Mass spectrometric investigations of caloric restriction mimetics.

Caloric restriction (CR) is an innovative therapy used in tumor tissue and tumor model studies to promote cell death and decrease cell viability. Caloric restriction mimetics (CRMs) are a class of drugs that induce CR and starvation conditions within a cell. When used simultaneously with other chemotherapy agents, the effects are synergistic and effective at promoting tumor cell death. In this review, we discuss CRMs and their potential as cancer therapeutics. Firstly, we establish an overview of CR and its impacts on healthy and tumor cells. CR and CRM drugs have shown to decrease age-related diseases and can act as an anti-cancer agent. As it can be challenging for an individual to diligently stick to a diet that would induce CR, CRMs are even more desirable. Then, we discuss the drug class by highlighting three CRMs: resveratrol, (-)-hydroxycitric acid, and rapamycin. These CRMs are commonly known for their dietary effects, but the underlying mechanisms that drive cellular metabolic and proteomic changes show promise as a cancer therapeutic. Lastly, we highlight the use of mass spectrometry and proteomic techniques on experiments utilizing CRM drugs to understand the cellular pathways impacted by this drug class, leading to a better understanding of the anti-cancer properties and potentials of CRM.

Trends in socioeconomic inequalities in the incidence of ovarian cancer among women in Canada: 1992-2010.

Ovarian cancer is the seventh most common cancer among women worldwide. We assessed the effect of socioeconomic status on ovarian cancer incidence in Canada between 1992 and 2010. We linked data from the Canadian Cancer Registry (CCR), Canadian Census of Population (CCP), and National Household Survey (NHS) to measure socioeconomic inequalities in the incidence of ovarian cancer among Canadian women over the study period. The age-standardized relative and absolute concentration index (RC and AC, respectively) were calculated to quantify income- and education-related inequalities in the incidence of ovarian cancer in Canadian women during this period. Despite a slight increase in the crude incidence of ovarian cancer in Ontario, Quebec, New Brunswick, Newfoundland and Labrador & Prince Edward Island, and Canada as a whole, the incidence of ovarian cancer in Canada has mostly remained stable, between 13 and 15 new cases per 100,000 per year between 1992 and 2010. The estimated age-standardized RC and AC values for the study period did not indicate any statistically significant relationship between income or education status, and the incidence of ovarian cancer in Canada. Future work should be directed at seeking related risk factors other than socioeconomic status that may contribute to the incidence of this disease.

Retinal imaging in Alzheimer's and neurodegenerative diseases.

In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.

Adsorption of Oligo-DNA on Magnesium Aluminum-Layered Double-Hydroxide Nanoparticle Surfaces: Mechanistic Implication in Gene Delivery.

Magnesium aluminum-layered double-hydroxide nanoparticles (LDH NPs) are promising drug-delivery vehicles for gene therapy, particularly for siRNA interference; however, the interactions between oligo-DNA and LDH surfaces have not been adequately elucidated. Through a mechanistic study, oligo-DNA initially appears to rapidly bind strongly to the LDH outer surfaces through interactions with their phosphate backbones via ligand exchange with OH- on Mg2+ centers and electrostatic forces with Al3+. These initial interactions might precede diffusion into interlayer spaces, and this knowledge can be used to design better gene therapy delivery systems.

Does peripheral retinal input explain the promising myopia control effects of corneal reshaping therapy (CRT or ortho-K) & multifocal soft contact lenses?

In the following point-counterpoint article, internationally-acclaimed myopia researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the named member of the editorial team provided an Introduction and Summary, both of which were reviewed by the other members of the editorial team. By their nature, views expressed in each section of the Point-Counterpoint article are those of the author concerned and may not reflect the views of all of the authors.

Longitudinal in vivo imaging of cones in the alert chicken.

PURPOSE: To demonstrate the feasibility of in vivo measurements of cones and their distributions as a function of normal growth without adaptive optics (AO) and also discuss the potential advantages and disadvantages of AO imaging in the chick, an animal model of myopia. METHODS: Chicks were obtained on the day of hatching. Axial length and retinoscopy measurements were performed on days 0 and 14. Chicks were imaged on the day of hatching and 14 days later in a custom-built confocal scanning laser ophthalmoscope. Angular densities, linear cone spacings, and cone packing arrangements were determined. RESULTS: Four subarrays of hexagonally packed cones were identified on both days and, from their angular spacings, appear to correspond to different cone types. There were no significant changes in angular cone density with growth and linear spacings of cones increased with growth. This is true for both overall densities and those of the cone subtypes. There was no change in the percent of hexagonally packed cones with growth. CONCLUSIONS: Cones can be imaged longitudinally in vivo in the awake chick. The packing arrangement of cones is 40% hexagonally packed. Although AO is not necessary to visualize the cones, including the subarrays of like cones, some closely spaced cones of different types may not be resolved. Most importantly, there is a need to use a larger pupil with growth to maintain the same linear resolution in the larger eye. Novel longitudinal imaging techniques and methods in animal models are shown here to give insights into normal development and, in future, will give insights into visual disorders and diseases, including myopia.

Maternal mortality and severe maternal morbidity surveillance in Canada.

The Canadian Perinatal Surveillance System has provided a comprehensive review of maternal mortality and severe maternal morbidity in Canada, and has identified several important limitations to existing national maternal data collection systems, including variability in the detail and quality of mortality data. The Canadian Perinatal Surveillance System report recommended the establishment of an ongoing national review and reporting system, as well as consistency in definitions and classifications of maternal mortality and severe maternal morbidity, in order to enhance surveillance of maternal mortality and severe maternal morbidity. Using review articles and studies that examined maternal mortality in general as opposed to maternal mortality associated with particular management strategies or conditions, maternal mortality and severe morbidity classifications, terminology, and comparative statistics were reviewed and employed to evaluate deficiencies in past and current methods of data collection and to seek solutions to address the need for enhanced and consistent national surveillance of maternal mortality and severe maternal morbidity in Canada.

Predicting Thioflavin Fluorescence of Retinal Amyloid Deposits Associated With Alzheimer's Disease from Their Polarimetric Properties.

Purpose: To use machine learning in those with brain amyloid to predict thioflavin fluorescence (indicative of amyloid) of retinal deposits from their interactions with polarized light. Methods: We imaged 933 retinal deposits in 28 subjects with post mortem evidence of brain amyloid using thioflavin fluorescence and polarization sensitive microscopy. Means and standard deviations of 14 polarimetric properties were input to machine learning algorithms. Two oversampling strategies were applied to overcome data imbalance. Three machine learning algorithms: linear discriminant analysis, supporting vector machine, and random forest (RF) were trained to predict thioflavin positive deposits. For each method; accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve were computed. Results: For the polarimetric positive deposits, using 1 oversampling method, RF had the highest area under the receiver operating characteristic curve (0.986), which was not different from that with the second oversampling method. RF had 95% accuracy, 94% sensitivity, and 97% specificity. After including deposits with no polarimetric signals, polarimetry correctly predicted 93% of thioflavin positive deposits. Linear retardance and linear anisotropy were the dominant polarimetric properties in RF with 1 oversampling method, and no polarimetric properties were dominant in the second method. Conclusions: Thioflavin positivity of retinal amyloid deposits can be predicted from their images in polarized light. Polarimetry is a promising dye-free method of detecting amyloid deposits in ex vivo retinal tissue. Further testing is required for translation to live eye imaging. Translational Relevance: This dye-free method distinguishes retinal amyloid deposits, a promising biomarker of Alzheimer's disease, in human retinas imaged with polarimetry.

Depolarization properties of the optic nerve head: the effect of age.

The degree of polarization (DOP) of the light reflected from the optic nerve head has been assessed by means of a polarimetric scanning laser ophthalmoscope as a function of the age of the participants. Four fundus images corresponding to independent polarization states in the recording pathway were used to compute the spatially-resolved DOP. This was not uniform across the optic nerve head and depended on both the location and the participant's age. Along a peripapillary annulus the DOP followed a double-peak pattern. Moreover, the values along this annulus decreased significantly with increasing age. This depolarization appears to originate in part in the retinal nerve fiber layer. Detailed age-dependent knowledge of the ocular depolarization properties may help to improve clinical diagnosis of the retinal nerve fiber layer.

Blur on the retina due to higher-order aberrations: comparison of eye growth models to experimental data.

In the simplest model of eye growth, the ocular optics uniformly scale upwards, as do monochromatic higher-order aberrations (HOA) and linear blur on the retina. However, measured HOA remain constant or decrease with growth in some species. A new model, which holds HOA and the associated linear blur on the retina constant, was used to predict changes in HOA and resulting image quality on the retina during growth, in each of chick, monkey, and human. Models used rates of growth in each of the three species. Angular optical quality on the retina due to HOA, and its metrics improved, in contrast to the constancy predicted by uniform scaling. The model with constant linear HOA blur predicts well the improvement in human optical quality between infant and adult. Overall, in chick and monkey, angular blur improves at a rate faster than that predicted by the constant linear blur model, implying that linear retinal blur due to HOA decreases with age. On the other hand, in chick, angular blur due to third-order aberrations decreased at a rate predicted by the constant linear blur model. Growth changes in retinal blur due to HOA are species dependent but can be better understood by comparison with the new model predictions.

Maturation of the mucosal immune system underlies colitis susceptibility in interleukin-10-deficient (IL-10-/-) mice.

Elevated mucosal IL-12/23p40 and IFN-gamma accompany early inflammation in IL-10-deficient (IL-10(-/-)) mice and then later decline while inflammation persists. This report addresses whether this cytokine profile reflects disease progression or inherent, age-related changes in mucosal immunity. IL-10(-/-) and wild-type (WT) mice were maintained in an ultrabarrier facility or transferred to conventional housing at 3, 12, or 30 weeks of age. Weight, stool changes, and histologic features were followed. Lamina propria mononuclear cells were cultured for cytokine analysis by ELISA. Ultrabarrier-housed IL-10(-/-) mice are statistically indistinguishable from WT mice by weight, disease activity index, and histologic inflammation. IL-10(-/-) mice but not WT, transferred at 3 weeks, develop colitis gradually, reaching a significant, sustained maximum by 15 weeks of age. Transfer at 12 weeks induces rapid disease onset in both strains, maximal at 15 weeks of age. Inflammation persists in IL-10(-/-), and WT recover. IL-10(-/-) and WT mice transferred at 30 weeks demonstrate transient diarrhea and weight loss but no chronic inflammation. Probiotics delay symptom onset only in the 12-week-old group. IFN-gamma production from ultrabarrier-housed IL-10(-/-) mice is elevated at 12 weeks of age, and older animals have decreased IFN-gamma and increased IL-4. IL-10 is important for suppressing inflammation after transfer at 3 weeks of age and limiting inflammation after transfer at 12 weeks but has little influence at 30 weeks of age. Colitis onset, progression, and response to probiotic therapy vary with immune system age, suggesting that a distinct, Th1-driven, age-dependent cytokine profile may contribute to increased colitis susceptibility in otherwise healthy mice.

The Influence of Native Language on Auditory-Perceptual Evaluation of Vocal Samples Completed by Brazilian and Canadian SLPs.

OBJECTIVE: This study aimed to determine the influence of native language on the auditory-perceptual assessment of voice, as completed by Brazilian and Anglo-Canadian listeners using Brazilian vocal samples and the grade, roughness, breathiness, asthenia, strain (GRBAS) scale. STUDY DESIGN: This is an analytical, observational, comparative, and transversal study conducted at the Speech Language Pathology Department of the Federal University of Minas Gerais in Brazil, and at the Communication Sciences and Disorders Department of the University of Alberta in Canada. METHODS: The GRBAS scale, connected speech, and a sustained vowel were used in this study. The vocal samples were drawn randomly from a database of recorded speech of Brazilian adults, some with healthy voices and some with voice disorders. The database is housed at the Federal University of Minas Gerais. Forty-six samples of connected speech (recitation of days of the week), produced by 35 women and 11 men, and 46 samples of the sustained vowel /a/, produced by 37 women and 9 men, were used in this study. The listeners were divided into two groups of three speech therapists, according to nationality: Brazilian or Anglo-Canadian. The groups were matched according to the years of professional experience of participants. The weighted kappa was used to calculate the intra- and inter-rater agreements, with 95% confidence intervals, respectively. RESULTS: An analysis of the intra-rater agreement showed that Brazilians and Canadians had similar results in auditory-perceptual evaluation of sustained vowel and connected speech. The results of the inter-rater agreement of connected speech and sustained vowel indicated that Brazilians and Canadians had, respectively, moderate agreement on the overall severity (0.57 and 0.50), breathiness (0.45 and 0.45), and asthenia (0.50 and 0.46); poor correlation on roughness (0.19 and 0.007); and weak correlation on strain to connected speech (0.22), and moderate correlation to sustained vowel (0.50). CONCLUSION: In general, auditory-perceptual evaluation is not influenced by the native language on most dimensions of the perceptual parameters of the GRBAS scale.

Vision science and adaptive optics, the state of the field.

Adaptive optics is a relatively new field, yet it is spreading rapidly and allows new questions to be asked about how the visual system is organized. The editors of this feature issue have posed a series of question to scientists involved in using adaptive optics in vision science. The questions are focused on three main areas. In the first we investigate the use of adaptive optics for psychophysical measurements of visual system function and for improving the optics of the eye. In the second, we look at the applications and impact of adaptive optics on retinal imaging and its promise for basic and applied research. In the third, we explore how adaptive optics is being used to improve our understanding of the neurophysiology of the visual system.

Optical analysis of an accommodating intraocular lens.

PURPOSE: To model the feasibility of an accommodating intraocular lens (IOL) that allows near vision by means of an anterior translation within the capsular bag. SETTING: University of Waterloo, Waterloo, Ontario, Canada. METHODS: Model eyes were constructed and analyzed based on experimental data using Code V, a computerized optical design tool. The potential near vision of IOLs of different powers was calculated as they were moved anteriorly within the capsular bag. The conditions under which a spherical lens performs well and when an aspheric design should be considered were determined. RESULTS: Accommodation (the dioptric change from the far to the near point) varies linearly with lens movement and is sensitive to corneal and IOL powers. Simple equations were derived and accurately predicted induced accommodation. Retinal image quality varies significantly with pupil size and IOL power. However, image quality is minimally affected by the amount of induced accommodation. CONCLUSIONS: From an optical standpoint accommodation with adequate image quality can be achieved by anterior movement of a spherical IOL within the capsular bag.

Clear speech for adults with a hearing loss: does intervention with communication partners make a difference?

Spouses of persons with hearing loss served as talkers to examine the benefits of clear speech intervention. One talker received intervention on clear speech. A second talker was simply instructed to speak clearly. Each talker was recorded reading sentences in three conditions: conversational speech, clear speech one week postintervention, and clear speech one month postintervention. Speech acoustic measures were obtained. Then the sentences were presented to subjects with normal hearing and subjects with hearing loss to measure speech recognition. Results showed that simply asking a talker to speak clearly was effective in eliciting clear speech; however, providing intervention yielded changes in more speech parameters, more stable changes, and better speech recognition. When listening to the talker who received intervention, subjects with hearing loss achieved the same performance as subjects with normal hearing. However, they performed worse than subjects with normal hearing when listening to the talker who received clear speech instructions only. Individuals with hearing loss would receive speech recognition benefits if their partners were provided with clear speech intervention.

Cone-Photoreceptor Density in Adolescents With Type 1 Diabetes.

PURPOSE: Changes to retinal structure and function occur in individuals with diabetes before the onset of diabetic retinopathy. It is still unclear if these changes initially affect vascular or neural retina, or if particular retinal areas are more susceptible than others. This paper examines the distribution of cone photoreceptor density in the retina of adolescents with type 1 diabetes. METHODS: This cross-sectional prospective study includes 29 adolescents and young adults with type 1 diabetes and no diabetic retinopathy and 44 control participants recruited at the Hospital for Sick Children. Adaptive-optics enhanced retinal imaging of the cone photoreceptor mosaic was performed in four quadrants at an eccentricity of ∼7° from the fovea. After image registration and averaging, cone photoreceptors were counted and photoreceptor density was calculated. Analysis of variance with repeated measures was used to assess the differences in photoreceptor density between groups. RESULTS: Cone density was similar in both control participants and participants with diabetes. There was a small effect of retinal hemisphere; participants with diabetes did not show the expected radial asymmetry observed in control participants. CONCLUSIONS: Cone density in the parafoveal retina is not reduced in adolescents with type 1 diabetes.

Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic-pituitary-adrenal axis in late gestation.

We investigated the effects of moderate maternal periconceptional undernutrition from 60 d before to 30 d after mating on fetal hypothalamic-pituitary-adrenal axis function in late gestation. Ewes were sampled regularly during the period of undernutrition for circulating hormone levels. Vascular catheters were inserted into ewes and their singleton fetuses at 112 d gestation (term, 145 d), and fetal ACTH(1-24) and metyrapone challenge tests were performed at 127 and 128 d. Postmortems were performed at 132 d. Fetuses of undernourished ewes (UN, n = 12) had elevated baseline cortisol concentrations (P < 0.05), compared with fetuses of ad libitum-fed ewes (n = 10). There were no differences between groups in fetal responses to ACTH challenge, but only UN fetuses demonstrated ACTH and 11-deoxycortisol responses to metyrapone (P < 0.05). UN fetuses had increased mRNA levels for proopiomelanocortin and prohormone convertase-1, but not -2, in the pars intermedia of the pituitary gland (P < 0.05). Glucocorticoid receptor mRNA levels were not different between groups in pituitary or hypothalamus. Maternal cortisol and ACTH levels during undernutrition were profoundly suppressed (P < 0.001), rather than elevated, in UN ewes. Furthermore, the normal pregnancy rise in maternal serum progesterone concentrations was delayed in undernourished mothers. These data demonstrate that events around the time of conception have profound effects on fetal hypothalamic-pituitary-adrenal development in late gestation and that factors other than fetal exposure to excess glucocorticoids may be important.

Adaptive optics scanning laser ophthalmoscopy.

We present the first scanning laser ophthalmoscope that uses adaptive optics to measure and correct the high order aberrations of the human eye. Adaptive optics increases both lateral and axial resolution, permitting axial sectioning of retinal tissue in vivo. The instrument is used to visualize photoreceptors, nerve fibers and flow of white blood cells in retinal capillaries.

Overview of nine computerized, home-based auditory-training programs for adult cochlear implant recipients.

BACKGROUND: Computerized, home-based auditory-training programs could be attractive to cochlear implant (CI) recipients who cannot obtain direct intensive training services and also to busy clinicians who would like to enable CI recipients to benefit from these programs. However, it is difficult for either group to know which of the many programs available might best suit individual needs. PURPOSE: Selecting a computerized home-based program can be challenging because each offers different features. This article provides an overview of currently available programs to help clinicians and recipients choose one that is most suitable. DATA COLLECTION AND ANALYSIS: A narrative literature review and an advanced Google search of Web sites linked to auditory-training programs were conducted. This overview builds on and updates information from previous literature. RESULTS: Nine computerized, home-based auditory-training programs were identified for overview. Twenty-nine information items and features for each of the nine programs are presented, categorized by general product and purchase information, design features of the training paradigm, and auditory and communication targets. CONCLUSIONS: This article provides a descriptive overview of computerized, home-based auditory-training programs for the use of clinicians, CI recipients, researchers, and hearing aid users.

Phenotypic characteristics including in vivo cone photoreceptor mosaic in KCNV2-related "cone dystrophy with supernormal rod electroretinogram".

PURPOSE: To report phenotypic characteristics including macular cone photoreceptor morphology in KCNV2-related "cone dystrophy with supernormal rod electroretinogram" (CDSR). METHODS: Seven patients, aged 9 to 18 years at last visit, with characteristic full-field electroretinographic (ERG) features of CDSR were screened for mutations in the KCNV2 gene. All patients underwent detailed ophthalmological evaluation, which included distance and color vision testing, contrast sensitivity measurement, fundus photography, fundus autofluorescence (FAF) imaging, and spectral domain-optical coherence tomography (SD-OCT). Follow-up visits were available in six cases. Rod photoreceptor function was assessed using a bright white flash ERG protocol (240 cd·s/m(2)). Macular cone photoreceptor morphology was assessed from 2° by 2° zonal images obtained using adaptive optics scanning laser ophthalmoscopy (AOSLO) in six cases. RESULTS: Pathogenic mutations in KCNV2 were identified in all seven cases. Best corrected vision was 20/125 or worse in all cases at the latest visit (20/125-20/400). Vision loss was progressive in two cases. Color vision and contrast sensitivity was abnormal in all cases. Retinal exam revealed minimal pigment epithelial changes at the fovea in four cases. A peri- or parafoveal ring of hyperfluorescence was the most common FAF abnormality noted (five cases). The SD-OCT showed outer retinal abnormalities in all cases. The rod photoreceptor maximal response was reduced but rod sensitivity was normal. AOSLO showed markedly reduced cone density in all six patients tested. CONCLUSIONS: Central vision parameters progressively worsen in CDSR. Structural retinal and lipofuscin accumulation abnormalities are commonly present. Macular cone photoreceptor mosaic is markedly disrupted early in the disease.