Chronic free-choice drinking in crossed HAP (cHAP) mice leads to sustained blood ethanol levels and metabolic tolerance without evidence of liver damage

Background Crossed High Alcohol Preferring (cHAP) mice were selectively bred from a cross of the HAP1xHAP2 replicate lines, and demonstrate blood ethanol concentrations (BECs) during free-choice drinking that are reminiscent of those observed in alcohol-dependent humans. Therefore, this line may provide an unprecedented opportunity to learn about the consequences of excessive voluntary ethanol consumption, including metabolic tolerance and liver pathology. Cytochrome p450 2E1 (CYP 2E1) induction plays a prominent role in driving both metabolic tolerance and ethanol-induced liver injury. In this report, we sought to characterize cHAP drinking by assessing whether pharmacologically relevant BEC levels are sustained throughout the active portion of the light-dark cycle. Given that cHAP intakes and BECs are similar to those observed in mice given an ethanol liquid diet, we assessed whether free-choice exposure results in metabolic tolerance, hepatic enzyme induction, and hepatic steatosis. Methods In Experiment 1, blood samples were taken across the dark portion of a 12:12 light-dark cycle to examine the pattern of ethanol accumulation in these mice. In Experiments 1 and 2, mice were injected with ethanol following 3–4 weeks of access to water or 10% ethanol and water, and blood samples were taken to assess metabolic tolerance. In Experiment 3, 24 mice had 4 weeks access to 10% ethanol and water or water alone, followed by necropsy and hepatological assessment. Results In experiment 1, cHAP mice mean BEC values exceeded 80 mg/dl at all sampling points, and approached 200 mg/dl during the middle of the dark cycle. In experiments 1 and 2, ethanol-exposed mice metabolized ethanol faster than ethanol-naïve mice, demonstrating metabolic tolerance (p < .05). In experiment 3, ethanol-drinking mice showed greater expression of hepatic CYP 2E1 than water controls, consistent with the development of metabolic tolerance (p < .05). Ethanol access altered neither hepatic histology nor levels of ADH and ALDH. Conclusions These results demonstrate that excessive intake by cHAP mice results in sustained BECs throughout the active period, leading to the development of metabolic tolerance and evidence of CYP 2E1 induction. Together these results provide additional support for the cHAP mice as a highly translational rodent model of alcoholism

What's on TV? Detecting age-related neurodegenerative eye disease using eye movement scanpaths

Purpose: We test the hypothesis that age-related neurodegenerative eye disease can be detected by examining patterns of eye movement recorded whilst a person naturally watches a movie. Methods: Thirty-two elderly people with healthy vision (median age: 70, interquartile range [IQR] 64–75 years) and 44 patients with a clinical diagnosis of glaucoma (median age: 69, IQR 63–77 years) had standard vision examinations including automated perimetry. Disease severity was measured using a standard clinical measure (visual field mean deviation; MD). All study participants viewed three unmodified TV and film clips on a computer set up incorporating the Eyelink 1000 eyetracker (SR Research, Ontario, Canada). Eye movement scanpaths were plotted using novel methods that first filtered the data and then generated saccade density maps. Maps were then subjected to a feature extraction analysis using kernel principal component analysis (KPCA). Features from the KPCA were then classified using a standard machine based classifier trained and tested by a 10-fold cross validation which was repeated 100 times to estimate the confidence interval (CI) of classification sensitivity and specificity. Results: Patients had a range of disease severity from early to advanced (median [IQR] right eye and left eye MD was −7 [−13 to −5] dB and −9 [−15 to −4] dB, respectively). Average sensitivity for correctly identifying a glaucoma patient at a fixed specificity of 90% was 79% (95% CI: 58–86%). The area under the Receiver Operating Characteristic curve was 0.84 (95% CI: 0.82–0.87). Conclusions: Huge data from scanpaths of eye movements recorded whilst people freely watch TV type films can be processed into maps that contain a signature of vision loss. In this proof of principle study we have demonstrated that a group of patients with age-related neurodegenerative eye disease can be reasonably well separated from a group of healthy peers by considering these eye movement signatures alone

Eye movements and reading in glaucoma: observations on patients with advanced visual field loss

Purpose To investigate the relationship between reading speed and eye movements in patients with advanced glaucomatous visual field (VF) defects and age-similar visually healthy people. Methods Eighteen patients with advanced bilateral VF defects (mean age: 71, standard deviation [SD]: 7 years) and 39 controls (mean age: 67, SD: 8 years) had reading speed measured using short passages of text on a computer set-up incorporating eye tracking. Scanpaths were plotted and analysed from these experiments to derive measures of ‘perceptual span’ (total number of letters read per number of saccades) and ‘text saturation’ (the distance between the first and last fixation on lines of text). Another eye movement measure, termed ‘saccadic frequency’ (total number of saccades made to read a single word), was derived from a separate lexical decision task, where words were presented in isolation. Results Significant linear association was demonstrated between perceptual span and reading speed in patients (R2=0.42) and controls (R2=0.56). Linear association between saccadic frequency during the LDT and reading speed was also found in patients (R2=0.42), but not in controls (R2=0.02). Patients also exhibited greater average text saturation than controls (P=0.004). Conclusion Some, but not all, patients with advanced VF defects read slower than controls using short text passages. Differences in eye movement behaviour may partly account for this variability in patients. These patients were shown to saturate lines of text more during reading, which may explain previously-reported difficulties with sustained reading

Eye movements during visual search in patients with glaucoma

Background: Glaucoma has been shown to lead to disability in many daily tasks including visual search. This study aims to determine whether the saccadic eye movements of people with glaucoma differ from those of people with normal vision, and to investigate the association between eye movements and impaired visual search. Methods: Forty patients (mean age: 67 [SD: 9] years) with a range of glaucomatous visual field (VF) defects in both eyes (mean best eye mean deviation [MD]: –5.9 (SD: 5.4) dB) and 40 age-related people with normal vision (mean age: 66 [SD: 10] years) were timed as they searched for a series of target objects in computer displayed photographs of real world scenes. Eye movements were simultaneously recorded using an eye tracker. Average number of saccades per second, average saccade amplitude and average search duration across trials were recorded. These response variables were compared with measurements of VF and contrast sensitivity. Results: The average rate of saccades made by the patient group was significantly smaller than the number made by controls during the visual search task (P = 0.02; mean reduction of 5.6% (95% CI: 0.1 to 10.4%). There was no difference in average saccade amplitude between the patients and the controls (P = 0.09). Average number of saccades was weakly correlated with aspects of visual function, with patients with worse contrast sensitivity (PR logCS; Spearman’s rho: 0.42; P = 0.006) and more severe VF defects (best eye MD; Spearman’s rho: 0.34; P = 0.037) tending to make less eye movements during the task. Average detection time in the search task was associated with the average rate of saccades in the patient group (Spearman’s rho = −0.65; P < 0.001) but this was not apparent in the controls. Conclusions: The average rate of saccades made during visual search by this group of patients was fewer than those made by people with normal vision of a similar average age. There was wide variability in saccade rate in the patients but there was an association between an increase in this measure and better performance in the search task. Assessment of eye movements in individuals with glaucoma might provide insight into the functional deficits of the disease

Opportunities for organoids as new models of aging.

The biology of aging is challenging to study, particularly in humans. As a result, model organisms are used to approximate the physiological context of aging in humans. However, the best model organisms remain expensive and time-consuming to use. More importantly, they may not reflect directly on the process of aging in people. Human cell culture provides an alternative, but many functional signs of aging occur at the level of tissues rather than cells and are therefore not readily apparent in traditional cell culture models. Organoids have the potential to effectively balance between the strengths and weaknesses of traditional models of aging. They have sufficient complexity to capture relevant signs of aging at the molecular, cellular, and tissue levels, while presenting an experimentally tractable alternative to animal studies. Organoid systems have been developed to model many human tissues and diseases. Here we provide a perspective on the potential for organoids to serve as models for aging and describe how current organoid techniques could be applied to aging research

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness

East Chisenbury Midden 2015−17: further investigations of the late prehistoric midden deposits, enclosure and associated settlement

After a gap of almost two decades further investigations were initiated at this remarkable late prehistoric midden site, supported by Operation Nightingale/Breaking Ground Heritage. Geophysical survey clarified the extent of the broadly contemporary enclosure surrounding the midden, as well as other related features, while subsequent excavations provided new information on the midden, the enclosure and settlement. Two small trenches in the northeast half of the midden revealed a different sequence and produced far fewer finds than the 1992−3 excavations in the southwest half, demonstrating that it is not a homogeneous mound. A substantial ditch and associated bank, largely levelled by the late Roman period, may have been contemporary with or pre-dated the early development of the midden, while some 150 postholes attested to the presence of numerous roundhouses and other structures within the enclosure. Overall, a date range of c. 1000−500 cal. BC and possibly later is suggested from radiocarbon dating and pottery, the main phase of midden development perhaps later than the majority of the settlement. Furthermore, recent results of radiocarbon dating of material from the earlier excavations suggest the site sequence may continue as late as c. 400 cal. BC. Radiocarbon dating of the few human remains has also highlighted the likelihood that some were curated, the probable intervals between the dates of death and deposition ranging from a few decades to three centuries. Finds and environmental assemblages are generally consistent with those previously found, but a few sherds of scratch cordoned bowl represent a significant new discovery, as does a unique copper alloy ‘pendant’ of possible continental origin. Evidence now indicates that cattle, as well as sheep and pigs, were intensively managed and slaughtered on site, with the isotope data suggesting local origins for most of the animals, though some cattle may have been raised on pasturage further afield

A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus.

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma