A case series of the rifampin-warfarin drug interaction: focus on practical warfarin management.

PURPOSE: To provide practical guidance by providing weekly descriptions of warfarin requirements for the onset and offset of the rifampin-warfarin interaction. METHODS: A retrospective chart review within an outpatient Anticoagulation Clinic (AC). Patients were eligible for the onset phase provided they had known ambulatory-based warfarin steady-state requirements prior to rifampin initiation. For the offset phase, warfarin must be managed by the AC following rifampin discontinuation. Each phase was described separately with warfarin proportionate dose changes (median, IQR) for weeks 1, 2, and 4 as well as the change required to reach warfarin steady state. RESULTS: Ten patients with 11 courses of warfarin-rifampin were included. For onset, clinicians should anticipate proportionate warfarin dose increases of 30-80% from week 1 to week 2 and a further 20-100% from week 2 to 4, with an overall warfarin dose increase of 165% (IQR 99, 227) to reach steady state at 30 days. For offset, clinicians should anticipate proportionate warfarin dose decreases of 15-25% for both week 1 and 2, and a further 20% for both week 3 and 4, resulting in an overall warfarin decrease of 67% (IQR - 70, - 58) to reach steady state at 4 weeks for most patients. CONCLUSION: Close monitoring with at least twice weekly INRs for weeks 1 to 2 of both phases is needed to respond to substantially changing warfarin dose requirements. While inter- and intra-patient variability for proportionate warfarin dose changes for both the onset and offset of this drug interaction exists, our data provides general guidance.

Male Goal-Tracker and Sign-Tracker Rats Do Not Differ in Neuroendocrine or Behavioral Measures of Stress Reactivity.

Environmental cues attain the ability to guide behavior via learned associations. As predictors, cues can elicit adaptive behavior and lead to valuable resources (e.g., food). For some individuals, however, cues are transformed into incentive stimuli and elicit motivational states that can be maladaptive. The goal-tracker (GT)/sign-tracker (ST) animal model captures individual differences in cue-motivated behaviors, with reward-associated cues serving as predictors of reward for both phenotypes but becoming incentive stimuli to a greater degree for STs. While these distinct phenotypes are characterized based on Pavlovian conditioned approach (PavCA) behavior, they exhibit differences on a number of behaviors relevant to psychopathology. To further characterize the neurobehavioral endophenotype associated with individual differences in cue-reward learning, neuroendocrine and behavioral profiles associated with stress and anxiety were investigated in male GT, ST, and intermediate responder (IR) rats. It was revealed that baseline corticosterone (CORT) increases with Pavlovian learning, but to the same degree, regardless of phenotype. No significant differences in behavior were observed between GTs and STs during an elevated plus maze (EPM) or open field test (OFT), nor were there differences in CORT response to the OFT or physiological restraint. Upon examination of central markers associated with stress reactivity, we found that STs have greater glucocorticoid receptor (GR) mRNA expression in the ventral hippocampus, with no phenotypic differences in the dorsal hippocampus or prelimbic cortex (PrL). These findings demonstrate that GTs and STs do not differ on stress-related and anxiety-related behaviors, and suggest that differences in neuroendocrine measures between these phenotypes can be attributed to distinct cue-reward learning styles.

Use of hydroxychloroquine and interferon alpha-2b for the prophylaxis of COVID-19.

The ongoing pandemic of COVID-19 infection demands efforts to reduce spread. In order to eradicate an infectious disease, a method of prevention with low social cost is the most effective way. While we wait for new therapies and a vaccine, we are proposing a solution based on the existing knowledge in biomedical sciences. Here we propose to use low doses of hydroxychloroquine (50-100 mg daily orally) and intranasal interferon alpha-2b (IFN α-2b) spray (0.5 × 106 IU twice daily) for the prophylaxis of COVID-19. Although there are ongoing clinical trials to test the efficacy of hydroxychloroquine for prophylaxis, there has not been any proposal to test the efficacy of IFN α-2b together with hydroxychloroquine to increase protection against COVID-19. Since the two act on two different mechanisms, we strongly believe that the two could have additive effects in prophylaxis against COVID-19. We recommend using a randomized control study to prove efficacy and safety.

Direct visualization of CaMKII at postsynaptic densities by electron microscopy tomography.

Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) is a major component of postsynaptic densities (PSDs) involved in synaptic regulation. It has been previously shown that upon activity CaMKII from the spine reversibly aggregates at the cytoplasmic surfaces of PSDs, where it encounters various targets for phosphorylation. Targets for CaMKII are also present within the PSD, but there has been no reliable method to pinpoint whether, or where, CaMKII is located inside the PSD. Here we show that CaMKII can be mapped molecule-by-molecule within isolated PSDs using negative stain electron microscopy tomography. CaMKII molecules found in the core of the PSD may represent a pool distinct from the CaMKII residing at the cytoplasmic surface.