Bronchiolar columnar cell dysplasia—genetic analysis of a novel preneoplastic lesion of peripheral lung

Atypical adenomatous hyperplasia is the only known precursor lesion of lung adenocarcinomas (ACs) so far. Here, we describe a new dysplastic lesion in the bronchioles of peripheral lung for which we propose the name bronchiolar columnar cell dysplasia (BCCD). Eight of fourteen BCCDs were successfully analyzed by means of comparative genomic hybridization (CGH). The average number of chromosomal aberrations was 2.6 in BCCD and 14.7 in concomitant AC. Among the aberrations were losses of 3p, 9, 13, 14 and gains of 1q, 17, 19q and 20q. Summarizing our data from morphological and genetic analysis, we conclude that BCCD is a preneoplasia of the bronchiolar epithelium and most probably represents an additional precursor lesion of lung adenocarcinomas.     

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1) is an autosomal dominant disorder characterised by progressive degeneration of right ventricular myocardium, arrhythmias and risk of sudden death. By linkage analysis, we previously mapped the involved gene to chromosome 14q24.3. In the present study we report on linkage analysis of one additional and unrelated family, which enabled to confirm previous locus assignment. Another family is reported, in which genetic and clinical data suggest linkage to the same locus. Direct sequencing of DNA from individuals belonging to established ARVD1 families failed to detect causative mutations in exonic sequences of four genes (POMT2, TGFbeta3, KIAAA1036 and KIAA0759) expressed in the heart and which defects could possibly induce plasma membrane instability or apoptosis, key features of ARVD pathogenesis.     

Increased probability of remaining in remission from panic disorder with agoraphobia after drug treatment in patients who received concurrent cognitive-behavioural therapy: a follow-up study

BACKGROUND: Many short-term trials suggested that the combination of psychotherapy with medication might be more effective than either treatment alone. However, only few studies examined the long-term effectiveness of this combination. METHODS: A private practice sample of consecutive patients with DSM-III-R panic disorder with agoraphobia who achieved remission after drug treatment with or without concurrent cognitive-behavioural psychotherapy were followed up. Patients were assessed before treatment, after treatment and at each follow-up contact with the Marks-Sheehan Phobia Scale, the Hamilton Anxiety Rating Scale, and the Hamilton Depression Rating Scale. Kaplan-Meier survival analysis was performed on the time to panic disorder relapse. Cox regression analysis was used to control for the possible confounding effect of factors other than treatment. RESULTS: Of patients who received medication alone (n = 32), 25 (78.1%) relapsed, prevalently (65.6%) during the first year. The estimated mean survival time was 12 months (95% CI 7-17). Of patients who received integrated treatment (n = 21), only 3 (14.3%) relapsed. The estimated mean survival time was 65 months (95% CI 44-86). Treatment was the only variable associated with the occurrence of relapse, with a hazard ratio of 12.6 (95% CI 2.5-63.3) for patients who received only medication. CONCLUSIONS: Some methodological limitations, such as treatment allocation by preference, suggest caution in the interpretation of our results. However, the long-term therapeutic advantage of integrated treatment over medication alone was large and independent from known prognostic factors. The long-term effectiveness of integrated treatment should be tested with a randomised controlled trial.     

Relevance of Akt phosphorylation in cell transformation induced by Jaagsiekte sheep retrovirus

Expression of the JSRV envelope (Env) is sufficient to transform immortalized rodent fibroblasts. A putative docking site for the PI3-K kinase (Y(590)-X-X-M(593)) in the cytoplasmic tail of the transmembrane domain of the JSRV Env is a major determinant of viral-induced cell transformation. Akt is constitutively phosphorylated in rodent fibroblasts transformed by the JSRV Env. However, recent data suggest that Y590 and M593 are not necessary for JSRV Env-induced transformation of the immortalized chicken fibroblasts cell line DF-1. In this study we found that JSRV-induced transformation of DF-1 cells is Akt-independent. In addition, a replication-competent avian vector expressing the JSRV Env (RCASBP(A)+JE) was also able to induce transformation of primary chicken embryo fibroblasts (CEF). Vectors expressing JSRV Env Y590 mutants were still able to induce CEF cells transformation but not as efficiently as the vectors expressing the wild-type Env. In CEF cells, as in DF-1 cells, only the expression of the wild-type Env induced constitutive phosphorylation of Akt. Thus, in chicken cells, the degree of transformation induced by the JSRV Env is maximum in the presence of Y590 and Akt phosphorylation. We addressed the significance of Akt phosphorylation in rat 208F cells transformed by the JSRV Env and showed that Akt is indeed activated and shows kinase activity. Inhibitors of the PI-3K/Akt pathway reproducibly decreased the transformation efficiency of the JSRV Env. In vivo, we found phosphorylated Akt only in nasal tumors induced by the enzootic nasal tumor virus (ENTV), a JSRV-related beta-retrovirus. No evidence of Akt phosphorylation was found in lung tumor sections of sheep affected by pulmonary adenocarcinoma. As a whole, these results suggest that the activation of the PI-3K/Akt pathway contributes to the process of JSRV-induced cell transformation but most likely is not the primary determinant both in vitro and in vivo.     

Clinical features and progression of perinatally acquired hepatitis C virus infection

The purpose of this prospective-retrospective study was to provide information about the clinical features and progression of hepatitis C virus (HCV) infection transmitted perinatally. Seventy children born to HCV infected woman were enrolled consecutively in five European centers between 1990 and 1999, provided they had HCV RNA in the serum during the first year of life and/or were still anti-HCV positive at 18 months. Sixty-two infants were followed up to 24 months of age or more (range, 24 months-11 years; average, 4.8 +/- 2.3 years). A wide range of ALT elevation was observed in 93% of the infants in the first year of life. During the follow-up, a sustained ALT normalization with loss of HCV RNA was seen in 12/62 (19%) of the children within 30 months of life; 66% of the infants had developed an ALT peak greater than 5x normal at onset (vs. 28% of children with persistent viremia; P < 0.05), and 50% had HCV genotype 3 (vs. 17% of viremic children). Conversely the cumulative probability of chronic progression was 81%. Chronic infection was asymptomatic and liver disease was mild in all 11 children who underwent a biopsy. In conclusion the early stage of acquired perinatally HCV infection is characterized by a wide range of ALT abnormalities, suggesting the interaction of multiple host and virus factors. The chronic progression rate of infection is high, but the associated liver disease is usually mild. High ALT levels at onset seem to offer greater opportunity of biochemical remission and loss of viremia during follow-up.     

Total HCV core antigen assay: a new marker of hepatitis C viremia for monitoring the progress of therapy

The ability of the total hepatitis C virus (HCV) core antigen assay was evaluated for monitoring the therapeutic responses of HCV-infected patients treated with interferon. The ability to detect and quantitate an independent structural protein component of HCV, in the presence of circulating antibodies, makes this assay a valuable new tool in diagnosis and treatment monitoring. Measurement of total core antigen showed a strong dynamic correlation with HCV RNA data and may serve as an alternative direct marker of viral infection. In addition, with the advent of additional treatment protocols, a rapid, reliable assay for changes in HCV load may permit more frequent patient assessment and tailoring of the therapeutic regimen.     

Altered sonographic umbilical cord morphometry in early-onset preeclampsia

OBJECTIVE: To determine whether the sonographic morphometry of the umbilical cord components is different in preeclamptic compared with healthy pregnant women. METHODS: Consecutive women admitted after 20 weeks' gestation with the diagnosis of preeclampsia and whose fetus was normally grown (cases) were included in the study. Each case was matched to a healthy pregnant woman (controls) who had ultrasonography at the same gestational age (+/- 3 days). The sonographic cross-sectional areas of the umbilical cord and umbilical vessels were obtained in all patients and plotted on reference ranges. The umbilical artery resistance index was measured in all patients with preeclampsia. RESULTS: Twenty-five preeclamptic women were enrolled. The proportion of cases with a lean (below the tenth centile) umbilical cord was higher in cases than in controls (12 of 25 versus 1 of 25, P <.001). The Wharton's jelly area was lower in cases than in controls (median 105.8 mm(2) [range 49.6-212.9 mm(2)] versus 138.7 mm(2) [79.7-226.6 mm(2)], P =.024). The umbilical vein area was less in cases than in controls (median 29.2 mm(2) [range 8.0-52.8 mm(2)] versus 37.4 mm(2) [13.8-70.8 mm(2)], P =.032). The proportion of patients with a lean umbilical cord was higher among those with early-onset preeclampsia than in those with late-onset preeclampsia (12 of 19 versus 0 of 6, P =.014). CONCLUSION: Early-onset preeclampsia frequently is associated with reduced Wharton's jelly area and umbilical vein area compared with normal pregnancy. Sonographic umbilical cord morphometry might have clinical value for prompt identification of women at risk for preeclampsia.     

Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case-control study

OBJECTIVE: A role of female hormones, including oral contraceptives, has been suggested in the etiology of focal nodular hyperplasia of the liver. There is, however, no epidemiologic quantification of this relationship. STUDY DESIGN: A hospital-based case-control study was conducted in Italy of 23 women with histologically confirmed focal nodular hyperplasia of the liver and 94 controls in the hospital for acute diseases. Odds ratios (ORs) were computed by use of multiple logistic regression models. RESULTS: Focal nodular hyperplasia was not associated with menstrual and reproductive factors. Ever oral contraceptive use was reported by 83% of cases and 59% of controls. The multivariate OR was 2.8 (95% confidence interval [CI], 0.8-9.4) for ever use, and 4.5 (95% CI, 1.2-16.9) for use > or = 3 years. The trend in risk with duration was statistically significant. CONCLUSIONS: This study confirms previous clinical observations, and provides a quantitative estimate of the association between use of oral contraceptives and focal nodular hyperplasia of the liver.