Effect of Glucosamine on Intraocular Pressure and Risk of Developing Glaucoma.

PRCIS: Glucosamine supplementation is common but can be associated with increased intraocular pressure (IOP) and could contribute to the pathogenesis of glaucoma. It may be prudent for ophthalmologists to elicit any history of glucosamine use from their patients and advise them accordingly. Further studies on the role of glucosamine in glaucoma are warranted. BACKGROUND: The most frequently recommended slow-acting medication for osteoarthritis symptoms is glucosamine, although its effectiveness is questionable. Widely used glucosamine sulfate supplements may increase IOP. METHODS: In the current study, we analyzed online databases such as UK Biobank, MedWatch, and FinnGen to evaluate the relationship between glucosamine and IOP and glaucoma. We included budesonide and fluticasone in the analysis for comparison since these drugs are associated with increased IOP. RESULTS: In UK Biobank subjects, glucosamine use was associated with increased corneal compensated IOP ( P =0.002, 2-tailed t test). This was also true in subjects without glaucoma ( P =0.002, 2-tailed t test). However, no significant association between glucosamine and IOP was detected in subjects with a diagnosis of glaucoma. In MedWatch, 0.21% of subjects taking glucosamine reported glaucoma, 0.29% of subjects using budesonide reported glaucoma, and 0.22% of subjects using fluticasone reported glaucoma. In contrast, 0.08% of subjects using any other drug reported glaucoma. This variability is significant ( P <0.001, 2-tailed Fisher exact test). Data from FinnGen on the risk of primary open angle glaucoma or glaucoma in subjects using glucosamine before the diagnosis of the disease revealed a significantly increased risk for both primary open angle glaucoma (hazard ratio: 2.35) and glaucoma (hazard ratio: 1.95). CONCLUSION: Glucosamine supplementation is common but can be associated with increased IOP and could contribute to the pathogenesis of glaucoma. It may be prudent for ophthalmologists to elicit any history of glucosamine use from their patients and advise them accordingly. Further studies on the role of glucosamine in glaucoma are warranted.

The retrosplenial cortex of Carollia perspicillata, Seba's short-tailed fruit bat.

Retrosplenial cortex (RSC) is a brain region involved in critical cognitive functions including memory, planning, and spatial navigation and is commonly affected in neurodegenerative diseases. Subregions of RSC are typically described as Brodmann areas 29 and 30, which are defined by cytoarchitectural features. Using immunofluorescence, we studied the distributions of neurons immunoreactive for NeuN, latexin, and calcium binding proteins (calbindin, calretinin, and parvalbumin) in RSC of Carollia perspicillata, Seba's short-tailed fruit bat. We observed that latexin was specifically present in areas 29a and 29b but not 29c and 30. We further identified distribution patterns of calcium binding proteins that group areas 29a and 29b separately from areas 29c and 30. We conclude first that latexin is a useful marker to classify subregions of RSC and second that these subregions contain distinct patterns of neuronal immunoreactivity for calcium binding proteins. Given the long lifespan of Carollia, bat RSC may be a useful model in studying age-related neurodegeneration.

Differential distribution of inhibitory neuron types in subregions of claustrum and dorsal endopiriform nucleus of the short-tailed fruit bat.

Few brain regions have such wide-ranging inputs and outputs as the claustrum does, and fewer have posed equivalent challenges in defining their structural boundaries. We studied the distributions of three calcium-binding proteins-calretinin, parvalbumin, and calbindin-in the claustrum and dorsal endopiriform nucleus of the fruit bat, Carollia perspicillata. The proportionately large sizes of claustrum and dorsal endopiriform nucleus in Carollia brain afford unique access to these structures' intrinsic anatomy. Latexin immunoreactivity permits a separation of claustrum into core and shell subregions and an equivalent separation of dorsal endopiriform nucleus. Using latexin labeling, we found that the claustral shell in Carollia brain can be further subdivided into at least four distinct subregions. Calretinin and parvalbumin immunoreactivity reinforced the boundaries of the claustral core and its shell subregions with diametrically opposite distribution patterns. Calretinin, parvalbumin, and calbindin all colocalized with GAD67, indicating that these proteins label inhibitory neurons in both claustrum and dorsal endopiriform nucleus. Calretinin, however, also colocalized with latexin in a subset of neurons. Confocal microscopy revealed appositions that suggest synaptic contacts between cells labeled for each of the three calcium-binding proteins and latexin-immunoreactive somata in claustrum and dorsal endopiriform nucleus. Our results indicate significant subregional differences in the intrinsic inhibitory connectivity within and between claustrum and dorsal endopiriform nucleus. We conclude that the claustrum is structurally more complex than previously appreciated and that claustral and dorsal endopiriform nucleus subregions are differentially modulated by multiple inhibitory systems. These findings can also account for the excitability differences between claustrum and dorsal endopiriform nucleus described previously.

Carollia perspicillata: A Small Bat with Tremendous Translational Potential for Studies of Brain Aging and Neurodegeneration.

As the average human lifespan lengthens, the impact of neurodegenerative disease increases, both on the individual suffering neurodegeneration and on the community that supports those individuals. Studies aimed at understanding the mechanisms of neurodegeneration have relied heavily on observational studies of humans and experimental studies in animals, such as mice, in which aspects of brain structure and function can be manipulated to target mechanistic steps. An animal model whose brain is structurally closer to the human brain, that lives much longer than rodents, and whose husbandry is practical may be valuable for mechanistic studies that cannot readily be conducted in rodents. To demonstrate that the long-lived Seba's short-tailed fruit bat, Carollia perspicillata, may fit this role, we used immunohistochemical labeling for NeuN and three calcium-binding proteins, calretinin, parvalbumin, and calbindin, to define hippocampal formation anatomy. Our findings demonstrate patterns of principal neuron organization that resemble primate and human hippocampal formation and patterns of calcium-binding protein distribution that help to define subregional boundaries. Importantly, we present evidence for a clear prosubiculum in the bat brain that resembles primate prosubiculum. Based on the similarities between bat and human hippocampal formation anatomy, we suggest that Carollia has unique advantages for the study of brain aging and neurodegeneration. A captive colony of Carollia allows age tracking, diet and environment control, pharmacological manipulation, and access to behavioral, physiological, anatomical, and molecular evaluation.

Association between otitis media infection and failed hearing screenings in children.

This study aims to assess prospectively whether there is an association between frequencies of upper respiratory tract infections (URTI) or asthma in early childhood and failed otoacoustic emission (OAE) screenings later in life. There are no clear recommendations for hearing testing following acute otitis media (AOM) infection. This is a retrospective, practice based chart review. Participants from a primary care setting were 517 pre-adolescent and adolescent children (49.9% female) (ages 10-21; mean, 15 y/o), who had presented with at least one specific bacterial URTI (AOM, Group A Streptococcus (GAS) tonsillitis, or Influenza) during childhood. Hearing testing was recorded incidentally at all subsequent routine health care maintenance visits (OAE hearing screen). Simple linear regression analyses were performed using R (v3.4.4). We found that number of episodes of AOM infections strongly correlated with number of failed OAE screenings later in life (F = 76.37; P = <0.001; R2 = 0.1279), while GAS (F = 1.859; P = 0.1733; R2 = 0.0016) or Influenza infection (F = 2.624; P = 0.1059; R2 = 0.0031) were not associated with failed OAE screening. Correlation between number of AOM infections and number of failed OAE screenings was not strengthened by presence of asthma. This study found evidence of an association between childhood history of AOM and failed OAE screenings in adolescence. Since this population may be at a higher risk for developing permanent or fluctuating hearing losses, further studies to clarify indications and timing of standard audiological testing among these children should be considered.

DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy.

Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of DUX4 in skeletal muscle cells. DUX4 is a transcription factor that activates genes normally associated with stem cell biology and its mis-expression in FSHD cells results in apoptosis. To identify genes and pathways necessary for DUX4-mediated apoptosis, we performed an siRNA screen in an RD rhabdomyosarcoma cell line with an inducible DUX4 transgene. Our screen identified components of the MYC-mediated apoptotic pathway and the double-stranded RNA (dsRNA) innate immune response pathway as mediators of DUX4-induced apoptosis. Further investigation revealed that DUX4 expression led to increased MYC mRNA, accumulation of nuclear dsRNA foci, and activation of the dsRNA response pathway in both RD cells and human myoblasts. Nuclear dsRNA foci were associated with aggregation of the exon junction complex component EIF4A3. The elevation of MYC mRNA, dsRNA accumulation, and EIF4A3 nuclear aggregates in FSHD muscle cells suggest that these processes might contribute to FSHD pathophysiology.

JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks.

The accumulation of damage caused by oxidative stress has been linked to aging and to the etiology of numerous age-related diseases. The longevity gene, sirtuin 6 (SIRT6), promotes genome stability by facilitating DNA repair, especially under oxidative stress conditions. Here we uncover the mechanism by which SIRT6 is activated by oxidative stress to promote DNA double-strand break (DSB) repair. We show that the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), phosphorylates SIRT6 on serine 10 in response to oxidative stress. This post-translational modification facilitates the mobilization of SIRT6 to DNA damage sites and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs. Our results demonstrate a post-translational mechanism regulating SIRT6, and they provide the link between oxidative stress signaling and DNA repair pathways that may be critical for hormetic response and longevity assurance.

SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age.

L1 retrotransposons are an abundant class of transposable elements that pose a threat to genome stability and may have a role in age-related pathologies such as cancer. Recent evidence indicates that L1s become more active in somatic tissues during the course of ageing; however the mechanisms underlying this phenomenon remain unknown. Here we report that the longevity regulating protein, SIRT6, is a powerful repressor of L1 activity. Specifically, SIRT6 binds to the 5'-UTR of L1 loci, where it mono-ADP ribosylates the nuclear corepressor protein, KAP1, and facilitates KAP1 interaction with the heterochromatin factor, HP1α, thereby contributing to the packaging of L1 elements into transcriptionally repressive heterochromatin. During the course of ageing, and also in response to DNA damage, however, we find that SIRT6 is depleted from L1 loci, allowing the activation of these previously silenced retroelements.