TGF-beta1 increases tyrosine hydroxylase expression by a mechanism blocked by BMP-2 in human neuroblastoma SH-SY5Y cells

Human neuroblastoma SH-SY5Y cells were used to study the effects of transforming growth factor beta1 (TGF-beta1) and bone morphogenetic protein 2 (BMP-2) on neuronal differentiation and acquisition of a catecholaminergic phenotype. SH-SY5Y cells express the intracellular factors activated through the receptors of the TGFbeta superfamily members, Smad1 and Smad4, as in basal conditions or after differentiation with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or retinoic acid (RA). TGF-beta1 and BMP-2 induce differentiation in SH-SY5Y cells by different pathways: the effect of TGF-beta1 is potentiated by TPA and the effect of BMP-2 is blocked by RA. Cell differentiation due to TGF-beta1 treatment is accompanied by an increase in tyrosine hydroxylase (TH) expression, more pronounced in the presence of TPA or RA and counteracted by BMP-2. BMP-2 and RA both induce noncatecholaminergic cell differentiation, and together they may induce choline acetyltransferase expression in serum-cultured cells. In conclusion, our results suggest that TGF-beta1 and BMP-2 may contribute, in opposite ways, to regulation of the neuronal catecholaminergic phenotype.     

Novelty-related activation within the medial temporal lobes

Functional magnetic resonance imaging (fMRI) was used to examine whether (1) verbal associative encoding activates the medial temporal lobes (MTL) and related regions more than non-associative encoding, (2) verbal associative novelty is related to enhanced MTL activation, and (3) verbal item novelty is related to enhanced MTL activation and, if so, whether these activations are in different or overlapping sites. No increase in MTL activation was found during verbal associative encoding relative to non-associative encoding, although associative encoding was related to a relative increase in activation in the posterior cingulate cortex. In contrast, verbal associative novelty was found to activate the MTL and posterior cingulate cortex. Verbal item novelty did not significantly activate any brain region. The verbal associative novelty-related effect occurred despite subjects having little awareness of associative novelty. The verbal associative novelty-related activation in the MTL may be related either to unconscious novelty detection or to a priming effect at encoding. We argue that if the priming explanation is correct then this may account for our failure to observe an associative encoding MTL activation.     

Quality of data on subsequent events in a routine Medical Birth Register

BACKGROUND: The maintenance of health registers has become routine. The main prerequisite for their use is that registers be complete and that their contents correspond to reality. METHODS: Data on all primiparous women who gave birth between 1987 and 1989 (N=73009) and on their second (N=55388) and third births (N=22904) in the 1987-1998 period were retrieved from the Finnish Medical Birth Register (MBR). The consistency of the MBR data on reproductive history and on previous Caesarean section was investigated by comparing the records on subsequent births. MAIN RESULTS: In total 98.5% of the information on reproductive history corresponded with the previous data in the MBR. Data quality decreased over time and with increasing parity. There were problems with the registration of rare cases, e.g. several extrauterine pregnancies or stillbirths. The quality deteriorated in the late 1990s, because no data on previous induced abortions and extrauterine pregnancies were collected between 1991 and 1995. The quality of data on previous Caesarean section was poor in 1987-1990, a period when the data were collected by using ICD-9 codes, but the quality improved after the introduction of a check-box format in 1991. CONCLUSIONS: Changes in question formats may change the quality of register data significantly. Check-boxes seem to improve quality compared to open-ended questions. The data on reproductive history and previous Caesarean sections could be combined routinely to improve the quality of the MBR.     

Dead Sea treatment - principle for outpatient use in atopic dermatitis: safety and efficacy of synchronous balneophototherapy using narrowband UVB and bathing in Dead Sea salt solution

Safety and efficacy of this new treatment modality for out-patients were evaluated by an uncontrolled multicenter trial under GCP-conditions. Patients had to undergo 3-5 treatment sessions per week up to 35 in total. SCORAD (SC) was assessed at baseline, after 20 and 35 sessions. For patients with early study withdrawal the last-observation-carry-forward-principle was used. 615 intention-to-treat (itt)- (baseline SC: 59.4) and 143 according-to-protocol (atp)-patients (baseline SC: 60.1) could be analysed. 289 patients (47%) (baseline SC: 59.1) underwent less than 35 sessions. Main reasons were: lack of time (16%), non-compliance (12%), good improvement (7%), lack of efficacy (6%), intercurrent disease (4%) and side effects (3%). Mean number of sessions in atp-group was 35, in itt 26, and in patients with early study withdrawal 15.8. SC decreased in atp-group to 37.5 (itt: 44.5/patients with early study withdrawal: 46.1) after 20 sessions and to 27.1 (35.2/42.6) at end of treatment. Relative SC-improvement was statistically significant in atp- (55%), itt-group (41%), and in patients with early study withdrawal (26%). Most frequent side effects were: erythema in 7.3%, burning of skin due to salt solution in 3.6%. Safety and efficacy could be proven in both atp- and itt-group. A marked difference in efficacy between atp and itt underlines the importance of evaluating itt-data providing a more realistic assessment of a treatment modality in practice. This treatment is especially recommended for patients with chronic type of AD, high compliance and time free for therapy.     

Using deeply trapped intermediates to map the cytochrome c folding landscape

Replacement of iron with cobalt(III) selectively introduces a deep trap in the folding-energy landscape of the heme protein cytochrome c. Remarkably, neither the protein structure nor the folding thermodynamics is perturbed by this metal-ion substitution, as shown by data from spectroscopic and x-ray diffraction experiments. Through kinetics measurements, we have found parallel folding pathways involving several different misligated Co(III) species, and, as these folding intermediates persist for several hours under certain conditions, we have been able to elucidate fully their spectroscopic properties. The results, along with an analysis of the fluorescence energy-transfer kinetics during refolding, show that rapidly equilibrating populations of compact and extended polypeptide conformations are present until all molecules have reached the native structure. These measurements provide direct evidence that collapsed denatured structures are not substantially more stable than extended conformations of cytochrome c.     

Antithrombin-independent anticoagulation by hypersulfated low-molecular-weight heparin

Low-molecular-weight heparin (LMWH) inhibits the activity of the intrinsic factor X activation complex, a property that persists when LMWH is rendered low affinity (LA) for antithrombin, but is reduced when it is N-desulfated. When LA-LMWH is hypersulfated (sLA-LMWH), its potency against intrinsic tenase is increased and it acquires inhibitory activity against prothrombinase. sLA-LMWH functions by interfering with the association of enzyme and cofactor in both activation complexes. In a rabbit carotid artery thrombosis prevention model, sLA-LMWH is superior to LMWH. Because of its low affinity for antithrombin and multiple sites of action, sLA-LMWH may prove to be safer and more effective than other anticoagulants.