Fundus autofluorescence findings in a mouse model of retinal detachment

Purpose. Fundus autofluorescence (fundus AF) changes were monitored in a mouse model of retinal detachment (RD). Methods. RD was induced by transscleral injection of hyaluronic acid (Healon) or sterile balanced salt solution (BSS) into the subretinal space of 4-5-day-old albino Abca4 null mutant and Abca4 wild-type mice. Images acquired by confocal scanning laser ophthalmoscopy (Spectralis HRA) were correlated with spectral domain optical coherence tomography (SD-OCT), infrared reflectance (IR), fluorescence spectroscopy, and histologic analysis. Results. In the area of detached retina, multiple hyperreflective spots in IR images corresponded to punctate areas of intense autofluorescence visible in fundus AF mode. The puncta exhibited changes in fluorescence intensity with time. SD-OCT disclosed undulations of the neural retina and hyperreflectivity of the photoreceptor layer that likely corresponded to histologically visible photoreceptor cell rosettes. Fluorescence emission spectra generated using flat-mounted retina, and 488 and 561 nm excitation, were similar to that of RPE lipofuscin. With increased excitation wavelength, the emission maximum shifted towards longer wavelengths, a characteristic typical of fundus autofluorescence. Conclusions. In detached retinas, hyper-autofluorescent spots appeared to originate from photoreceptor outer segments that were arranged within retinal folds and rosettes. Consistent with this interpretation is the finding that the autofluorescence was spectroscopically similar to the bisretinoids that constitute RPE lipofuscin. Under the conditions of a RD, abnormal autofluorescence may arise from excessive production of bisretinoid by impaired photoreceptor cells.     

The Cataract National Dataset electronic multi-centre audit of 55,567 operations: risk indicators for monocular visual acuity outcomes

Aims

To report risk factors for visual acuity (VA) improvement and harm following cataract surgery using electronically collected multi-centre data conforming to the Cataract National Dataset (CND).

Methods

Routinely collected anonymised data were remotely extracted from the electronic patient record systems of 12 participating NHS Trusts undertaking cataract surgery. Following data checks and cleaning, analyses were performed to identify risk indicators for: (1) a good acuity outcome (VA 6/12 or better), (2) the pre- to postoperative change in VA, and (3) VA loss (doubling or worse of the visual angle).

Results

In all, 406 surgeons from 12 NHS Trusts submitted data on 55 567 cataract operations. Preoperative VA was known for 55 528 (99.9%) and postoperative VA outcome for 40 758 (73.3%) operations. Important adverse preoperative risk indicators found in at least 2 of the 3 analyses included older age (3), short axial length (3), any ocular comorbidity (3), age-related macular degeneration (2), diabetic retinopathy (3), amblyopia (2), corneal pathology (2), previous vitrectomy (2), and posterior capsule rupture (PCR) during surgery (3). PCR was the only potentially modifiable adverse risk indicator and was powerfully associated with VA loss (OR=5.74).

Conclusion

Routinely collected electronic data conforming to the CND provide sufficient detail for identification and quantification of preoperative risk indicators for VA outcomes of cataract surgery. The majority of risk indicators are intrinsic to the patient or their eye, with a notable exception being PCR during surgery.     

Air pollution and DNA methylation: interaction by psychological factors in the VA Normative Aging Study

DNA methylation is a potential pathway linking air pollution to disease. Studies indicate that psychological functioning modifies the association between pollution and morbidity. The authors estimated the association of DNA methylation with ambient particulate matter less than 2.5 μm in diameter (PM(2.5)) and black carbon, using mixed models. DNA methylation of the inducible nitric oxide synthase gene, iNOS, and the glucocorticoid receptor gene, GCR, was measured by quantitative polymerase chain reaction pyrosequencing of 1,377 blood samples from 699 elderly male participants in the VA Normative Aging Study (1999-2009). The authors also investigated whether this association was modified by psychological factors including optimism or pessimism, anxiety, and depression. iNOS methylation was decreased after acute exposure to both black carbon and PM(2.5). A 1-μg/m(3) increase in exposure to black carbon in the 4 hours preceding the clinical examination was associated with a 0.9% decrease in 5-methylcytosine (95% CI: 0.4, 1.4) in iNOS, and a 10-μg/m(3) increase in exposure to PM(2.5) was associated with a 0.6% decrease in 5-methylcytosine (95% CI: 0.03, 1.1) in iNOS. Participants with low optimism and high anxiety had associations that were 3-4 times larger than those with high optimism or low anxiety. GCR methylation was not associated with particulate air pollution exposure.     

Differences in the neuromuscular capacity and lean muscle tissue in old and older community-dwelling adults

BACKGROUND: This study investigated whether there was a worsening of the neuromuscular capacity of older adults after the seventh decade of life. METHODS: Fifteen healthy community-dwelling old (< 70 years of age) and 15 older adults (> or = 70 years of age) were assessed for maximal isometric strength (MVC) and force production characteristics, a one-repetition maximum (1-RM) performance, electromyographic (EMG) activity, and bone-free lean tissue (BFLT) mass of the lower extremity. RESULTS: The isometric MVC, 1-RM, and BFLT mass values in the old group were significantly greater than in the older group. In addition, the individual BFLT mass values correlated significantly with the isometric MVC values (r = .85) and the 1-RM scores of the thigh muscle groups (r = .54-.80). The old group generated significantly greater isometric maximal rate of torque development than the older group and performed significantly better at all intervals of the absolute and relative force-time curves. The voluntary muscle activation of the knee extensors of the old group produced significantly higher integrated EMG (iEMG) activity at each epoch in the early iEMG-time curve compared with the old group. CONCLUSIONS: The results suggest that the age-related deterioration in maximal strength measures and rapid force production characteristics in older adults could be related to a reduction in the mass and neural activation of the thigh muscles. The deterioration of the neuromuscular system of community-dwelling older adults may contribute to an increased difficulty in performing daily activities and may increase their risks of tripping and falling.     

Isolation and characterization of a retinal pigment epithelial cell fluorophore: an all-trans-retinal dimer conjugate

Several lines of investigation suggest that the nondegradable fluorophores that accumulate as lipofuscin in retinal pigment epithelium (RPE) cells contribute to the etiology of macular degeneration. Despite evidence that much of this fluorescent material may originate as inadvertent products of the retinoid cycle, the enzymatic pathway by which the 11-cis-retinal chromophore of rhodopsin is generated, the only fluorophores of the RPE to be characterized as yet have been A2E and its isomers. Here, we report the isolation and structural characterization of an additional RPE lipofuscin fluorophore that originates as a condensation product of two molecules of all-trans-retinal (ATR) dimer and forms a protonated Schiff base conjugate with phosphatidylethanolamine (PE), the latter conjugate (ATR dimer-PE) having UV-visible absorbance maxima at 285 and 506 nm. ATR dimer was found to form natively in bleached rod outer segments in vitro and when rod outer segments were incubated with ATR. HPLC analysis of eye-cups that included RPE and isolated neural retina from Abcr-/- mice and RPE isolated from human donor eyes revealed the presence of a pigment with the same UV-visible absorbance and retention time as synthetic ATR dimer-PE conjugate. Evidence that ATR dimer undergoes a photooxidation process involving the addition of oxygens at double bonds as well as an aromatic demethylation also may indicate a role for this molecule, or its derivatives, in the photoreactivity of RPE lipofuscin.     

Analysis of dose-response curves to methacholine. An approach suitable for population studies

Dose-response curves to methacholine were examined in 9 normal and 10 asthmatic volunteers to determine whether the relationship between dose and response can be adequately summarized by means of a single, continuous measure that is not censored at lower levels of bronchial responsiveness. Subjects underwent a standard methacholine challenge test. There was a strong linear relationship between percent decline FEV1 and cumulative dose methacholine. We summarized each dose-response curve by the slope of a line extending from the origin to the last data point obtained. This summary dose-response slope effectively separated asthmatic from normal subjects, and there was a greater than 3,000-fold difference between the least and most responsive subjects. There was a high degree of correlation between the dose-response slope determined by the standard methacholine challenge protocol and that determined by an abbreviated protocol currently being used to examine nonspecific airway responsiveness in a large, longitudinal study of aging. Among the participants of the latter study, there is a unimodal, skewed distribution of dose-response slope. Dose-response slope is proposed as a quantitative measure of nonspecific airway responsiveness that avoids censoring and that may be particularly useful in epidemiologic studies.     

Blockade of the corticotropin releasing factor type 1 receptor attenuates elevated ethanol drinking associated with drinking in the dark procedures

Background: Drinking in the dark (DID) procedures have recently been developed to induce high levels of ethanol drinking in C57BL/6J mice, which result in blood ethanol concentrations (BECs) reaching levels that have measurable affects on physiology and/or behavior. The present experiments determined whether the increased ethanol drinking caused by DID procedures can be attenuated by pretreatment with CP‐154,526; a corticotropin releasing factor type‐1 (CRF₁) receptor antagonist. Methods: In Experiment 1, male C57BL/6J mice received ethanol (20% v/v) in place of water for 4 hours, beginning with 3 hours into the dark cycle. On the fourth day, mice were given an intraperitoneal injection of one of the 4 doses of CP‐154,526 (0, 1, 3, 10 mg/kg) 30 minutes before receiving their ethanol bottle. In Experiment 2, C57BL/6J mice had 2 hours of access to the 20% ethanol solution, beginning with 3 hours into the dark cycle on days 1 to 3, and 4 hours of access to the ethanol bottle on day 4 of DID procedures. Mice were given an intraperitoneal injection of one of the 4 doses of CP‐154,526 (0, 1, 3, 10 mg/kg) 30 minutes before receiving their ethanol bottle on day 4. Tail blood samples were collected immediately after the 4‐hour ethanol access period on the fourth day of each experiment. Additional control experiments assessed the effects of CP‐154,526 on 4‐hour consumption of a 10% (w/v) sucrose solution and open‐field locomotor activity. Results: In Experiment 1, the vehicle‐treated group consumed approximately 4.0 g/kg/4 h of ethanol and achieved BECs of approximately 30 mg%. Furthermore, pretreatment with the CRF₁ receptor antagonist did not alter ethanol consumption. On the other hand, procedures used in Experiment 2 resulted in vehicle‐treated mice consuming approximately 6.0 g/kg/4 h of ethanol with BECs of about 80 mg%. Additionally, the 10 mg/kg dose of CP‐154,526 significantly reduced ethanol consumption and BECs to approximately 3.0 g/kg/4 h and 27 mg%, respectively, relative to vehicle‐treated mice. Importantly, the 10 mg/kg dose of the CRF₁R antagonist did not significantly alter 4‐hour sucrose consumption or locomotor activity. Conclusions: These data indicate that CRF₁R signaling modulates high, but not moderate, levels of ethanol drinking associated with DID procedures.     

Predictors of prognosis in severe chronic heart failure.

A total of 127 patients with chronic heart failure referred to our exercise laboratory were studied retrospectively to identify parameters predictive of prognosis. Patients were followed for a mean of 14.6 months. The group as a whole had severe ventricular dysfunction with a median ejection fraction of 17% and a median peak rate of oxygen consumption of 13.7 ml/kg/min. During the follow-up period 23 patients (18%) died and 18 (14%) underwent cardiac transplantation. The effect of the following variables on outcome (death or transplantation) were examined: age, cause of heart failure, cardiothoracic ratio on chest radiography, left ventricular end-systolic dimension on echocardiography, left ventricular ejection fraction on radionuclide ventriculography, mean dose of diuretic, plasma sodium and urea concentrations, and peak oxygen consumption during exercise. Although all variables except cause of heart failure affected outcome on univariate analysis, multivariate analysis identified three variables that were statistically significant and independent predictors of outcome. In order of importance these were plasma sodium level, left ventricular ejection fraction and peak oxygen consumption. Even in this group of patients with severe heart failure, these variables were predictive of outcome.     

Recovery of leukotriene E4 from the urine of patients with airway obstruction.

The urinary excretion of leukotriene E4 (LTE4) was measured in subjects presenting for emergency treatment of airway obstruction. A total of 72 subjects presenting with airway obstruction performed peak flow determinations before and after three treatments with nebulized albuterol given at 20-min intervals. Of these subjects, 22 more than doubled their peak flow rates, while 19 failed to increase their peak flow rates more than 25% during the treatment period. These groups were designated "responders" and "nonresponders," respectively. Urinary LTE4 excretion was determined in 16 of the 22 responders and 12 of the 19 nonresponders as well as 13 normal subjects by precolumn extraction, analytic reversed-phase high-performance liquid chromatography, and enzyme immunoassay. In the normal subjects the urinary LTE4 excretion was significantly (p less than 0.0001) less than the urinary LTE4 measured in the responder subjects, but not less than the urinary LTE4 excretion in the nonresponder group (p = 0.071). The enhanced recovery of LTE4 from the urine of subjects with acutely reversible airway narrowing is consistent with a bronchoconstrictor role for the cysteinyl leukotrienes in spontaneous acute asthma.