B). Thumbprint patches at the border between necrotic and scanty normal retina could be observed, and also diffuse vascular attenuation. Figure 1 (A) Fundus appearance of …