Regulatorische Aspekte der Anwendung humaner Stammzellen

Human stem cells can be the active ingredient of medicinal products for somatic cell therapy or may be used as the starting or source material for their manufacture. The regulations covering pre-clinical and clinical studies in Germany involving the use of somatic cell therapy drugs, which are medicinal products according to §2 of the German Drug Law (AMG; Arzneimittelgesetz), are defined in the AMG and allow rapid initiation of manufacture and clinical trials. “Points to Consider on the manufacture and quality control of human somatic cell therapy medicinal products (CPMP/BWP/41450/98)” were published by the “Biotechnology Working Party” at the European Agency for the Evaluation of Medicinal Products (EMEA). Although somatic cell therapy drugs will mostly be used as individually prepared medicinal products, clinical trials seem suitable for an objective analysis of the safety and efficacy of these drugs. The transformation of the so-called Good Clinical Practice (GCP)-Directive into German drug regulations, which is currently being considered, will involve the introduction of an approval of clinical trials by a competent authority. Currently, the positive appraisal of the competent local ethics committee is of main relevance for the initiation of clinical trials. If individually prepared somatic cell therapy drugs will be industrially manufactured, obtaining marketing authorisation via the EMEA may be considered in the future.     

Treatment of disordered and ordered systems of polymer chains by lattice methods

Classical lattice theories of systems of long-chain molecules provide estimates of the number Z of random configurations to the exclusion of ordered ones. The decrease of Z thus estimated to values [unk]1 with decrease in chain flexibility at high densities is genuine, but it does not take account of eligible ordered configurations; the latter are not a subset of the configurations whose numbers are estimated by classical lattice methods. Failure to recognize this fact and the fundamental distinction between disordered and ordered states has engendered misinterpretations and has cast doubt on the validity of lattice-statistical methods. In a system at equilibrium, the decline of Z (disordered) with decrease in chain flexibility must be arrested by a first order transition to an ordered state. The inference that approach of Z (disordered) to values <1 presages a thermodynamic transition of second order is tenable only if the array of ordered configurations, not comprehended by theories in which the mean field of unoccupied lattice sites is random, can be ignored.     

The polyphenol quercetin protects from glucotoxicity depending on the aggresome in Caenorhabditis elegans

European Journal of Nutrition - Impaired proteostasis, i.e., protein homeostasis, is considered as a consequence of high-glucose exposure and is associated with reduced survival. The previous...     

Characterization of exposure to byproducts from firing lead-free frangible ammunition in an enclosed,ventilated firing range

U.S. Air Force small arms firing ranges began using copper-based, lead-free frangible ammunition in the early 2000s due to environmental and health concerns related to the use of lead-based ammunition. Exposure assessments at these firing ranges have routinely detected chemicals and metals in amounts much lower than their mass-based occupational exposure limits, yet, instructors report work-related health concerns including respiratory distress, nausea, and headache. The objective of this study at one firing range was to characterize the aerosol emissions produced by weapons during firing events and evaluate the ventilation system's effectiveness in controlling instructor exposure to these emissions. The ventilation system was assessed by measuring the range static air pressure differential and the air velocity at the firing line. Air flow patterns were near the firing line. Instructor exposure was sampled using a filter-based air sampling method for metals and a wearable, real-time ultrafine particle counter. Area air sampling was simultaneously performed to characterize the particle size distribution, morphology, and composition. In the instructor's breathing zone, the airborne mass concentration of copper was low (range = <1 µg/m³ to 16 µg/m³), yet the ultrafine (nanoscale) particle number concentration increased substantially during each firing event. Ultrafine particles contained some copper and were complex in morphology and composition. The ventilation assessment found that the average velocity across all shooting lanes was acceptable compared to the recommended guideline (20% of the ideal 0.38 m/s (75 ft/min). However, uniform, downrange airflow pattern requirements were not met. These results suggest that the mass-based occupational exposure limits, as applied to this environment, may not be protective enough to eliminate health complaints reported by instructors whose full-time job involves training personnel on weapons that fire lead-free frangible ammunition. Using an ultrafine particle counter appears to be an alternative method of assessing ventilation effectiveness in removing ultrafine particulate produced during firing events.     

In vivo selective inhibition of mitogen-activated protein kinase kinase 1/2 in rabbit experimental osteoarthritis is associated with a reduction in the development of structural changes

OBJECTIVE: The primary aim of this study was to investigate, using an experimental rabbit model of osteoarthritis (OA), the effect of a selective mitogen-activated protein kinase kinase 1/2 (MEK-1/2) inhibitor, PD 198306, on the development of structural changes. Additional aims were to assess the effects of the inhibitor on levels of phosphorylated extracellular signal-regulated kinase 1/2 (phospho-ERK-1/2) and matrix metalloproteinase 1 (MMP-1; collagenase 1) in OA chondrocytes. METHODS: After surgical sectioning of the anterior cruciate ligament of the right knee joint, rabbits with OA were separated into 3 experimental groups: oral treatment with placebo or with PD 198306 at a therapeutic concentration of 10 mg/kg/day or 30 mg/kg/day. Each treatment started immediately after surgery. The animals were killed 8 weeks after surgery. Macroscopic and histologic studies were performed on the cartilage and synovial membrane. The levels of phospho-ERK-1/2 and MMP-1 in OA cartilage chondrocytes were evaluated by immunohistochemistry. Normal, untreated rabbits were used as controls. RESULTS: OA rabbits treated with the highest dosage of MEK-1/2 inhibitor showed decreases in the surface area (size) of cartilage macroscopic lesions (P < 0.002) and in osteophyte width on the lateral condyles (P = 0.05). Histologically, the severity of synovial inflammation (villous hyperplasia) was also reduced (P < 0.02). In cartilage from placebo-treated OA rabbits, a significantly higher percentage of chondrocytes in the superficial layer stained positive for phospho-ERK-1/2 and MMP-1 compared with normal controls. Rabbits treated with the highest dosage of PD 198306 demonstrated a significant and dose-dependent reduction in the level of phospho-ERK-1/2 and a lower level of MMP-1. CONCLUSION: This study demonstrates that, in vivo, PD 198306, a selective inhibitor of MEK-1/2, can partially decrease the development of some of the structural changes in experimental OA. This effect was associated with a reduction in the level of phospho-ERK-1/2 in OA chondrocytes, which probably explains the action of the drug.     

Thiacetazone: in vitro activity against Mycobacterium avium and M. tuberculosis.

Bacteriostatic and bactericidal activity of thiacetazone was determined for 68 M. avium clinical isolates and 14 wild drug-susceptible M. tuberculosis strains. The drug had equally low bactericidal activity against both mycobacterial species. The inhibitory activity against most of the M. avium strains was greater than it was against M. tuberculosis. The broth determined MICs for 65 of 68 M. avium strains were between 0.02 and 0.15 micrograms/ml, while the MICs for M. tuberculosis ranged from 0.08 to 1.2 micrograms/ml.     

Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms

OBJECTIVE: To evaluate the role of the MEK/ERK MAP kinase pathway in murine collagen-induced arthritis (CIA) using the selective MEK inhibitor PD184352. We examined the effects of the inhibitor in cytokine-stimulated synovial fibroblasts and in cytokine-induced arthritis in rabbits to investigate its antiinflammatory mechanisms. METHODS: Murine CIA was used to assess the effects of the selective MEK inhibitor on paw edema, clinical scores, weight loss, histopathologic features, and joint levels of p-ERK. Western blotting and immunohistochemistry techniques were used to assess p-ERK in human and rabbit synovial fibroblasts and synovial tissue from rheumatoid arthritis (RA) patients. Interleukin-1alpha (IL-1alpha)-stimulated stromelysin production in rabbit synovial fibroblasts was assessed by enzyme-linked immunosorbent assay. A rabbit IL-1alpha-induced arthritis model was used to assess the effects of the inhibitor on IL-1alpha-induced MEK activity, stromelysin production, and cartilage degradation. RESULTS: In the CIA model, PD184352 inhibited paw edema and clinical arthritis scores in a dose-dependent manner. Disease-induced weight loss and histopathologic changes were also significantly improved by treatment. Inhibition of disease-induced p-ERK levels in the joints was seen with the inhibitor. Levels of p-ERK in the synovium were higher in RA patients than in normal individuals. PD184352 reduced IL-1alpha-induced p-ERK levels in human RA synovial fibroblasts. The production of p-ERK and stromelysin was also inhibited in IL-1alpha-stimulated rabbit synovial fibroblasts. We observed IL-1alpha-induced p-ERK in the synovial lining, subsynovial vasculature, and articular chondrocytes. IL-1alpha-induced stromelysin production and proteoglycan loss from the articular cartilage were reduced by PD184352. CONCLUSION: These data demonstrate the inhibition of murine CIA by PD184352, support the hypothesis that antiinflammatory activity contributes to the mechanism of action of the inhibitor, and suggest that a selective inhibitor may effectively treat RA and other inflammatory disorders.