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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 predominant histological types of esophageal cancer are adenocarcinoma and squamous cell carcinoma. Since these two histological types present as different diseases in terms of their epidemiology, pathologenesis, and tumor biology, separate therapeutic approaches should be developed against each type. While surgical resection remains the dominant therapeutic intervention for patients with operable esophageal squamous cell carcinoma (ESCC), their high rates of tumor recurrence have prompted investigation of multimodality therapies that combine surgery with chemotherapy, radiotherapy, and chemoradiotherapy. In Japan, preoperative chemotherapy with cisplatin (CDDP) plus 5-fluorouracil (5-FU) followed by radical esophagectomy has been accepted as the standard therapeutic approach for resactable clinical Stage II/III ESCC. Similarly, the CDDP and 5-FU regimen has been accepted as the first-line treatment for metastatic and unresectable ESCCs in Japan. Thus, in Japan chemotherapy is an indispensable component of therapy for both resectable and unresectable ESCCs. This review discusses the current knowledge, rationale, and available data regarding chemotherapy for resectable and unresectable ESCCs.

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 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.

Both internal and external oxidative stresses act on DNA and can induce carcinogenesis. 8-hydroxydeoxyguanosine (8-OHdG) is an indicator of oxidative stress and it leads to transversion mutations and carcinogenesis. 8-OHdG is excision-repaired by 8-OHdG DNA glycosylase (OGG1). The purpose of this study is to clarify the effect of oxidative DNA damage and repair enzymes on esophageal carcinogenesis. The levels of 8-OHdG and OGG1 were immunohistochemically evaluated in resected specimens, including squamous cell carcinoma (SCC) in 97 patients with esophageal cancer. Higher levels of 8-OHdG in normal esophageal epithelium were associated with a higher smoking index (P = 0.0464). The 8-OHdG level was higher in cancerous areas than in normal epithelia (P = 0.0061), whereas OGG1 expression was weaker in cancerous areas than in normal epithelia (P0.0001). An increase of OGG1 expression in normal epithelium was observed as 8-OHdG levels increased (P = 0.0011). However, this correlation was not observed in cancerous areas. High OGG1 expression in the cytoplasm was related to deeper tumors (P = 0.0023), node metastasis (P = 0.0065) and stage (P = 0.0019). Oxidative DNA damage, which is attributable to smoking as well as disturbances in DNA repair systems, appears to be closely related to esophageal carcinogenesis and its progression.

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.

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.

To assess tissue characterization relating with neck metastasis of invasive tongue cancer, we investigate the usefulness of intra-oral ultrasonography (US).The patients with squamous cell carcinoma of the tongue (n = 110) were preoperatively evaluated with intra-oral US. The US images were compared with histological sections. The histological and ultrasonographic parameters were evaluated for their correlation with neck metastasis.High-quality ultrasonic images were obtained, and all lesions over 1 mm thickness by histology were detected. There was a significant correlation (P0.0001) between measurements of tumor thickness by US and histology. Univariate analysis showed that the histological parameters influencing neck metastasis were mode of invasion (P = 0.0006), muscular invasion (P0.0001), stromal reaction (P = 0.0002), and tumor thickness (P = 0.0004). Of the ultrasonographic parameters, shape of margin (P = 0.019), pattern of margin (P = 0.033), internal echo signal (P = 0.035), and tumor thickness (P0.0001) showed a significant correlation with neck metastasis. Ultrasound images of oral tongue cancer reflected the histological structures. Tumors with diffuse invasive mode shows an irregular and unclear tumor margins on US image. Thickness of 8 mm by ultrasound is useful as a cut-off point of predicting risk of neck metastasis of tongue cancer. Intra-oral US is a reliable tool in objectively predicting subclinical neck metastasis in tongue cancer.

In this study we analyzed induction therapy for locally advanced non-small cell lung cancer. Eligible patients had mediastinoscopic proven N2 disease and T4 with mediastinal involvement. From January 1997 to May 2005, 56 patients entered the study. They received 2 cycle chemotherapy (platinums based 2 or 3 drugs), in 32 patients with concurrent radiotherapy followed by surgery. Response rates were 57.1%. Fifty-one patients underwent surgery. A radical resection was possible in 39 patients. Complication occurred in 14 patients (27.5%). Overall 5-year survival was 27.5%. In N2 disease, there was no statistically significant difference in survival between the induction group and the historical group. In T4 disease, overall 5-year survival was 30.2% for the induction group and 5.2% for historical group. There was significant difference in survival between the groups (p0.05).

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.

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.

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.

A 60-year-old asthmatic woman was admitted to our department because of bloody sputum and pneumonia. She had been treated with inhaled becromethasone dipropionate (800 micrograms/day) on an outpatient basis for 3 years. Fiberoptic bronchoscopy revealed polypoid lesions in the trachea, most of which were removed with forceps during the procedure. Numerous lymphocytes were observed in the biopsy specimen. Because immunohistochemical staining denied a monoclonal origin for the accumulated lymphocytes, the lesion was diagnosed as an inflammatory polyp. The patient was treated successfully with antibiotics for her pneumonia, and on a follow-up bronchoscopy 6 months later, only a small remnant of the lesion was noted. This is the fourth report about inflammatory polyps in asthmatics. In the previous 3 cases, however, marked eosinophil infiltration was consistently reported. The lymphocyte predominance in the present case therefore suggests a distinct etiology rather than asthmatic airway inflammation.

We report a 26-year-old woman who showed recurrent migrainous attacks and convulsions since her childhood. Neurological examination revealed no focal abnormality except mental retardation (MR). T2-and fluid-attenuated inversion-recovery (FLAIR)-weighted brain MRI revealed apparent high intensities in the deep subcotical white matter. Ultrastructual studies revealed an abnormal deposition of granular osmiophilic materials (GOM) on the surface of vascular smooth muscle cells in dermis. Her mother developed recurrent strokes without risk factor since age 41. A heterozygosis Arg133Cys mutation of Notch 3 gene has already presented in patient and her mother. This case might be an early stage in CADASIL before stroke onset and suggested that systemic vasculopathy was presented in this stage. The correlation between MR and phenotype of CADASIL were unclear.

This study examined the relationship between Chlamydia pneumoniae (C. pneumoniae) infection and the accelerated development of coronary artery disease (CAD) in patients with chronic renal failure (CRF).Two-hundred and fourteen patients undergoing coronary angiography, including 67 controls and 147 patients with CAD (97 without CRF and 50 with CRF), were enrolled in this study. Anti-C. pneumoniae specific IgG and IgA antibodies were measured using an enzyme-linked immunosorbent assay (ELISA).Coronary artery disease (expressed as CAD score) was more severe in patients with than without CRF (14.9 +/- 6.0 vs. 11.3 +/- 6.0, p0.01). Seropositive rates of IgG and IgA antibodies against C. pneumoniae were higher in all CAD patients than in the controls (76.2% vs. 44.8%, p0.001 for IgG; 59.9% vs. 40.3%, p0.01 for IgA). In both CAD subgroups, IgG seropositive rates were similarly elevated (82.0% and 73.2% vs. 44.8% for control, p0.001, respectively), whereas those of IgA were significantly elevated only in CAD with CRF (68.0% vs. 55.7% for control, p0.01). The mean antibody index of IgG was elevated in all CAD patients compared with the controls (1.9 +/- 1.0 vs. 1.3 +/- 0.9, p0.0001), but that of IgA was not (1.5 +/- 1.0 vs. 1.2 +/- 0.9). Levels of IgG were elevated in all patients with CAD compared with the control (2.4 +/- 1.1 and 1.8 +/- 1.0 vs. 1.3 +/- 0.9, p0.001 and p0.001, respectively), whereas those of IgA were elevated only in CAD with CRF (1.8 +/- 1.1 vs. 1.2 +/- 0.9, p0.05). Stepwise logistic regression analysis revealed that the elevated IgG antibody index was an independent risk factor for CAD regardless of CRF (odds ratios 1.9, 1.8, and 2.3), whereas the IgA index was a risk factor only in CAD with CRF (odds ratio 1.7).Chlamydia pneumoniae infection may be related to the accelerated CAD in patients with CRF, which was specifically suggested by an elevated IgA level. In other words, the prevalence of active C. pneumoniae infection is higher in patients with CAD and CRF than that in those with CAD without CRF.

Elevated levels of acute-phase proteins, a systemic marker for inflammation, predict coronary events; Chlamydia pneumoniae (C. pneumoniae) infection is associated with coronary atherosclerosis. The present study investigated whether inflammation or infection is involved in the pathogenesis of acute coronary syndrome (ACS) and which one has the more important role. The study group comprised 49 patients with angiographically diagnosed ACS, 48 cases of chronic coronary heart disease (CCHD), and 44 subjects with a normal coronary profile. The levels of serum C-reactive protein (CRP), fibrinogen and anti-C. pneumoniae IgG antibody were measured. The IgG antibody against C. pneumoniae was higher in the ACS and CCHD groups compared with the control group after adjusting for age and gender. The levels of CRP and fibrinogen were significantly increased in patients with ACS compared with controls and CCHD patients. Multiple stepwise logistic regression analysis revealed that C. pneumoniae IgG antibody is an independent risk factor for both ACS and CCHD (odds ratio 2.3 and 2.1, respectively), but the CRP level is a risk factor only for ACS (odds ratio 6.9). The inflammatory response, as indicated by acute-phase proteins, especially CRP, rather than C. pneumoniae infection, may contribute more to the clinical course of ACS.

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.

We reported here a case of symptomatic partial epilepsy following acute necrotizing encephalopathy of childhood associated with influenza A virus infection. This 2-year-old boy underwent repeated EEG recordings, which at the acute stage was dominated by diffuse 1-2 Hz slow waves. The background activity was 5 Hz theta waves on the 49th day. Paroxysmal activities appeared after the 89th day of illness. On the 231st day, EEG showed spike-and-waves on the left and right frontal areas. Interestingly, paroxysmal activities preceded the onset of epileptic seizures by 7 months, and spike-and-waves by 2 months. After 10 months, he had generalized seizures with fever, and partial seizures on awakening without fever. Interictal EEG showed spike-and-waves on the bilateral frontal areas, and diffuse polyspikes and slow waves were occasionally seen. Though the background activity improved, his consciousness level did not recover probably because the thalamus, basal ganglia, brainstem were damaged more severely than the cerebral cortex.

The focus of this symposium was to present new information on the morphogenesis of Candida albicans, particularly how it relates to signal transduction pathways and other genes involved in the regulation of morphogenesis. In addition, we discuss the role of adherence and colonization of the oral cavity by the organism and discuss the role of mannan as an adhesin that recognizes the human red blood cell. C. albicans utilizes at least two signal pathways to regulate its conversion from a yeast form to filamentous growth (hyphae). One of these two pathways is similar to the Saccharomyces cerevisiae pseudohyphal/mating pathway, which utilizes the regulatory protein, Cphlp. The other pathway is not totally defined but requires a second regulatory protein, referred to as Efg1p. Other signal pathways may exist, which include a two-component histidine kinase and response regulator proteins. The latter pathway(s) may include proteins such as Chk1p, Ssk1p, Shi1p and Cos1p/Nik1p. Mutations in strains, which specifically target these proteins, result in morphogenesis defects and avirulence or attenuation of strains. A growth regulatory gene has also been recently defined whose expression is associated with growth cessation and which appears to be a necessary prerequisite in conversion of the organism to a filamentous growth form. Starvation of yeast cells induces exponentially grown cells (and usually non-germinative) to germinate. This phenomenon is also observed in cells that are transiently treated with metabolic inhibitors. During each of these treatments (starvation, metabolic inhibition), expression of a growth regulatory gene (CGRI) increases. Adherence of C. albicans to host cells and tissues is complex; several proteins, which appear to have host recognition functions, have been defined. In the oral cavity, C. albicans selectively adheres to salivary proteins, which are absorbed to many oral surfaces. This mechanism enables the cells to colonize surfaces of the oral cavity. An understanding of these interactions may lead to strategies to prevent oral disease. Mannan from C. albicans may provide a host recognition function for C. albicans. Recent experiments indicate that mannan binds to human red blood cells and causes hemolysis. Binding of mannan to the band 3 protein of human red blood cells has been established. This activity may be associated with the ability of the organism to utilize hemoglobin (and iron).

To investigate the relationship between oxidative stress and apoE phenotype in dementia of Alzheimer type (DAT).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.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.Our findings suggest that apoE4 and SOD individually influence oxidative stress in DAT.

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.

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.

Cytokines that regulate monocyte migration were found in membrane tissue surrounding loosened prosthetic implants. Monocyte migration inhibition factor (MIF) is able to inhibit macrophage migration. Monocyte chemoattractant protein (MCP) and macrophage inflammatory protein (MIP) are potent macrophage chemoattractants. These cytokines may be expressed as part of the foreign body response to prosthetic particulate debris. Chemotaxis analysis and macrophage activation experiments were performed to determine the effects of MIF, MCP-1, and MIP-1alpha on macrophage migration and activation in vitro. We demonstrated that MIF had its maximal migration inhibitory effect for unchallenged and particle challenged macrophages at 1 ng/mL. MCP-1 and MIP-1alpha stimulated macrophage chemotaxis maximally at 1 to 10 ng/mL. Dose-response studies with MIF, MCP-1, and MIP-1alpha demonstrated that these cytokines did not modulate activation of unchallenged or particle challenged macrophages as evaluated by IL-6 and TNF-alpha release. However, these cytokines do not appear to affect macrophage release of proinflammatory mediators in vitro.

A 63-year-old man was admitted to our hospital because of left back pain and dysesthesia in his left arm. On physical examination, the patient had ptosis, myosis, and anhydrosis on the left side, suggesting Horner's syndrome. A chest computed tomographic scan disclosed a mass lesion adjoining to the left posterior mediastinum. Although the mass lesion showed a slight decrease in size after the systemic administration of corticosteroids, no further improvement was obtained. Open chest examination revealed extended thickening of the parietal pleura with massive involvement of the upper thoracic sympathetic trunk. The diagnosis was malignant mesothelioma of sarcomatous type. Horner's syndrome is a rare but possible complication in the clinical course of malignant pleural mesothelioma.

Deoxyribonuclease I (DNase I) was purified from Xenopus laevis pancreas to apparent electrophoretic homogeneity using a series of column chromatographies. The purified enzyme showed a molecular mass of about 36 kDa and maximum activity at pH 7.0-8.0, required divalent cations, Ca2+ and Mg2+, for its activity, and was inhibited by EDTA, EGTA and an antibody specific to the enzyme, but not by G-actin. The N-terminal amino acid sequence of the enzyme up to the 37th residue shared 38-44% homology with that of mammalian DNases I derived from bovine, ovine, porcine, rat, mouse, rabbit and human. A systematic survey of DNase I activity distribution in 20 different kinds of frog tissues showed that the pancreas and rectum produced higher amounts than other tissues. This is the first report concerning the purification and chemical and immunological characterization of frog pancreatic DNase I.

Particulate wear debris is associated with periprosthetic inflammation and loosening in total joint arthroplasty. We tested the effects of titanium alloy (Ti-alloy) and PMMA particles on monocyte/macrophage expression of the C-C chemokines, monocyte chemoattractant protein-1 (MCP-1), monocyte inflammatory protein-1 alpha (MIP-1alpha), and regulated upon activation normal T expressed and secreted protein (RANTES). Periprosthetic granulomatous tissue was analysed for expression of macrophage chemokines by immunohistochemistry. Chemokine expression in human monocytes/macrophages exposed to Ti-alloy and PMMA particles in vitro was determined by RT-PCR, ELISA and monocyte migration. We observed MCP-1 and MIP-1alpha expression in all tissue samples from failed arthroplasties. Ti-alloy and PMMA particles increased expression of MCP-1 and MIP-1alpha in macrophages in vitro in a dose- and time-dependent manner whereas RANTES was not detected. mRNA signal levels for MCP-1 and MIP-1alpha were also observed in cells after exposure to particles. Monocyte migration was stimulated by culture medium collected from macrophages exposed to Ti-alloy and PMMA particles. Antibodies to MCP-1 and MIP-1alpha inhibited chemotactic activity of the culture medium samples. Release of C-C chemokines by macrophages in response to wear particles may contribute to chronic inflammation at the bone-implant interface in total joint arthroplasty.

Two short tandem repeat (STR) systems, HumTPO and HumLPL, were investigated in 218 unrelated Japanese living in Gunma and Fukui Prefectures by means of discontinuous, horizontal polyacrylamide gel electrophoresis and silver staining. Five and six alleles were identified at the HumTPO and HumLPL loci, respectively. No deviations from the Hardy-Weinberg equilibrium or differences in genotype frequency were found between the two Japanese populations in the two systems. Our detection methods offered several advantages including time-saving and safe electrophoretic procedures, and fast and easy silver-staining, in comparison with standard and conventional STR analysis using vertical polyacrylamide gel electrophoresis.

Amplification of the CDK4 gene, which encodes a key molecule in the cell cycle, has been shown in some types of human neoplasms, including bone and soft tissue tumors. It is also reported that the CDK4 gene is coamplified with other sequences in the 12q13-15 region, including the MDM2 and SAS genes. Using 146 DNA samples derived from a variety of bone and soft tissue tumors, we have studied the pattern of amplification of these three genes, CDK4, MDM2, and SAS, to investigate whether there are any tumor type specific patterns of amplification. Amplification of at least one of these three genes was found in 18 tumors, and five different patterns of amplification were observed. Amplification of all of these three genes was detected in 9 cases. Amplification of the CDK4 gene without MDM2 amplification was observed in osteosarcomas and a chondrosarcoma but not in soft tissue tumors, whereas amplification of MDM2 gene alone was observed in malignant fibrous histiocytomas (MFHs), liposarcomas, and lipomas, but not in bone tumors. These results suggested that the CDK4 region is the primary target for amplification in bone tumors, whereas the MDM2 region is in soft tissue tumors. We also investigated the relationship of CDK4 amplification with retinoblastoma (RB) gene mutations in osteosarcomas, for which we have already performed the mutation analyses in detail. Interestingly, contrary to the prevailing theory that CDK4 amplification is an alternative mechanism for RB gene mutation, we found that three of four cases with amplification of the CDK4 gene showed loss of expression of the RB protein, one of which was proved to have an gross DNA alteration in the RB locus. This redundancy of mutations may indicate that the amplification of CDK4 may have some roles other than the inactivation of the RB protein in the development of osteosarcomas.

We exposed human macrophages isolated from the peripheral blood of healthy donors to metal and bone-cement particles from 0.2 to 10 microm in size. Zymography showed that macrophages exposed to titanium alloy and polymethylmethacrylate (PMMA) particles released a 92- and 72-kDa gelatinase in a dose- and time-dependent manner. Western immunoblotting confirmed that the 92- and 72-kDa gelatinolytic activities corresponded to matrix metalloproteinase-9 and matrix metalloproteinase-2 (MMP-9, MMP-2), respectively. Western immunoblotting also indicated that titanium alloy and PMMA particles increased the release of MMP-1. Northern blotting showed elevated mRNA signal levels for MMP-1, MMP-2, and MMP-9 after exposure to both types of particle. Collagenolytic activity also increased in the macrophage culture medium in response to both types of particle. Our findings support the hypothesis that macrophages release MMPs in proportion to the amount of particulate debris within periprosthetic tissues.

This study tested whether macrophages respond differently to retrieved titanium-alloy particles than they do to machined titanium-alloy particles and assessed whether pretreatment of machined titanium-alloy particles with human serum would influence macrophage activation and cytokine release in vitro. Human monocyte/macrophages were isolated from normal healthy donors and exposed to increasing concentrations of machined and retrieved titanium-alloy particles. The profile of cytokine release was determined by commercially available ELISA kits. Machined titanium-alloy particles were opsonized with human serum and added to macrophage cultures. Serum protein binding was confirmed by SDS-PAGE analysis. The results showed that machined titanium-alloy particles and retrieved titanium-alloy particles stimulate a similar level of cytokine release when tested at comparable concentrations. Opsonization of the machined particles with human serum increased the macrophage release of cytokines in the first 12 h after exposure compared to nonopsonized particles. At 24 h, the opsonized particles stimulated significantly higher levels of cytokine release, but only at the greatest particle concentrations. This study demonstrates that machined titanium alloy induces a metabolic response in macrophages similar to that of titanium-alloy particles retrieved from failed total hip arthroplasty. In addition, these data show that serum protein binding to orthopedic biomaterial debris alters the macrophage reaction to the particles.

An operated case of inflammatory pseudotumor of the lung is reported. A 27-year-old female was pointed out a coin lesion in the left lower lung field on chest X-ray and the size of mass increased. She had a history of thymomectomy for thymoma, and resection of right intrathoracic dissemination. Therefore operation was performed on suspicion of metastasizing thymoma. A partial resection including the mass with VATS was performed and histopathologic examination revealed inflammatory pseudotumor. The postoperative course was uneventful, and there has been no evidence of recurrence thereafter. In Japan, sixty-eight cases of inflammatory pseudotumor of the lung including our case have been reported in the literature.

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.

We have cloned and sequenced the cDNA of the human brain ryanodine receptor (RyR3), which is composed of 4866 amino acids and shares characteristic structural features with the rabbit RyR3. Northern blot analysis shows that the human RyR3 mRNA is abundantly expressed in hippocampus, caudate nucleus and amygdala as well as in skeletal muscle. The human RyR3 mRNA is also detected in several cell lines derived from human brain tumors. Functional expression of RyR3 and a chimeric RyR suggests that RyR3 forms a calcium-release channel with a very low Ca2+ sensitivity.

We previously estimated the turning point of reflux nephropathy irreversibly deteriorating to end stage renal disease, mainly based on findings in renal biopsy (Eur. Urol., 26: 153-159, 1994). In this study, we aim to evaluate clinical parameters which may be closely associated with progression of reflux nephropathy to end stage renal disease.Ninety five patients (84 children and 11 adults; 41 men and 54 women) with renal scar and/or reflux (/ = grade 3), mean aged 9.4 +/- 9.1 years (3 months-53 years) were followed up for 3.7 years +/- 2.7 (6 months-18 years). Vesicoureteral reflux was bilateral in 64 and unilateral in 31; primary in 85 and secondary in 10 patients. Clinical parameters including body weight, height, blood pressure, 24 hour urinary protein excretion, serum creatinine, 99m Tc-DTPA GFR and 99 m Tc-DMSA uptake were monitored over time. All patients underwent antireflux surgery (with or without other reconstructive surgery) and open renal biopsy. Three patients progressing to end stage renal disease underwent subsequent biopsy.Over-5 year observation period, the prevalence of new scare formation and further extension in scar was significantly higher in the group of renal functional deterioration (35%) than in the group of stable renal function (6.0%). Over the same period DMSA uptake decreased significantly (0.05) in the group of scar b (Smellie's classification), suggesting most kidneys of scar b eventually resulting in atrophic kidney (scar c). Proteinuria more than 100 mg/day appeared to be a critical level for predicting irreversible deterioration in renal function. Glomerular hypertrophy was closely related to the increase in urinary protein excretion and serum creatinine, contrary to the decrease in DTPA-GFR. In addition, bilateral renal scar b, glomerular hypertrophy (2 SD), proteinuria (300 mg/day), low GFR (mean: 49 ml/min), and diastolic hypertension seemed to be implicated in the genesis of ESRD.Glomerular damage due to either reflux nephropathy or dysplasia may cause proteinuria. Proteinuria of 100 mg/day was significantly (p0.01) associated with 2 SD of glomerular hypertrophy on histology and clinical observation (suggesting hyperfiltration). Thereafter, a rapid increase in proteinuria followed by diastolic hypertension appears be significant for predicting ESRD.

Inactivation of the p53 tumor suppressor gene is considered to be a late event involved in the malignant transformation of colorectal adenoma to cancer. Thus, its detection is thought to provide useful information for the clinical management of colorectal neoplasms. We devised a rapid screening test for allelic loss of the p53 gene by non-radioisotopic single-strand conformation polymorphism analysis.Biopsy materials from 119 colorectal tumors obtained at endoscopy were examined. Three intragenic polymorphic sites were amplified by polymerase chain reaction using DNA extracted from these materials, and amplified DNA fragments were subjected to non-radioisotopic single-strand conformation polymorphism.This method can detect a loss of heterozygosity (LOH) of the p53 locus from samples containing over 40% tumor derived DNA, and the combination of the three polymorphic markers encompassed 62.4% of Japanese patients as informative. In adenocarcinoma, an LOH was detected in 51.5% (17 of 33) of the samples and in 12.2% (4 of 33) of tubular and/or tubulovillous adenomas. The p53 gene was mutated only in samples carrying an LOH, that is 64.7% (11 of 17) of carcinomas and 25.0% (1 of 4) of adenomas, but there were no mutation in samples retaining both alleles. The presence of an LOH was statistically correlated both with p53 mutation and malignant histology (chi 2 test, p0.05).This method can detect LOH from biopsy material obtained at endoscopy. LOH in the p53 locus precedes mutation of the p53 gene, and its detection provides useful information of malignancy in colorectal tumors.

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.

Recently, much attention has been paid to the arterial gene transfer technique using several vector systems. In the present study, we experimentally examined the transfection efficiency of the exogenous gene, the duration of gene expression, and the cytotoxic effect of the hemagglutinating virus of Japan (HVJ) liposome on the intact arterial wall to evaluate its effectiveness for the study of arterial diseases. To evaluate the transfection efficiency and duration of gene expression, pSV beta-galactosidase was transferred into the carotid arterial wall of rabbits. The cytotoxic effect of HVJ liposomes on the vascular cell components was also evaluated by a neutral red assay in vitro and scanning electron microscopy in vivo. HVJ liposomes could achieve highly efficient gene transfection into the medial smooth muscle cells of intact arteries at 150 and 760 mmHg of pressure (mean = 85.3% and 93.5% of total smooth muscle cells, respectively) without any inflammatory reaction. The introduced exogenous gene was expressed for at least 14 days. In addition, the cytotoxicity for the arterial smooth muscle cells and endothelial cells induced by HVJ liposome vehicles at routinely used concentrations (5,000 to 10,000 hemagglutinating activity units/ml) was minimal both in vitro and in vivo. As an example, we introduced human vascular endothelial growth factor cDNA, which was driven with cytomegalovirus enhancer and beta-actin promoter, into the rabbit carotid arteries, and it induced not only angiomatoid proliferation of endothelial cells forming irregular vascular channels but also intimal hyperplasia. Based on these findings, we conclude that HVJ liposome-mediated arterial gene transfer is a highly efficient, noninvasive, and effective gene delivery method for the study of vascular disorders.