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Background Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics of HER2-positive NSCLC have not been systematically defined. Methods Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations. Results Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 [26%]) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively. Conclusions This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations. Trial Registry UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691

Background: Neutropenia is a common adverse reaction of chemotherapy. We assessed whether chemotherapy-induced neutropenia could be a predictor of survival for patients with non-small-cell lung cancer (NSCLC). Methods: A total of 387 chemotherapy-naïve patients who received chemotherapy (vinorelbine and gemcitabine followed by docetaxel, or paclitaxel and carboplatin) in a randomised controlled trial were evaluated. The proportional-hazards regression model was used to examine the effects of chemotherapy-induced neutropenia and tumour response on overall survival. Landmark analysis was used to lessen the bias of more severe neutropenia resulting from more treatment cycles allowed by longer survival, whereby patients who died within 126 days of starting chemotherapy were excluded. Results: The adjusted hazard ratios for patients with grade-1 to 2 neutropenia or grade-3 to 4 neutropenia compared with no neutropenia were 0.59 (95% confidence interval (CI), 0.36–0.97) and 0.71 (95% CI, 0.49–1.03), respectively. The hazard ratios did not differ significantly between the patients who developed neutropenia with stable disease (SD), and those who lacked neutropenia with partial response (PR). Conclusion: Chemotherapy-induced neutropenia is a predictor of better survival for patients with advanced NSCLC. Prospective randomised trials of early-dose increases guided by chemotherapy-induced toxicities are warranted.

We report the first case to our knowledge of chronic pancreatitis associated with mitochondrial encephalopathy with the A8344G mitochondrial DNA (mtDNA) mutation. This 10-year-old-girl had suffered from recurrent abdominal pain with elevated serum amylase and lipase since the age of 6, and easy fatigability, tremor and astatic seizures since the age of 8. A biopsy of quadriceps muscle revealed ragged-red-fibers and cytochrome c oxidase deficiency. Analysis of mtDNA in peripheral blood identified an A8344G mutation in the mitochondrial tRNA(Lys) gene. Taken together with physical signs of myoclonic seizures and cerebellar dysfunction, we diagnosed her as myoclonic epilepsy with ragged-red fibers associated with chronic pancreatitis. Although no association between mitochondrial disease and pancreatitis has yet been established, this case suggests it is necessary to consider the participation of mitochondrial abnormality in the pathogenesis of recurrent pancreatitis.

The aim of this study was to examine the roles of various cytokines in histamine synthesis by macrophages in bone marrow. Pure (> 99% nonspecific esterase-, CD14-, and Mac-1-positive) macrophage populations were obtained after long term culture of bone marrow cells (bone marrow-derived macrophages). Culture of the cells in the presence of Escherichia coli LPS caused a slight, but dose-dependent, increase in histidine decarboxylase-associated histamine synthesis with a concomitant increase in the expression of CD14, a LPS receptor, as well as the Mac-1 Ag on their surface. Granulocyte/macrophage CSF (GM-CSF) or IL-3 strongly enhanced LPS-induced histamine formation and expression of CD14 on bone marrow-derived macrophages, without affecting the expression of Mac-1 Ag. GM-CSF and IL-3 also caused a marked accumulation of both histidine decarboxylase and IL-6 mRNAs in the cells. Macrophage CSF and IL-1-alpha also potentiated LPS-dependent histamine formation when it was stimulated with GM-CSF or IL-3. In contrast to these cytokines, IFN-gamma suppressed LPS-induced histamine production regardless of whether it was stimulated by GM-CSF or IL-3, and inhibited CD14 expression. Neither IL-6 nor granulocyte CSF had any appreciable effect on LPS-induced histamine production even in combination with GM-CSF or IL-3. These results suggest that GM-CSF and IL-3 enhance LPS-induced histamine production in bone marrow-derived macrophages and that macrophage CSF and IL-1 alpha augment the actions of GM-CSF and IL-3. Possible implication of CD14 molecule in the reactions is discussed.

Streptococcus mutans, a major pathogen of dental caries, is occasionally isolated from the blood of patients with infective endocarditis. Bacterial attachment of exposed collagen tissue in the impaired endothelium is an important step in the onset of infective endocarditis. In our previous studies, some S. mutans strains were shown to possess collagen-binding activities and most of them had an approximately 120-kDa cell-surface collagen-binding protein called Cnm. However, several strains without Cnm proteins show collagen-binding properties. In the present study, another collagen-binding protein, Cbm, was characterized and its coding gene cbm was sequenced in these strains. The amino acid alignment in the putative collagen-binding domain of Cbm was shown to have approximately 80% identity and 90% similarity to the comparable region of Cnm. Cbm-deficient isogenic mutant strains constructed by insertional inactivation of the cbm gene, lacked collagen-binding properties, which were recovered in the complemented mutant. Analyses of a large number of clinical isolates from Japan, Thailand and Finland revealed that cbm-positive strains were present in all of these countries and that cnm-positive and cbm-positive strains were detected in the oral cavity of approximately 10 and 2% of systemically healthy subjects, respectively. In addition, cnm-positive strains were predominantly identified in the serotype f group, whereas cbm-positive strains were frequently detected in serotype k. These results suggest that Cbm as well as Cnm are major cell surface proteins of S. mutans associated with binding to type I collagen and predominantly identified in serotype k strains.

The nuclear DNA contents of atypical mesothelial cells from five patients who had an eosinophilic pleural effusion (EPE) were studied by the use of DAPI (4',6-diamidino-2-phenylindole dihydrochloride) DNA staining. Analysis of the nuclear DNA content revealed a polyploid pattern, with a major peak in the tetraploid region. Using an immunocytochemical technique, the atypical mesothelial cells showed a positive reaction for cytokeratin. In contrast carcinoembryonic antigen (CEA) was always negative in these cells. It is suggested that the atypical mesothelial cells with EPE had a higher rate of proliferation than did the normal mesothelial cells.

Porphyromonas gingivalis was recently shown to cause intimal hyperplasia in a mouse model by a novel cholesterol-independent mechanism, suggesting to be a pathogen-specific feature of cardiovascular diseases. The aim of this study was to characterize the clinical and histopathological features of aortic aneurysms in cardiovascular disease patients harboring oral P. gingivalis.Aortic aneurysm specimens were collected from 76 Japanese patients who underwent surgery, of whom dental plaque specimens were also collected from 31 patients. Bacterial DNA was extracted from each specimen to detect P. gingivalis by polymerase chain reaction. Histopathological analyses of the aortic aneurysm specimens, including immunohistochemical staining for embryonic myosin heavy chain isoform (SMemb) and S100 calcium-binding protein A9 (S100A9), were also performed.The number of aneurysms occurring in the distal aorta was significantly higher in subjects positive for P. gingivalis in dental plaque compared with those who were negative. The expressions of S100A9 and SMemb were also significantly greater in the subjects positive for P. gingivalis in dental plaque. On the other hand, there were no significant differences in adipocellular accumulation between the groups.These results suggest that aortic aneurysms in patients harboring oral P. gingivalis have greater expression of S100A9 and proliferative smooth muscle cells, which was different from the present patients without oral P. gingivalis.

The purpose of this study was to construct a method to predict CYP3A4 induction in the clinical setting from in vitro data using cryopreserved human hepatocytes. We recently developed an approach with in vitro assays of HepaRG cell lines for predicting CYP3A4 induction by using a novel value, termed the relative factor (RF), determined from the ratio of the concentration of an inducer to the reference standard. In this study, the applicability of the RF approach was expanded to cryopreserved human hepatocytes. Induction assays were performed in vitro using hepatocytes from four individual donors and eight typical inducers. The obtained RF values were related to the free plasma concentration of each inducer (expressed as Css,u/RF). A good relationship between the Css,u/RF values and the in vivo induction response was found for all donors. Inducers were classified by the Css,u/RF values into three categories for CYP3A4 induction risk (high, medium and low potency), and thereby the degree of CYP3A4 induction in vivo in humans could be predicted from the Css,u/RF values. The RF approach is applicable to human cryopreserved hepatocytes. Thus, a method to predict the potency of CYP3A4 inducers was constructed using cryopreserved human hepatocytes.

In general, Notch is a representative signal which controls morphosis and differentiation of cells, but its role in human odontogenic neoplasms, especially in ameloblastoma and its malignant counterpart, ameloblastic carcinoma, is not known.We examined Notch1 peptide and its gene (mRNA) in an ameloblastoma (case 1: 27-year-old female, right mandibular tumor) and an ameloblastic carcinoma (case 2: 93-year-old female, right mandibular tumor), using immunohistochemistry (IHC) and in situ hybridization (ISH) techniques.Notch1 intracellular domain (NICD) positive products were observed in the cells at the peripheral layer of most proliferating epithelial tumor nests in case 1. In case 2, positive products were similarly detected. In particular, small numbers of mitoses were identified in the nuclear region with intense NICD positive reaction.Notch signaling plays some role in cytological differentiation or acquisition of tissue specific characteristics in neoplastic cells of odontogenic neoplasms, including ameloblastoma and ameloblastic carcinoma. Notch1 may also contribute to cell cycle arrest induced by Notch1 activation in ameloblastic carcinoma.

There is scant information available regarding the distribution of periodontal bacterial species in children and adolescents over an extended period. The purpose of this study was to compare bacterial profiles in the same individuals over a period of 7 years.Twenty-six children and adolescents from whom dental plaque and saliva specimens were obtained during both the first (1999-2000) and second (2006-2007) periods, were analyzed. Bacterial DNA was extracted from each specimen and the presence of 10 periodontal bacterial species was determined using a PCR method, with a focus on the red complex species of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia.Subjects with red complex species in saliva specimens obtained during the second collection possessed a significantly higher number of total bacterial species than those without. The detection rate of the red complex species in the second collection period samples was significantly greater in subjects who had two or more species detected in samples taken during the first collection compared with the other subjects.Subjects possessing red complex species may be at possible risk for infection with a high number of periodontal bacterial species during adolescent and younger adult years.

A new reliable genotyping method, multilocus sequence typing (MLST), was used to evaluate vertical transmission of the cariogenic pathogen Streptococcus mutans. A total of 136 S. mutans strains were isolated from saliva samples of 20 Japanese mother-child pairs, including 5 girls and 5 boys with primary dentition, and 5 girls and 5 boys with mixed dentition. The nucleotide sequences of 8 partial housekeeping genes, aroE, murI, gltA, glnA, glk, tkt, lepC, and gyrA, were analyzed and a similarity for all of those sequences between strains from a mother-child pair was regarded as indicating transmission, which was shown in 70% of the pairs. Interestingly, the rate of transmitted strains from mothers was significantly higher in the girls (90%) than in the boys (p = 0.001). Furthermore, the S. mutans sequence type (ST) with the highest distribution percentage in each maternal saliva sample was found to be transferred to their children. In addition, variations in two large conjugative-transfer associated regions, TnSmu1 and TnSmu2, were determined and compared with the STs defined by MLST. No variations in those two regions shown by PCR patterns were present in any of the strains isolated from the same families with the same STs, though isolates of some STs from different families showed distinct patterns for TnSmu2. Our results indicate that mothers are the main source for transmission of S. mutans to their children, while the present MLST method was also shown to be useful for investigating bacterial transmission.

Porphyromonas gingivalis is a periodontal pathogen whose fimbriae are classified into six genotypes (types I-V and Ib) based on the diversity of the fimA genes encoding the fimbrial subunits. Accumulated evidence suggests that P. gingivalis strains with type II fimbriae are more virulent as compared to those with other types. However, it is unknown if strong virulence is uniformly conserved among clones with type II fimbriae. In the present study, we compared infectious inflammatory changes in clinical isolates of P. gingivalis with type II fimbriae using a mouse abscess model to examine their pathogenic heterogeneity and heterogeneity-related factors.Suspensions of nine different clinical isolates with type II fimbriae were subcutaneously injected into female BALB/c mice and inflammatory parameters, such as serum sialic acid concentration, were compared.Many of the type II fimbrial isolates caused severe inflammation in the mice, though some were less causative, as was the control strain ATCC 33277 (type I fimbria strain). These results showed that pathogenic heterogeneity exists among P. gingivalis clones with type II fimbriae. Further, the heterogeneity-related factors of P. gingivalis strains were analyzed and the pathogenic potentials showed positive relationships to gingipain activities and invasive efficiency but not to hydrophobicity or autoaggregation. In addition, invasive efficiency was related to the activities of gingipains that were extracellularly secreted.These results suggest that pathogenic heterogeneity has relationships with the invasive and proteolytic activities of P. gingivalis clones with type II fimbriae.

This paper describes a rare case of bilateral completely erupted supernumerary teeth found in the incisor region of the mandible of a 19-year-old Japanese female.

The contribution of the microsatellite polymorphisms of TNFa and TNFb, and the TNFB + 252 (TNFB) dimorphism to the pathogenesis of rheumatoid arthritis (RA) was studied among Japanese patients.The TNFa and TNFb microsatellite polymorphisms, and the TNFB dimorphism were determined in Japanese RA patients and normal subjects using electrophoresis followed by specific PCR amplification. HLA-DRB1*04 typing was carried out by the PCR-SSCP method.The allele frequency of TNFa11 showed a significant increase in RA with DRB1*0405 when compared to that in RA without DRB1*0405 (28.5% Vs 12.9%, respectively, p = 0.022). An association analysis indicated that TNFa11 was not primary, but secondary to the increase in HLA-DRB1*0405, because TNFa11 showed a strong positive association with HLA-DRB1*0405 in Japanese controls. The slight increase in the TNFb4 allele observed in RA with DRB1*0405 (50.0%) may be reflective of the increase in TNFa11 and DRB1*0405. In RA with DRB1*0405, the allele frequency of TNFB*2 significantly increased compared to that of normal controls (75.0% Vs 55.3%, respectively, p = 0.007) and compared to that of RA without DRB1*0405 (45.0%, p = 0.001). No significant positive association of TNFB*2 with HLA-DRB1*0405 or TNFa11 in Japanese controls might suggest that the increase in the TNFB*2 allele might not be secondary to the increase in DRB1*0405, and that TNFB*2 might contribute additively to DRB1*0405-positive RA in Japanese.TNFB*2 may contribute additively to Japanese RA with HLA-DRB1*0405, while TNFa11 and TNFb4 are not independent genetic markers of RA among Japanese.

To examine the expression level and function of follistatin-related protein gene (FRP, also referred to as FSTL1) in rheumatoid arthritis (RA), and possible association of its polymorphisms with genetic susceptibility to RA.FRP mRNA expression levels in the synovial tissues from 10 patients with RA and 5 patients with OA were measured using real-time RT-PCR. Effects on the growth of synovial cells were evaluated by stably introducing FRP cDNA into a rheumatoid synovial cell line, E11. Screening of genomic DNA variations was done using DNA from 12 patients with RA and 12 healthy individuals by direct sequencing. Genotypes at the detected polymorphic sites were determined in 224 patients with RA and 220 healthy individuals using PCR-single strand conformation polymorphism.FRP mRNA was overexpressed in synovial tissues from RA patients by 2.3-fold as compared with those from OA. A rheumatoid synovial cell line (E11) transfected with FRP exhibited reduced proliferation, probably mediated by secreted FRP molecule. 16 genomic variations were identified, among which 4 were polymorphisms within the promoter region and exons, and the remainder were either rare variations or intronic polymorphisms. Genotyping of 4 polymorphic sites did not reveal statistically significant association with the susceptibility to RA.FRP mRNA is overexpressed in RA synovium, the product of which exerts inhibitory activity on synovial cell growth. Although new polymorphic sites were identified, they were not associated with susceptibility to RA, suggesting that overexpression of FRP is secondarily caused by synovial environment of RA.

OBJECTIVE: To determine how polymorphism of transporter associated with antigen processing 1 and 2 (TAP1 and 2) alleles contributed to the pathogenesis of systemic lupus erythematosus (SLE) in Japanese patients. METHODS: TAP1 and TAP2 typing was carried out in 52 Japanese patients with SLE and 95 normal subjects by the PCR-RFLP (restriction fragment length polymorphism) method. HLA-DR typing and HLA-DRB1*15 genotyping were carried out by the PCR method and PCR-SSCP (single stranded DNA conformation polymorphism) method, respectively. RESULTS: No particular TAP 1 allele was associated with Japanese SLE or with immunological subgroup of SLE. TAP2H showed a tendency towards increased frequency in SLE (5.8% v 0% in control), but the corrected P value was not significant. No other particular association of TAP2 allele was observed. Furthermore, these was no evidence for linkage disequilibrium between any TAP1/TAP2 alleles and HLA-DRB1*1501--which is reported to be weakly but significantly association with Japanese SLE--in either the normal control or the SLE patient group. CONCLUSIONS: Neither the TAP1 nor the TAP2 gene appears to determine disease susceptibility to SLE in Japanese, and these results are in keeping with those reported in Caucasian SLE patients.

The roles of histamine formed by the macrophage - T lymphocyte system were evaluated in the regulation of lymphocyte proliferation using mice lacking histamine receptors.Mice deficient in histamine type 1 (H1R), type 2 (H2R) or both receptors were employed to estimate possible intervention of the receptors in the histamine-dependent lymphocyte proliferation.Histamine was produced de novo by spleen cells. Con A-dependent T cell proliferation decreased when histamine produced in the culture was degraded by the addition of histaminase. The H2R-deficient mice also showed a significant decrease in the Con A-dependent T cell proliferation, whereas it was not modulated in the H1R-deleted mice. Consistent with the reduction in T cell proliferation, there was a significant down-regulation of the production of IL-2, a T cell growth factor, in the H2R-deficient mice. Con A-dependent IL-2 synthesis was abrogated by the addition of histaminase.Con A-dependent T cell proliferation is (up)regulated by histamine produced de novo through the H2R, suggesting that histamine is a newly found regulator of T cell proliferation.

To evaluate left ventricular function during exercise after aortic annular enlargement 15 patients with either aortic (group I, n = 8) or aortomitral (group II, n = 7) annuloplasty for small aortic annuli and eight patients (group III) with standard valve replacement for aortic stenosis without small aortic annuli received gated cardiac pool imagining by technetium-99m-labelled red blood cells at rest and during exercise at a mean of 23 months after operation. Left ventricular ejection fraction, preload requitable stroke work and stroke power index (preload requitable stroke work/systolic ejection period) were measured. Compared with resting values, left ventricular performance and stroke work rate on exercise after aortic annular enlargements increased significantly, as did those after standard aortic valve replacement. These results suggest that aortic annular enlargement can be indicated for surgical treatment of valvular heart diseases associated with small aortic annuli.

A case of dense bone island in a girl aged 10 years, 1 month old is presented. The lesion was asymptomatic and was an incidental finding on a radiograph taken for another purpose. Nine months after the patient's first visit, an obvious inclination of adjacent teeth was identified. The size and density of the lesion had increased by 10 and 7%, respectively. As the patient was still in adolescence, the lesion may increase in size and density, potentially resulting in further problems such as increased inclination of the adjacent teeth. In addition, the presence of the lesion may complicate any future orthodontic treatment. The lesion should be kept under observation until its growth ceases.

For a pancreatic body or tail tumor, distal pancreatectomy with splenectomy (DPS) is a standard operation. Spleen-preserving distal pancreatectomy (SPDP) was introduced in order to preserve the organ and thus provide the patient with a better quality of life. Clinical data were compared between 38 Japanese patients with DPS and 9 with SPDP for benign tumors or tumor-like lesions at the body or tail of the pancreas at preoperative, early postoperative (3 months after operation), and late postoperative periods (6 months after operation). The preoperative findings were not different between the two groups except for the significantly higher serum amylase levels in the SPDP group. Operation time, operative blood loss, and length of postoperative hospital stay were not different between the two groups. Pancreatic fistula occurred in 3 (8%) of the 38 patients in the DPS group and in 1 (11%) of the 9 patients in the SPDP group, abdominal abscess in 5 (13%) of the 38 patients in the DPS group and none (0%) in the 9 patients in the SPDP group. At short-term, clinical findings were not different between the two groups except for a significantly greater platelet count in the DPS group than in the SPDP group (46.8 x 10(4)/microl versus 29.6 x 10(4)/microl, P = 0.0081). At long-term after the operation, clinical findings, including the platelet count, were not different between the two groups. Computed tomography revealed a pseudocyst in 9 (53%) of 17 patients examined in the DPS group and in 3 (75%) of 4 patients examined in the SPDP group at short-term after operation. All patients with pseudocysts were asymptomatic. Two asymptomatic patients (one in the DPS group and one in the SPDP group) first developed a pseudocyst at long-term after the operation. The alteration of glucose tolerance was similar between the two groups. Postoperative pancreatic exocrine function (the N-benzol-L-tyrosyl-p-aminobenzoic acid test) was not different between the two groups. These data suggest that SPDP with preservation of the splenic vessels can be satisfactorily performed without elongating operative time and postoperative hospital stay or increasing risk of postoperative complications, with the exception of increased platelet count in the DPS group at short-term after the operation. Thus, SPDP is worth considering as one of the options for the treatment of benign lesions of the body or tail of the pancreas.

In this report we describe the respiratory patterns of six patients with Leigh syndrome, including two individual cases with accompanying clinical phenotypes of Alpers disease and mitochondrial encephalopathy with ragged red fibers. In five cases where sleep apnea was monitored, each one showed isolated or post-sigh central apnea, hiccup, apneusis-like breathing and obstructive apnea in various combinations. The remaining patient with Alpers/Leigh overlap syndrome showed an apneusis-like pattern of dyspnea. The sleep structure was examined in three patients. Two patients with brainstem lesions showed a decrease in the deep sleep stages and an absence of REM sleep. Medullary lesions were found in four patients by magnetic resonance imaging or at autopsy and involved predominantly the dorsal respiratory group (DRG) of medullary neurons. The role of DRG lesions in the pathophysiology of respiratory symptoms in Leigh syndrome is discussed.

The dental basement membrane (BM) putatively mediates epithelial-mesenchymal interactions during tooth morphogenesis and cytodifferentiation. Type IV collagen alpha chains, a major network-forming protein of the dental BM, was studied and results disclosed distinct expression patterns at different stages of mouse molar germ development. At the dental placode and bud stage, the BM of the oral epithelium expressed alpha 1, alpha 2, alpha 5 and alpha 6 chains while the gubernaculum dentis, in addition to the above four chains, also expressed a 4 chain. An asymmetrical expression for alpha 4, alpha 5 and alpha 6 chains was observed at the bud stage. At the early bell stage, the BM associated with the inner enamel epithelium (IEE) of molar germ expressed alpha 1, alpha 2 and alpha 4 chains while the BM of the outer enamel epithelium (OEE) expressed only alpha 1 and a 2 chains. With the onset of dentinogenesis, the collagen a chain profile of the IEE BM gradually disappeared. Howeverfrom the early to late bell stage, the gubernaculum dentis consistently expressed alpha 1, alpha 2, alpha 5 and a 6 chains resembling fetal oral mucosa. These findings suggest that stage- and position-specific distribution of type IV collagen alpha subunits occur during molar germ development and that these changes are essential for molar morphogenesis and cytodifferentiation.

Four out of 522 streptococcal isolates from the peripheral blood of patients with bacteremia exhibited typical properties of Streptococcus mutans in terms of sucrose-dependent adhesion, expression of glucosyltransferases, fermentation profiles of sugars, the presence of surface protein antigen, and DNA-DNA hybridization. Two strains were determined as serotype f and e by immunodiffusion, whereas the other two isolates did not react with the specific antiserum to S. mutans serotype c. e. or f of the eight different serotypes of mutans streptococci. The latter two untypable isolates, however, expressed a new antigenic determinant that was different from serotype c/e/f specificity as revealed by immunodiffusion. Analysis of the cell wall polysaccharides revealed very low contents of glucose in the untypable isolates. Furthermore, Southern blot analysis demonstrated that the untypable strains lacked at least one gene corresponding to a glucose-adding enzyme. These results indicate that the serologically untypable nature is due to the loss of glucosidic residue from the serotype-specific polysaccharide antigens of S. mutans.

With the concept of less invasive surgery, PpPD (pylorus-preserving pancreatoduodenectomy) has taken the place of conventional Whipple pancreatoduodenectomy (Whipple) as a standard operation for pancreatic head carcinoma. The aim of this paper is to compare early and late postoperative results of PpPD and Whipple for pancreatic head carcinoma.Postoperative clinical follow-up data and outcome of 50 Japanese patients with pancreatic head carcinoma who underwent pancreatoduodenectomy with or without pylorus preservation were reviewed to scrutinize the demerits and merits of the pylorus preservation.Preoperative and postoperative serum chemistry was not different between the two groups. Mean operation time of the Whipple group was 517 minutes, which was significantly shorter than 624 minutes of the PpPD group (P = 0.0006). Cumulative stage was not different between the two groups. Cumulative curability of the PpPD group was superior to the Whipple group; of the 27 patients with Whipple, A in 4, B in 5 and C in 18, while of the 23 patients with PpPD, A in 12, B in 2 and C in 9 (P = 0.0182). Gastric tube was removed on POD 6.0 in the Whipple group, while on POD 39 in the PpPD group (P0.0001). Oral intake was started on POD 14.0 in the Whipple group, while on POD 28.3 in the PpPD group (P = 0.0018). Discharge was on POD 57.8 in the Whipple group, while POD 86.9 in the PpPD group (P = 0.0023). At the time of discharge and postoperative 6, 12, and 18 months, body weight loss from the preoperative level was 1kg smaller in the PpPD group than in the Whipple group. 1-year and 3-year survival rates of the Whipple group was 53.8% and 15.8%, while 62.8% and 19.6% of the PpPD group, showing no significant difference.These data show that delayed gastric emptying is evident in the PpPD group, resulting in longer hospital stay, while long-term body weight loss is smaller in this group. The clinical outcome is similar between the two groups. PpPD can be accepted as a standard operation for pancreatic head carcinoma.

We examined the indication of upper mediastinal lymphadenectomy for a squamous cell carcinoma of the lower thoracic oesophagus.49 patients underwent a curative oesophagectomy with upper mediastinal lymphadenectomy for a squamous cell carcinoma of the lower thoracic oesophagus. Node status and clinicopathological characteristics of these patients were reviewed retrospectively.16 (94.1%) of 17 patients with superficial tumours had no positive node in the upper mediastinum. Nine (29.0%) of 31 patients with transmural tumours had positive nodes in the upper mediastinum (P = 0.04). Ten (20.4%) of 49 patients had many positive nodes in the upper mediastinum. Of these 10 patients, 6 patients had 5 or more positive nodes in all. The 5-year survival rate for patients with 5 or more positive nodes was 7.7%, which was significantly poorer than patients with 4 or fewer positive nodes.Upper mediastinal lymphadenectomy is unnecessary in most of the superficial squamous carcinomas of the lower thoracic oesophagus.

Advanced glycation end products (AGEs) are a risk factor for diabetic complications. We have developed an assay method for N-(carboxymethyl)valine (CMV) of the hemoglobin (CMV-Hb), which is an AGE generated from HbA1c. Herein we describe the clinical utility of CMV-Hb measurement for the diagnosis of diabetic nephropathyBALB/c mice were immunized with carboxy-methylated Hb and monoclonal antibody raised against CMV-Hb. This antibody was characterized by a surface plasmon resonance. We developed a latex immunoassay using the antibody and measured CMV-Hb from erythrocytes in type 2 diabetic patients and healthy control subjects (age 64.6 +/- 12.0 vs. 61.1 +/- 13.2 years, NS: HbA1c 69 +/- 1.5 vs. 5.2 +/- 0.4%, P0.0001).A monoclonal antibody against CMV-Hb beta-chain NH2-terminal and an assay method for measurement for CNMV-Hb were both developed in our laboratory. CMV-Hb levels were significantly greater in the diabetic patients than in the control subjects (18.2 +/- 6.9 vs. 12.7 +/- 0.9 pmol CMV/mg Hb, P0.0001). No correlation was found between CMV-Hb and HbA1c or CMV-Hb and glycated albumin. Levels of CMV-Hb increased as the diabetic nephropathy progressed.We established an assay method for CMV-Hb and confirmed the presence of CMV-Hb in circulating erythrocytes. CMV-Hb was more prevalent in diabetic patients than in healthy subjects. Furthermore, it was significantly higher in patients with diabetic nephropathy, suggesting that the presence of CMV-Hb may be a valuable marker for the progression of diabetic nephropathy.

Less invasive pancreatic head resection, such as pylorus preserving pancreatoduodenectomy (PPPD) and duodenum preserving pancreatic head resection (DPPHR) has been introduced for the treatment of pancreatoduodenal lesions, especially for benign conditions, in consideration of postoperative quality of life. Surgical stress and exocrine and endocrine function of the residual pancreas were examined in 44 patients with PPPD, 10 with conventional pancreatoduodenectomy (PD) and six with DPPHR. Clinical findings including serum levels of C reactive protein (CRP), fasting blood sugar, a 120-min value of the 75-g oral glucose tolerance test (OGTT), N-benzol-L-tyrosyl-p-aminobenzoic acid (BT-PABA) excretion value (a pancreatic exocrine function test), and volume of postoperative pancreatic juice drainage were compared among the three different variants of pancreatectomy. Operation time and operative blood loss in PD were largest of the three, followed by PPPD and DPPHR. Postoperative elevation of serum CRP on postoperative day (POD) 2 or 3 was similar among the three different types of operation. Fasting blood sugar concentrations were not different among the three groups at short- and long-term after the operation, while the 120-min value of the GTT showed a marked elevation at long-term only after PPPD. The volume of pancreatic juice drainage increased up to POD 4 and became constant thereafter. The total amount of pancreatic juice drainage from POD 4 to 13 was smallest in PD (637 ml) followed by PPPD (1,255 ml) and DPPHR (1,431 ml). The BT-PABA value declined after PD (-20.3%, P = 0.0437) and PPPD (-20.2%, P = 0.0239) at short term, but not after DPPHR (8.2%). These findings suggest that the early impairment of the pancreatic exocrine function after PD and PPPD but not after DPPHR may indicate that the invasiveness of pancreatic head resection to the pancreatic functions is greater in PD and PPPD than in DPPHR.

This paper describes definition and classification of Eating Disorders which centered on the atypical cases. Eating disorders in DSM-IV were further classified into 3 groups. Three groups were Anorexia Nervosa, Bulimia Nervosa and Eating Disorders Not Otherwise Specified. Binge Eating Disorders frequently transfer to obese patient. This disease entity become independent of Anorexia Nervosa and Bulimia Nervosa. Body weight changing trend evaluated not only cross section but also longitudinal observation. There are some experience cases which Anorexia Nervosa cause by diet therapy of obesity patient. A lot of Eating Disorder patients revealed atypical courses during clinical treatment. The symptom of disturbances in the way in which their body weight and sharp could not easy to confirm routine history taking. One type of eating disorders eat throughout the day with no planned mealtimes.

Because three-field dissection for esophageal carcinoma is one of the most invasive operations, this procedure should be selected only when strictly indicated; but there are no useful criteria for it. The goal of this study was to identify the useful clinicopathologic factors for indicating three-field dissection.In this study, we reviewed the survival of patients after three-field dissection and identified factors associated with metastases in cervical nodes (CN), especially internal jugular nodes and supraclavicular nodes. Eighty-six patients who underwent curative esophagectomy with three-field dissection for squamous cell carcinoma of the thoracic esophagus were enrolled in this study. Survival rates were compared with respect to the presence of nodal metastasis. The relationship between recurrent nerve nodal (RNN) involvement and CN metastasis (bilateral internal jugular nodes, supraclavicular nodes, or both) was examined. Clinicopathologic factors possibly influencing CN metastasis were studied by multivariate logistic regression analysis.The overall 5-year survival rate was 45.1%. The 5-year survival rate for patients without metastatic nodes was 67.5%, for patients with one to four metastatic nodes it was 53.1%, and for patients with five or more it was 9.1 %. The prognosis of those with five or more metastatic nodes was significantly poorer than those of the other two groups. In the positive-node group, the 5-year survival rate for patients with RNN metastasis was 21.7%, and for patients with negative RNN it was 47.0% (p = 0.2). In the positive-node group, the 5-year survival rate for patients with positive CN was 13.7% and for patients with negative CN it was 45.8% (p = 0.01). Fifty-six (88.9%) of 63 patients without RNN metastasis had no CN metastasis in contrast to 13 of 23 patients (56.5%) with RNN metastasis who had no CN metastasis (p = 0.001). The positive predictive value, negative predictive value, sensitivity, and specificity were 43.5%, 88.8%, 58.8%, and 81.2%, respectively. The number of metastatic nodes (5 or more versus 0-4) (odds ratio: 2.9, 95% Confidence Interval (CI) = 1.6-5.5, p = 0.0008) and RNN involvement (odds ratio: 4.5, 95% CI = 1.3-15.9, p = 0.02) were the significant factors associated with CN metastasis in the multivariate analysis.RNN involvement is associated with CN metastasis as is the number of metastatic nodes and may be an indicator for the selection of three-field dissection in thoracic esophageal carcinoma.

To evaluate the difference between benign proliferative lesions of regenerative bone calluses and malignant tumors in rats by simultaneous analysis of nuclear DNA content and size.Nuclei were stained with DAPI and measured by cytofluorometry. Five regenerative bones and five osteosarcoma samples were used. Two-dimensional dispersion diagrams between relative nuclear DNA content and nuclear size were drawn up and their regression lines were compared.It was possible to distinguish between osteosarcomas and regenerative bones by simultaneous analysis of nuclear size and DNA content during the cell cycle. The results yielded coefficients of correlation and regression. All five regression lines of osteosarcomas were situated dramatically higher on dispersiongrams than those of regenerative bones.Differential diagnosis between regenerative lesions and malignant tumors may now be possible using simultaneous measurement of nuclear DNA content and size.

To establish a suitable method for measurement of nuclear DNA content in breast tissues from frozen storage after frozen section diagnosis.For fundamental research, rat liver samples preserved in a deep freezer were used. Four protocols were used (1. fixation with 70% ethanol followed by naked nuclei preparation; 2. fixation with 10% neutral buffered formalin followed by naked nuclei preparation; 3. preparation for naked nuclei prior to fixation with 70% ethanol; and 4. preparation for naked nuclei prior to fixation with 70% neutral buffered formalin). For clinical research, 13 separate fresh frozen breast tissue samples were analyzed after frozen section diagnosis. One contained a malignant phyllodes tumor (MPT) consisting of 2 components, benign epithelial cells and malignant stromal cells; 3 were benign tumors containing fibroadenoma; and 9 cases were carcinomas, consisting of 5 scirrhous, 3 papillotubular and 1 mucinous.Protocols 1, 2 and 3 were not suitable methods for our purpose because remaining cytoplasm or cohesive nuclei were observed. In protocol 4 the cytoplasm was completely undetectable, and nuclei were suitably separated for nuclear DNA content measurement. Benign epithelial cell component nuclei presented a diploid pattern, and the malignant stromal cell component nuclei indicated a euploid pattern in MPT. All 3 cases of benign constituents in fibroadenoma showed a diploid pattern, as did the 3 carcinoma cases (1 mucinous, 1 scirrhous and 1 papillary). Four scirrhous and 2 papillary carcinomas showed an aneuploid pattern.Our findings show that it is possible to measure nuclear DNA content of human frozen storage tissues after frozen section diagnosis.

Significance of three-field lymhpadenectomy for carcinoma of the thoracic esophagus was examined retrospectively based on depth of tumor infiltration, lymph nodal involvements and long-term survival.One hundred and fifty-two consecutive patients who underwent curative esophagectomy for thoracic carcinoma invading to submucosa (pT1) or deeper layers of the esophageal wall from 1983 to 1996 were examined. Sixty-six patients underwent three-field lymphadenectomy (3F) and 86 underwent two-field lymphadenectomy (2F). Survival curves were compared between 3F and 2F after stratifications according to depth of tumor infiltration, the number of positive nodes (0, 1 to 4, 5 or more), and positive intrathoracic recurrent nerve-chain nodes.Overall 5-year survival rate for 3F was 43.8%, while it was 30.2% for 2F (p = 0.07). In 41 patients with pT1 cancers, the 5-year survival rate for 3F was 55.7%, while it was 41.4% for 2F (p = NS). In patients with cancers invading to muscularis propria (pT2), the 5-year survival rate for 3F was 49.4%, while it was 30.7% for 2F (p = 0.06). In patients with tumors invading to adventitia, there was no significant difference. In patients with one to four positive nodes, the 5-year survival rates for 3F was 50.1%, while it was 24.1% for 2F (p = 0.01). There was no significant difference in the subgroups with no positive nodes and five or more. In subgroups with positive recurrent nerve-chain nodes, the 5-year survival rate for 3F was 27.9%, while it was 0% for 2F (p = 0.01).Significance of three-field lymphadenectomy was found in patients with one to four positive nodes or positive intrathoracic recurrent nerve-chain nodes.

The Src protein tyrosine kinase is overexpressed and activated in a number of human cancers, including some human ovarian cancers. To determine whether Src activity plays a role in ovarian tumor growth, stable derivatives of the SKOv-3 human ovarian cancer cell line that exhibited reduced Src tyrosine kinase activity were generated by transfection with an antisense c-src construct. Comparison of these cell lines with parental SKOv-3 cells and stable sense c-src vector-transfected control lines revealed no phenotypic alterations in anchorage-dependent proliferation, adherence, density saturation, or wound migration. However, reduction in Src activity was associated with altered cellular morphology, dramatically reduced anchorage-independent growth, and, when assessed for tumor development in a xenograft nude mouse model, diminished tumor growth. Furthermore, reduction of Src activity in the antisense c-src cell lines was associated with reduced vascular endothelial growth factor mRNA expression in vitro, and tumors derived from these cell lines displayed a phenotype indicative of abortive microvessel vascularization. These results strongly suggest that Src is involved in critical oncogenic pathways that modulate tumor growth from this ovarian cell line. Furthermore, this evidence suggests that as in other tumor systems, Src activity is required for vascular endothelial growth factor induction and angiogenic development.

We undertook a retrospective study of elderly patients with stage III non-small cell lung cancer who had been treated solely with radiotherapy during the period 1986 to 1995. Our study was designed to assess the influence of age on survival and malnutrition in patients aged 75 years or older (elderly group) and patients aged 74 years or younger (younger group). Radiotherapy alone resulted in a median survival period of 11.5 months in the younger group and 6.3 months in the elderly group (p = 0.0043). With the Cox multivariate model, good performance status, age less than 75 years, and good response were significant favorable independent predictors. Furthermore, the elderly group patients more frequently died of respiratory infections and had lower prognostic nutritional indexes than the younger group patients before and after radiotherapy. These findings suggested elderly patients with stage III non-small cell lung cancer who had been treated with radiotherapy alone had a poor prognosis and that malnutrition caused by radiotherapy was a factor contributing to the risk of death from respiratory infection in such patients.

Malaria is relatively rare in Japan. Of 13 patients referred to our laboratory for malarial screening in the past 4 years, malarial parasites were detected in 8. Conventional screening procedures commonly detect hepatic dysfunction, thrombocytopenia, elevated LDH activity, and increased CRP levels in malaria patients. More notably, the 8 malaria patients identified by our laboratory also demonstrated reactive lymphocytosis. In the absence of additional clinical information, reactive lymphocytosis alone may be enough to warrant laboratory blood smear tests on the suspicion of malaria. Conventional microscopic methods have often proved inconclusive in identifying malarial parasite species or detecting mixed infections. However, by combining the methods of DNA analysis with those of microscopy, we were able to conclusively diagnose all cases of suspected malaria. As a test of their skills, 9 laboratory technicians relatively inexperienced with malarial parasites were asked to screen 6 samples: 3 containing malarial parasites, and 3 that were malaria-free. Although none of the technicians were able to accurately identify the samples without additional clinical information, 4 accurately identified all malarial samples when that information was provided. Experience is a crucial determinant of ability to detect malarial parasites by microscopic methods alone. Nonetheless, the findings of our study suggested the diagnostic accuracy of laboratory screening procedures for malaria can be significantly improved if combined with minimal clinical data and the techniques of DNA analysis.

The patient, a 42-year-old woman, was admitted to our hospital because of abnormal shadows on chest X-ray films obtained during a routine medical check-up. Her medical history included a uterine myomectomy at the age of 21, and thereafter, periodic lumbago and back pain for which she had not sought any medical treatment. Chest computed tomography detected a number of pulmonary nodules in both whole lung fields, and magnetic resonance imaging revealed many spherical metastatic lesions in the thoracic and lumbar vertebrae. Although we initially suspected lung cancer, no primary lesion was found. A thoracoscopic lung biopsy revealed leiomyomatous tumors that were histologically similar to the uterine myoma removed 21 years previously. The final diagnosis was so-called benign metastasizing leiomyoma (BML). Because the removed tumor contained a high concentration of progesterone receptors (240 fmol/mg), a gonadotropin-releasing hormone analogue was administered, and proved effective in relieving the patient's periodic lumbago and back pain. The findings in this case suggested that the so-called BML was in fact a metastasis of a low-grade uterine leiomyosarcoma.

Atrial fibrillation (AF) is a relatively common complication in elderly patients with an atrial septal defect (ASD). However, use of the simultaneous maze procedure for AF associated with ASD remains controversial. We examined the efficacy and risk of the use of the maze procedure in these patients.Between March 1992 and April 1997, 26 patients underwent the maze procedure as a concomitant operation with ASD closure (maze group). Kosakai's modified maze procedure was performed in 17 patients, the modified Cox maze II or III procedure was performed in 6, and the restrictive right-sided maze procedure was performed in 3. The mean +/- SD age at surgery was 58.2 +/- 9.1 years. The mean +/- SD duration of AF was 7.8 +/- 8.5 years. The mean +/- SD left atrial dimension was 47 +/- 9 mm, and 24 patients (92%) had a larger-than-normal (35 mm) left atrium. The mean +/- SD follow-up period was 2.7 +/- 1.7 years. There were no hospital or late deaths. There was no thromboembolic episode in the late follow-up period. Sinus rhythm was regained in all patients who underwent conventional the right- and left-sided maze procedure except for 1 patient. However, 3 patients who underwent the restrictive right-sided maze procedure showed a return to AF rhythm. The atrial A wave was detected with the use of pulsed Doppler study in all patients who had a restored sinus rhythm. During the same period, 45 patients who were40 years old and without AF underwent only ASD closure (control group). The incidence of reopening the chest for bleeding was significantly (P = 0.046) higher in the maze group (12%) than in the control group (0%). Paroxysmal AF more frequently (P = 0.023) occurred in the control group (18%) than in the maze group (0%).These results suggest that the standard maze procedure should be considered in patients with AF associated with ASD. The restrictive right-sided maze procedure was not reliable, probably due to preoperative enlargement of the left atrium.

To evaluate whether or not the combination of sagittal and coronal spin-echo (SE) T1 and sagittal gradient echo (GRE) T2* weighted imaging is adequate to diagnose internal derangement of the knee, a study was done in 300 knees of 293 consecutive patients who underwent both MR imaging of the knee and arthroscopy. In prospective analysis, the MR imaging had an accuracy, sensitivity and specificity of more than 90% in the evaluation of medial meniscus (MM) and of 97% in the evaluation of anterior cruciate ligament (ACL). In the evaluation of lateral meniscus (LM), accuracy was 83%, sensitivity 76%, and specificity 88%. In a review of false-negative MR diagnoses (n = 42) of menisci, the most significant lesion was not in the meniscus but in the ACL in 32 knees (76%). Conservative treatment was selected in 25 knees (60%), rather than partial meniscectomy (n = 13) or meniscoresis (n = 4). There were 21 false-positive MR diagnoses of menisci even in retrospective analysis, and 17 of them (81%) had findings of tear in the posterior zone, which is known to be a difficult area for arthroscopic examination. The results were similar to those of other authors' with SE T1 and/or proton density and T2 weighted images. The combination of sagittal and coronal SE T1 and sagittal GRE T2* weighted images could be sufficient as a routine MR protocol for diagnosing the internal derangement of the knee.

From April 1993 to May 1997, 21 patients underwent surgical treatment for prosthetic valve endocarditis (PVE). There were 13 males and eight females aged from 46 to 79 years old (mean 62 years). There were four cases of early PVE (onset of PVE within 60 days from previous valve replacement), and 17 cases of late PVE (after 60 days). The predominant organisms were Staphylococcus epidermidis (eight cases), Staphylococcus aureus (two cases), MRSA (one case), streptococcal species (three cases), Candida (two cases), Pseudomonas cepacia (one case) and Enterococcus (one case). The predominant organisms were identified in 16 of 20 cases by preoperative blood culture, and in 11 of 20 cases by intraoperative tissue culture, and in 19 cases in all. There were four cases of preoperative cerebral complications, and three cases resurged. The hospital mortality rate was 24% (five patients). Reoperation was required in four patients for recurrence of PVE. Autopsy was performed in four of five patients. Intramyocardial abscess was detected in three patients. Earlier diagnosis and earlier surgical treatment could prevent emboli due to vegetations, which might cause catastrophic results, and could achieve better outcomes. Identification of the predominant organisms, especially from operative tissue cultures, is required.

Crossline is a novel advanced glycation endproduct (AGE) which has both a crosslink and fluorescence similar to AGE-protein in vivo. To assess the association of AGEs to the development of diabetic retinopathy we developed a sensitive and specific enzyme-linked immunosorbent assay (ELISA) for crossline in blood samples and investigated the association of the development of retinopathy and erythrocyte membrane protein (EMP)-crossline concentrations in patients with Type 2 diabetes mellitus (Type 2 DM). Crossline formation in EMP exceeded that in haemoglobin and was detectable in normal EMP samples without pretreatment by this ELISA system. Mean (+/-SE) EMP crossline levels were elevated 1.6-fold in diabetic patients without retinopathy (7.6 +/- 0.5 pmol mg(-1), p0.005), 2.2-fold in diabetic patients with non-proliferative retinopathy (10.5 +/- 0.6 pmol mg(-1), p0.001) and 2.6-fold in diabetic patients with proliferative retinopathy (12.0 +/- 0.6 pmol mg(-1), p0.001) compared with healthy control subjects (4.7 +/- 0.5 pmol mg(-1)). Type 2 DM patients with retinopathy had significantly higher EMP-crossline levels than those without retinopathy (p0.005). Our data suggest that elevated EMP-crossline concentrations are associated with the presence of retinopathy in patients with Type 2 DM and EMP-crossline measured by our ELISA may provide a useful marker for assessing the role of glycation in the development of diabetic retinopathy.

We have carried out the maze procedure for atrial fibrillation (AF) as a combined operation with mitral valve surgery in a consecutive fashion until December 1994 (period 1). Therefore, the success rate in sinus rhythm conversion remained unsatisfactory. We have selected the patients according to arbitrarily decided new criteria since January 1995 (period 2), and examined the results prospectively.Between May 1992 and February 1997, we carried out the maze procedure in 220 patients as a combined operation with mitral valve surgery. During period 2, we carried out the maze procedure in 63 cases who satisfied all the new criteria (voltage of f-wave in V1 lead0.1 mV, cardiothoracic ratio (CTR)70%, LA dimension70 mm), and 37 patients out of these criteria. Success was defined as sinus rhythm restoration without sick sinus syndrome.There were 4 hospital deaths (1.8%) and 4 late deaths (1.8%). Success rate was significantly (P = 0.0089) higher in period 2 (82%) than in period 1 (65%). Success rate was significantly higher in patients within criteria than out of criteria both in period 1, period 2, and total (77 versus 48%, P = 0.018; 90 versus 66%, P = 0.004, and 83 versus 55%, P = 0.0001).The maze procedure is highly reliable when combined with mitral valve surgery if patients are selected properly.

The contribution of the polymorphism of complement C4A and C4B alleles to the pathogenesis of systemic sclerosis (SSc) was studied in Japanese patients.C4A and C4B typing was carried out in 44 SSc patients and in 83 normal subjects using electrophoresis followed by immunofixation and immunoblotting. HLA-DR typing and HLA DRB1*15 and *08 genotyping were carried out by the PCR method and the PCR-SSCP method, respectively.In SSc with diffuse scleroderma, the frequency of C4BQ0 was significantly increased (44.4%, p0.001, pc0.01). In SSc with antitopoisomerase I antibody (a-Scl-70) C4BQ0 was also increased (50.0%, p0.001, pc0.01). Association analysis indicated that the increase in C4BQ0 was not primary but reflected an increase in HLA-DRB1*1502. In contrast, C4A/Q0 was significantly increased in limited scleroderma (53.8%, p0.005, pc0.05) and SSc without a-SCL-70 (53.8%, p0.005, pc0.05).Diffuse scleroderma with SSC with a-Scl-70 have different genetical backgrounds from limited scleroderma and SSc without a-Scl-70, respectively, in Japanese patients. C4AQ0 were independent genetic markers for each clinical subgroup and for a a-Scl-70 positivity.

We report a pilot study of three oral doses of coenzyme Q10 (CoQ10) (200 mg administered two, three, or four times per day for 1 month) in 15 subjects with Parkinson's disease. Oral CoQ10 caused a substantial increase in the plasma CoQ10 level. It was well tolerated, but at the highest dose (200 mg four times per day) mild, transient changes in the urine were noted. CoQ10 did not change the mean score on the motor portion of the Unified Parkinson's Disease Rating Scale. There was a trend toward an increase in complex I activity in the subjects.

Diabetes mellitus positive for antibodies to glutamate decarboxylase is heterogeneous as far as the degree of impairment of endogenous insulin release, though antibodies to glutamate decarboxylase are the most useful marker for future insulin deficiency. To investigate what determines the prognosis of diabetes mellitus positive for antibodies to glutamate decarboxylase, we measured HLA-DRB1 alleles in three groups: 77 cases of insulin-dependent diabetes mellitus (IDDM), 44 of non-insulin-dependent diabetes mellitus (NIDDM) with secondary failure of oral hypoglycemic therapy, and 22 of NIDDM well controlled by diet and/or sulfonylurea agents. The proportion of susceptible and resistant alleles to IDDM determined the degree of insulin deficiency, and comparison of IDDM to NIDDM well controlled by diet and/or sulfonylurea agents revealed significant differences in DRB1*0405 (P0.05; RR = 2.82 and RR = 0.89, respectively) and DRB1*1502 (P0.001; RR = 0.02 and RR = 2.19, respectively). This study revealed that HLA-DRB1 alleles contribute to determining the prognosis of Japanese diabetes mellitus positive for antibodies to glutamate decarboxylase.

In terms of valve-related complication and ventricular function, mitral valve repair (MVR) is superior to valve replacement. To date, chordae shortening and transposition have been used for diffuse prolapses. We have used artificial chordae implantation for MVR since 1986, and here review our long-term results.Pericardial strips were used in nine patients, and e-PTFE (Gore-Tex) sutures in 58. A degenerative lesion was present in 69% of cases, endocarditis in 16% and rheumatic valvulitis in 7%. Implantation of artificial chordae was indicated for treatment of diffuse prolapse. Annuloplasty was performed in patients with or without prosthetic ring.Actuarial survival rate was 78% for the pericardial chordae group at nine years, and 94% for the Gore-Tex chordae group at eight years. Thromboembolic events occurred in two pericardial chordae patients, and three Gore-Tex chordae patients required reoperation. Freedom from reoperation was 100% for pericardial chordae after nine years and 96% for Gore-Tex chordae after eight years. Quality of life among survivors is good: 83% are in NYHA class I, 89% are free from anticoagulation, and 60% require no medication. Mitral valve orifice area, estimated echocardiographically, was similar in both groups at discharge and at follow up.MVR with artificial chordae provided satisfactory valve function for up to nine years. Gore-Tex chordae are less prone to deterioration than pericardial chordae. Follow up observations support the use e-PTFE chordae to correct diffuse leaflet prolapse.

Mitral valvuloplasty (MVP) for the prolapse of the anterior mitral leaflet (AML) is more difficult than that for the posterior mitral leaflet. The introduction of artificial chordae (November, 1986) and the concomitant maze operation (November, 1992) were surgical 'turning points' in our 17 years' experience.In total, 163 surgical cases of AML prolapse based on the above turning points, and carried out between 1979 and 1996, were reviewed. These included 110 MVP and 53 mitral valve replacements. MVP was performed in only 46% (29/63) of patients before October 1986 (Group I); in 72% (42/58) of patients between November 1986 and October 1992 (Group II); and in 93% (39/42) of patients after November 1992 (Group III).Reoperation was required in nine patients. The reoperation-free rate after MVP was 79% at 17 years in all cases, 82% at 17 years in Group I, 86% at 10 years in Group II and 97% at four years in Group III. Besides reoperation cases, grade 3/4 mitral regurgitation (MR), assessed by color Doppler echocardiography, was detected in seven patients. The event-free (reoperation, MR, thromboembolism) rate was 69% at 17 years in all cases, 78% at 17 years in Group I, 71% at 10 years in Group II and 92% at 4 years in Group III. A concomitant maze operation was performed in 19 of 20 current patients with atrial fibrillation. The percentage of sinus rhythm after operation in Group I, II and III was 53%, 60% and 84%, respectively.During 17 years' experience, mortality and morbidity after MVP for AML prolapse were satisfactory. With the use of artificial chordae, we have been able to perform MVP in more than 90% of current patients with AML prolapse. Further, a concomitant maze procedure could provide a higher incidence of postoperative sinus rhythm.

Between January 1993 and June 1996, 108 patients with non-rheumatic mitral regurgitation (MR) underwent surgical treatment. Mitral valvuloplasty (MVP) was performed in 94 patients (87%) and mitral valve replacement (MVR) was performed in 14 patients. The patients were reviewed based on the location of the prolapse, active endocarditis, and re-valvuloplasty. The proportion of MVP patients to the total number of cases was 92%, 96% and 94% for prolapse of the anterior mitral leaflet (MVP: n = 22), the posterior mitral leaflet (n = 47) and of both leaflets (n = 15), respectively; it was 60% and 33% in the patients with active infective endocarditis (n = 3) and in reoperation cases (n = 3). Reoperation was required in 2 patients. Other than reoperation cases, 3/4 grade MR was detected by color Doppler echocardiography in 6 patients although they were asymptomatic. Thromboembolism occurred in 3 patients. The event-free rate at 42 months was 80.4%. Concomitant maze procedure was performed in 36 of 39 patients with atrial fibrillation and normal sinus rhythm was obtained in 25 of the 36 patients. Only 6 patients received warfarin anticoagulation after MVP. In current cases with non-rheumatic MR, the MVP could be performed in 87% of all patients and in 94% of the patients with simple prolapse, regardless of the prolapse area. Concomitant maze procedure might provide a better quality of life after MVP.

Little comparative information exists on the outcome of the valve replacement with bioprostheses or mechanical valves in the elderly. This study was carried out to make such a comparison.Follow up data were examined from 219 patients agedor = 65 years who underwent aortic and/or mitral valve replacement using bioprosthetic (n = 67) or mechanical valve (n = 152) between April 1979 and December 1993. The mean follow up periods were 6.3 +/- 2.8 years after bioprosthesis and 4.9 +/- 2.1 years after mechanical valve implantation.Although the actuarial rate of structural deterioration was higher in patients with bioprosthetic valves than in those with mechanical valves (58% versus 100% freedom at 10 years after surgery, p0.01), no such prosthesis-related difference was seen in the subgroup of patients agedor = 70 (100% versus 100% at nine years, p = N.S.). The actuarial rate of major bleeding was higher after mechanical valve implantation than after bioprosthetic valve placement (90% versus 100% freedom at 10 years, p0.05); this lower rate with bioprosthetic valves was maintained in patients agedor = 70 (78% versus 100% at nine years, p0.05). There were no significant differences in the incidences of thromboembolism and bacterial endocarditis between the two valve types.Structural degeneration of bioprosthetic devices was a major problem in patients aged 65-70 years, but it was essentially negligible in those agedor = 70 years. Anticoagulant-related bleeding was a major problem with mechanical valves in both age groups. Therefore, for patients older than 70 years, valve replacement with a bioprosthesis appears to be the method of choice.