Prognostic factors for successful surgical outcome with preoperative prism adaptation test in patients with superior oblique palsy.

PURPOSE: This study evaluated the surgical outcome of patients managed with preoperative prism adaptation test (PAT) and investigated prognostic factors for successful motor alignment in adult patients with superior oblique palsy. METHODS: Prospective study of preoperative PAT was performed. Fifty-seven patients with superior oblique palsy, aged 16 to 81 years, participated in this study. Patients were assigned to surgery with the target angle based on either the original angle or the prism compensated angle. When the amount of neutralizing prism exceeded 4delta or more compared to the original angle of deviation, the patient was defined as having prism compensation, and the target angle for surgery was based on the amount of neutralizing prism. The motor success rate was compared between the 2 groups at the 3-month postoperative follow-up. RESULTS: The prism responders group showed a superior outcome compared to that of the prism non-responders group (77% successful outcome compared with 46%, p = 0.0397). The presence of prism compensation and the amount of vertical deviation were significant prognostic factors for successful motor alignment. CONCLUSION: Preoperative PAT is a useful prognostic indicator of successful surgical outcome in patients with superior oblique palsy.     

Monophosphoryl lipid A provides biphasic cardioprotection against ischaemia-reperfusion injury in rat hearts

1 We utilized a rat model of myocardial infarction to investigate whether cardioprotection by monophosphoryl lipid A (MLA) is provided in the early and late phases, as well as to determine whether this cardioprotection may be related to the activation of manganese superoxide dismutase (Mn-SOD), an intrinsic radical scavenger. 2 Pretreatment with MLA (0.5 or 1.0 mg kg-1, i.v.) 24 h prior to 20-min left coronary artery (LCA) occlusion and 48-h reperfusion significantly decreased the incidence of ventricular fibrillation (VF) during ischaemia, as well as infarct size. Pretreatment with lower concentrations of MLA, however, was ineffective. 3 When we examined the time course of MLA (0.5 mg kg-1)-induced cardioprotection, both infarct size and the incidence of VF were significantly reduced in rats pretreated with MLA 0.5 h and 24 h before occlusion. We observed no differences, however, 2 and 72 h after MLA treatment. 4 The activity of Mn-SOD paralleled the cardioprotective effects of MLA. Mn-SOD activity in the myocardium was significantly enhanced in rats pretreated with MLA (0.5 mg kg-1) 0.5 and 24 h before. Mn-SOD activity was not altered, however, in rats pretreated 2 or 72 h before. Lower MLA concentrations were not effective even 24 h after the treatment. 5 We conclude that MLA treatment induced a biphasic pattern of cardioprotection. The pattern of Mn-SOD activity suggests that this enzyme may play a major role in the acquisition of cardioprotection against ischaemia-reperfusion injury.     

Some observations in the fine structure of age changes of the mouse retinal pigment epithelium

Summary Age changes of the fine structure in the CF-1 mouse retinal pigment epithelium were studied from 1–24 months old. The change most characteristic of the senescence of the retinal pigment epithelium was found to be the appearance of wavy undulating 12 nm wide filaments having a periodicity of about 80 nm after the 12th month. In addition, the retinal pigment epithelial cells of the aging eye were found to have a marked accumulation of lysosomal dense bodies measuring about 0.3 to 1.2 m in diameter especially in the apical portion of the cytoplasm. Extended and enlarged basal cytoplasmic infoldings of the retinal pigment epithelial cells were another prominent age change in the old mouse. In these basal infoldings densely fixed amorphous materials by tannic acid and very fine filaments are recognized. Age-related changes of the retinal pigment epithelial cell of the CF-1 mouse may take place as the degeneration of cytoplasmic materials, the appearance of bundles consisting of parallel undulating filaments, and the extending process of basal infolding from the choroid side.     

Pelvic insufficiency fractures in postmenopausal woman with advanced cervical cancer treated by radiotherapy.

PURPOSE: To assess the predisposing factors and clinical characteristics of pelvic insufficiency fractures (PIF) in postmenopausal women with pelvic irradiation. MATERIAL AND METHODS: A total 335 postmenopausal patients with cervical cancer of the intact uterus treated with radiation therapy between 1983 and 1998 were reviewed. Total external dose was delivered between 45 and 50.4 Gy with parallel opposed anteroposterior portals. Total brachytherapy dose at point A was delivered between 10 and 36 Gy. PIF were diagnosed by bone scintigraphy and confirmed by computed tomography. The cumulative incidence of symptomatic PIF was estimated by actuarial methods. Potential risk factors (age, weight, type II diabetes, delivery, menopause, total external dose, total brachytherapy dose) were assessed. RESULTS: Fifty-seven (17.0%) of 335 patients were diagnosed as having PIF. Forty-seven patients were symptomatic and ten were asymptomatic. Parameters carrying a significant association with PIF were body weight 49 kg or below (P=0.044) in stepwise logistic regression analysis. The cumulative incidence of symptomatic PIF at 5 years was 17.9% calculated by the Kaplan-Meier method. A body weight of 49 kg or below and more than three deliveries were identified as having a significant effect on symptomatic PIF in univariate analysis (P=0.021, P=0.003, log-rank test) and Cox life table regression analysis (P=0.038, P=0.013). Five patients required narcotic agents and eight patients required hospital admission. CONCLUSIONS: We should consider reducing the dose contribution to the sacrum and sacroilac joints, without underdosing the tumor, especially in postmenopausal women with many deliveries or low body weight.     

A Proposal for a New Histological Classification Scheme for Predicting Short-term Tumor Recurrence and Death in Patients with Invasive Ductal Carcinoma of the Breast

Tumor recurrence rate (TRR) and mortality rate (MR) of invasive ductal carcinoma (IDC) of the breast in short-term follow-up are relatively low. Nevertheless, it is extremely important to identify patients at risk of early recurrence or death after surgery. The aim of this study was to establish a new histological prognostic classification scheme for IDC in order accurately to predict the short-term outcome. The following histological parameters were analyzed in 201 IDCs: 1) tumor size, 2) structural atypia, 3) nuclear atypia, 4) number of mitotic figures, 5) fibrotic focus (FF), 6) vascular invasion, 7) tumor necrosis, 8) skin invasion, 9) muscle invasion, 10) nodal status and 11) extramammary fat invasion. Multivariate analysis showed that nuclear atypia, presence of FF, and the invasive length of fat invasion (ILFI) were the most important histological parameters correlated with TRR or MR of IDCs. Accordingly, a new histological classification based on nuclear atypia, FF and ILFI (Nucleus-Fibrotic focus-Fat invasion, NFF) was devised. Comparative studies were performed with the following existing prognostic classifications: 1) histological grade, 2) modified Scarff-Bloom-Richardson histological grade, 3) prognostic index and 4) pathological TNM (pTNM) stage classifications. Patient grouping defined by NFF classification significantly correlated with tumor recurrence or death of IDCs in all cases, cases at stages I and II, those without lymph node metastasis and those who were estrogen receptor (ER)-positive after adjustment for the other four classifications, using multivariate analysis. NFF classification appeared superior to existing prognostic classifications for the accurate prediction of the short-term outcome for patients with IDCs in low risk groups.     

Detection of thyroid system-disrupting chemicals using in vitro and in vivo screening assays in Xenopus laevis.

We developed a thyroid hormone (TH) inducible primary screening assay for the identification and assessment of man-made chemicals that interfere with the TH-signalling pathway within target cells. The assay was developed in a Xenopus laevis cell line that was transduced with a self-inactivating (SIN) lentivirus vector (LV) containing a luciferase gene. The luciferase activation in this cell line was TH-specific: 3,3',5-L-triiodothyronine (T(3)) > 3,3'5-L-triiodothyroacetic acid (Triac) > 3,3',5-D-triiodothyronine (D-T(3)), > L-thyroxine (T(4)) > 3,3',5'-L-triiodothyronine (rT(3)). The application of the ligand-dependent luciferase assay for screening for thyroid system-disrupting chemicals revealed that three phthalates (dicyclohexyl phthalate, n-butylbenzyl phthalate, and di-n-butyl phthalate), two herbicides (ioxynil and pentachlorophenol) and a miticide (dicofol) had 3,3',5-L-triiodothyronine- T(3)- antagonist activity at concentrations ranging from 10(-6) to 10(-5) M. These chemicals also inhibited the expression of the endogenous primary T(3)-response TH nuclear receptor beta (TRbeta) gene. The inhibitory characteristics of these chemicals were similar for both assays performed, although the assay for T(3)-dependent activation of TRbeta gene was more sensitive than the luciferase assay. These results indicate that the luciferase assay was a rapid method with a small intra-assay variation for the primary screening of thyroid system-disrupting chemicals. Of the six chemicals, only n-butylbenzyl phthalate and pentachlorophenol exhibited T(3)-antagonist activity in an in vivo metamorphosis-based assay. It should be noted that chemicals elicited thyroid system-disrupting activity in the luciferase assay did not always interfere with the thyroid system in vivo.     

HLA‐A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese

Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is constantly associated with Epstein–Barr virus type 1 (EBV‐1) infection. We carried out a genome‐wide association study (GWAS) of 575,247 autosomal SNPs in 184 NPC patients and 236 healthy controls of Malaysian Chinese ethnicity. Potential association signals were replicated in a separate cohort of 260 NPC patients and 245 healthy controls. We confirmed the association of HLA‐A to NPC with the strongest signal detected in rs3869062 (p = 1.73 × 10^?9). HLA‐A fine mapping revealed associations in the amino acid variants as well as its corresponding SNPs in the antigen peptide binding groove (p_{HLA‐A‐aa‐site‐99} = 3.79 × 10^?8, p_rs1136697 = 3.79 × 10^?8) and T‐cell receptor binding site (p_{HLA‐A‐aa‐site‐145} = 1.41 × 10^?4, p_rs1059520 = 1.41 × 10^?4) of the HLA‐A. We also detected strong association signals in the 5′‐UTR region with predicted active promoter states (p_rs41545520 = 7.91 × 10^?8). SNP rs41545520 is a potential binding site for repressor ATF3, with increased binding affinity for rs41545520‐G correlated with reduced HLA‐A expression. Multivariate logistic regression diminished the effects of HLA‐A amino acid variants and SNPs, indicating a correlation with the effects of HLA‐A*11:01, and to a lesser extent HLA‐A*02:07. We report the strong genetic influence of HLA‐A on NPC susceptibility in the Malaysian Chinese.     

Functional expression of TWEAK in human colonic adenocarcinoma cells

The TNF-like weak inducer of apoptosis (TWEAK) can induce diverse cellular responses, including cell death, inflammation, migration, and proliferation in various transformed cell lines. We investigated TWEAK sensitivity, TWEAK effects on nuclear factor-kappaB activation, and expression of TWEAK in the HT-29, LS180, SK-CO-1 and SW480 human colonic adenocarcinoma cell lines, all of which express the TWEAK receptor (Fn14). TWEAK alone induced cell death in SW480 cells and induced cell death of HT-29 cells after addition of IFN-gamma, actinomycin D or cycloheximide. TWEAK did not affect cell viability of LS-180 or SK-CO-1 cells. Activation of NF-kappaB was not obviously influenced by TWEAK in any of the cell lines. All four human colonic adenocarcinoma cell lines constitutively expressed TWEAK mRNA, protein and membrane-bound TWEAK antigen, as detected by RT-PCR, Western blotting and flow cytometry. Stimulation by an anticancer drug (camptothecin) augmented cell surface expression of TWEAK and all human colonic adenocarcinoma tissue samples studied (n=59) demonstrated positive staining for TWEAK antigen. Soluble TWEAK was detected in culture medium of these cell lines by ELISA and conditioned medium from SW480 cells incubated with anti-TWEAK antibody significantly inhibited endothelial cell tube formation in Matrigels. Thus, functional expression of TWEAK from human colonic adenocarcinoma cells may contribute to neovascularization.     

Genetic variations and haplotype structures of the ABC transporter gene ABCC1 in a Japanese population

Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3'-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5'-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on > or = 10 chromosomes accounted for > or = 91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese.