Diagnostic and therapeutic strategies for porphyrias.

Porphyrias are rare metabolic disorders. Lack of awareness and knowledge about the clinical features of porphyrias results in diagnostic and therapeutic delays for many patients. Delays in diagnosing and treating porphyrias can result in severe, progressive morbidity (and mortality) and psychological distress for patients. This review discusses the pathophysiology, diagnosis, treatment, and follow-up of the most prevalent porphyrias: acute intermittent porphyria, porphyria cutanea tarda, and erythropoietic protoporphyria.

Estimation of the respiration quotient in a bicarbonate buffered batch cell cultivation.

In bicarbonate buffered media the carbon dioxide balance is affected by accumulation and therefore the RQ can not directly be calculated from gas flow and gas concentration measurements. To cope with the buffering capacity of such media a Kalman Filter was designed as a software sensor to estimate the RQ. To eliminate the role of a priori knowledge of cell and medium kinetics on the performance of the Kalman Filter all carbonate was lumped to one term. As a result only physical constants are required. A reference experiment verified the performance of the software sensor. Subsequently several experiments were performed with insect cells to show the progress of the RQ-values during cultivation.

Advanced process monitoring: the ultimate alternative.

Parametric release has the possibility to be the ultimate alternative for the use of animal tests. It involves the release of a product using evaluation of tightly controlled physical parameters, without the performance of a test on the final product. This practice is strengthened if there is a lack of validity for the final test to indicate quality or consistency. That suggests that in-process monitoring should replace the finished product controls when among others, batch-to-batch consistency has been formally validated. Currently, parametric release is a common practice for terminally sterilised and aseptically filled biologicals. An example is the production of inactivated cells of Bordetella pertussis which shows that new techniques are able to monitor the process in detail. Furthermore, it is shown that the production of Bordetella pertussis is well defined and highly predictable. In parallel with the tests for terminally sterilised biologicals, mouse potency tests are statistically hardly capable of indicating batch-to-batch variation. Monitoring on-line process parameters provides a better assurance of consistency and quality, thus giving the opportunity for batch release and regulatory approval without the use of animal tests.

Dual-substrate utilization by Bordetella pertussis.

To improve the cultivation of Bordetella pertussis and take advantage of the newest techniques in monitoring and control, a quantitative description of substrate utilisation is necessary. Growth of the organism is limited by two main substrates. However neither interactive nor non-interactive modelling seem appropriate. A model that combines essential and enhanced kinetics was developed based on experimental observation. Instead of fitting all model parameters at once, a step-wise experimentation procedure was used. Finally two cultivations showed the accuracy of the model.