No abstract

Purpose High sustained antibody titers complicate many disorders treated with a therapeutic protein, including those treated with enzyme replacement therapy, such as Pompe disease. Although enzyme replacement therapy with alglucosidase alfa (Myozyme) in Pompe disease has improved the prognosis of this otherwise lethal disorder, patients who develop high sustained antibody titers to alglucosidase alfa enter a prolonged phase of clinical decline resulting in death despite continued enzyme replacement therapy. Clinically effective immune-tolerance induction strategies have yet to be described in the setting of an entrenched immune response characterized by high sustained antibody titers, wherein antibody-producing plasma cells play an especially prominent role. Methods We treated three patients with infantile Pompe disease experiencing marked clinical decline due to high sustained antibody titers. To target the plasma cell source of high sustained antibody titers, a regimen based on bortezomib (Velcade) was used in combination with rituximab, methotrexate, and intravenous immunoglobulin. Results The treatment regimen was well tolerated, with no obvious side effects. Patient 1 had a 2,048-fold, and patients 2 and 3 each had a 64-fold, reduction in anti-alglucosidase alfa antibody titer, with concomitant sustained clinical improvement. Conclusion The addition of bortezomib to immunomodulatory regimens is an effective and safe treatment strategy in infantile Pompe disease, with potentially broader clinical implications.

Evidence has begun to accumulate which suggests that lack of awareness of illness in schizophrenia is related to and possibly the result of a cognitive deficit involving prefrontal cerebral dysfunction. This study further explores this relationship along with other domains of self-awareness in chronic schizophrenics and other subjects with serious mental disorders. One hundred eight schizophrenics and 21 bipolar subjects from three separate sites in Britain, Germany, and Canada were administered the Wisconsin Card Sorting Test and three measures of self-awareness. Lack of illness awareness and other domains of self-knowledge were significantly more related to poorer neuropsychological performance in schizophrenia patients than in the other subjects. The results support the hypothesis that lack of illness awareness is related to defective frontal lobe functioning as indexed by neuropsychological measures.

Background Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates. Purpose The objective of this study was to determine whether supplements with glutamine (400 mg/kg per day), citrate (7.5 mEq/kg per day), or ornithine α-ketoglutarate (400 mg/kg per day) (anaplerotic agents that could fill up the citric acid cycle) would affect plasma levels of glutamine and ammonia, the urinary excretion of Krebs cycle intermediates, and the clinical outcome in 3 patients with propionic acidemia. Methods Each supplement was administered daily for four weeks with a two week washout period between supplements. The supplement that produced the most favorable changes was supplemented for 30 weeks following the initial study period and then for a 2 year extension. Results The urinary excretion of the Krebs cycle intermediates, α-ketoglutarate, succinate, and fumarate increased significantly compared to baseline during citrate supplementation, but not with the other two supplements. For this reason, citrate supplements were continued in the second part of the study. The urinary excretion of methylcitric acid and 3-hydroxypropionic acid did not change with any intervention. No significant changes in ammonia or glutamine levels were observed with any supplement. However, supplementation with any anaplerotic agents normalized the physiological buffering of ammonia by glutamate, with plasma glutamate and alanine levels significantly increasing, rather than decreasing with increasing ammonia levels. No significant side effects were observed with any therapy and safety labs (blood counts, chemistry and thyroid profile) remained unchanged. Motor and cognitive development was severely delayed before the trial and did not change significantly with therapy. Hospitalizations per year did not change during the trial period, but decreased significantly (p<0.05) in the 2 years following the study (when citrate was continued) compared to the 2 years before and during the study. Conclusions These results indicate that citrate entered the Krebs cycle providing successful anaplerotic therapy by increasing levels of the downstream intermediates of the Krebs cycle: α-ketoglutarate, succinate and fumarate. Citrate supplements were safe and might have contributed to reduce hospitalizations in patients with propionic acidemia.

This review article discusses various cognitive and behavioral interventions that have been developed with the goal of promoting self-controlled responding. Self-control can exert a significant impact on human health and impulsive behaviors are associated with a wide range of diseases and disorders, leading to the suggestion that impulsivity is a trans-disease process. The self-control interventions include effort exposure, reward discrimination, reward bundling, interval schedules of reinforcement, impulse control training, and mindfulness training. Most of the interventions have been consistently shown to increase self-control, except for mindfulness training. Some of the successful interventions are long-lasting, whereas others may be transient. Most interventions are domain-specific, targeting specific cognitive and behavioral processes that relate to self-control rather than targeting overall self-control. For example, effort exposure appears to primarily increase effort tolerance, which in turn can improve self-control. Similarly, interval schedules primarily target interval timing, which promotes self-controlled responses. A diagram outlining a proposed set of intervention effects on self-control is introduced to motivate further research in this area. The diagram suggests that the individual target processes of the interventions may potentially summate to produce general self-control, or perhaps even produce synergistic effects. In addition, it is suggested that developing a self-control profile may be advantageous for aligning specific interventions to mitigate specific deficits. Overall, the results indicate that interventions are a promising avenue for promoting self-control and may help to contribute to changing health outcomes associated with a wide variety of diseases and disorders.