Annals of the New York Academy of Sciences
-
Systems biology, the approach that combines reduction and integration to explore dynamic structure-function interrelations across biomedically relevant spatio-temporal scales, is applied to heart research.
-
The discovery that loss-of-function mutations in the gene DOCK8 are responsible for most forms of autosomal recessive hyper-IgE syndrome and some forms of combined immunodeficiency without elevated serum IgE has led to studies into the immunopathogenesis of this disease. In this review, we relate the clinical features of this disease to studies using patients' cells and a mouse model of Dock8 deficiency, which have revealed how DOCK8 regulates T and B cell numbers and functions. The results of these studies help to explain how the absence of DOCK8 contributes to patients' susceptibility to viral, fungal, and bacterial infections. However, unanswered questions remain regarding how the absence of DOCK8 also leads to high IgE and allergic disease, predisposition for malignancy, and unusual clinical features, such as CNS abnormalities and autoimmunity, observed in some patients.
-
Ann. N. Y. Acad. Sci. · Dec 2011
Comparative StudyNovel, nonreflex tests detect analgesic action in rodents at clinically relevant concentrations.
We propose that predictive validity of tests for analgesia may be improved by looking to reinstate specific, innate behaviors suppressed by pain, e.g., burrowing, because effective plasma concentrations in the rat are closer to effective clinical plasma concentrations than those generally used in rodent reflex withdrawal assays.
-
Ann. N. Y. Acad. Sci. · Dec 2011
ReviewUnderstanding the regulatory hurdles for antibacterial drug development in the post-Ketek world.
The antibiotic telithromycin (Ketek, Sanofi-aventis) had two of three treatment indications withdrawn after postmarketing reports of serious and fatal adverse events. The rationale for the withdrawal of specific indications (acute bacterial sinusitis and acute exacerbations of chronic bronchitis), while permitting the drug to remain available for the treatment of community-acquired pneumonia, focused on the lack of demonstrated efficacy from clinical trials that included an active control to which the investigational drug, telethromycin, was determined to be statistically noninferior. ⋯ New clinical trial guidelines have been published that will increase the time and resources required to achieve regulatory marketing approval. This paper reviews recent regulatory actions and discusses the impact these new guidelines will have on future antibacterial clinical trial designs and challenges.