Tumor necrosis factor-{alpha} up-regulates Bcl-2 expression and decreases calcium-dependent apoptosis in human B cell lines

Group I and Epstein–Barr virus-negative Burkitt's lymphomacell lines and the B104 lymphoma cell line which expresses aphenotype of immature B cells undergo apoptosis after cross-linkingof their surface Ig receptors or after exposure to a calciumionophore. We show here that tumor necrosis factor (TNF)- protectsthese B cell lines against Ca²⁺-dependent apoptosis. Protectionwas associated with up-regulatlon of bcl-2 mRNA and proteinexpression. The increase of Bcl-2 expression induced by TNF-was inhibited by chelerythrine, a specific inhibitor of proteinkinase C (PKC), suggesting that Bcl-2 expression was dependenton PKC activation. Furthermore, we show that phorbol estersand cyclosporin A (CsA), which prevent Ca²⁺-dependent apoptosis,up-regulated Bcl-2 expression. The effect of CsA on Bcl-2 expressionis controlled by calcineurin since we have shown that FK506but not rapamycin had the same effect on Bcl-2 expression, whereasokadaic acid, an inhibitor of phosphatases 1, 2A and 2C, wasineffective. These data provide direct evidence that TNF- preventsCa²⁺-dependent apoptosis by a Bcl-2-dependent mechanism mediatedby PKC.     

Osteoclastome-like giant cell thyroid carcinoma controlled by intensive radiation and adriamycin,in a patient with meningioma and multiple myeloma treated by radiation and cytoxan

The eighth case of osteoclastome-like giant cell carcinoma of the thyroid, and the first one to be treated with adriamycin in addition to surgery and radiation, is reported. This rare variant of anaplastic thryoid carcinoma appeared in a patient operated on for meningioma and treated for multiple myeloma with cranial radiation and chronic administration of cytoxan.     

Fabry disease and vascular risk factors: future strategies for patient-based studies and the knockout murine model

Fabry disease is secondary to deficiency of the lysosomal enzyme α-galactosidase A, leading to altered glycosphingolipid metabolism and accumulation that is often associated with endothelial dysfunction. Current evidence suggests that there is impairment of the vascular nitric oxide pathway, with abnormalities evident in the cerebral circulation and in the dermal vasculature of patients with Fabry disease. Some of these findings have been confirmed in a mouse model of Fabry disease. The murine model, however, allows investigation of Fabry disease at a non-clinical level and a near complete investigation of biological processes within an affected tissue. This is of particular utility in allowing gene expression analysis of clinically inaccessible tissues such as the aorta.
Conclusion: Future developments in array technology for proteins and DNA single nucleotide polymorphism analysis, together with gene expression microarray analysis, may open a new chapter in our understanding of the biology of lysosomal storage disorders.     

Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1-TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia.

PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients. EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL. CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.     

Infection with IBV DMV/1639 at a Young Age Leads to Increased Incidence of Cystic Oviduct Formation Associated with False Layer Syndrome

Infectious bronchitis virus (IBV) is an avian coronavirus that causes respiratory disease but can affect the reproductive tract of laying-type chickens. If infection occurs in pullets, false layer syndrome, which is characterized by the development of large, fluid-filled cystic oviducts, can occur. Recently, IBV strain DMV/1639 has been detected in parts of Canada and the U.S., where false layer syndrome has occurred, though it is not clear if IBV is the sole cause or if age at infection is an influencing variable. Our study investigates the role and timing of IBV infection on the development of false layer syndrome, using the IBV types DMV/1639 and Massachusetts (Mass). Six groups of 120 SPF chickens were challenged at either three, seven, or fourteen days of age, using either DMV/1639 or Mass IBV. Cystic oviducts were seen in all the challenged groups, and the pullets challenged at 14 days of age had fewer cystic oviducts than pullets challenged at 3 or 7 days of age. The highest percentage of severe histology lesion scores were seen in the 3-day challenge groups. The data collected in this experiment confirm that IBV DMV/1639 causes cystic oviducts and indicate that age at infection plays a role in the pathogenesis of false layer syndrome.     

Efficacy of routine follow-up in patients with recurrent uterine cancer

OBJECTIVE: To evaluate the efficacy of routine follow-up in patients with recurrent uterine cancer. METHODS: In a single institution study, a total of 2637 patients were treated curatively for uterine cancer from 1990 to 2006. A total of 438 patients experienced disease recurrence. Data for detailed analysis were available from 280 of the 438 patients. Prior to the diagnosis of recurrence, all patients had regular follow-up and were investigated through internal examination, vaginal vault cytology and imaging. Overall survival (OS) was the main study endpoint and was calculated from recurrence diagnosis to death or date censored. RESULTS: Clinical and histopathological features as well as patterns of recurrence were similar in symptomatic and asymptomatic patients. Eighty-one patients (28.9%) were diagnosed with asymptomatic recurrence while 199 patients (71.1%) presented with symptomatic recurrence. The overall survival probability at 5 years was 41.0% and 28.9% respectively for asymptomatic and symptomatic patients (log-rank p=0.013). Those patients with stage 1 or 2 tumors of endometrioid type were found to have an overall survival probability at 5 years of 38.0% and 25.7% respectively for asymptomatic and symptomatic recurrence (log-rank p=0.05). The absence of symptoms did not impact on the outcome of patients with stage 3 tumors or tumors of non-endometrioid type. CONCLUSIONS: While patients at low/intermediate risk of recurrence may benefit from intensive follow-up including internal examinations, routine vaginal vault cytology and imaging, high-risk patients might gain more from an alternate follow-up strategy with emphasis on imaging in conjunction with symptom education.     

Neonatal and 5-year outcomes after birth at 30-34 weeks of gestation

OBJECTIVE: To evaluate the rates of in-hospital death, neonatal complications, and 5-year outcomes of infants born at 30-34 weeks of gestation. METHODS: In nine regions of France, all 2,020 stillbirths and live births at 30, 31, and 32 weeks in 1997 and all 457 births at 33 and 34 weeks in April and October 1997 were recorded. Survivors were evaluated at 5 years of age. RESULTS: Increasing gestational age from 30 to 34 weeks was associated with progressive decreases in in-hospital mortality (from 8.1% to 0.4%) and neonatal complications (respiratory distress syndrome, 43.8% to 2.6%; maternofetal infections, 7.2% to 2.6%; and severe white matter injury, 5.5% to 1.3%). Although infants at 33 and 34 weeks of gestation rarely experienced necrotizing enterocolitis, bronchopulmonary dysplasia, or nosocomial infections, they still required endotracheal ventilation, antibiotics, or parenteral nutrition. At 5 years of age, older gestational age was associated with significant decreases in rates of cerebral palsy (6.3% at 30 weeks and 0.7% at 34 weeks) and mild to severe cognitive impairments (35.3% at 30 weeks and 23.9% at 34 weeks). In singletons, preterm rupture of membranes or preterm labor carried an increased risk of cerebral palsy but not of cognitive impairment. CONCLUSION: Neonates born at 30-34 weeks experienced substantial morbidity and often required admission to neonatal intensive care units. These outcomes suggest that prolonging pregnancies beyond 34 weeks may be desirable whenever possible. Infants born at 30-34 weeks should be carefully monitored to ensure prompt detection and management of neurodevelopmental impairment.     

How important is consent in maternal serum screening for Down syndrome in France? Information and consent evaluation in maternal serum screening for Down syndrome: a French study

OBJECTIVES: To evaluate the level of information and informed consent for maternal serum screening (MSS) for Down syndrome (DS) in the second trimester of pregnancy and analyse the exercise of autonomy towards the test by the women concerned. METHODS: We studied the population of pregnant women attending obstetric consultations in two French hospitals over a 3-month period. The women were assigned to three groups according to MSS results for DS: women at high risk of having a child with DS (group 1), women at low risk (group 2) and women who did not undergo the test (group 3). A questionnaire was completed before the medical consultation, to assess the quality of consent before amniocentesis for the group at high risk and before the second-trimester ultrasound scan for the other two groups. RESULTS: We analysed 305 questionnaires for 89, 137 and 79 women belonging to groups 1, 2 and 3 respectively. In total, 123 women (40.3% [IC 95%, 35-46%]) were considered to be well informed; 33 (10%, [IC 95%, 8-12%]) had a high level of knowledge, but made choices not consistent with their stated attitude, and 149 (49.7% [IC 95%, 45-56%]) were considered uninformed. Logistic regression analysis showed that maternal consent depended on three independent components: The score attributed to the doctor for information about MSS (t = 4.216, p < 0.001).Whether the patient belonged to group 1 (t = -2.631, p < 0.009).Educational level (< high-school diploma, high-school diploma or at least two years of higher education after high school) (t = 2.324, p < 0.02). The rate of consent increased with educational level and was highest for the women in group 1 and for those whose doctor had a high information score. CONCLUSIONS: Our findings clearly show that women are provided with insufficient information concerning MSS screening for DS in the second trimester of pregnancy for real and valid consent to be obtained.