Mice with an induced mutation in collagen 8A2 develop larger eyes and are resistant to retinal ganglion cell damage in an experimental glaucoma model

PURPOSE: To study susceptibility to glaucoma injury as it may be affected by mutations in ocular connective tissue components. METHODS: Mice homozygous for an N-ethyl-N-nitrosourea induced G257D exchange (Gly to Asp) missense mutation (Aca23) in their collagen 8A2 gene were studied to measure intraocular pressure (IOP), axial length and width, number of retinal ganglion cells (RGC), and inflation responses. Three month old homozygous Aca23 mutant and wild type (WT) mice had 6 weeks exposure to elevated IOP induced by polystyrene microbead injection. Additional Aca23 and matched controls were studied at ages of 10 and 18 months. RESULTS: Aca23 mice had no significant difference from WT in IOP level, and in both strains IOP rose with age. In multivariable models, axial length and width were significantly larger in Aca23 than WT, became larger with age, and were larger after exposure to glaucoma (n=227 mice). From inflation test data, the estimates of scleral stress resultants in Aca23 mice were similar to age-matched and younger WT C57BL/6 (B6) mice, while the strain estimates for Aca23 were significantly less than those for either WT group in the mid-sclera and in some of the more anterior scleral measures (p<0.001; n=29, 22, 20 eyes in Aca23, older WT, younger WT, respectively). With chronic IOP elevation, Aca23 eyes increased 9% in length and 7% in width, compared to untreated fellow eyes (p<0.05, <0.01). With similar elevated IOP exposure, WT eyes enlarged proportionately twice as much as Aca23, increasing in length by 18% and in nasal-temporal width by 13% (both p<0.001, Mann-Whitney test). In 4 month old control optic nerves, mean RGC axon number was not different in Aca23 and WT (46,905±7,592, 43,628±11,162, respectively; p=0.43, Mann-Whitney test, n=37 and 29). With chronic glaucoma, Aca23 mice had a mean axon loss of only 0.57±17%, while WT mice lost 21±31% (median loss: 1% versus 10%, n=37, 29, respectively; p=0.001; multivariable model adjusting for positive integral IOP exposure). CONCLUSIONS: The Aca23 mutation in collagen 8α2 is the first gene defect found to alter susceptibility to experimental glaucoma, reducing RGC loss possibly due to differences in mechanical behavior of the sclera. Detailed study of the specific changes in scleral connective tissue composition and responses to chronic IOP elevation in this strain could produce new therapeutic targets for RGC neuroprotection

Bridging the Gap: Collaboration between a School of Pharmacy, Public Health, and Governmental Organizations to provide Clinical and Economic Services to Medicare Beneficiaries

Objective: Promoting healthy communities through the provision of accessible quality healthcare services is a common mission shared by schools of pharmacy, public health departments, and governmental agencies. The following study seeks to identify and detail the benefits of collaboration between these different groups. Methods: In total, 112 mobile clinics targeting Medicare beneficiaries were held in 20 cities across Northern/Central California from 2007 to 2016. Under the supervision of licensed pharmacists, trained student pharmacists provided vaccinations, health screenings, Medicare Part D plan optimization services, and Medication Therapy Management (MTM) to patients at each clinic site. Clinic support was extended by public health departments, governmental agency partners, and a health professional program. Results: Since clinic inception, 8,996 patients were provided services. In total, 19,441 health screenings and 3,643 vaccinations were collectively provided to clinic patients. We assisted 5,549 beneficiaries with their Part D benefit, resulting in an estimated aggregate out-of-pocket drug cost savings of $5.7 million. Comprehensive MTM services were provided to 4,717 patients during which 8,184 medication-related problem (MRP) were identified. In 15.3% of patients, the MRP was determined severe enough to warrant prescriber follow-up. In total, 42.9% of clinic patients were from racial/ethnic minority groups and 25.5% had incomes ≤150% of the Federal Poverty Level. Conclusion: Collaboration between a school of pharmacy, public health departments, and governmental organizations can effectively serve Medicare beneficiary populations and result in: 1) lower out-of-pocket drug costs, 2) minimization of medication-related problems, 3) increased vaccination uptake, and 4) increased utilization of health screenings. Conflict of Interest We declare no conflicts of interest or financial interests that the authors or members of their immediate families have in any product or service discussed in the manuscript, including grants (pending or received), employment, gifts, stock holdings or options, honoraria, consultancies, expert testimony, patents and royalties. Treatment of Human Subjects: IRB review/approval required and obtained   Type: Original Researc

Bridging the Gap: Collaboration between a School of Pharmacy, Public Health, and Governmental Organizations to provide Clinical and Economic Services to Medicare Beneficiaries

Objective: Promoting healthy communities through the provision of accessible quality healthcare services is a common mission shared by schools of pharmacy, public health departments, and governmental agencies. The following study seeks to identify and detail the benefits of collaboration between these different groups. Methods: In total, 112 mobile clinics targeting Medicare beneficiaries were held in 20 cities across Northern/Central California from 2007 to 2016. Under the supervision of licensed pharmacists, trained student pharmacists provided vaccinations, health screenings, Medicare Part D plan optimization services, and Medication Therapy Management (MTM) to patients at each clinic site. Clinic support was extended by public health departments, governmental agency partners, and a health professional program. Results: Since clinic inception, 8,996 patients were provided services. In total, 19,441 health screenings and 3,643 vaccinations were collectively provided to clinic patients. We assisted 5,549 beneficiaries with their Part D benefit, resulting in an estimated aggregate out-of-pocket drug cost savings of $5.7 million. Comprehensive MTM services were provided to 4,717 patients during which 8,184 medication-related problem (MRP) were identified. In 15.3% of patients, the MRP was determined severe enough to warrant prescriber follow-up. In total, 42.9% of clinic patients were from racial/ethnic minority groups and 25.5% had incomes ≤150% of the Federal Poverty Level. Conclusion: Collaboration between a school of pharmacy, public health departments, and governmental organizations can effectively serve Medicare beneficiary populations and result in: 1) lower out-of-pocket drug costs, 2) minimization of medication-related problems, 3) increased vaccination uptake, and 4) increased utilization of health screenings. Conflict of Interest We declare no conflicts of interest or financial interests that the authors or members of their immediate families have in any product or service discussed in the manuscript, including grants (pending or received), employment, gifts, stock holdings or options, honoraria, consultancies, expert testimony, patents and royalties. Treatment of Human Subjects: IRB review/approval required and obtained   Type: Original Researc

A prediction model for good neurological outcome in successfully resuscitated out-of-hospital cardiac arrest patients

Abstract Background In the initial hours after out-of-hospital cardiac arrest (OHCA), it remains difficult to estimate whether the degree of post-ischemic brain damage will be compatible with long-term good neurological outcome. We aimed to construct prognostic models able to predict good neurological outcome of OHCA patients within 48 h after CCU admission using variables that are bedside available. Methods Based on prospectively gathered data, a retrospective data analysis was performed on 107 successfully resuscitated OHCA patients with a presumed cardiac cause of arrest. Targeted temperature management at 33 °C was initiated at CCU admission. Prediction models for good neurological outcome (CPC1–2) at 180 days post-CA were constructed at hour 1, 12, 24 and 48 after CCU admission. Following multiple imputation, variables were selected using the elastic-net method. Each imputed dataset was divided into training and validation sets (80% and 20% of patients, respectively). Logistic regression was fitted on training sets and prediction performance was evaluated on validation sets using misclassification rates. Results The prediction model at hour 24 predicted good neurological outcome with the lowest misclassification rate (21.5%), using a cut-off probability of 0.55 (sensitivity = 75%; specificity = 82%). This model contained sex, age, diabetes status, initial rhythm, percutaneous coronary intervention, presence of a BIS 0 value, mean BIS value and lactate as predictive variables for good neurological outcome. Discussion This study shows that good neurological outcome after OHCA can be reasonably predicted as early as 24 h following ICU admission using parameters that are bedside available. These prediction models could identify patients who would benefit the most from intensive care

Losartan Treatment Protects Retinal Ganglion Cells and Alters Scleral Remodeling in Experimental Glaucoma

<div><p>Purpose</p><p>To determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice.</p><p>Methods</p><p>We produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by β-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry.</p><p>Results</p><p>Losartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP.</p><p>Conclusions</p><p>The neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head.</p></div

Multivariable model for percent axon loss.

<p>^† Treatments that share a</p><p>^¶ are not significantly different at p ≤ 0.05;</p><p>* Tukey adjustment for multiple comparisons.</p><p>Multivariable model for percent axon loss.</p

Primary antibodies used for histological studies and Immunoblot.

<p>(W) Western blot, (S) Immunohistochemistry sections, (WM) Immunohistochemistry wholemount.</p><p>Primary antibodies used for histological studies and Immunoblot.</p

Axial length and width.

<p>Data are mean (standard deviation) in mm.</p><p>Axial length and width.</p

Axon loss by treatment group.

<p>* p = 0.0001, t test for difference from zero percent loss; SD = standard deviation; n = number of animals providing data per group.</p><p>Axon loss by treatment group.</p