Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE₂) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE₂ receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE₂/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.     

Influence of pain and urinary symptoms on quality of life in young men with chronic prostatitis-like symptoms

BACKGROUND: Our aims in the present study were to estimate the influences of pain and urinary symptoms on quality of life, and to determine which of these two variables has the most predictive power with respect to quality of life in young men with chronic prostatitis-like symptoms. METHODS: Chronic prostatitis-like symptoms were measured by the National Institutes of Health-Chronic Prostatitis Symptom Index. Of the 28,841 men aged 20 years who lived in the study community, 18,495 men (a response rate 64.1%) agreed to participate in the study. A total of 1057 men who complained of symptoms indicative of chronic prostatitis were included in the study. The influences of pain and urinary symptoms on quality of life were determined using logistic regression analysis. The receiver operating characteristic (ROC) curve was used to estimate the predictive ability of each of these variables with respect to quality of life. RESULTS: Results from multivariate analysis showed that both pain and urinary symptoms were associated with an increased likelihood of impaired quality of life, although pain contributed more to a reduced quality of life than urinary symptoms. Relative to men who experienced mild pain, men who experienced moderate pain had a 3.9-fold risk of poor quality of life (odds ratio [OR], 3.87; 95% confidence interval [CI], 2.86-5.23; P < 0.001) and those who experienced severe pain had a 15.7-fold risk of reduced quality of life (OR, 15.68; 95% CI, 6.59-37.35; P < 0.001). Moderate urinary symptoms were associated with a 1.4-fold risk of bother (OR, 1.41; 95% CI, 1.01-1.99; P < 0.001) and severe urinary symptoms were associated with 2.4-fold risk (OR, 2.39; 95% CI, 1.37-4.12; P < 0.001), relative to mild urinary symptoms. Comparison of the effects of pain and urinary symptoms showed that pain severity had the most predictive power for bother, quality of life, and quality-of-life impact. The areas under the ROC curves for bother, quality of life, and quality-of-life impact were 71.3%, 69.3% and 72.5%, respectively. CONCLUSION: Urinary symptoms and pain might be associated with an increased likelihood of impaired quality of life in young men with chronic prostatitis-like symptoms. In addition, our findings suggest that pain severity is the most influential variable for determining quality of life in this population.     

Changes to the ocular biota with time in extended- and daily-wear disposable contact lens use.

Gram-negative bacteria may play a role in the etiology of certain soft contact lens (SCL)-related diseases. Contact lens (CL) wear may modify the normal ocular biota, providing a more favorable environment for potential pathogens. This study reports temporal changes in ocular biota in daily-wear (DW) and extended-wear (EW) disposable SCL use in experienced and neophyte wearers. Lid margin and bulbar conjunctival biota were sampled prior to CL fitting in 26 previous DW SCL users, 18 previous EW SCL users, and 26 neophytes. Wearers were fitted with an etafilcon A CL in one eye and a polymacon CL in the fellow eye. Lenses were worn on a daily basis by the 26 previous DW SCL wearers and on an EW basis by the remaining 44 subjects. The ocular biota was further sampled after 1, 3, 6, 9, and 12 months of wear. The ocular biota consisted of coagulase-negative staphylococci, Corynebacterium spp., Micrococcus spp., and Propionibacterium spp. Potential pathogens were rarely isolated at baseline. No significant trend of increasing ocular colonization was shown for extended CL wear. Lid and conjunctival colonization increased with DW SCL use (P < 0.001), although this increase occurred for nonpathogenic species only. Fewer potential pathogens were isolated from DW SCL than from EW SCL users (P < 0.05). The lid margin consistently showed greater colonization than the conjunctiva and may be a source of potential pathogens during CL wear. Hydrogel CL wear appears to modify the ocular biota. An increased number of commensal organisms were present in DW SCL use. EW SCL use altered the spectrum of organisms isolated. These alterations may suppress the normal ocular defense mechanisms and may be relevant in the pathogenesis of CL-related disease.     

The Dk project: an interlaboratory comparison of Dk/L measurements

The oxygen transmissibilities (Dk/L) of a set of 48 contact lenses made from 8 different materials were measured by 4 laboratories. The L/Dk measurements from each laboratory were compared and correlated. Samples which were not masked with a fixed front surface aperture during measurement were corrected for edge effects. This paper shows that provided L/Dk is calculated for each lens using the same technique and Dk is derived using a graphical method of calculation, similar results can be obtained by all laboratories. However, the agreement was less good for materials of Dk greater than 70 x 10(-11) (cm2/s) (ml O2/ml x mm Hg).     

Performance standards for toric soft contact lenses.

PURPOSE: To simplify the clinical assessment of toric soft contact lens (TSCL) on-eye behavior by establishing a set of standard clinical evaluation techniques. The likely performance range expected among the TSCL wearing population was determined for a series of lens designs and acceptable performance standards indicated for each variable. METHODS: Four prism-ballast, two peri-ballast and one dynamic stabilization TSCL designs were each worn by groups of 20 subjects in a nondispensing study. After 20 min of lens wear, lenses were assessed, in right eyes only, for subjective comfort (100-point scale), lens mislocation (degrees deviation from vertical) and rotational recovery after deliberate 30 degrees mislocation (degrees/10 blinks). The percentage of lenses orienting within +/-10 degrees of target orientation (zero rotation) and the variability of orientation (standard deviation of mislocation) were also calculated for each lens group. RESULTS: Based on partitioning of the data distributions for each variable, performance was designated as excellent, acceptable or poor. Corresponding performance cut-offs were determined at > or =90, 89 to 80, and <80 for subjective comfort, < or =+/-6 degrees , +/-7 degrees to 10 degrees , and >+/-10 degrees for mislocation, >10 degrees /10 blinks, 10 degrees to 6 degrees /10 blinks, and <6 degrees /10 blinks for rotational recovery. For groups of wearers the appropriate cut-offs were > or =90%, 89 to 70%, and <70% of lenses orienting within +/-10 degrees of target orientation and <+/-6 degrees , +/-6 degrees to 10 degrees , and >+/-10 degrees for variability of orientation. CONCLUSION: Techniques suitable for the evaluation of TSCL clinical performance have been described and guidelines for the assessment of such lenses established. In the process, we have identified potential performance differences that may relate to variations in TSCL design.     

Response of subpopulations of the FSall C fibrosarcoma to low dose x-rays and various potential enhancing agents.

The effectiveness of various oxygen carrying treatments in sensitizing subpopulations of the FSallC fibrosarcoma to low doses of radiation was assessed, and compared with survivals obtained with the same cells after in vivo irradiation under normally oxygenated or hypoxic conditions. FSallC tumors were treated with 2-10 Gray then the Hoechst 33342 dye diffusion method was used to separate the tumor into bright (enriched in normally oxygenated cells) and dim (enriched in hypoxic cells) subpopulations. There was good agreement between the survival of normally oxygenated cells in culture and bright cells from tumors and between hypoxic cells in culture and dim cells from tumors over a radiation dosage range of 2-5 Gray. At 10 Gray bright cells from tumors were minimally less sensitive to the radiation dose than normally oxygenated cells in vivo. When maximally effective doses of perfluorochemical emulsions (F44E at 4 g PFC/kg or Fluosol-DA at 2.4 g PFC/kg) or a purified bovine hemoglobin solution (PBHS at 1.32 g protein/kg) were administered 1 hr. prior to radiation therapy with carbogen (95% O2, 5% CO2) breathing prior to and during radiation delivery, low single doses of x-ray (2-5 Gray) were measurably more cytotoxic toward both FSallC tumor cell subpopulations. These results indicate that perfluorochemical emulsions or purified bovine hemoglobin preparations along with carbogen breathing may be able to increase tumor radiosensitivity to the relatively low radiation doses per fraction used in the clinic.