Succinic Semialdehyde Dehydrogenase Deficiency: An Update.

Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients.

High pressure gases: role of dynamic intracellular pH in pasteurization.

Certain dense gases, including CO(2) and N(2)O, are known to deactivate food pathogens safely. Complete deactivation requires disabling intracellular metabolic pathways by extracellular processing that causes membrane disruption, irreversible denaturation of proteins, or extraction of cell contents. At present, neither the precise physical and metabolic mechanisms nor their kinetics behind dense gas pasteurization are known. The mechanisms depend strongly on both the organism and the environment and may combine membrane disruption, membrane permeabilization, and altering pH. Herein we elucidate the mechanisms of dense gas inactivation with the aid of a novel approach for measuring intracellular pH (pH(i)) under high gas pressure. Using a pH-sensitive GFP-variant of S. cerevisiae as the probe, we demonstrate that membrane permeabilization by a non-acidic gas, N(2)O, contributes to inactivation but at a rate that is relatively low compared to CO(2). CO(2) not only permeabilizes the membrane but also brings about a rapid drop in pH(i), leading to greater deactivation. Mechanistic understanding is vital to develop safe and effective dense gas technologies for food treatment. Knowledge of pH(i) is also important in other cellular processes, including enzyme activity, gene transcription, and protein synthesis. The GFP technique has been demonstrated to be versatile even under pressure.

Human pathogens, nosocomial infections, heat-sensitive textile implants, and an innovative approach to deal with them.

Implantable polymers, as used for biomedical applications, inherently have to be sterile. Nonetheless, most implants, particularly those comprised of biomaterials developed in recent years for tissue engineering, are heat sensitive. Therefore, use of hazardous (radio)chemicals--due to lack of alternative methods--is still state of the art for sterilization processes. The drawbacks of these techniques, both drastic and well known, lead to the demand for an alternative sterilization method, which is equally obvious and urgent. High-pressure fluid treatment is a low-temperature technique that is already in use for pasteurization of liquid food products. This paper explores inactivation of vegetative microorganisms, spores, and endotoxins adherent to solid surfaces using compressed CO(2). Pressures ranging from 50 to 100 bar and temperatures from 25 °C to 50 °C were explored to investigate liquid, gaseous or supercritical state. Analysis of variance (ANOVA) and statistical modeling were used to identify the optimum parameter settings for inactivation of pathogenic bacteria and fungi (Candida albicans, Staphylococcus aureus). The addition of small amounts of ozone ensures inactivation of persistent spores (Bacillus stearothermophilus, B. subtilis) up to 10(6) cfu/ml, while endotoxins remain in practically unchanged concentration on the polymer surface. We then discuss environmental issues of the process and inactivation mechanisms. The replacement of conventional chemicals with nonpersistent ones resolves organizational and safety-related issues and protects natural resources as well as handling staff. The pressurized-fluid-based method exhibits mild treatment parameters, thus protecting sensitive textures. Finally, an outlook on possible applications of this innovative technique is presented.