Ocular Side Effects of Common Systemic Medications and Systemic Side Effects of Ocular Medications.

When prescribing medications, it is important to consider the ocular side effects of common systemic therapy as well as potential systemic side effects of ocular medications. Although not an exhaustive list of medications/classes of medications, this article does include many commonly used drugs and also provides information on some topical therapies commonly used by ophthalmologists. These ocular medications may result in systemic effects and/or alter patients' management of systemic conditions.

Optimal in-hospital defibrillator placement.

AIMS: To determine if mathematical optimization of in-hospital defibrillator placements can reduce in-hospital cardiac arrest-to-defibrillator distance compared to existing defibrillators in a single hospital. METHODS: We identified treated IHCAs and defibrillator placements in St. Michael's Hospital in Toronto, Canada from Jan. 2013 to Jun. 2017 and mapped them to a 3-D computer model of the hospital. An optimization model identified an equal number of optimal defibrillator locations that minimized the average distance between IHCAs and the closest defibrillator using a 10-fold cross-validation approach. The optimized and existing defibrillator locations were compared in terms of average distance to the out-of-sample IHCAs. We repeated the analysis excluding intensive care units (ICUs), operating theatres (OTs), and the emergency department (ED). We also re-solved the model using fewer defibrillators to determine when the average distance matched the performance of existing defibrillators. RESULTS: We identified 433 treated IHCAs and 53 defibrillators. Of these, 167 IHCAs and 31 defibrillators were outside of ICUs, OTs, and the ED. Optimal defibrillator placements reduced the average IHCA-to-defibrillator distance from 16.1 m to 2.7 m (relative decrease of 83.0%; P = 0.002) compared to existing defibrillator placements. For non-ICU/OT/ED IHCAs, the average distance was reduced from 24.4 m to 11.9 m (relative decrease of 51.3%; P = 0.002. 8-9 optimized defibrillator locations were sufficient to match the average IHCA-to-defibrillator distance of existing defibrillator placements. CONCLUSIONS: Optimization-guided placement of in-hospital defibrillators can reduce the distance from an IHCA to the closest defibrillator. Equivalently, optimization can match existing defibrillator performance using far fewer defibrillators.

Traumatic Brain Injury Severity, Neuropathophysiology, and Clinical Outcome: Insights from Multimodal Neuroimaging.

BACKGROUND: The relationship between the acute clinical presentation of patients with traumatic brain injury (TBI), long-term changes in brain structure prompted by injury and chronic functional outcome is insufficiently understood. In this preliminary study, we investigate how acute Glasgow coma score (GCS) and epileptic seizure occurrence after TBIs are statistically related to functional outcome (as quantified using the Glasgow Outcome Score) and to the extent of cortical thinning observed 6 months after the traumatic event. METHODS: Using multivariate linear regression, the extent to which the acute GCS and epileptic seizure occurrence (predictor variables) correlate with structural brain changes (relative cortical atrophy) was examined in a group of 33 TBI patients. The statistical significance of the correlation between relative cortical atrophy and the Glasgow Outcome Score was also investigated. RESULTS: A statistically significant correlative relationship between cortical thinning and the predictor variables (acute GCS and seizure occurrence) was identified in the study sample. Regions where the statistical model was found to have highest statistical reliability in predicting both gray matter atrophy and neurological outcome include the frontopolar, middle frontal, postcentral, paracentral, middle temporal, angular, and lingual gyri. In addition, relative atrophy and GOS were also found to be significantly correlated over large portions of the cortex. CONCLUSION: This study contributes to our understanding of the relationship between clinical descriptors of acute TBI, the extent of injury-related chronic brain changes and neurological outcome. This is partly because the brain areas where cortical thinning was found to be correlated with GCS and with seizure occurrence are implicated in executive control, sensory function, motor acuity, memory, and language, all of which may be affected by TBI. Thus, our quantification suggests the existence of a statistical relationship between acute clinical presentation, on the one hand, and structural/functional brain features which are particularly susceptible to post-injury degradation, on the other hand.

Viral Retinopathy in Experimental Models of Zika Infection.

Purpose: Emerging evidence has shown that both congenital and adult Zika virus (ZIKV) infection can cause eye diseases. The goals of the current study were to explore mechanisms and pathophysiology of ZIKV-induced eye defects. Methods: Wild-type or A129 interferon type I receptor-deficient mice were infected by either FSS13025 or Mex1-7 strain of ZIKV. Retinal histopathology was measured at different time points after infection. The presence of viral RNA and protein in the retina was determined by in situ hybridization and immunofluorescence staining, respectively. Growth curves of ZIKV in permissive retinal cells were assessed in cultured retinal pigment epithelial (RPE) and Müller glial cells. Results: ZIKV-infected mice developed a spectrum of ocular pathologies that affected multiple layers of the retina. A primary target of ZIKV in the eye was Müller glial cells, which displayed decreased neurotrophic function and increased expression of proinflammatory cytokines after infection. ZIKV also infected RPE; and both the RPE and Müller cells expressed viral entry receptors TYRO3 and AXL. Retinitis, focal retinal degeneration, and ganglion cell loss were observed after the clearance of viral particles. Conclusions: Our data suggest that ZIKV can infect infant eyes with immature blood-retinal barrier and cause structural damages to the retina. The ocular findings in microcephalic infants may not be solely caused by ZIKV-induced impairment of neurodevelopment.

Structures of cGMP-Dependent Protein Kinase (PKG) Iα Leucine Zippers Reveal an Interchain Disulfide Bond Important for Dimer Stability.

cGMP-dependent protein kinase (PKG) Iα is a central regulator of smooth muscle tone and vasorelaxation. The N-terminal leucine zipper (LZ) domain dimerizes and targets PKG Iα by interacting with G-kinase-anchoring proteins. The PKG Iα LZ contains C42 that is known to form a disulfide bond upon oxidation and to activate PKG Iα. To understand the molecular details of the PKG Iα LZ and C42-C42' disulfide bond, we determined crystal structures of the PKG Iα wild-type (WT) LZ and C42L LZ. Our data demonstrate that the C42-C42' disulfide bond dramatically stabilizes PKG Iα and that the C42L mutant mimics the oxidized WT LZ structurally.

Crystal structure of the cGMP-dependent protein kinase II leucine zipper and Rab11b protein complex reveals molecular details of G-kinase-specific interactions.

cGMP-dependent protein kinase (PKG)-interacting proteins (GKIPs) mediate cellular targeting of PKG isoforms by interacting with their leucine zipper (LZ) domains. These interactions prevent aberrant signaling cross-talk between different PKG isotypes. To gain detailed insight into isotype-specific GKIP recognition by PKG, we analyzed the type II PKG leucine zipper domain and found that residues 40-83 dimerized and specifically interacted with Rab11b. Next, we determined a crystal structure of the PKG II LZ-Rab11b complex. The PKG II LZ domain presents a mostly nonpolar surface onto which Rab11b docks, through van der Waals interactions. Contact surfaces in Rab11b are found in switch I and II, interswitch, and the ß1/N-terminal regions. This binding surface dramatically differs from that seen in the Rab11 family of interacting protein complex structures. Structural comparison with PKG Iα and Iß LZs combined with mutagenic analysis reveals that GKIP recognition is mediated through surface charge interactions.