Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1

Replication licensing ensures once per cell cycle replication and is essential for genome stability. Overexpression of two key licensing factors, Cdc6 and Cdt1, leads to overreplication and chromosomal instability (CIN) in lower eukaryotes and recently in human cell lines. In this report, we analyzed hCdt1, hCdc6, and hGeminin, the hCdt1 inhibitor expression, in a series of non-small-cell lung carcinomas, and investigated for putative relations with G(1)/S phase regulators, tumor kinetics, and ploidy. This is the first study of these fundamental licensing elements in primary human lung carcinomas. We herein demonstrate elevated levels (more than fourfold) of hCdt1 and hCdc6 in 43% and 50% of neoplasms, respectively, whereas aberrant expression of hGeminin was observed in 49% of cases (underexpression, 12%; overexpression, 37%). hCdt1 expression positively correlated with hCdc6 and E2F-1 levels (P = 0.001 and P = 0.048, respectively). Supportive of the observed link between E2F-1 and hCdt1, we provide evidence that E2F-1 up-regulates the hCdt1 promoter in cultured mammalian cells. Interestingly, hGeminin overexpression was statistically related to increased hCdt1 levels (P = 0.025). Regarding the kinetic and ploidy status of hCdt1- and/or hCdc6-overexpressing tumors, p53-mutant cases exhibited significantly increased tumor growth values (Growth Index; GI) and aneuploidy/CIN compared to those bearing intact p53 (P = 0.008 for GI, P = 0.001 for CIN). The significance of these results was underscored by the fact that the latter parameters were independent of p53 within the hCdt1-hCdc6 normally expressing cases. Cumulatively, the above suggest a synergistic effect between hCdt1-hCdc6 overexpression and mutant-p53 over tumor growth and CIN in non-small-cell lung carcinomas.     

Cure of multidrug-resistant Acinetobacter baumannii fixation device-related orthopedic infections in two patients with intravenous colistin

We report our experience with two cases of fixation device-related orthopedic infections due to multidrug-resistant Acinetobacter baumannii strains. Both patients were successfully treated with intravenous administration of colistin, despite the reported poor penetration of this medication to these tissues, in the old literature. No serious colistin-associated toxicity developed and no recurrence of the infection occurred on follow up.     

Maternal uniparental isodisomy 20 in a foetus with trisomy 20 mosaicism: clinical,cytogenetic and molecular analysis

The clinical significance of trisomy 20 mosaicism detected prenatally remains uncertain due to the rarity of liveborn cases with inconsistent clinical findings, and lack of long-term follow-up and outcome. We describe a case of true trisomy 20 mosaicism in a liveborn girl with maternal uniparental isodisomy of chromosome 20 in the diploid blood cells. Trisomy 20 mosaicism was originally detected in amniotic fluid (98%) and was confirmed in the term placenta (100%), as well as in the blood (10%) and urine sediment (100%) of the neonate. There was intrauterine and postnatal growth retardation, but otherwise the newborn manifested no gross abnormalities. At 9 months of age moderate psychomotor retardation, central hypotonia with peripheral hypertonia, numerous minor morphogenetic variants, marked kyphosis, and extensive Mongolian spot were observed. To our knowledge this represents the first case of trisomy 20 mosaicism detected prenatally and confirmed in different tissues of the newborn, where uniparental disomy was demonstrated in the diploid cell line. The clinical and laboratory findings in our patient are compared with those of five previously reported cases of UPD20, suggesting that maternal UPD20 might be associated with a characteristic phenotype.     

Changes in linear and nonlinear EEG measures as a function of task complexity: evidence for local and distant signal synchronization

The purpose of the present study was threefold: First, to replicate previous findings of changes in local gamma band power as a function of the complexity of a visuo-semantic processing task, second, to extend these findings in tasks delivered in the auditory modality, and third to explore the use of non-linear algorithms as indices of complexity and distant synchronization in the EEG signal. EEG was recorded from 28 scalp locations as participants performed three visual discrimination tasks designed to tap into increasingly more complex operations regularly involved in the recognition of living animate objects. Two auditory processing tasks involving the same stimuli, but requiring no semantic processing, served as controls. The degree of complexity of the semantic decision was associated with the predicted changes in local gamma power, as well as with broadband changes in the non-linear predictability of the signal (an index derived using an artificial neural network algorithm). These changes were observed at all scalp regions, a finding consistent with the wide cortical distribution of component processes involved in the tasks. In addition, the synchronization between temporal and parieto-occipital electrodes and the remaining recording sites was highest in the gamma bands and lowest in the alpha bands for the task that required the most complex visuo-semantic decision. This trend reversed with reduced task complexity, consistent with the view that multidimensional semantic decisions require the involvement of distributed cortical networks in auditory and visual association areas and in the frontal lobes.     

Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group.

PURPOSE: To investigate whether docetaxel plus platinum regimens improve survival and affect quality of life (QoL) in advanced non-small-cell lung cancer (NSCLC) compared with vinorelbine plus cisplatin as first-line chemotherapy. PATIENTS AND METHODS: Patients (n = 1,218) with stage IIIB to IV NSCLC were randomly assigned to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 every 3 weeks (DC); docetaxel 75 mg/m2 and carboplatin area under the curve of 6 mg/mL * min every 3 weeks (DCb); or vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2 every 4 weeks (VC). RESULTS: Patients treated with DC had a median survival of 11.3 v 10.1 months for VC-treated patients (P =.044; hazard ratio, 1.183 [97.2% confidence interval, 0.989 to 1.416]). The 2-year survival rate was 21% for DC-treated patients and 14% for VC-treated patients. Overall response rate was 31.6% for DC-treated patients v 24.5% for VC-treated patients (P =.029). Median survival (9.4 v 9.9 months [for VC]; P =.657; hazard ratio, 1.048 [97.2 confidence interval, 0.877 to 1.253]) and response (23.9%) with DCb were similar to those results for VC. Neutropenia, thrombocytopenia, infection, and febrile neutropenia were similar with all three regimens. Grade 3 to 4 anemia, nausea, and vomiting were more common (P <.01) with VC than with DC or DCb. Patients treated with either docetaxel regimen had consistently improved QoL compared with VC-treated patients, who experienced deterioration in QoL. CONCLUSION: DC resulted in a more favorable overall response and survival rate than VC. Both DC and DCb were better tolerated and provided patients with consistently improved QoL compared with VC. These findings demonstrate that a docetaxel plus platinum combination is an effective treatment option with a favorable therapeutic index for first-line treatment of advanced or metastatic NSCLC.     

Complete left atrial obliteration due to localized tamponade after coronary artery perforation during PTCA

Coronary artery perforation is a rare but important complication of percutaneous revascularization (PTCA). Clinical events following coronary perforation may include cardiac tamponade. After bypass graft operation (CABG), however, cardiac tamponade with subsequent hemodynamic instability is unusual due to the development of pericardial adhesions. We report an unusual case of localized tamponade after coronary artery perforation during PTCA in a patient with previous CABG. Cathet. Cardiovasc. Diagn. 45:61–63, 1998. © 1998 Wiley-Liss, Inc.     

The TNF‐863A allele strongly associates with anticentromere antibody positivity in scleroderma

Objective

Scleroderma is characterized by the presence of 3 predominant, yet almost mutually exclusive, antibodies: anticentromere antibody (ACA), antitopoisomerase antibody, and anti–RNA polymerase antibody. The purpose of this study was to investigate tumor necrosis factor (TNF) polymorphisms in scleroderma, with the specific aim of determining whether TNF polymorphisms would prove to be stronger markers for ACA than class II major histocompatibility complex (MHC).

Methods

We studied 214 UK white scleroderma patients and 354 healthy controls. All subjects were investigated for 5 TNF promoter region polymorphisms by sequence‐specific polymerase chain reaction.

Results

We showed that an NF‐κB binding site polymorphism (known to be functionally relevant) in the TNF promoter region was present in 51.8% of patients with ACA and 16.3% of patients without ACA (χ² = 25.1, P = 0.000004 [corrected P = 0.00002]). Using haplotype mapping, we showed that this was a primary TNF association that could explain the previous weak links between ACA production and class II MHC alleles. In marked contrast to our ACA results, HLA class II (especially DRB1*11) appeared to be primary in that it could explain the weaker TNF association with antitopoisomerase production. Further, we observed a separate TNF haplotype to be associated with scleroderma per se, although the level of significance was much lower (χ² = 8.7, P = 0.003 [corrected P = 0.02]).

Conclusion

We believe these findings may have importance both for the directional pathogenesis of scleroderma progression and for the treatment of scleroderma with anti‐TNF agents.

     

Noninvasive risk factors for the prediction of inducibility on programmed ventricular stimulation in post‐myocardial infarction patients with an ejection fraction ≥40% at risk for sudden cardiac arrest: Insights from the PRESERVE‐EF study

BackgroundIn the PRESERVE‐EF study, a two‐step sudden cardiac death (SCD) risk stratification approach to detect post‐myocardial infarction (MI) patients with left ventricle ejection fraction (LVEF) ≥40% at risk for major arrhythmic events (MAEs) was used. Seven noninvasive risk factors (NIRFs) were extracted from a 24‐h ambulatory electrocardiography (AECG) and a 45‐min resting recording. Patients with at least one NIRF present were referred for invasive programmed ventricular stimulation (PVS) and inducible patients received an Implantable Cardioverter ‐ Defibrillator (ICD).MethodsIn the present study, we evaluated the performance of the NIRFs, as they were described in the PRESERVE‐EF study protocol, in predicting a positive PVS. In the PRESERVE‐EF study, 152 out of 575 patients underwent PVS and 41 of them were inducible. For the present analysis, data from these 152 patients were analyzed.ResultsAmong the NIRFs examined, the presence of signal averaged ECG‐late potentials (SAECG‐LPs) ≥ 2/3 and non‐sustained ventricular tachycardia (NSVT) ≥1 eposode/24 h cutoff points were important predictors of a positive PVS study, demonstrating in the logistic regression analysis odds ratios 2.285 (p = .027) and 2.867 (p = .006), respectively. A simple risk score based on the above cutoff points in combination with LVEF < 50% presented high sensitivity but low specificity for a positive PVS.ConclusionCutoff points of NSVT ≥ 1 episode/24 h and SAECG‐LPs ≥ 2/3 in combination with a LVEF < 50% were important predictors of inducibility. However, the final decision for an ICD implantation should be based on a positive PVS, which is irreplaceable in risk stratification.     

Actinomycosis of the appendix and pelvis: a case report

BACKGROUND: Actinomycosis is a chronic infection caused by Actinomyces israeli, a gram-positive saprophytic anaerob, a normal inhabitant of the upper intestinal tract. CASE: We report a case of a 35-year-old female with an intrauterine device (IUD) who appeared in the emergency department with clinical characteristics of appendicitis. Ultrasound and computed tomography were performed, revealing an ovarian tumor formation and acute appendicitis. The patient underwent exploratory laparotomy, unilateral ovarectomy due to acute abscess and finally appendectomy. Diagnosis of actinomycosis was established with the presence of sulphur granules microscopically. The patient received penicillin for an extended period. Two years have passed and no clinical recurrence was mentioned. CONCLUSION: Actinomycosis is not easily apparent because of its rarity. Inflammatory intestinal and pelvic disease can easily mislead the diagnosis, giving the impression of a neoplastic process. The drug of choice is penicillin, initiating a long-term aggressive therapy. The antimicrobial treatment lasts from 6 months to a year. Prognosis is very good. The role of IUD as a factor in the dissemination of the infection is very important. Physicians should be aware of actinomycosis in cases of abdominopelvic infiltrating masses.