For decades, photoreceptors have been an outstanding model system for elucidating basic principles in sensory transduction and biochemistry and for understanding many facets of neuronal cell biology. ...In recent years, new knowledge of the kinetics of signaling and the large-scale movements of proteins underlying signaling has led to a deeper appreciation of the photoreceptor's unique challenge in mediating the first steps in vision over a wide range of light intensities.
The gratitude paradox Chisholm‐Burns, Marie; Formica, Richard N.
Journal of internal medicine,
June 2024, 2024-Jun, 2024-06-00, 20240601, Letnik:
295, Številka:
6
Journal Article
Abstract
Purpose
The purpose of this review is to (1) provide information concerning the opioid crisis including origins, trends, and some important related laws/policies; and (2) summarize the ...current involvement and impact of pharmacists in helping to address the crisis, as well as examine practices in other healthcare disciplines from which pharmacists might derive guidance and strategies.
Summary
Contributors to the opioid crisis included campaigns to treat pain as a fifth vital sign and to use opioids in treatment of non-cancer-related pain, as well as aggressive marketing of opioid analgesics by pharmaceutical companies. To address the crisis, numerous strategies have been implemented at the policy/legislative, health-system, and patient levels, such as prescription drug monitoring programs (PDMPs), increased regulation of pain clinics, and expanded use of naloxone. Pharmacists have a critical role to play in interventions to address opioid misuse and reduce harm resulting from misuse. Such interventions include patient screening and risk stratification, patient and community education and outreach concerning appropriate pain management, medication reviews/medication therapy management, education on safe storage and disposal, distribution of naloxone/opioid rescue kits and training on their proper use, and referral of patients to addiction treatment, among other strategies.
Conclusion
Pharmacists have multiple, complex roles in addressing the opioid crisis. Outcomes of several studies provide substantial evidence that pharmacists can make an impact through appropriate pain management, use of PDMPs, opioid overdose prevention training, and medication reviews and counseling, among other interventions.
Neuroinflammation commonly accompanies neurodegeneration, but the specific roles of resident and infiltrating immune cells during degeneration remains controversial. Much of the difficulty in ...assessing myeloid cell-specific functions during disease progression arises from the inability to clearly distinguish between activated microglia and bone marrow-derived monocytes and macrophages in various stages of differentiation and activation within the central nervous system. Using an inducible model of photoreceptor cell death, we investigated the prevalence of infiltrating monocytes and macrophage subpopulations after the initiation of degeneration in the mouse retina. In vivo retinal imaging revealed infiltration of CCR2
leukocytes across retinal vessels and into the parenchyma within 48 hours of photoreceptor degeneration. Immunohistochemistry and flow cytometry confirmed and characterized these leukocytes as CD11b
CD45
cells. Single-cell mRNA sequencing of the entire CD11b
CD45
population revealed the presence of resting microglia, activated microglia, monocytes, and macrophages as well as 12 distinct subpopulations within these four major cell classes. Our results demonstrate a previously immeasurable degree of molecular heterogeneity in the innate immune response to cell-autonomous degeneration within the central nervous system and highlight the necessity of unbiased high-throughput and high-dimensional molecular techniques like scRNAseq to understand the complex and changing landscape of immune responders during disease progression.
The Food and Drug Administration (FDA) held a public meeting and scientific workshop in September 2016 to obtain perspectives from solid organ transplant recipients, family caregivers, and other ...patient representatives. The morning sessions focused on the impact of organ transplantation on patients’ daily lives and the spectrum of activities undertaken to maintain grafts. Participants described the physical, emotional, and social impacts of their transplant on daily life. They also discussed their posttransplant treatment regimens, including the most burdensome side effects and their hopes for future treatment. The afternoon scientific session consisted of presentations on prevalence and risk factors for medication nonadherence after transplantation in adults and children, and interventions to manage it. As new modalities of Immunosuppressive Drug Therapy are being developed, the patient perceptions and input must play larger roles if organ transplantation is to be truly successful.
The authors summarize a FDA public meeting considering the benefits and challenges of immunosuppressive therapy and how medications impact recipients’ lives, the challenges of medication adherence, and future considerations that can guide the FDA in approving future immunosuppressive therapy.
Abstract
Melanosomes, lipofuscin, and melanolipofuscin are the three principal types of pigmented granules found in retinal pigment epithelium (RPE) cells. Changes in the density of melanosomes and ...lipofuscin in RPE cells are considered hallmarks of various retinal diseases, including Stargardt disease and age-related macular degeneration (AMD). Herein, we report the potential of an in vivo multimodal imaging technique based on directional back-scattering and short-wavelength fundus autofluorescence (SW-FAF) to study disease-related changes in the density of melanosomes and lipofuscin granules in RPE cells. Changes in the concentration of these granules in
Abca4
−/−
mice (a model of Stargardt disease) relative to age-matched wild-type (WT) controls were investigated. Directional optical coherence tomography (dOCT) was used to assess melanosome density in vivo, whereas the autofluorescence (AF) images and emission spectra acquired with a spectrometer-integrated scanning laser ophthalmoscope (SLO) were used to characterize lipofuscin and melanolipofuscin granules in the same RPE region. Subcellular-resolution ex vivo imaging using confocal fluorescence microscopy and electron microscopy was performed on the same tissue region to visualize and quantify melanosomes, lipofuscin, and melanolipofuscin granules. Comparisons between in vivo and ex vivo results confirmed an increased concentration of lipofuscin granules and decreased concentration of melanosomes in the RPE of
Abca4
−/−
mice, and provided an explanation for the differences in fluorescence and directionality of RPE scattering observed in vivo between the two mouse strains.
Both resident microglia and invading peripheral immune cells can respond to injury and degeneration in the central nervous system. However, after dead and dying neurons have been cleared and ...homeostasis is re-established, it is unknown whether resident immune cells fully resume normal functions and to what degree the peripheral immune cells take up residence.
Using flow cytometry, in vivo retinal imaging, immunohistochemistry, and single-cell mRNA sequencing, we assess resident microglia and monocyte-derived macrophages in the retina during and after the loss of photoreceptors in the Arr1
mouse model of inducible degeneration.
We find that photoreceptor loss results in a small, sustained increase in mononuclear phagocytes and, after degeneration wanes, these cells re-establish a spatial mosaic reminiscent of healthy retinas. Transcriptomic analysis revealed the population remained unusually heterogeneous, with several subpopulations expressing gene patterns consistent with mildly activated phenotypes. Roughly a third of "new resident" cells expressed markers traditionally associated with both microglial and monocytic lineages, making their etiology ambiguous. Using an inducible Cre-based fluorescent lineage tracing paradigm to confirm the origins of new resident immune cells, we found approximately equal numbers of microglia and monocyte-derived macrophages after degeneration had subsided. In vivo retinal imaging and immunohistochemical analysis showed that both subpopulations remained functionally responsive to sites of local damage, though on average the monocyte-derived cells had less morphological complexity, expressed higher levels of MHCII, and had less migratory activity than the native resident population.
Monocytic cells that infiltrate the retina during degeneration differentiate into monocyte-derived macrophages that can remain in the retina long-term. These monocyte-derived macrophages adopt ramified morphologies and microglia-like gene expression. However, they remain distinguishable in morphology and gene expression from resident microglia and appear to differ functionally, showing less responsiveness to subsequent retinal injuries. These findings support the idea that persistent changes in the local immune population that occur in response to cell loss in aging and progressive retinal diseases may include the establishment of subpopulations of bone marrow-derived cells whose ability to respond to subsequent insults wanes over time.
Rod photoreceptors generate amplified, reproducible responses to single photons via a G protein signaling cascade. Surprisingly, genetic perturbations that dramatically alter the deactivation of the ...principal signal amplifier, the GPCR rhodopsin (R∗), do not much alter the amplitude of single-photon responses (SPRs). These same perturbations, when crossed into a line lacking calcium feedback regulation of cGMP synthesis, produced much larger alterations in SPR amplitudes. Analysis of SPRs from rods with and without feedback reveal that the consequences of trial-to-trial fluctuations in R∗ lifetime in normal rods are also dampened by feedback regulation of cGMP synthesis. Thus, calcium feedback trumps the mechanisms of R∗ deactivation in determining the SPR amplitude, attenuating responses arising from longer R∗ lifetimes to a greater extent than those arising from shorter ones. As a result, rod SPRs achieve a more stereotyped amplitude, a characteristic considered important for reliable transmission through the visual system.
► Rhodopsin (R∗) lifetime weakly affects single photon response (SPR) amplitudes ► Ca-activated cGMP synthesis disproportionately attenuates SPRs of long-lived R∗s ► Feedback to cGMP synthesis also reduces trial-to-trial variation in SPR amplitude ► SPR reproducibility is accounted for by measured and established mechanisms
In retinal rods, the single-photon response does not vary proportionately with the active lifetime of rhodopsin. Here, Gross et al. demonstrate that calcium feedback to cGMP synthesis stabilizes the response against genetic perturbations and stochastic trial-to-trial variability of rhodopsin deactivation.
In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are ...posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.
To evaluate income trends among pharmacists and other select health professions (dentists, nurse practitioners, registered nurses, and physicians) in the US for the 10-year period of 2012 to 2021, with special attention given to the first 2 years of the COVID-19 pandemic (2020 and 2021).
A retrospective analysis was conducted of 2012 to 2021 income data for select health professions, collected from the American Community Survey. Univariate time series analysis was conducted using exponential smoothing to examine income patterns over the 10-year study period and forecast income for the next 5-year period (2022 to 2026) for each health profession. Additionally, time series regression models were constructed for each health profession. Descriptive statistics (mean percent change in income and SD) were calculated for each health profession for the prepandemic era (2012 to 2019) and the first 2 years of the pandemic (2020 and 2021).
Goodness-of-fit statistics for each forecast model indicate highly accurate forecasts. The model for each health profession indicates a significant positive trajectory in income (P < 0.001), although pharmacists are projected to have a lower rate of income growth among the 5 health professions for the next 5-year period, 2022 to 2026. During the first 2 years of the pandemic, pharmacists had the lowest mean percent change in income (mean, 2.0%; SD, 2.0%) among the 5 health professions.
Growth in pharmacist income is projected to lag behind that in other health professions in the near future. Individual-, organization-, and profession-level strategies may facilitate opportunities for income growth among pharmacists.
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