Does safety make a difference in selecting the right TNF antagonist?

Tumor necrosis factor (TNF) antagonists are biologic response modifiers that have significantly improved the outcomes in patients with rheumatoid arthritis (RA). At this report, safety data were collected on approximately 271,000 patients administered infliximab (as of February 2002), 121,000 patients administered etanercept (as of December 2001), and on 2400 patients who received adalimumab in trials in connection with the regulatory approval process (approval granted December 2002 in the US and September 2003 in European Union). Infliximab and etanercept have predictable and manageable safety profiles, and preliminary data suggest that the profile of adalimumab is comparable. Safety issues involving the anti-TNF agents as a class include the risk of injection-site reactions or infusion-related reactions, infection (for example, serious, opportunistic, or tubercular), malignancy, autoimmunity, and demyelinating and neurologic disorders. Injection-site and infusion-related reactions are most often easily managed and rarely lead to discontinuation of therapy. Infections can be minimized or prevented by screening and careful monitoring and follow-up; most infections respond to appropriate medical treatment. More studies are needed to evaluate the occurrence of malignancies in patients with RA to determine the potential risk posed by therapy. Antibody formation can follow the administration of any biologic agent. Although demyelinating disease has been reported with anti-TNF agents, it is not clear whether a causal relationship exists. Overall, the anti-TNF agents are well tolerated and have demonstrated a favorable benefit-to-risk profile in patients with RA.     

Does the platelet-activating factor affect the antioxidant defense system?

The platelet-activating factor (PAF) is an inflammatory mediator and it may exert some of its effects by reactive oxygen species (ROS). We investigated the effects of PAF and hyperbaric oxygenation (HBO) on copper (Cu) and zinc (Zn) levels in plasma and the intracellular antioxidant enzyme activities of rats. PAF administration caused a decrease in erythrocyte catalase (CAT) and glutathione peroxidase (GPx) activities and in the plasma zinc level. Following PAF administration, exposure to HBO also caused a decrease in erythrocyte GPx activity. These results support the hypothesis that PAF may produce free oxygen radicals and HBO enhances this effect. The enzyme activities of the antioxidant defense system were found to be affected by these oxidative processes. This is likely to be the result of excessive production of ROS or overutilization and/or inhibition of the antioxidant enzymes.     

Continent-specific Intake Fractions and Characterization Factors for Toxic Emissions: Does it make a Difference?

Goal and Scope The goal of this study is to explore the potentials and limitations of using LCA as the basis for setting ecolabelling criteria in developing countries. The practicality of using LCA for this purpose, as required by ISO 14020, has been criticised as lacking in transparency and scientific rigour. Furthermore, ecolabelling is not widespread in developing countries. The application of LCA has therefore been illustrated by using the specific case of shrimp aquaculture in Thailand, as a basis for ecolabelling criteria for a typical product intended for export from a developing country. Method For the LCA case study, the functional unit is the standard consumer-package size, containing 1.8 kg of frozen shrimp produced by conventional intensive aquaculture in Thailand, subject to an appropriate environmental management system. The impact assessment method used in this study is CML 2 Baseline 2000. Results According to the results from the LCA study, farming appears to be the key life cycle stage generating the most significant environmental impacts: abiotic depletion and global warming, which arise mainly from the use of energy; and eutrophication caused by wastewater discharged from the shrimp ponds. It is possible to cover these impacts by quantitative ecolabelling criteria. Other important impacts could not be quantified by the LCA: depletion of wild shrimp broodstock, impacts of trawling on marine biodiversity and the choice of suitable farm sites. These impacts, which are also related to the farming stage, must be covered by 'hurdle criteria'. Conclusions and recommendations. For the present case, LCA provides a basis for quantifying a number of important ecolabelling criteria related to the use of abiotic resources and to emissions. Other important issues, connected with the use of biotic natural resources and land, are not quantifiable by current LCA methodology, but were also revealed and clarified by using an LCA framework for the analysis. Thus, focussing the assessment on life cycle considerations, as required by ISO 14024, was effective in identifying all key environmental issues. In the light of this case study, main limitations and barriers associated with the application of LCA to setting ecolabelling criteria particularly in developing countries are discussed, including recommendations on how to overcome them.     

Will nanotechnology make the world a better place?

Nanotechnology could produce a revolutionary wave of innovation in society. The form that such a revolution might take will depend upon many things but certainly upon the context, content and purposes of research projects and agendas decided by existing political and corporate institutions. Lessons from the genetically modified organism debate indicate that the behaviour of these institutions is at least as important as the 'risk' in informing public acceptability. This article argues that current research priorities need to shift in favour of environmental and health protection to engender public support and/or an ongoing need to remain sensitive to emerging societal preferences.     

Does the anterior cruciate have a modeling threshold? A case for the affirmative

Growing evidence supports a 1972 proposal that dynamic tension strains of a ligament above a threshold range, but below its ultimate strength, would make its cells synthesize more collagen to thicken and strengthen it. If so, when that strengthening reduced later strains to the bottom of that threshold range this "diametric modeling" would stop. A) Such a mechanism must create a "strength-safety factor" that would minimize or prevent voluntary activities from rupturing healthy ligaments, so chiefly injuries would rupture them. B) Such a mechanism should also make the usual largest loads on a healthy anterior cruciate ligament (ACL) determine its strength, and would make smaller loads mixed with large ones have little effect on its strength. C) In principle, when an ACL's strains exceeded that threshold range, diametric modeling would turn on, strengthen it, and reduce subsequent strains from the same loads. When its strains remained smaller, this mechanically-controlled modeling would turn off. Normal ACLs do have a strength-safety factor so they could have a diametric modeling threshold too, as we now know bone does. In healthy young adult humans available evidence suggests that threshold's value could lie in the region of 23 Newtons/mmC of the ACL's cross section area. If similar relationships applied to fascia, tendons and other ligaments (I suggest they do), they would form fundamental biomechanical properties of collagenous tissue organs.     

Is methylglyoxal a causative factor for hypertension development?

Hypertension is a life-threatening disease that is associated with increased cardiovascular risks. Causes and mechanisms for hypertension development remain poorly understood. Methylglyoxal (MG), a highly reactive molecule, is a metabolite of sugar. Increased circulation and tissue levels of MG have been documented not only in diabetes but also in hypertension. Many recent studies also link MG-induced vascular damage to the pathogenic process of hypertension. As such, an etiological role of MG in hypertension development is proposed.     

Does the pentose cycle play a major role for NADPH supply in the heart?

It was attempted to determine the substrate flux through the pentose cycle in isolated rat hearts which performed pressure-volume work employing 14CO2 production from [1-14C]glucose (Kühn & Scholz (1982) Eur. J. Biochem. 124, 611-617). Even under conditions of increased NADPH requirements (infusion of tert-butylhydroperoxide) and a diminished 14CO2 production from glucose via the citrate cycle (in the presence of oleate as additional substrate) or enhanced activity of glucose-6-phosphate dehydrogenase (pretreatment with isoproterenol), a substrate flux through the pentose cycle was not detectable. The lower limit of detection is 0.01 mumol/(min X g). The increase in 14CO2 production from [1-14C]- and [6-14C]glucose and the acceleration in the washout when tert-butylhydroperoxide was present suggest an increase of substrate flux through the citrate cycle; therefore it is concluded that NADPH required for the removal of peroxides via the glutathione system is derived from the isocitrate dehydrogenase reaction.     

Does the Kunitz domain from the Alzheimer's amyloid beta protein precursor inhibit a kallikrein responsible for post-translational processing of nerve growth factor precursor?

Alternative splicing of the Alzheimer's amyloid beta protein precursor (ABPP) message leads to the production of several variants of this precursor polypeptide. Two of these variants contain a domain that is highly homologous to members of the Kunitz class of protease inhibitors. In order to initiate a study of the physiological role of this domain, we have produced active ABPP Kunitz inhibitor by constructing and expressing a synthetic gene in E. coli. Nerve growth factor (NGF) deficiency has been suggested as a possible cause of the neural degeneration characteristic of Alzheimer's disease, and trypsin and gamma-NGF are the two enzymes that have been shown to be capable of processing beta-NGF precursor to active, mature beta-NGF in vitro, therefore, the specificity of purified recombinant ABPP Kunitz inhibitor was analyzed with respect to these two proteases. Binding of isolated ABPP Kunitz domain both to trypsin (Ki,app less than 10 nM and to gamma-NGF (Ki,app = 300 nM) was observed. This difference in binding to the two proteases correlates with the approximately 20-fold higher rate observed for in vitro processing of the beta-NGF precursor by trypsin compared to processing by gamma-NGF, indicating that perhaps the inhibitor mimics the interaction of the beta-NGF precursor with proteases. The kallikrein actually responsible for beta-NGF precursor processing in vivo is unknown, but these results suggest that it is capable of being significantly inhibited by exposure to the ABPP Kunitz domain.     

Does FASing out new fat in the hypothalamus make you slim?

Fatty acid synthase (FAS) is a key enzyme for lipogenesis. A recent study (Chakravarthy et al., 2007) shows that the targeted deletion of FAS in hypothalamic neurons produces hypophagic, lean mice and suggests that PPARalpha signaling is an important mediator of the effects of FAS on energy homeostasis.     

Does prothymosin alpha affect the phosphorylation of elongation factor 2?

Prothymosin alpha is a small, acidic, essential nuclear protein that plays a poorly defined role in the proliferation and survival of mammalian cells. Recently, Vega et al. proposed that exogenous prothymosin alpha can specifically increase the phosphorylation of eukaryotic elongation factor 2 (eEF-2) in extracts of NIH3T3 cells (Vega, F. V., Vidal, A., Hellman, U., Wernstedt, C., and Domínguez, F. (1998) J. Biol. Chem. 273, 10147-10152). Using similar lysates prepared by four methods (detergent lysis, Dounce homogenization, digitonin permeabilization, and sonication) and three preparations of prothymosin alpha, one of which was purified by gentle means (the native protein, and a histidine-tagged recombinant prothymosin alpha expressed either in bacteria or in COS cells), we failed to find a response. A reconstituted system composed of eEF-2, recombinant eEF-2 kinase, calmodulin, and calcium was also unaffected by prothymosin alpha. However, unlike our optimized buffer, Vega's system included a phosphatase inhibitor, 50 mM fluoride, which when evaluated in our laboratories severely reduced phosphorylation of all species. Under these conditions, any procedure that decreases the effective fluoride concentration will relieve the inhibition and appear to activate. Our data do not support a direct relationship between the function of prothymosin alpha and the phosphorylation of eEF-2.