Ocular Pathology Relevant to Glaucoma in a Gja1(Jrt) Mouse Model of Human Oculodentodigital Dysplasia

PURPOSE. Oculodentodigital dysplasia (ODDD) is a human disorder caused by mutations in the gap junction alpha 1 (GJA1) gene encoding the connexin43 (Cx43) gap junction protein. Causal links between GJA1 mutations and glaucoma are not understood. The purpose in this study was to examine the ocular phenotype for Gja1(Jrt/+) mice harboring a Cx43 G60S mutation. METHODS. In young Gja1(Jrt/+) mice, Cx43 abundance was assessed with a Western blot, and Cx43 localization was visualized using immunohistochemistry and confocal microscopy. Intraocular pressure (IOP) was measured by rebound tonometry, and eye anatomy was imaged using ocular coherence tomography (OCT). Hematoxylin and eosin (H&E)-stained eye sections were examined for ocular histopathology related to the development of glaucoma. RESULTS. Decreased Cx43 protein levels were evident in whole eyes from Gja1(Jrt/+) mice compared with those of wild-type mice at postnatal day 1 (P = 0.005). Cx43 immunofluorescence in ciliary bodies of Gja1(Jrt/+) mice was diffuse and intracellular, unlike the gap junction plaques prevalent in wildtype mice. IOP in Gja1(Jrt/+) mice changed during postnatal development, with significantly lower IOP at 21 weeks of age in comparison to the IOP of wild-type eyes. Microphthalmia, enophthalmia, anterior angle closure, and reduced pupil diameter were observed in Gja1(Jrt/+) mice at all ages examined. Ocular histology showed prominent separations between the pigmented and nonpigmented ciliary epithelium of Gja1(Jrt/+) mice, split irides, and alterations in the number and distribution of nuclei in the retina. CONCLUSIONS. Detailed phenotyping of Gja1(Jrt/+) eyes offers a framework for elucidating human ODDD ocular disease mechanisms and evaluating new treatments designed to protect ocular synaptic network integrity

Relationship between retinal blood flow and arterial oxygen

Retinal blood flow (RBF) increases in response to a reduction in oxygen (hypoxia), but decreases in response to increased oxygen (hyperoxia). However, the relationship between blood flow and the arterial partial pressure of oxygen has not been quantified and modeled in the retina in particular the vascular reserve and resting tonus of the vessels. The objective of this study was to determine the limitations of the retinal vasculature by modeling the relationship between RBF and oxygen. Retinal vascular responses were measured in 13 subjects for 8 different blood gas conditions, with the end-tidal partial pressure of oxygen (PET O2 ) ranging from 40-500 mmHg. Retinal vascular response measurements were repeated twice; using the Canon Laser Blood Flowmeter (CLBF) during the first visit, and using Doppler Spectral Domain Optical Coherence Tomography (Doppler SD-OCT, RTVue) during the second visit. We determined that the relationship between RBF and PaO2 can be modeled as a combination of hyperbolic and linear functions. We concluded that RBF compensated for decreases in arterial oxygen content for all stages of hypoxia used in this study, but can no longer compensate below a PET O2 of 32-37 mmHg. These vessels have a great vascular range of adjustment, increasing diameter (8.5% arteriolar and 21% total venous area) with hypoxia (40 mmHg PET O2 ; p<0.001) and decreasing diameter (6.9% arteriolar and 23% total venous area) with hyperoxia (500 mmHg PET O2 ; p<0.001) to the same extent; indicating that the resting tonus is near the midpoint of the adjustment ranges at resting PaO2 where sensitivity is maximum

Scratching the surface: Elastic rotations beneath nanoscratch and nanoindentation tests

In this paper, we investigate the residual deformation field in the vicinity of nanoscratch tests using two orientations of a Berkovich tip on an (001) Cu single crystal. We compare the deformation with that from indentation, in an attempt to understand the mechanisms of deformation in tangential sliding. The lattice rotation fields are mapped experimentally using high-resolution electron backscatter diffraction (HR-EBSD) on cross-sections prepared using focused ion beam (FIB). A physically-based crystal plasticity finite element model (CPFEM) is used to simulate the lattice rotation fields, and provide insight into the 3D rotation field surrounding a nano-scratch experiment, as it transitions from an initial static indentation to a steady-state scratch. The CPFEM simulations capture the experimental rotation fields with good fidelity, and show how the rotations about the scratch direction are reversed as the indenter moves away from the initial indentation

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely