Search

Pharmacogenetics is the relationship between an individual’s genetic variations and their response to pharmacological treatment. We conducted an overview of reviews on the use of post-treatment pharmacogenetic testing for oncology, based on clinically relevant gene–drug pairs. We conducted a search on Medline, Embase and Cochrane Library, from their inception to 18 June 2020. We selected six eligible systematic reviews. The most studied drug categories were estrogen agonists/antagonists and fluoropyrimidines associated with cytochrome P450 and dihydropyrimidine dehydrogenase genes ( CYP2D6 and DPYD), but many studies were classified as being of critically low or low quality. There is a need for more high-quality primary studies and systematic reviews that assess the risk of bias, with consistent definitions of clinical outcomes to consider the benefits of pharmacogenetic testing for oncology.

The aim of this study was to evaluate the pharmacokinetic profile of daclatasvir (DCV) and asunaprevir (ASV) dual therapy in haemodialysis patients infected with hepatitis C virus (HCV). Eighteen haemodialysis patients and 54 patients with normal renal function were treated with DCV and ASV dual therapy for 24 weeks. We evaluated the pharmacokinetic profiles of DCV and ASV and examined the rate of sustained virological response 12 weeks after the end of treatment (SVR12 ) and incidence of adverse events during treatment of haemodialysis patients infected with chronic HCV genotype 1 infection. To adjust for potential differences in baseline characteristics between haemodialysis patients and patients with normal renal function, we used propensity scores case-control matching methods. Area under the plasma concentration time curve from 0 to 6 h (AUC0-6 h ) of DCV was slightly lower in haemodialysis patients than in patients with normal renal function (P > 0.6). AUC0-6 h of ASV was significantly lower in haemodialysis patients (P = 0.012). SVR12 rates were 100% (18/18) for haemodialysis and 96.2% (52/54) for patients with normal renal function. Changes in mean log10 HCV RNA levels and viral response were higher in haemodialysis patients compared to patients with normal renal function. No discontinuations due to adverse events occurred. In conclusion, DCV and ASV dual therapy for HCV infection is effective and safe with similar results in haemodialysis patients compared to patients with normal renal function.

Summary Chronic HCV–infected patients tend to have vitamin D deficiency, suggesting that vitamin D supplementation may enhance the efficacy of treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV). We therefore assessed the effects of vitamin D supplementation on viral response to PEG-IFN/RBV. Eighty-four patients with HCV genotype 1b were randomized, 42 to oral vitamin D supplementation (1000 IU/day) and 42 to nonsupplementation (control), from week 8 to the end of PEG-IFN/RBV therapy. The primary end point was undetectable HCV RNA at week 24 (viral response [VR]). VR rate at week 24 was significantly higher in the vitamin D than in the control group (78.6% vs 54.8% P = 0.037). Adverse events were similar in both groups. When patients were subdivided by IL28B SNP rs8099917 genotype, those with the TT genotype group showed a significantly higher VR rate at week 24 with than without vitamin D supplementation (86.2% vs 63.3% vs P = 0.044). Although patients with the TG/GG genotype, who were relatively resistant to PEG-IFN treatment, had similar VR rates at week 24 with and without vitamin D supplementation, the decline in viral load from week 8 to week 24 was significantly greater with than without vitamin D supplementation. Multivariate analysis showed that rs8099917 genotype and vitamin D supplementation contributed significantly to VR at week 24. SVR rates were similar in the vitamin D and control groups [64.3% (27/42) vs 50% (21/42), P = 0.19]. Vitamin D supplementation may enhance the effects of PEG-IFN/RBV in HCV genotype 1b–infected patients.

Human papillomaviruses (HPV) are double-stranded DNA viruses, which selectively infect keratinocytes in stratified epithelia. After an initial infection, many patients clear HPV. In some patients, however, HPV persist, and dysfunctional innate immune responses to HPV infection could be involved in the ineffective clearing of these viruses. In this study, the mechanisms of HPV-induced immune responses in keratinocytes were investigated. Binding of viral DNA leads to AIM2 inflammasome activation and IL-1β release, while IFI16 activation results in IFN-β release. Using immunohistochemistry, AIM2 and IFI16-two recently identified sensors for cytosolic DNA-were also detected in HPV positive skin lesions. CISH stainings further confirmed the presence of cytosolic HPV16 DNA in biopsy samples. Moreover, active IL-1β and cleaved caspase-1 were detected in HPV infected skin, suggesting inflammasome activation by viral DNA. In subsequent functional studies, HPV16 DNA triggered IL-1β and IL-18 release via the AIM2 inflammasome in normal human keratinocytes. Although HPV DNA did not induce IFN-β in keratinocytes, IFN-β secretion was observed when AIM2 was blocked. Meanwhile, blocking of IFI16 increased HPV16 DNA-induced IL-1β, but not IL-18, secretion. These findings suggest crosstalk between IFI16 and AIM2 in the immune response to HPV DNA. In sum, novel aspects concerning HPV-induced innate immune responses were identified. Eventually, understanding the mechanisms of HPV-induced inflammasome activation could lead to the development of novel strategies for the prevention and treatment of HPV infections.

Hepatitis C virus (HCV) subtype 1b, which infects approximately 70% of Japanese carriers, is likely to be more eradicable by a telaprevir regimen than subtype 1a because of the higher genetic barrier of Val(36) and Arg(155) substitutions. The aims of this exploratory study were to evaluate the virological response and safety of 24-week oral administration of telaprevir alone in chronic HCV subtype 1b infection. Fifteen treatment-naive patients were treated with telaprevir 750 mg every 8 h for 24 weeks. All patients were Japanese whose median age was 58.0 years (range: 45-68), and six patients (40%) were men. Median baseline HCV RNA level was 6.80 log(10) IU/mL (range: 3.55-7.10). The HCV RNA levels decreased to undetectable in five patients (33%) within 8 weeks. Three patients (20%) with negative HCV RNA by Week 4 achieved end of treatment response. One patient (7%) who achieved sustained virological response had a low baseline viraemia of 3.55 log(10) IU/mL. Most of the adverse events including anaemia and skin disorders were mild to moderate. Developed variants were T54A and A156V/T/F/Y with or without secondary substitutions rather than V36M ± R155K. Telaprevir alone for 24 weeks in Japanese patients with HCV subtype 1b resulted in an sustained viral response rate of 7% (1/15) and was well tolerated for 24 weeks. These results will support the implementation of further studies on oral combination of telaprevir with other direct-acting antiviral agents in patients infected with HCV subtype 1b.

To compare visual acuity and ocular higher-order aberrations (HOAs) in eyes with waterclefts, a type of crystalline lens opacity, and in normal eyes.Department of Ophthalmology, Kanazawa Medical University, Ishikawa, Japan, and Faculty of Medicine, University of Iceland, Reykjavik, Iceland.In this nested case-control study of subjects attending the third examination of the Reykjavik Eye Study in 2008, eyes with pure waterclefts and control eyes with no lenticular opacity were evaluated. All candidates had complete ophthalmic examinations and wavefront analysis. Higher-order aberrations in the watercleft group and the control group were compared.The watercleft group comprised 30 eyes and the control group, 194 eyes. The mean corrected distance visual acuity (CDVA) in the watercleft group was statistically significantly lower than in the control group (P.01). There was a significant relationship between CDVA and HOA in both groups. Total HOA and trefoil and coma aberrations were statistically significantly higher in the watercleft group than in the control group (P.05).Waterclefts significantly affected CDVA. Eyes with waterclefts had higher coma and trefoil aberrations, suggesting that the increased HOAs caused reduced visual acuity in eyes with waterclefts.

This study examined the influence of regular training in competitive cycling on individual muscle volume of the thigh and psoas major cross-sectionally and longitudinally. T1-weighted magnetic resonance (MR) images of the trunk and right thigh were obtained from eight experienced varsity male cyclists (experience: 4 years) and 10 untrained men (experiment 1), and from 12 (10 males, two females) varsity cyclists before and after competitive cycling training for 6 months (experiment 2). From the MR images, the volumes of each of the quadriceps femoris and hamstrings, total adductors, gracilis, sartorius, and psoas major were determined. The volumes of the monoarticular thigh muscles, semitendinosus, and psoas major muscles were significantly greater in the experienced cyclists than in the untrained men (experiment 1), and increased significantly after the competitive training for 6 months (experiment 2). In contrast, the volumes of the other biarticular thigh muscles were similar among the experienced cyclists and untrained men (experiment 1), and did not change by competitive cycling training (experiment 2). The results indicate that competitive cycling training induces muscle-specific hypertrophy of the synergistic muscles, especially between the monoarticular and biarticular muscles, leading to quantitative profiles of the musculature in experienced cyclists.

It is difficult to study the long-term outcome of hepatitis C virus (HCV) infection because chronic infection is often asymptomatic and duration of the disease is prolonged. The clinical outcome of HCV infection remains unclear in patients of advanced age.Among 575 patients consecutively diagnosed with hepatocellular carcinoma (HCC) from 1988 to 1999 at Hiroshima University, we examined 430 with HCV. We studied the differences between males and females in the following characteristics: age at first diagnosis of HCC, Child grade, various tumour factors, history of blood transfusion, duration to development of HCC, and history of alcohol intake.The incidence of HCC patients with HCV increased in elderly persons, including female patients. Background liver function was significantly better for female patients (P0.001). In both genders, the duration between blood transfusion and diagnosis of HCC was significantly shorter when the patients received blood transfusion at an older age (P0.001). In habitual drinkers, the average age at first diagnosis of HCC was significantly younger (P0.001), and duration to development of HCC significantly shorter (P0.05). The percentage of atomic bomb survivors among HCV-positive HCC patients was significantly higher than that among HCV-negative HCC patients (P0.05).Patients with HCV might exhibit slow disease progression and develop HCC finally with aging regardless of gender. Patients of advanced age with HCV, even female patients, should therefore be closely followed.

We previously reported our data on telaprevir (TVR) used in combination with pegylated-interferon and ribavirin (PEG-IFN/RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). TVR substantially increases the blood levels of immunosuppressive agents such as cyclosporine and tacrolimus for drug-drug interactions. On the other hand, the effect of simeprevir (SMV) on the blood levels of these immunosuppressive agents is unclear. We report 2 patients who achieved viral responses with little effect on the blood levels of cyclosporine and tacrolimus using SMV plus PEG-IFN/RBV treatment. The first was a 71-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. She was treated with 40 mg/d of cyclosporine, and received SMV plus PEG-IFN/RBV treatment. The second was a 65-year-old man with HCV-related liver cirrhosis who failed to respond to PEG-IFN/RBV after living donor LT. He was treated with 3 mg/d of tacrolimus, and received SMV plus PEG-IFN/RBV treatment. Serum HCV RNA became undetectable using TaqMan polymerase chain reaction (PCR) test after 4 weeks of treatment in both patients, and no remarkable fluctuation in blood concentration was observed either in cyclosporine or tacrolimus during the 12 weeks of SMV treatment. Completion of 12-week SMV triple therapy was followed by PEG-IFNα2b plus RBV, and both patients achieved sustained virological response 12 weeks after the end of treatment. SMV plus PEG-IFNRBV treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.

Persistent dry cough is an occasional but clinically important adverse reaction to angiotensin I-converting enzyme (ACE) inhibitors (ACEI). Its reported incidence is variable, and why cough occurs in only certain individuals has been unclear. An insertion/deletion (I/D) polymorphism of the ACE gene is associated with serum ACE activity. We have previously shown that susceptibility to cough induced by ACEI is associated with this polymorphism such that patients with genotype II are more susceptible to cough than patients with other genotypes. In order to confirm and extend our previous observation, we conducted a randomized, placebo-controlled, double-blind, cross-over study in 10 healthy volunteers with genotype II and 10 with genotype DD. The cough threshold was determined by the concentration of inhaled capsaicin causing two or more coughs. After the usage of an ACEI, cilazapril, for 4 weeks, changes in the cough threshold in subjects with genotype II [before: 6.6+/-3.7 nM (mean+/-SD); after: 5.0+/-4.6 nM] significantly differed from those in subjects with genotype DD (before: 9.0+/-9.4 nM; after: 9.3+/-9.1 nM). Skin responses to intradermal bradykinin, which is a substrate of ACE and tussigenic, were significantly increased in subjects with genotype II (before: 1.6+/-0.6 vs. after: 2.6+/-0.5 cm2, P

The effect of macrophage-colony stimulating factor (M-CSF), which regulates the growth and differentiation of haematopoietic progenitor cells on the growth of ovarian cancer cells was investigated in three ovarian cancer cell lines in vitro . The spontaneous growth of these cells was significantly inhibited by the addition of M-CSF in a concentration-dependent manner over 96 h of culturing. The maximum response was obtained with 10 ng/ml (3857 U/ml) of M-CSF by counting the viable cell number using the trypan blue exclusion assay. [ 3 H]-thymidine incorporation by these cells was also suppressed following a 96-h incubation with M-CSF. The inhibitory effect of M-CSF was reversed by the addition of anti-M-CSF monoclonal antibody. Flow cytometric analysis revealed that the treated ovarian cancer cells arrested at the G0/G1 phase of the cell cycle. These cells expressed M-CSF receptors on their surface as detected by Scatchard plot analysis using 125 I-labelled M-CSF. These results indicate that M-CSF has an antitumour activity for ovarian cancer cells and suggest that it can be applied for the treatment of this disease.

p73 gene, a new p53 homologue, has been identified: it supposedly acts as tumour suppressor gene in neuroblastoma. To clarify whether p73 might be involved in lung carcinogenesis, we examined p73 expression in resected lung cancer and paired normal lung in 60 cases using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). We also examined p73 gene status in three representative cases using Southern blot, and p53 gene alteration in 49 cases using PCR-single-strand conformation polymorphism (PCR-SSCP) and direct sequence. In 87% of the cases (52/60) p73 expression in tumour was more than twice as high as that in paired normal lung tissues, and the difference between p73 expression in tumour and normal lung tissue was significant (P < 0.0001). However, Southern blot analysis revealed that none of the cases showed p73 gene amplification. Compared with clinicopathological characteristics, p73 expression correlates significantly with histological differences and age of patient, independently (P < 0.05). Concerning p53 gene status, 43% (21/49) showed p53 gene alteration, but there was no correlation between p73 overexpression and p53 gene alteration. Our results suggest that need for further functional analysis of the role of p73 in lung carcinogenesis. © 1999 Cancer Research Campaign

Steady-state serum concentrations of carbamazepine (CBZ) and valproic acid (VPA) were investigated in normal weight (body mass index; BMI 20 to 25), lean (smaller than 20 BMI) and moderately obese subjects (greater than 25 BMI) who received either 400 mg/day of CBZ or 800 mg/day of VPA. The CBZ serum concentration in lean subjects was significantly higher than that in normal weight subjects. However, no significant differences in VPA serum concentration were found between the three groups. The CBZ serum concentration decreased with increases in total body weight, and the VPA serum concentration decreased with increases in ideal body weight. However, both serum concentrations were not correlated with BMI. These results suggest that VPA doses should be calculated using ideal body weight and that degree of obesity may affect CBZ serum concentration rather than VPA serum concentration.

In an attempt to further evaluate the role of neutrophil elastase (NE) in the development of emphysema, we examined the immunologic quantity of NE bound to alpha 1-protease inhibitor (PI), the NE inhibitory activity, and the molecular pattern of alpha 1-PI in unconcentrated bronchoalveolar lavage fluid (BALF) supernatant from 36 community-based older volunteers. They were classified into three groups: 10 current smokers with low attenuation areas (LAAs) on the lung computed tomography (CT) scans who were considered to have subclinical emphysema, 13 current smokers who had a comparable smoking history but no LAA, and 13 noncurrent smokers without LAA. The concentration of NE-alpha 1-PI complex was significantly increased in the subjects with subclinical emphysema when compared not only with the noncurrent smokers (0.52 +/- 0.10 versus 0.21 +/- 0.03 SEM micrograms/mg albumin, p < 0.01) but also with the LAA(-) current smokers (0.52 +/- 0.10 versus 0.23 +/- 0.07 SEM micrograms/mg albumin, p < 0.01). NE inhibitory activity measured by a spectrophotometric method using methoxysuccinyl-alanyl-alanyl-prolyl-valyl-paranitroanilide did not show any significant difference between the two groups of current smokers. There was no difference in the pattern or density of native and proteolysed alpha 1-PI bands between the three groups by Western blotting. We conclude that NE-alpha 1-PI complex in BALF is a factor that may differentiate smokers who are potentially developing emphysema from those who are not.

The biphasic nature of the ventilatory response to sustained hypoxia (< 1 h) is thought to occur as a result of combined effects of stimulation and depression with hypoxia. If the depressant effect of hypoxia on ventilation occurs later than the stimulatory effect, the magnitude of the ventilatory response to progressive hypoxia may be different according to the time required for a given fall in PaO2 during the test. In this study, we measured, in 10 healthy adult volunteers, ventilatory responses to isocapnic progressive hypoxia (HVR) using three different protocols (4 min, 6 min, and 15 min for SaO2 to decrease from the baseline to 80%) with or without pretreatment using theophylline (300 mg twice a day), an adenosine receptor antagonist, in a 2-d, single-blind crossover design. The slope values of HVR with the placebo were 0.31 +/- 0.04 (SE) (L/min/% fall of SaO2) in the 4-min protocol, 0.26 +/- 0.04 in the 6-min protocol, and 0.18 +/- 0.04 in the 15-min protocol. The HVR for the 15-min protocol was significantly lower than that for the 4-min or 6-min protocol. The HVR with theophylline was 0.46 +/- 0.08 for the 4-min protocol, 0.54 +/- 0.09 for the 6-min protocol, and 0.66 +/- 0.11 for the 15-min protocol, among which there were no significant differences. The dependency of HVR on the rate of change in PaO2, that was seen with a placebo run, disappeared after pretreatment with theophylline.(ABSTRACT TRUNCATED AT 250 WORDS)

The genetic linkage of atopy to chromosome 11q13 through maternally derived alleles has been previously reported. Linkage analysis in Japanese families did not confirm the existence of a major gene for atopy at this locus under the model of autosomal dominant inheritance. However, we observed a significant association between serum total IgE levels and genetic markers at this locus both in 14 Japanese atopic families and in 120 unrelated Japanese subjects. We detected eight alleles at the D11S97 locus and eight alleles in the CA/GT repeat region in the fifth intron of the Fc epsilon RI beta gene. A significantly increased frequency of the D11S97/PstI 0.96 kb allele was observed in the chromosomes of the subjects with high serum total IgE levels both in the family study (p < 0.001) and in the population study (p < 0.05). However, multipoint linkage analysis again did not show any evidence for the existence of a major gene regulating atopy on chromosome 11q13 with location scores to -35 under the model of maternal inheritance. Evidence against linkage was confirmed by the non-parametric linkage analysis, using the affected pedigree member method. Also, there was no substitution of isoleucine for leucine in the fourth transmembrane domain of Fc epsilon RI beta (Leu181), which was reported to be responsible for a subset of atopy in the British population. Therefore, the association of serum total IgE levels with chromosome 11q13 indicates that a gene or genes at this locus may contribute to the expression of high IgE levels in the Japanese population as well as in the British population, but the heterogeneity of the genetic regulation of serum total IgE levels is evident between the two populations.

We focused on the role of neutrophil elastase (NE) in alveolar macrophages (AMs), and evaluated the esterolytic activity using an NE-sensitive substrate, methoxysuccinyl-alanyl-alanyl-prolyl-valyl paranitroanilide (MEOSAAPVNA) in AMs from 36 older healthy volunteers (61 +/- 2 yr mean age +/- standard error) and examined the relationship to chronic effects of cigarette smoking and also to the presence of low attenuation areas (LAAs) on the computed tomographic (CT) scans. The AMs from the subjects with LAAs showed significantly higher activity than those from the current smokers without LAA (1.16 +/- 0.40 versus 0.34 +/- 0.07 nM, respectively, p0.05). Although the study of inhibitory profile revealed that the esterolytic activity could not be attributed to NE alone, the NE activity seemed to dominate in AMs at least from some who had higher esterolytic activity. We then examined the releasability of NE from cultured AMs in 10 subjects. The immunologic NE complex with alpha 1-protease inhibitor (alpha 1-PI) was released significantly higher in the LAA(+) group than in the LAA(-) group (17.4 +/- 6.5 versus 1.8 +/- 0.6 micrograms/L, respectively, p0.05). These data suggest that NE in AMs may play a role in the development of emphysematous changes in susceptible smokers.

Serum concentrations of human hepatocyte growth factor (hHGF) were measured in normal menstrual cycles and during uncomplicated pregnancies. In the normal menstrual cycle, the concentrations of hHGF increased through the mid and the late luteal phases to reach the highest peak during the menstrual phases, followed by a gradual decline during the follicular phase toward the trough levels seen in the ovulatory and the very early luteal phases. During pregnancy, serum hHGF concentrations increased continuously from the late luteal levels and constituted 4 distinct peaks. By immunostaining, c-Met protein, a receptor for hHGF, was localized not in the stromal but in the epithelial layer of the endometrium. In cultured isolated endometrial cells, hHGF stimulated the proliferation of both the epithelial and the stromal cells. It is likely that hHGF is involved in the repair or reconstruction process of the endometrium after menstrual shedding and implantation.

This prospective, controlled split-mouth study evaluated the stability of dental implants placed in the augmented mandibular areas with alveolar segmental "sandwich" osteotomies using nonceramic hydroxyapatite (ncHA) or autogenous bone.This study included 11 bilaterally partially edentulous mandibular patients in a split-mouth design. Alveolar augmentation osteotomies were performed bilaterally with interpositional ncHA graft (test group) or interpositional intraoral autogenous bone graft (control group). After 6 months of healing, four implants (two implants in each side) were placed in each patient. Forty-four implants were inserted and loaded after 6-month healing period. At 1-year follow-up, radiographic, prosthetic, and resonance frequency analysis parameters were assessed. Success criteria included absence of pain, sensitivity, suppuration, and implant mobility; absence of continuous peri-implant radiolucency; and distance between the implant shoulder and the first visible bone contact (DIB)2 mm.After a 1-year loading period, the overall implant survival rate was 95.45%, with two implant losses (one of each group). Among the surviving implants (42 out of 44), two did not fulfill the success criteria; therefore, the implant success was 90.90%. DIB was 0.71 ± 0.70 and 0.84 ± 0.72 mm for ncHA and autogenous bone grafts, respectively (p.05). Implant stability measurements were similar between the groups during the 12-month follow-up (p.05).Within the limits of this study, the implants placed either in sites augmented with ncHA or autogenous bone seem to represent a safe and successful procedure, at least, after 12-month follow-up.

We report the successful application of gene rearrangement analysis to the lymphocytes obtained by bronchoalveolar lavage (BAL) for the diagnosis of pulmonary malignant lymphoma. A 45-yr-old female patient who had been suffering from back pain was shown to have macroglobulinemia and pulmonary infiltrative shadow by chest radiography. Transbronchial lung biopsy revealed a small B-cell infiltrate with monotypic immunoglobulin expression (IgM/kappa light chain), and malignant lymphoma was highly suspected. BAL was performed to evaluate the cell profiles. The phenotyping of lavaged lymphocytes by flow cytometry revealed that the major component of the lymphocytes was CD3-positive T cells, and that CD21-positive B cells accounted for only 10% of all lymphocytes. This result was contradictory to the immunohistochemical population of lymphocytes in biopsied specimens. However, gene analysis of lavaged lymphocytes revealed positive immunoglobulin heavy chain rearrangement and negative immunoglobulin light chain and T-cell receptor rearrangement, suggesting that B cells making up a minor population of lavaged lymphocytes were proliferating monoclonally. Thus, in this case, gene analysis was an effective procedure for detecting the origin of tumor cells and distinguishing monoclonality from reactive accumulations. To our knowledge, this case represents the first reported application of gene rearrangement analysis to cells obtained by BAL. The sensitivity and usefulness of this analysis for the accurate evaluation of pulmonary lymphoproliferative lesions, when applied to BAL cells, should be emphasized.

The present study was designed to determine the predictive factors for the viral response to pegylated interferon-alpha plus ribavirin combination therapy (PEGIFN/RBV) administered after curative treatment for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). The study group was 78 patients treated between January 2005 and January 2009. The sustained viral response (SVR) rate was 25.8% (15/58) in patients infected with HCV-genotype 1 and 55.0% (11/20) in those with genotype 2. Among the 78 patients, 32 (41.0%) could not complete the treatment protocol, and this was because of HCC recurrence in 17 (53%) of them. Multivariate analysis identified partial early viral response (pEVR) as the only independent determinant of SVR [odds ratio (OR) 14.73, P = 0.013] for patients with genotype 1. Multivariate analysis identified male gender (OR 8.72, P = 0.001) and interleukin-28B (IL-28B) genotype (rs8099917) TT (OR 7.93, P = 0.007) as independent predictors of pEVR. Multivariate analysis also identified IL-28B genotype GG+TG (OR 14.1, P = 0.021) and α-fetoprotein30 (OR 5.4, P = 0.031) as independent predictors of null response. Patients with SVR showed a better survival rate than those without SVR (P = 0.034). The second HCC recurrence rate tended to be lower in patients with SVR than in those without SVR (P = 0.054). With regard to the prognosis of patients with SVR, it is desirable to achieve SVR with interferon therapy even when administered after HCC treatment. IL-28B genotype is a potentially useful marker for the response to PEGIFN/RBV therapy administered after curative treatment of HCV-related HCC.

BACKGROUND--Granulocyte-macrophage colony stimulating factor (GM-CSF) has several proinflammatory effects, some of which potentially favour granuloma formation. Its mRNA expression by the inflammatory cells recovered from lungs of patients with pulmonary sarcoidosis has been previously reported. In this study an association between GM-CSF expression and manifestations of the disease was explored. METHODS--GM-CSF mRNA was detected by reverse transcription polymerase chain reaction in the cells of bronchoalveolar lavage (BAL) fluid of 20 patients with pulmonary sarcoidosis. RESULTS--GM-CSF mRNA expression was positive in 15 of 20 patients with sarcoidosis. Fourteen of the 15 patients with positive mRNA expression had worsening or unchanged disease during the year preceding this study, on the basis of radiographic or physical findings, or both, whereas all five "negative" patients were judged to be improving. Similarly, serum levels of angiotensin converting enzyme, the proportion of lymphocytes in BAL fluid, and the CD4+/CD8+ ratio of lymphocytes in BAL fluid were significantly higher in the positive patients. CONCLUSIONS--There was an association between the presence of GM-CSF mRNA in the cells in BAL fluid and other indices of disease activity in sarcoidosis.

To assess the screening method for detection of methicillin-resistant Staphylococcus aureus recommended by Thornsberry and McDougal J. Clin Microbiol 1983; 18 : 1084–1901, the growth of S. aureus and Staphylococcus epidermidis strains on Mueller Hinton agar containing 4% NaCl and 6 mg 1 −1 oxacillin, after 24 h incubation at 35 °C, was investigated. The strains used for this study were characterized for possession of the mec A gene by the polymerase chain reaction. All 39 strains of S. aureus with the mec A gene grew on this agar, and all 12 strains of S. aureus without the mec A gene did not grow. On the other hand, three of 12 strains of S. epidermidis did not grow on this agar, although all these strains possessed the mec A gene. These results suggest that Thornsberry and McDougal's screening method is suitable for detecting S. aureus strains with mec A gene. Introduction of this method, to detect methicillin-resistant S. aureus more precisely, is simple and cheap for any laboratory in any part of the world.

Purpose: To describe the pattern of expression of the cyclin-dependent kinase inhibitors (CDKIs) p16, p21 and p27, and the cell cycle in SRA 01/04 cells relative to contact inhibition. Methods: SRA 01/04 cells were grown to overconfluence under normal conditions. At various phases of the cell growth, cells were assayed by flow cytometry and Western blotting for the expression of CDKIs. Results: Expression of p16 was detected from early logarithmic growth to stationary phases, during which the number of cells in G₀/G1 increased from 46 to 69%. Expression of p21 was detected only during the overgrowth phase, when 60% of the cells were in G₀/G1. Expression of p27 was not observed in SRA 01/04 cells. Conclusions: p16 expression was likely mediated by G₀/G1 arrest to induce contact inhibition in SRA 01/04. p21 expression may be related to withdrawal, and p27 deficiency may be related to the immortality of this cell line. It is possible for p16 to stop proliferation of lens epithelial cells like progressing posterior capsular opacification, by overexpression to mimic contact inhibition.

Summary Objectives: Radiology reports are typically made in narrative form; this is a barrier to the implementation of advanced applications for data analysis or a decision support. We developed a system that generates structured reports for chest x-ray radiography. Methods: Based on analyzing existing reports, we determined the fundamental sentence structure of findings as compositions of procedure, region, finding, and diagnosis. We categorized the observation objects into lung, mediastinum, bone, soft tissue, and pleura and chest wall. The terms of region, finding, and diagnosis were associated with each other. We expressed the terms and the relations between the terms using a resource description framework (RDF) and developed a reporting system based on it. The system shows a list of terms in each category, and modifiers can be entered using templates that are linked to each term. This system guides users to select terms by highlighting associated terms. Fifty chest x-rays with abnormal findings were interpreted by five radiologists and reports were made either by the system or by the free-text method. Results: The system decreased the time needed to make a report by 12.5% compared with the free-text method, and the sentences generated by the system were well concordant with those made by free-text method (F-measure = 90%). The results of the questionnaire showed that our system is applicable to radiology reports of chest x-rays in daily clinical practice. Conclusions: The method of generating structured reports for chest x-rays was feasible, because it generated almost concordant reports in shorter time compared with the free-text method.

To evaluate the activation status of circulating CD4+, CD8+, and gammadelta T cells in patients with active and inactive Behçet's disease (BD).We studied 11 subjects with active BD, 28 with inactive BD, and 13 healthy controls. The expression of CD4, CD8, pan-gammadelta, Vdelta1, and Vdelta2 along with the early activation marker CD69 was analyzed by 3-color flow cytometry.Proportions of activated CD8+ and gammadelta T cells were significantly greater in patients with active BD than in those with inactive BD or healthy control subjects, but the proportion of activated CD4+ T cells did not differ among these 3 groups. In addition, significantly greater proportions of the Vdelta1+ and Vdelta2+ gammadelta T-cell subsets were activated in patients with active BD than in those with inactive BD or healthy controls; in active BD, the balance of activation between these subsets favored the Vdelta1+ T cells. No significant differences in these proportions were found between subjects with inactive BD and healthy controls. These findings were observed exclusively in patients with HLA-B51. A comparison of samples from 5 patients taken during active BD and after resolution of BD-related symptoms showed the proportions of activated CD8+ and gammadelta T cells dropped when the patients' BD became inactive.CD8+ and gammadelta T cells, rather than CD4+ T cells, were activated in vivo in patients with active BD and HLA-B51, but not in those with inactive BD, suggesting that these potentially cytotoxic T cells play a critical role in BD flares.

We studied the relationship between stroke power consistency and 2000 m rowing time besides determining maximal oxygen uptake (VO(2max)) and leg extension power. The subjects (n=16, male varsity rowers) carried out an incremental test to volitional exhaustion on a rowing ergometer, and the VO(2) at each stage was determined. The stroke power consistency was assessed by the coefficient of variation of power (CVP(high)) at the highest workload at which each subject could maintain power. Besides the incremental test, 2000 m all-out rowing was performed on the ergometer and leg extension power was measured. Stepwise multiple regression analysis indicated that the 2000 m rowing time could be predicted by VO(2max), leg extension power and CVP(high) in order of strength of standardized partial correlation coefficients as explanatory variables. The CVP(high) correlated with the residual of the regression between 2000 m rowing time and VO(2max). The findings suggest that the stroke power consistency contributes to maintenance of the power during ergometer rowing.

We performed preliminary tests of the feasibility of multi-detector computed tomographic lymphography (MDCT-LG) with interstitial injection of iopamidol for mapping cutaneous lymphatic drainage pathways. MDCT-LG images were obtained following cutaneous injection of a total of 1ml iopamidol bilaterally into hind legs of 10 dogs. The locations of the first draining lymph nodes were marked on the skin under MDCT-LG guidance. Five dogs served for postmortem examination of lymphatic anatomy, and the remaining 5 underwent MDCT-LG after ligation of the afferent lymphatic vessels of the first draining popliteal nodes. Clinically, MDCT-LG was attempted in 6 patients with cutaneous malignant melanoma and compared with Tc-99m-human serum albumin lymphoscintigraphy. MDCT-LG clearly visualized the first draining lymph nodes and their afferent lymphatic vessels draining from the contrast injection sites with detailed underlying anatomy in all dogs. At surgery, all these first draining nodes could be found at predicted locations under MDCT-LG guidance. MDCT-LG showed rerouting of lymphatic vessels after ligation of the afferent lymph vessels of the popliteal nodes in the second 5 dogs. Clinically, MDCT-LG also allowed accurate mapping and biopsy of the first draining nodes from primary tumors at predicted locations, with minimal skin incision. Lymphoscintigraphy failed to identify these nodes due to overlapping radioactivity of clustered nodes or transport of the radiotracer to subsequent distant nodes in 4 patients. Although a more extensive study is warranted for further validation, preoperative interstitial MDCT-LG appears to have the potential feasibility for accurate sentinel lymph node mapping and biopsy in patients with cutaneous melanoma.

Purpose To compare the characteristics of early cortical cataract localization in three groups in cataract epidemiologic surveys performed in Reykjavik, Melbourne, and Singapore. Methods Individuals who had right eyes with an area of cortical opacity less than 20% of the pupil when dilated 7 mm or more were selected as subjects. This included 197 subjects from the Reykjavik Eye Study, 231 from the Vitamin E, Cataract, and Age-Related Maculopathy (VECAT) study in Melbourne, and 92 from the Singapore-Japan Cooperative Cataract Study, all showing early-stage cataract in pupils dilated to 7 mm or more. Scheimpflug and retroilluminated photographs were used to locate opacities. Localization of cortical cataract was determined by dividing the retroillumination image into seven concentric circles with diameters of 1 through 7 mm, and eight sections of 45 degrees radial octants. The positive rate of opacification was then calculated for each quadrant. Results The highest positive rate of opacification was observed in the lower nasal quadrant in all groups. The relative risk of the prevalence of cortical opacity in the lower nasal oblique hemisphere to the upper temporal oblique hemisphere was the highest in the Singaporean subjects followed by those of Melbourne and then of Reykjavik. Conclusions The prevalence of cortical cataract was higher in the lower nasal quadrant than in the other quadrants for all subjects of diverse race in three climatically different locations. This higher prevalence was most pronounced in subjects living at low latitude. These results support the view that solar UV exposure is a possible risk factor for development of human cortical cataract.

Purpose: To predict the postoperative anterior chamber (AC) depth from the preoperative in situ position of the lens central clear zone (CCZ) using Scheimpflug slit photography. Methods: 111 eyes of 78 cases that underwent phacoemulsification and intraocular lens (IOL) implantation were examined. 748 eyes of 383 healthy subjects with transparent lenses were used as the control. Scheimpflug slit photography was done under maximal mydriasis, and biometry was performed on the photographs. Two types of acrylic IOLs (MA30BA and MA60BM, both from Alcon) were used in this study. The preoperative AC depth (L1), the distance between the anterior lens capsule and lens CCZ (L2) and the postoperative AC depth (I1) were determined. I2, the predicted postoperative AC depth, was then determined from a linear regression of L1 + L2 and I1. Results: L2 thickened by 0.014 mm/year, and L1 decreased by 0.016 mm/year in the transparent lenses. L1 + L2 changed little with aging in both cataractous and transparent lenses. L1 + L2 and I1 showed a linear correlation with r = 0.80 in the MA30BA and r = 0.77 in the MA60BM groups. The mean error values between I1 and I2 were 0.095 ± 0.096 and 0.123 ± 0.114 mm in MA30BA and MA60BM, respectively. The error between I1 and I2 was within ± 0.17 and ± 0.33 mm or less in 72.9 and 91.5% of MA30BA and in 82.7 and 96.2% of MA60BM. In contrast, the error between I2 and I1 when calculated using the SRK/T formula was much larger – in excess of ± 0.33 mm in 38.7% of the eyes. Conclusions: L1 + L2 changes little with aging and is considered a useful marker of the position of the crystalline lens in situ. There was a high correlation between I1 and L1 + L2. These allow a far more accurate prediction of I1 than previous methods. In combination with the conventional regression formula and ray tracing, a highly accurate IOL power calculation can be attained.

Five healthy men carried out a program of head-down bed rest (BR) for 20 days. Before and after BR, a series of cross-sectional scans of the thigh were performed using magnetic resonance imaging, from which volumes of the quadriceps muscles were determined and physiological cross-sectional areas (PCSA) were calculated. Muscle thickness and pennation angles of the triceps brachii, vastus lateralis, and triceps surae muscles were also determined by ultrasonography. During BR, subjects performed unilateral isokinetic knee extension exercises every day. The contralateral limb served as a control. Decrease in PCSA after BR was greater in the control (-10.2 +/- 6.3%) than in the trained limb (-5.2 +/- 4.2%). Among the quadriceps, vastus intermedius in the control limb was predominantly atrophied by BR with respect to the volume and PCSA, and the rectus femoris showed the greatest training effect and retained its size in the trained limb. Decreases in muscle thicknesses in leg muscles were not prevented by the present exercise protocol, suggesting a need for specific exercise training for these muscles. Neither trained nor control muscles showed significant changes in pennation angles in any muscles after BR, suggesting that muscle architecture does not change remarkably by muscle atrophy by up to 10%.

The purpose of this study was to investigate the viscoelastic properties of tendon structures in humans. Elongation of the tendon and aponeurosis of medial gastrocnemius muscle (MG) was directly measured by ultrasonography, while subjects (n=19) performed ramp isometric plantar flexion up to the voluntary maximum, followed by a ramp relaxation. The relationship between tendon elongation (L) and estimated muscle force (Fm) was fitted to a linear regression, the slope of which was defined as compliance of the tendon structures. The hysteresis was calculated as the ratio of the area within the L-Fm loop (elastic energy dissipated) to the area beneath the load portion of the curve (elastic energy input). The resulting L-Fm relationship was non-linear in form, as previously reported on animal and human tendons in vitro. The mean compliance was 4.5+/-1.1. 10-2 mm/N. However, there was a considerable inter-subject variability (2.9 to 7.2. 10-2 mm/N). The Young's modulus, i.e., the slope of the stress-strain curve, was 280 MPa, which tended to be lower than the previously reported values for human tendons. It was also found that the strain of the tendon structures was homogeneously distributed along their length. The mean hysteresis (energy dissipation) was 22.2+/-8.8%. However, again there was a considerable inter-subject variability (9.7 to 37.2%). The present results indicated that the tendon structures of human MG were considerably compliant and their hysteresis was in accordance with previously reported values.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by increased platelet clearance caused by anti-platelet autoantibodies, which bind to circulating platelets resulting in destruction. by the reticuloendothelial system. We have recently developed enzyme-linked immunospot assay to detect circulating B cells secreting anti-platelet antibody. An increase in anti-platelet antibody-producing B cells in peripheral blood was specifically detected in ITP patients, but in none of thrombocytopenic patients without ITP or healthy donors. While earlier studies reported the presence of platelet-reactive T cells in ITP patients, we have recently found that GPIIb-IIIa is one of major target antigens recognized by platelet-reactive CD4+ T cells. Since GPIIb-IIIa-reactive CD4+ T cells had helper activity promoting production of anti-platelet antibody, these autoreactive T cells are involved in production of pathogenic anti-platelet autoantibody in ITP patients. Suppression of GPIIb-IIIa-reactive CD4+ T cells may be of therapeutic use in treating refractory patients.

Deletions and point mutations of the p16 gene are detectable in more than 50% of ovarian cancer cells. In this study, we examined the effect of p16 gene transduction on the growth of ovarian cancer cells and on the effect of anti-cancer agents.p16-null human ovarian cancer cell lines, SKOV-3 and OVCAR-5, were used in this study. We transduced the full-length human p16 gene using recombinant adenovirus (AxCA-hp16).The spontaneous growth of these cells was significantly inhibited by hp16 transduction. MTT assay revealed that AxCA-hp16 infection induced chemoresistance in both cell lines. Flow cytometric analysis revealed that only hp16 -transduced SKOV-3, were arrested at the G1-phase for 3 days whereas those infected with AxCA-mock and OVCAR-5 infected with both recombinant viruses did not. Western blot analysis showed increased microtubule-associated proteins 4 (MAP4) in both cell lines.These results suggest that in SKOV-3 cells, G1-arrest induced by p16-transduction prevents paclitaxel- and vindesine-induced cell death, and in OVCAR-5 cells, the other unknown mechanisms play a role of chemoresistance.

Serological identification of tumor antigens by cDNA expression cloning is a technique used to isolate cDNAs encoding tumor antigens that are recognized by IgG antibodies in sera from cancer patients. It is also useful for the isolation of tumor antigens recognized by T cells. We applied this method to identify melanoma antigens recognized by the serum from a patient with a good prognosis who had T-cell-infiltrated melanoma and vitiligo. By screening a lambda phage cDNA library constructed from a highly pigmented melanoma cell line, SKmel23, with the patient's serum, 50 positive cDNA clones consisting of 26 distinct antigens were isolated. Of these, 20 encoded known proteins, and 6 encoded previously uncharacterized ones. The most frequently isolated clone, which we named KU-MEL-1, was unknown previously but was homologous to partial cDNA sequences registered in the expressed sequence tag database. Reverse transcription-PCR and Northern blot analysis demonstrated that KU-MEL-1 was strongly expressed in most melanoma cell lines, melanoma tissue samples, and cultured melanocytes and weakly expressed in cell lines derived from other types of tumors, as well as in some normal tissues, including testis. Western blot analysis with polyclonal murine antibody generated by immunization with the recombinant KU-MEL-1 protein demonstrated that the KU-MEL-1 protein was preferentially expressed in melanoma cells and melanocytes. IgG antibodies against KU-MEL-1 were detected in the sera from 9 of 26 melanoma patients and from some patients with other cancers, including brain tumor, esophageal cancer, colon cancer, and chronic myelogenous leukemia, but were not detected in sera from 30 healthy individuals. Although the IgG specific for KU-MEL-1 was not detected in sera from 12 vitiligo patients, it was detected in sera from 7 of 11 patients with Vogt-Koyanagi-Harada disease that is thought to be an autoimmune disease against melanocytes. These results suggest that KU-MEL-1 may be a useful target for the development of diagnostic and therapeutic methods for patients with various cancers, particularly with melanoma, as well as patients with autoimmune diseases against melanocytes.

Muscle force (MF) is linearly related to physiological cross-sectional area (CSA), which is obtained from muscle volume (MV) divided by fibre length. Taking into account the fact that joint torque (TQ) is determined by MF multiplied by the moment arm, the maximal TQ would be a function of MV. This proposition was tested in the present study by investigating the relationship between MV and TQ for elbow flexor (EF) and extensor (EE) muscles of 26 males. The MVs of EF and EE were determined from a series of muscle CSA by magnetic resonance imaging (MRI), and pennation angle (theta) and FL by ultrasonography (US). Maximal isometric TQ was measured at right angle of elbow joint for EF and EE. There was a highly significant correlation between MV and TQ both for EF and EE (r=0.95 and 0.96 respectively) compared with that between muscle CSA and TQ, suggesting the dependence of TQ on MV. Furthermore, prediction equations for MV (MVULT) from muscle thickness (MT) measured by US was developed with reference to MVMRI by the MRI on 26 subjects, and the equations were applied to estimate MV of healthy university students (CON; 160 males) and sports athletes (ATH; 99 males). There were significant linear relationships between MVULT and TQ both for EF (r=0.783) and EE (r=0.695) for all subjects (n=259). The MVULT was significantly higher in ATH (by 32% for EF and 33% for EE, respectively) than in CON. Similarly, significantly greater TQ was observed in ATH (by 35% for EF, 37% for EE, respectively). The theta for EE showed no difference between both groups (17.8 degrees for CON and 17.5 degrees for ATH). On the other hand, the TQ to MV ratio were identical for CON and ATH. The results reveal that the muscle volume of the upper arm is a major determinant of joint torque (TQ), regardless of athletic training.

Noninvasive method to screen for endogeneous hormone production is useful to diagnose hormone excess/deficiency, especially in children. There are currently some optimal test to diagnose, and these tests(for example, urinary GH, urinary cortisol, urinary cathecolamine...) has been widely used. Traditional 24-hour urine or midnight serum cortisol values may be difficult to obtain or elevated by venipuncture stress. Salivary cortisol measurement has been reported as a reliable way to screen for adrenocortical function. We tried to detect salivary cortisol level with drug loading test(Dexamethasone for Cushing syndrome, and ACTH for adrenal insufficiency) with time interval. Salivary cortisol measurement with drug loading test rules out both Cushing syndrome and adrenal insufficiency in nearly all cases. Salivary cortisol sampling is thus a simple, accurate way to screen for adrenocortical function.

This study was performed to assess the feasibility of weekly paclitaxel (TXL) and cisplatin (CDDP) in patients with recurrent ovarian cancer. Ten of eleven patients experienced recurrence after more than 6 months after first line CDDP-based chemotherapy. TXL and CDDP were given at initial doses of 60 mg/m2 and 30 mg/m2 on days 1, 8, and 15 in 2 patients and an increase in the respective dose level was planned to 60/35 in 5 patients, 70/35 in 2 patients, and 70/40 in 2 patients. Toxicities were well tolerated. None of the patients suffered from neurotoxicity or myalgia of more than grade 2. Gastrointestinal disorder was recognized as grade 1-2, and grade 3-4 hematological toxicity included leucocytopenia (64%), anemia (36%), and thrombocytopenia (9%). We set the recommended dose of TXL at 70 mg/m2 and that of CDDP at 35 mg/m2, considering toxicity and performed planned schedule. Of eleven patients, nine were assessable by computed tomographic scan. The overall response rate was 67% (CR: 1, PR: 5, NC: 1, PD: 2). One of two patients with standard TXL/CDDP therapy showed PR by switching to a weekly schedule. The median follow-up duration was 490 days and the median response duration was 371 days. From the results presented here, it is suggested that this regimen with increased DI might be quite effective and well tolerated in patients who experience relapse after CDDP-based chemotherapy.

Mediastinal lymphangioma is rare disease. Above all cavernous type of mediastinal lymphangioma is very rare. We report 5 cases of mediastinal lymphangioma including cavernous type. CT was performed in all and revealed that they were smoothly marginated and cystic. All were surgically resected and specimens were classified pathologically into cystic type (3 cases), cavernous type (1 case) and mixed type of the two (1 case). MRI was performed in the cavernous type and suggested that the mass was lymphangioma because of pathognomonic lesion. Despite preoperative diagnosis of mediastinal lymphangioma is difficult, MRI is able to useful examination. In the follow-ups there has been no recurrence in our series.

In July, 1999, an outbreak of vancomycin-resistant Enterococcus faecalis (VREF) with the vanB genotype occurred for the first time in Japan at Hokushin General Hospital, Nakano City, Nagano Prefecture. Four VREF strains were isolated from the clinical specimens of four inpatients, and 16 VREF strains were isolated by the screening of asymptomatic carriers and by surveillance of the hospital environment. All of the isolates possessed vanB genes. In a pulsed-field gel electrophoresis analysis, 19 out of 20 VREF isolates exhibited the indistinguishable restriction endonuclease digestion patterns of the chromosomal DNA. Additional investigation by Southern hybridization using the vanB probe implied that the vanB gene of these 19 isolates was encoded on a 110-kb plasmid. These findings indicate that the outbreak was principally caused by a single clone. The restriction endonuclease digestion patterns of the remaining single isolate was different from those of the other isolates. The vanB gene was encoded on the chromosome.

PRAME (Preferentially expressed antigen of melanoma) has been previously identified as a melanoma antigen recognized by cytotoxic T cells (CTLs) and found to be expressed in a variety of cancer cells including leukaemic cells. We have screened 98 Japanese patients with leukaemia and lymphoma for expression of the PRAME gene using semiquantitative reverse transcription polymerase chain reaction (RT-PCR). Forty-one patients (42%) showed high levels of PRAME expression. Eight of these patients were then monitored using real-time PCR for a period of 10-37 months. Significant reductions in the PRAME expression were observed in all patients after chemotherapy. An increased expression was detected in the two patients who relapsed, one of which was before cytological diagnosis. These changes were correlated with those of other known genetic markers, such as the bcr-abl gene. Therefore, quantitative monitoring of the PRAME gene using real-time PCR method may be useful for detecting minimal residual disease and to predict subsequent relapse, especially in patients without known genetic markers. In addition, a PRAME-positive leukaemia cell line and fresh leukaemic cells were found to be susceptible to lysis by PRAME-specific CTLs established from a patient with melanoma, suggesting that the PRAME peptide can also be a target leukaemia antigen for T cells.

A large number of biological factors that seem to have important prognostic significance have been identified in non-small cell lung cancers (NSCLCs). In the present study, we have characterized expression of cyclin D1 and cyclin E in a cohort of 217 resected NSCLCs from a single institution by immunohistochemistry to analyze their expression in relation to the growth fraction determined by Ki-67 and to prognosis, and then we have constructed a risk-stratification model of cancer death by multiple biological factors in p-stage I NSCLCs. The cyclin E labeling index (LI) was significantly associated with the Ki-67 LI (r = 0.45; P0.001). Tumors having high-level cyclin E expression (cyclin E LIor =30%) showed a significantly higher Ki-67 LI than tumors having low-level cyclin E expression (cyclin E LI30%; P0.001), whereas positive or negative cyclin D1 expression was not associated with the Ki-67 LI (P = 0.1). Cyclin E expression was a significant and independent unfavorable prognostic factor (hazards ratio = 2.09; P = 0.03), as reported previously (Clin. Cancer Res., 6: 11-16, 2000), whereas cyclin D1 expression was not. These findings indicate different roles of cyclin D1 and cyclin E in cell proliferation and in the prognosis of NSCLCs. Furthermore, we stratified this cohort of p-stage I NSCLCs into different survival groups by using biological factors, including cyclin E, Ki-67, and ras p21, which previously we have found to be independent prognostic factors among 10 factors studied in p-stage I NSCLCs. Four groups of patients with markedly different survivals were identified with 5-year survival rates that ranged from 96% for patients with no factors altered to 41% for patients with all three factors altered (P0.001). This combination of biological factors was a significant and independent prognostic factor (hazards ratio = 7.94; P = 0.001).

The frequency and characteristics of cortical cataract localization within a dilated pupillary area were investigated in a population-based cataract epidemiological survey performed in the city of Reykjavik in Iceland.Among 1045 randomly selected individuals, the right eyes of 277 persons with mild cortical lens opacification (Grade I) were selected for our study. The localization of cortical cataracts was examined using retroillumination images, which were divided into 56 circular and radial sections, and calculations were made of the percentages for each opacified area. A questionnaire was used to record the number of hours spent outdoors during week days, the time of the day and whether the subjects wore spectacles, sunglasses or hats when outside.The percentage of cortical opacification was significantly higher in the lower nasal quadrant than in all other quadrants (p0.05). Furthermore, the percentage of opacification localized in the lower nasal quadrant was higher in individuals with a longer history of outdoor activity than those without (p0.05). The percentage of opacification in individuals, who have had the habit of wearing sunglasses for outdoor activities lasting longer than half an hour during weekdays in their 20's and 30's was lower in all quadrants and statistically significantly lower in the upper temporal quadrant (p0.05) compared to those not wearing sunglasses.This suggests that wearing sunglasses is effective in preventing the development and/or progression of cortical cataracts.

To elucidate histopathologic features of the lacrimal gland in chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation.Lacrimal gland specimens from five patients who had dry eye as part of the symptoms of chronic GVHD were examined by immunohistochemistry and transmission electron microscopy. Lacrimal gland specimens from five patients with Sjögren's syndrome (SS) were used as control samples.Lymphocytes, predominantly T cells, were found primarily in the periductal areas of the lacrimal gland from patients with chronic GVHD, whereas B cells were the dominant infiltrating cells in the acinar areas of the lacrimal gland from patients with SS. Notable findings in the lacrimal gland from patients with chronic GVHD were marked fibrosis of the glandular interstitium and an increase in the number of CD34(+) stromal fibroblasts. These findings were more prominent in patients with severe dry eye than in those with mild dry eye. Electron microscopic observations of the lacrimal gland from patients with chronic GVHD revealed that stromal fibroblasts were attached to various inflammatory cells, especially T cells, through primitive or rudimentary contacts. In addition, the presence of a well-developed rough endoplasmic reticulum in the fibroblasts and newly synthesized collagen fibrils in the extracellular matrix indicated an active production of extracellular matrix components. Electron micrographs revealed multilayered and thickened basal laminae of blood vessels, ducts, and lobules in the lacrimal gland of patients with chronic GVHD; however, these observations were infrequently observed in the lacrimal glands of patients with SS.The results suggest substantial differences in the lacrimal gland histopathology of patients with chronic GVHD and SS. In addition, it is likely that stromal fibroblasts are actively involved in the pathogenic process of chronic GVHD in the lacrimal gland by producing excessive extracellular matrix components.

Susceptibility to asthma and other atopic diseases is known to be associated with elevated total IgE levels. Several investigators have linked the interleukin-4 (IL-4) gene and nearby markers located on chromosome 5q to elevated total IgE levels. A single nucleotide polymorphism in the IL-4 gene promoter region (C+33T) has recently been identified. As part of an effort to identify genetic variants contributing to the susceptibility to elevated total serum IgE levels, an association analysis of a newly identified promoter polymorphism (C+33T) with total serum IgE levels was conducted. The study was conducted using 240 Japanese subjects (120 asthmatics and 120 healthy controls). The IL-4 C+33T polymorphism was genotyped by PCR-restriction fragment length polymorphism analysis. The frequency of the T allele was 0.675 in asthmatic subjects and 0.671 in healthy controls. An ANOVA model adjusted for age, sex and disease status suggested a genetic association of C+33T polymorphism with elevated total serum IgE levels (P0.05). The data suggest that IL-4 promoter C+33T polymorphism may be one of the genetic polymorphisms that explain genetic linkage or association between elevated total serum IgE levels and markers on chromosome 5q.

To determine the effects of interferon treatment, we studied 77 Japanese patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase (ALT). Of 77 patients, 37 were given natural interferon-alpha for 24 weeks, and 40 not given interferon acted as controls. Serum samples were tested for HCV RNA and genotypes by polymerase chain reaction (PCR). HCV RNA levels were measured by competitive PCR. Of 37 treated patients, 11 (29.7%) had sustained elimination throughout a six-month follow-up, while HCV RNA was not eliminated in any untreated patients. At 24 months, the number of patients with elevated ALT was not significantly different between treated (13.5%) and untreated patients (15%). Interferon eliminates HCV RNA in patients with normal ALT without severe side effects. The natural history of HCV infection should be clarified so that the interferon treatment regimen can be tailored to the needs of each patient.