Online optimization of dynamic binding capacity and productivity by model predictive control.

In preparative and industrial chromatography, the current viewpoint is that the dynamic binding capacity governs the process economy, and increased dynamic binding capacity and column utilization are achieved at the expense of productivity. The dynamic binding capacity in chromatography increases with residence time until it reaches a plateau, whereas productivity has an optimum. Therefore, the loading step of a chromatographic process is a balancing act between productivity, column utilization, and buffer consumption. This work presents an online optimization approach for capture chromatography that employs a residence time gradient during the loading step to improve the traditional trade-off between productivity and resin utilization. The approach uses the extended Kalman filter as a soft sensor for product concentration in the system and a model predictive controller to accomplish online optimization using the pore diffusion model as a simple mechanistic model. When a soft sensor for the product is placed before and after the column, the model predictive controller can forecast the optimal condition to maximize productivity and resin utilization. The controller can also account for varying feed concentrations. This study examined the robustness as the feed concentration varied within a range of 50%. The online optimization was demonstrated with two model systems: purification of a monoclonal antibody by protein A affinity and lysozyme by cation-exchange chromatography. Using the presented optimization strategy with a controller saves up to 43% of the buffer and increases the productivity together with resin utilization in a similar range as a multi-column continuous counter-current loading process.

Lack of the serum- and glucocorticoid-inducible kinase SGK1 improves muscle force characteristics and attenuates fibrosis in dystrophic mdx mouse muscle.

Duchenne muscular dystrophy (DMD) is a human genetic disease characterized by fibrosis and severe muscle weakness. Currently, there is no effective treatment available to prevent progressive fibrosis in skeletal muscles. The serum- and glucocorticoid-inducible kinase SGK1 regulates a variety of physiological functions and participates in fibrosis stimulation. Here, we investigated whether SGK1 influences structure, function and/or fibrosis of the muscles from the mdx mouse, an animal model for DMD. As expected, mdx muscles showed the typical pathological features of muscular dystrophy including fiber size variations, central nuclei of muscle fibers, fibrosis in the diaphragm, and force reduction by 30-50 %. Muscles from sgk1 (-/-) mice were histologically overall intact and specific force was only slightly reduced compared to wild-type muscles. Surprisingly, soleus and diaphragm muscles of mdx/sgk1 (-/-) mice displayed forces close to wild-type levels. Most muscle fibers of the double mutants contained central nuclei, but fibrosis was not observed in any of the tested limb and diaphragm muscles. We conclude that the sole lack of SGK1 in mouse muscle does not lead to pronounced changes in muscle structure and function. However, dystrophin-deficient mdx muscle seems to benefit from SGK1 deficiency. SGK1 appears to be an important enzyme in the process of fibrotic remodeling and subsequent weakness of dystrophin-deficient mouse muscle.

Activation of serum/glucocorticoid-induced kinase 1 (SGK1) is important to maintain skeletal muscle homeostasis and prevent atrophy.

Maintaining skeletal muscle mass is essential for general health and prevention of disease progression in various neuromuscular conditions. Currently, no treatments are available to prevent progressive loss of muscle mass in any of these conditions. Hibernating mammals are protected from muscle atrophy despite prolonged periods of immobilization and starvation. Here, we describe a mechanism underlying muscle preservation and translate it to non-hibernating mammals. Although Akt has an established role in skeletal muscle homeostasis, we find that serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates muscle mass maintenance via downregulation of proteolysis and autophagy as well as increased protein synthesis during hibernation. We demonstrate that SGK1 is critical for the maintenance of skeletal muscle homeostasis and function in non-hibernating mammals in normal and atrophic conditions such as starvation and immobilization. Our results identify a novel therapeutic target to combat loss of skeletal muscle mass associated with muscle degeneration and atrophy.

Impact of a functional restoration program on pain and health-related quality of life in patients with chronic low back pain.

OBJECTIVE: Functional restoration programs for chronic low back pain (CLBP) have been shown to be successful in improving function and, to a lesser extent, in reducing pain. The Munich Functional Restoration Program (MFRP) is a 4-week outpatient program designed to reduce pain and to improve health-related quality of life in patients with a long history of CLBP. DESIGN: In a retrospective matched concurrent-controls therapeutic study, 44 patients with CLBP, who had either undergone MFRP or received an outpatient standard treatment (control) after initial evaluation at the pain center, completed questionnaires 1 year after the respective therapy (t1). The following parameters were assessed: health-related quality of life with Short Form-36 (SF-36), Pain Disability Index (PDI), Numeric Rating Scale (NRS) for pain, depression with the Center for Epidemiological Studies Depression Test (CES-D), and occupational situation. These data were compared with baseline values assessed by a questionnaire completed before starting the respective treatment (baseline, t0). RESULTS: Compared with control, NRS and PDI were significantly better in patients completing the MFRP. Patients of the MFRP group showed also a significant reduction in CES-D as well as an improvement in three of eight SF-36 subscales. No changes were detected in the control group receiving standard treatment. CONCLUSIONS: Compared with standard treatment, a functional restoration program for CLBP significantly improves some aspects of health-related quality of life. It results in a decrease of pain and pain-related disability even in patients with a long history of CLBP.