Potent activity of 5-fluoro-2'-deoxyuridine and related compounds against thymidine kinase-deficient (TK-) herpes simplex virus: targeted at thymidylate synthase

5-Fluorouracil, 5-fluorouridine (FUrd), 5-fluoro-2'-deoxyuridine (FdUrd), 5-fluorocytidine (FCyd), 5-fluoro-2'-deoxycytidine (FdCyd), 5-trifluoro-2'-deoxythymidine (F3dThd), and the 5'-monophosphates and 3',5'-cyclic monophosphates thereof were found to inhibit thymidine kinase-deficient (TK-) mutant strains of herpes simplex virus (HSV) at a much lower concentration than the wild-type (TK+) HSV strains. Other 5-substituted 2'-deoxyuridines that have previously been recognized as potent thymidylate synthase inhibitors behaved in a similar fashion. The activity of FdUrd, FdCyd, F3dThd, and their 3',5'-cyclic monophosphates against TK-HSV was readily reversed by 2'-deoxythymidine (dThd) but not by 2'-deoxyuridine (dUrd). These compounds also inhibited the incorporation of [6-3H]dUrd into DNA at a concentration which was up to 5 orders of magnitude lower than the concentration at which the incorporation of [methyl-3H] dThd was inhibited. Thus, while not being a target for the well established anti-HSV compounds in TK+HSV-infected cells, thymidylate synthase appears to be an important target in TK-HSV-infected cells. In addition to dTMP synthase, TK-HSV-infected cells appear to reveal other therapeutically exploitable targets such as OMP decarboxylase (towards pyrazofurin), CTP synthase (towards carbodine and its cyclopentenyl analogue), dihydrofolate reductase (towards methotrexate), and S-adenosylhomocysteine hydrolase (towards neplanocins).     

L’électroencéphalogramme n’est pas un examen légitime pour la confirmation du diagnostic de mort cérébrale

PURPOSE: In France, legislation mandates that the clinical diagnosis of brain death be confirmed by one paraclinical test before organ donation is allowed. That test may be either the electroencephalogram (EEG) or cerebral angiography. We report a case in which the clinical diagnosis of brain death was first confirmed by two EEGs performed according to the French guidelines, but ruled out by cerebral angiography. Considering that the EEG is no longer recommended to establish the diagnosis of brain death, we discuss the relevance of maintaining the EEG for brain death diagnosis in France. CLINICAL FINDINGS: A 58 yr-old man was admitted to the intensive care unit because of coma secondary to a massive subarachnoid hemorrhage with herniation below the falx shown by computed tomography. Clinical criteria of brain death were rapidly present. Two EEGs first confirmed the diagnosis but a four-vessel cerebral angiography was finally performed because the patient moved spontaneously. This cerebral angiography showed flow in the right internal carotid artery. A computed tomography performed the next day definitely confirmed the absence of brain death and organ donation did not occur. CONCLUSIONS: This case demonstrates the limitations of the EEG for this indication and suggests that angiography should be preferred. French legislation is probably maladjusted and would benefit by incorporating guidelines of other countries like Canada. International harmonization of criteria for brain death diagnosis would also be welcome.     

Development of the Qualeffo–31, an osteoporosis-specific quality-of-life questionnaire

Introduction Vertebral deformities are a common consequence of osteoporosis and are known to decrease quality of life. The Qualeffo–41 is a quality-of-life questionnaire especially developed for measuring quality of life in patients with vertebral deformities. It consists of 41 questions arranged in five domains: pain, physical function, social function, general health perception, and mental function. The objectives of this study were: (1) to develop a shorter version of the Qualeffo–41 by removing redundant questions; and (2) to investigate the scale characteristics, reliability, and validity of this shorter version. Methods The study was performed using data from the Qualeffo validation study and the Multiple Outcomes of Raloxifene Evaluation (MORE) study. The analyses were performed in patients with vertebral deformities (n=579). Factor analysis on polychoric correlations and an item response theory (IRT) model, i.e., the generalized partial credit model (GPCM), were used to create a shorter version of Qualeffo–41. Using GPCM, scoring weights were computed for all items. Results Three items were removed from the data set because of too many missing values. Factor analysis identified three instead of five domains: (1) pain, (2) physical function, and (3) mental function. Five items had factor loadings <0.4 and were not included in the GPCM. After excluding several items, the domains pain (four items), physical function (18 items), and mental function (nine items) showed a good, reasonable, and excellent fit, respectively. This indicates that the mental function domain and the pain domain are more unidimensional than the physical function domain. All three domains showed a very high correlation (r ≥0.95) with the corresponding domains of the Qualeffo–41. Conclusions Qualeffo–31 was developed, consisting of three domains with a reasonable to excellent fit to the GPCM. Although the fit to the GPCM supports the construct validity of the Qualeffo–31, validation in a new study should be performed before using it in practice.     

A novel mutation in the last exon of ATRX in a patient with α-thalassemia myelodysplastic syndrome

Abstract:  We describe a patient with acquired alpha-thalassemia myelodysplastic syndrome (ATMDS). A previously healthy 66-year-old man presented with hemoglobin of 9.3 g/dL, mean corpuscular volume 59 fL, and a bone marrow aspirate with increased erythroid precursors and hypolobulated megakaryocytes. Hemoglobin H inclusions were seen in most red cells after 1% brilliant cresyl blue supravital stain of the peripheral blood. At the molecular level, we identified of a novel mutation in the most 3' exon of the ATRX gene ( C GA→ T GA substitution in codon 2407) resulting in a premature termination codon (p.R2407X). This case provides further evidence for a link between ATRX mutations and ATMDS, and suggests a possible role for the conserved Q-box element in ATRX function.     

Genetic abnormalities and CNS tumors: report of two cases of ependymoma associated with Klinefelter’s Syndrome (KS)

Objects Genetic syndromes associated with ependymoma are uncommon, with the exception of NF2. We describe two cases of ependymoma presenting with Klinefelter’s Syndrome (KS) as co-morbid condition. Materials and methods The first patient was diagnosed for KS during pregnancy; he also presented a thyroid agenesis and a deficit of methyltetrahydrofolate reductase (MTHFR); at 30 months of age he was operated on for a grade II ependymoma of IV ventricle; after a multiple-stage surgery, he underwent oral chemotherapy and stereotactic radiotherapy, but after 15 months he presented a local recurrence and died. The second patient was diagnosed for KS at the age of 16 months; at 10 years of age, due to back pain, he underwent an MRI, which showed a cauda equine tumor. He underwent surgery and radiotherapy. Histology was of mixopapillary ependymoma. Conclusion In a review of literature, various neoplasms have been described in association with KS. To our knowledge, these are the first two cases reported of ependymoma associated to KS. A retrospective study of 44 monoinstitutional ependymoma cases demonstrated association with genetic syndromes in 22%.     

Interferon for non-A, non-B chronic hepatitis. A meta-analysis of randomised clinical trials

We reviewed randomised clinical trials evaluating the effect of lymphoblastoid or recombinant alpha-interferon in non-A, non-B chronic hepatitis. The outcomes assessed were the rates of serum alanine aminotransferase normalization and relapse during and after stopping interferon. Data were pooled by meta-analysis and a 50% overall rate difference, favouring treated patients, was found. Results showed homogeneity in direction of treatment effect both after short-term (2-6 months, greater than or equal to 2 mega-units thrice weekly) and long-term (9-18 months, variable dose) interferon course. Moreover, results did not change when type of publication (abstracts vs. full reports) and treatment duration or schedule were accounted for. About 50% of patients originally responding to treatment relapsed within 6 months of either dose reduction or stopping interferon, thus suggesting that only in about one out of four patients is benefit from treatment sustained up to 1 year. We conclude that larger trials are needed to identify an optimal schedule of treatment and to evaluate predictors of interferon effectiveness in patients with non-A, non-B chronic hepatitis.     

转化生长因子-β抑制剂Decorin抗眼结膜滤过泡瘢痕形成的实验研究

目的　探讨Decorin抑制结膜下瘢痕形成的作用机制并为临床应用提供理论依据。方法　新西兰大白兔分为Decorin组、磷酸盐缓冲液 (PBS)组、正常对照组。在滤过术后第 7,14,3 0天 ,应用链酶亲和素免疫组织化学法 (SABC法 )检测各组在结膜滤过泡中转化生长因子 - β1(TGF- β1)和转化生长因子 - βⅠ型受体 (TGF - βRⅠ )的含量 ;应用天狼星玫瑰红 -偏振光法检测各组Ⅰ、Ⅲ型胶原的含量。　结果　PBS组结膜滤过泡中TGF - β1、TGF - βRⅠ免疫组化染色和Ⅰ、Ⅲ型胶原染色呈强阳性表达 ,第 3 0天明显比第 7天增强 (P <0 .0 5 ) ;Decorin组结膜滤过泡中TGF - β1、TGF - βRⅠ免疫组化染色和Ⅰ、Ⅲ型胶原染色呈弱阳性表达 ,相同时相点比较 ,Decorin组比PBS组明显呈弱表达 (P <0 .0 1)。Decorin可使滤过泡瘢痕中TGF - β1和TGF - βRⅠ活性降低 ,Ⅰ、Ⅲ型胶原的含量减少。　结论　Decorin可作为抑制滤过泡瘢痕形成的辅助药物     

Disseminated intracerebral alveolar echinococcosis: CT and MRI

Cerebral alveolar echinococcosis is rare and has a poor prognosis. We report an unusual case presenting with disseminated intracranial lesions secondary to primary hepatic infection. Received: 2 May 1996 Accepted: 23 August 1996