Distinct promoters mediate constitutive and inducible Bcl-XL expression in malignant lymphocytes

Bcl-X(L) is a Bcl-2-related survival protein that is essential for normal development. Bcl-X(L) expression is rapidly induced by a wide range of survival signals and many cancer cells constitutively express high levels. The Bcl-X gene has a complex organization with multiple promoters giving rise to RNAs with alternate 5' non-coding exons. Here we have investigated the mechanisms that control basal and induced expression of Bcl-X(L) in B-lymphoma cells. Antisense experiments demonstrated that Bcl-X(L) was essential for survival of Akata6 B-lymphoma cells. The levels of RNAs containing the IB Bcl-X non-coding exon, derived from the distal 1B promoter, correlated with basal expression of Bcl-X(L) in primary malignant B cells and this promoter was highly active in B-cell lines. The activity of this promoter was largely dependent on a single Ets binding site and Ets family proteins were bound at this promoter in intact cells. CD40 ligand (CD40L)-induced cell survival was associated with increased Bcl-X(L) expression and accumulation of exon IA-containing RNAs, derived from the proximal 1A promoter. Nuclear factor-kappaB (NF-kappaB) inhibition prevented induction of Bcl-X(L) protein and exon IA-containing RNAs by CD40L. Therefore, the distal Bcl-X 1B promoter plays a critical role in driving constitutive expression-mediated via Ets family proteins in malignant B cells, whereas NF-kappaB plays a central role in the induction of Bcl-X(L) in response to CD40 signalling via the proximal 1A promoter.     

Fibromyalgiesyndrom bei Kindern und Jugendlichen

OBJECTIVE: The aim was to develop a guideline for diagnostic procedures and treatment of juvenile fibromyalgia syndrome (JFMS) in cooperation with 10 German medical and psychological associations and 2 patient self-help groups. METHODS: A systematic literature search, including all controlled studies evaluating diagnosis and treatment of JFMS, was performed in the Cochran Collaboration Reviews (1993-12/2006), Medline (1980-12/2006), PsychInfo (1966-12/2006) and Scopus (1980-12/2006). Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine. Grading of the strengths of recommendations was performed according to the German program for disease management guidelines. Standardized procedures to reach a consensus on recommendations were used. RESULTS: Pain in children/adolescents involving several body areas and lasting >3 months without an obvious somatic cause is called JFMS or pain amplification syndrome. Therapeutically, a multidisciplinary concept with psychotherapy and physiotherapy, relaxation techniques and patient education is recommended. CONCLUSION: These guideline will contribute to a better recognition and standardized care of patients with JFMS and facilitate clinical studies.     

Birth weight and the risk of testicular cancer: a meta-analysis

The high incidence of testicular cancer in young males indicates a potential role of events during early life. Birth weight has been identified as a factor possibly associated with the risk of cancers later in life. To investigate the association between birth weight and testicular cancer, we conducted a Systematic Review and Meta-Analysis of published studies investigating the association between birth weight and testicular cancer. Data were combined using a fixed-effects model. Thirteen epidemiologic studies, published between 1983 and 2004, were included in the analysis, encompassing 5,663 patients with testicular cancer. Men weighing less than 2,500 grams at birth had a higher risk for developing testicular cancer later in life than those with normal birth weight (2,500-4,000 g) (OR = 1.18; 95% confidence interval (CI) 1.01-1.38). A similar trend was found for men with a birth weight above 4,000 g, (OR = 1.12; 95% CI 1.02-1.22). When seminoma and nonseminoma testicular cancer cases were considered separately, low birth weight was a risk factor specifically for seminomas (OR = 1.44; 95% CI 1.11-1.88). A U-shaped association was observed between birth weight and the risk for testicular cancer. The underlying biological mechanisms for this phenomenon remain to be elucidated.     

(R)-α-Lipoic acid treatment restores ceramide balance in aging rat cardiac mitochondria

Inflammation results in heightened mitochondrial ceramide levels, which cause electron transport chain dysfunction, elevates reactive oxygen species, and increases apoptosis. As mitochondria in aged hearts also display many of these characteristics, we hypothesized that mitochondrial decay stems partly from an age-related ceramidosis that heretofore has not been recognized for the heart. Intact mitochondria or their purified inner membranes (IMM) were isolated from young (4–6 mo) and old (26–28 mo) rats and analyzed for ceramides by LC–MS/MS. Results showed that ceramide levels increased by 32% with age and three ceramide isoforms, found primarily in the IMM (e.g. C₁₆-, C₁₈-, and C_24:1-ceramide), caused this increase. The ceramidosis may stem from enhanced hydrolysis of sphingomyelin, as neutral sphingomyelinase (nSMase) activity doubled with age but with no attendant change in ceramidase activity. Because (R)-α-lipoic acid (LA) improves many parameters of cardiac mitochondrial decay in aging and lowers ceramide levels in vascular endothelial cells, we hypothesized that LA may limit cardiac ceramidosis and thereby improve mitochondrial function. Feeding LA [0.2%, w/w] to old rats for two weeks prior to mitochondrial isolation reversed the age-associated decline in glutathione levels and concomitantly improved Complex IV activity. This improvement was associated with lower nSMase activity and a remediation in mitochondrial ceramide levels. In summary, LA treatment lowers ceramide levels to that seen in young rat heart mitochondria and restores Complex IV activity which otherwise declines with age.     

Comparison of written reports of mammography, sonography and magnetic resonance mammography for preoperative evaluation of breast lesions, with special emphasis on magnetic resonance mammography

Patients with abnormal breast findings (n = 413) were examined by mammography, sonography and magnetic resonance (MR) mammography; 185 invasive cancers, 38 carcinoma in situ and 254 benign tumours were confirmed histologically. Sensitivity for mammography was 83.7%, for sonography it was 89.1% and for MR mammography it was 94.6% for invasive cancers. In 42 patients with multifocal invasive cancers, multifocality had been detected by mammography and sonography in 26.2%, and by MR mammography in 66.7%. In nine patients with multicentric cancers, detection rates were 55.5, 55.5 and 88.8%, respectively. Carcinoma in situ was diagnosed by mammography in 78.9% and by MR mammography in 68.4% of patients. Combination of all three diagnostic methods lead to the best results for detection of invasive cancer and multifocal disease. However, sensitivity of mammography and sonography combined was identical to that of MR mammography (ie 94.6%).     

Perfluoro-octane in the treatment of giant retinal tears with proliferative vitreoretinopathy.

Giant retinal tears complicated by proliferative vitreoretinopathy (PVR) pose one of the more complex problems in vitreoretinal surgery. The authors developed a technique using perfluoro-octane, a temporary vitreous substitute that is heavier than water, combined with vitrectomy, scleral buckling, fluid-gas exchange, and direct manipulation of the retina to treat these cases. Ten eyes with giant retinal tears and grade D-1 PVR or worse were treated. In all eyes, the retina was successfully reattached at the end of surgery. Nine of the ten retinas remained attached after 6 months of follow-up. Five eyes required a total of six reoperations for epiretinal membrane formation without retinal detachment. The one eye in which the retina did not remain reattached developed severe recurrent PVR and iris neovascularization. Visual acuity improved in 8 of 10 eyes. Final visual acuity was 20/400 or better in 8 of 10 eyes, and 20/80 or better in 4 eyes.     

Lens and peripheral retinal relationships during vitrectomy

Relationships between the posterior surface of the crystalline lens and instruments introduced into the vitreous cavity through pars plana incisions were evaluated in ten eyes from cadavers. Instruments were introduced 3.0 mm, 3.5 mm, and 4.0 mm posterior to the anterior part of the limbus. The distance between an instrument oriented toward the center of the vitreous cavity and the peripheral edge of the lens in that meridian was 1.6 mm when the sclerotomy was 3.0 mm from the limbus and 2.8 mm when the sclerotomy was 4.0 mm from the limbus. The arc length from the sclerotomy where the instrument was introduced to the most distal meridian of the ora serrata that could be reached without touching the lens ranged from 2.8 to 3.8 clock hours as the distance between the sclerotomy and the limbus increased from 3.0 mm to 4.0 mm. The distance between the ora serrata and the most peripherally accessible point on the retina in the meridian 180 degrees from the sclerotomy decreased from 6.0 mm to 3.1 mm as the distance between the limbus and the sclerotomy increased from 3.0 mm to 4.0 mm.     

The electrochemical proton gradient in the bloodstream form of Trypanosoma brucei is dependent on the temperature.

The membrane potential and pH gradient over the plasma membrane of the protozoan parasite Trypanosoma brucei were measured with radioactive indicators in combination with the silicone oil centrifugation technique over a range of temperatures. At 37 degrees C a small membrane potential and pH gradient of similar magnitude, but of opposite polarity, were measured. The resulting electrochemical proton gradient was almost zero. However, when the temperature was lowered from 37 degrees C to 22 degrees C, the internal pH was kept constant independent of the external pH and a membrane potential of between -100 and -150 mV was measured, depending on the external pH. Measurements at various temperatures between 15 degrees C and 37 degrees C revealed that above 26 degrees C the membrane potential collapsed and that this collapse correlated with a sudden increase in membrane fluidity. The uptake of 2-deoxy-D-glucose and of pyruvate, which are both mediated by facilitated diffusion carriers in the plasma membrane of the trypanosome, were also affected by this sudden increase in fluidity of the membrane. The overall rate of the conversion of glucose into its metabolites, which is independent of the plasma membrane, varied only gradually. We conclude (i) that major changes occur in the plasma membrane of T. brucei around 26 degrees C, that affect all membrane related processes; (ii) that the electrochemical proton gradient plays a minor role in the energy metabolism of T. brucei when it resides in the bloodstream of the mammalian host at 37 degrees C; and (iii) that below 26 degrees C an electrochemical proton gradient is maintained over the plasma membrane.