The hallmark of Gaucher's disease cellular pathogenesis is the lysosomal accumulation of glucosylceramide, which is caused by misfolding of mutated glucocerebrosidase (GC) and loss of lysosomal GC activity, and leads to depletion of [Ca(2+)](ER). We demonstrate that modulation of Ca(2+) homeostasis and enhancement of the cellular folding capacity synergize to rescue the folding of mutated GC variants. Lacidipine, an L-type Ca(2+) channel blocker that also inhibits [Ca(2+)](ER) efflux, enhances folding, trafficking, and activity of degradation-prone GC variants. Lacidipine remodels mutated GC proteostasis by simultaneously activating a series of distinct molecular mechanisms, namely modulation of Ca(2+) homeostasis, upregulation of the ER chaperone BiP, and moderate induction of the unfolded protein response. However, unlike previously reported proteostasis regulators, lacidipine treatment is not cytotoxic but prevents apoptosis induction typically associated with sustained activation of the unfolded protein response.
In 2006, the US Centers for Disease Control and Prevention issued recommendations supporting routine HIV testing in health care settings for all persons aged 13 to 64 years. Despite these recommendations, physicians are not offering HIV testing routinely. We apply a model that has previously identified 3 central, inter-related factors (knowledge-, attitude-, and behavior-related barriers) for why physicians do not follow practice guidelines in order to better understand why physicians are not offering HIV testing routinely. This model frames our review of the existing literature on physician barriers to routine HIV testing. Within the model, knowledge barriers include lack of familiarity or awareness of clinical recommendations, attitude barriers include lack of agreement with guidelines, while behavioral barriers include external barriers related to the guidelines themselves, to patients, or to environmental factors. Our review reveals that many physicians face these barriers with regards to implementing routine HIV testing. Several factors underscore the importance of determining how to best address physician barriers to HIV testing, including: provisions of the Affordable Care Act that are likely to require or incentivize major payers to cover HIV testing, evidence which suggests that a physician’s recommendation to test for HIV is a strong predictor of patient testing behavior, and data which reveals that nearly 20% of HIV-positive individuals may be unaware of their status. In April 2013, the US Preventive Services Task Force released a recommendation supporting routine HIV testing; strategies are needed to help address ongoing physician barriers to testing.
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