Co-involvement of Mitochondria and Endoplasmic Reticulum in Regulation of Apoptosis: Changes in Cytochrome c, Bcl-2 and Bax in the Hippocampus of Aluminum-treated Rabbits

Neurodegenerative diseases, including Alzheimer’s disease, are characterized by a progressive and selective loss of neurons. Apoptosis under mitochondrial control has been implicated in this neuronal death process, involving the release of cytochrome c into the cytoplasm and initiation of the apoptosis cascade. However, a growing body of evidence suggests an active role for the endoplasmic reticulum in regulating apoptosis, either independent of mitochondrial, or in concert with mitochondrial-initiated pathways. Members of the Bcl-2 family of proteins have been shown to either inhibit apoptosis, as is the case with Bcl-2, or to promote it, in the case of Bax. Investigations in our laboratory have focused on neuronal injury resulting from the intracisternal administration of aluminum maltolate to New Zealand white rabbits, an animal system relevant to a study of human disease in that it reflects many of the histological and biochemical changes associated with Alzheimer’s disease. Here we report that treatment of young adult rabbits with aluminum maltolate induces both cytochrome c translocation into brain cytosol, and caspase-3 activation. Furthermore, as assessed by Western blot analysis, these effects are accompanied by a decrease in Bcl-2 and an increase in Bax reactivity in the endoplasmic reticulum

First grade reading materials of high interest level for children from the ages of seven through twelve.

Thesis (Ed.M.)--Boston Universit

Interoceptive and metacognitive facets of fatigue in multiple sclerosis

Numerous disorders are characterised by fatigue as a highly disabling symptom. Fatigue plays a particularly important clinical role in multiple sclerosis (MS) where it exerts a profound impact on quality of life. Recent concepts of fatigue grounded in computational theories of brain-body interactions emphasise the role of interoception and metacognition in the pathogenesis of fatigue. So far, however, for MS, empirical data on interoception and metacognition are scarce. This study examined interoception and (exteroceptive) metacognition in a sample of 71 persons with a diagnosis of MS. Interoception was assessed by prespecified subscales of a standard questionnaire (Multidimensional Assessment of Interoceptive Awareness [MAIA]), while metacognition was investigated with computational models of choice and confidence data from a visual discrimination paradigm. Additionally, autonomic function was examined by several physiological measurements. Several hypotheses were tested based on a preregistered analysis plan. In brief, we found the predicted association of interoceptive awareness with fatigue (but not with exteroceptive metacognition) and an association of autonomic function with exteroceptive metacognition (but not with fatigue). Furthermore, machine learning (elastic net regression) showed that individual fatigue scores could be predicted out-of-sample from our measurements, with questionnaire-based measures of interoceptive awareness and sleep quality as key predictors. Our results support theoretical concepts of interoception as an important factor for fatigue and demonstrate the general feasibility of predicting individual levels of fatigue from simple questionnaire-based measures of interoception and sleep

Intrinsic Absorption in the Spectrum of Mrk 279: Simultaneous Chandra, FUSE, and STIS Observations

We present a study of the intrinsic X-ray and far-ultraviolet absorption in the Seyfert 1.5 galaxy Markarian 279 using simultaneous observations from the Chandra X-ray Observatory, the Space Telescope Imaging Spectrograph aboard the Hubble Space Telescope, and the Far Ultraviolet Spectroscopic Explorer (FUSE). We also present FUSE observations made at three additional epochs. We detect the Fe K-alpha emission line in the Chandra spectrum, and its flux is consistent with the low X-ray continuum flux level of Mrk 279 at the time of the observation. Due to low signal-to-noise ratios in the Chandra spectrum, no O VII or O VIII absorption features are observable in the Chandra data, but the UV spectra reveal strong and complex absorption from HI and high-ionization species such as O VI, N V, and C IV, as well as from low-ionization species such as C III, N III, C II, and N II in some velocity components. The far-UV spectral coverage of the FUSE data provides information on high-order Lyman series absorption, which we use to calculate the optical depths and line and continuum covering fractions in the intrinsic HI absorbing gas in a self-consistent fashion. The UV continuum flux of Mrk 279 decreases by a factor of ~7.5 over the time spanning these observations and we discuss the implications of the response of the absorption features to this change. From arguments based on the velocities, profile shapes, covering fractions and variability of the UV absorption, we conclude that some of the absorption components, particularly those showing prominent low-ionization lines, are likely associated with the host galaxy of Mrk 279, and possibly with its interaction with a close companion galaxy, while the remainder arises in a nuclear outflow.Comment: To appear in 2004 May ApJS; double-column format; 58 pages, incl. 29 figures, 9 tables; minor changes to tex

FLIP-LAC user guide

This is version 6.4 of the FLIP-LAC manual. The Food Labeling Information Program for Latin America (FLIP-LAC) for data collection and registration is a smartphone-based technology developed by the University of Toronto, Canada. The FLIP iPhone app is meant for quickly capturing a limited amount of information about a food product - most importantly the product barcode and photos of product. Once this information is captured, the data and the photos are later uploaded to the FLIP website where the rest of the data entry can be completed based on photos of the product

Recognizing differentiating clinical signs of CLN3 disease (Batten disease) at presentation

Purpose To help differentiate CLN3 (Batten) disease, a devastating childhood metabolic disorder, from the similarly presenting early-onset Stargardt disease (STGD1). Early clinical identification of children with CLN3 disease is essential for adequate referral, counselling and rehabilitation. Methods Medical chart review of 38 children who were referred to a specialized ophthalmological centre because of rapid vision loss. The patients were subsequently diagnosed with either CLN3 disease (18 patients) or early-onset STGD1 (20 patients). Results Both children who were later diagnosed with CLN3 disease, as children who were later diagnosed with early-onset STGD1, initially presented with visual acuity (VA) loss due to macular dystrophy at 5-10 years of age. VA in CLN3 disease decreased significantly faster than in STGD1 (p = 0.01). Colour vision was often already severely affected in CLN3 disease while unaffected or only mildly affected in STGD1. Optic disc pallor on fundoscopy and an abnormal nerve fibre layer on optical coherence tomography were common in CLN3 disease compared to generally unaffected in STGD1. In CLN3 disease, dark-adapted (DA) full-field electroretinogram (ERG) responses were either absent or electronegative. In early-onset STGD1, DA ERG responses were generally unaffected. None of the STGD1 patients had an electronegative ERG. Conclusion Already upon presentation at the ophthalmologist, the retina in CLN3 disease is more extensively and more severely affected compared to the retina in early-onset STGD1. This results in more rapid VA loss, severe colour vision abnormalities and abnormal DA ERG responses as the main differentiating early clinical features of CLN3 disease

Challenges and opportunities for implementing integrated mental health care: a district level situation analysis from five low- and middle-income countries.

BACKGROUND: Little is known about how to tailor implementation of mental health services in low- and middle-income countries (LMICs) to the diverse settings encountered within and between countries. In this paper we compare the baseline context, challenges and opportunities in districts in five LMICs (Ethiopia, India, Nepal, South Africa and Uganda) participating in the PRogramme for Improving Mental health carE (PRIME). The purpose was to inform development and implementation of a comprehensive district plan to integrate mental health into primary care. METHODS: A situation analysis tool was developed for the study, drawing on existing tools and expert consensus. Cross-sectional information obtained was largely in the public domain in all five districts. RESULTS: The PRIME study districts face substantial contextual and health system challenges many of which are common across sites. Reliable information on existing treatment coverage for mental disorders was unavailable. Particularly in the low-income countries, many health service organisational requirements for mental health care were absent, including specialist mental health professionals to support the service and reliable supplies of medication. Across all sites, community mental health literacy was low and there were no models of multi-sectoral working or collaborations with traditional or religious healers. Nonetheless health system opportunities were apparent. In each district there was potential to apply existing models of care for tuberculosis and HIV or non-communicable disorders, which have established mechanisms for detection of drop-out from care, outreach and adherence support. The extensive networks of community-based health workers and volunteers in most districts provide further opportunities to expand mental health care. CONCLUSIONS: The low level of baseline health system preparedness across sites underlines that interventions at the levels of health care organisation, health facility and community will all be essential for sustainable delivery of quality mental health care integrated into primary care

The interaction of adverse childhood experiences and gender as risk factors for depression and anxiety disorders in US adults: a cross-sectional study

Background Exposure to adverse childhood experiences (ACEs) and being female are distinct risk factors for having a major depressive episode (MDE) or an anxiety disorder (AD) in adulthood, but it is unclear whether these two risk factors are synergistic. The purpose of this study was to determine whether exposure to ACEs and being female are more than additive (synergistic) in their association with MDE and AD in US adults. Methods We pooled cross-sectional survey data in the Midlife in the United States study from two nationally-representative cohorts of English-speaking US adults. Data from the first cohort were collected in 2004–2006 and from the second in 2011–2014. Data from both cohorts included the 12-month prevalence of MDE and AD (generalized anxiety disorder or panic disorder) assessed with the Composite International Diagnostic Interview Short Form, gender (here termed female and male), and the count of five categories of exposure to ACEs: physical, sexual, or emotional abuse; household alcohol or substance abuse; and parental separation or divorce. Results Of the 5834 survey respondents, 4344 (74.5%) with complete data on ACEs were included in the analysis. Mean (SD) age was 54.1 (13.8) years and 53.9% were female. The prevalences of MDE, AD, and exposure to 3–5 categories of ACEs were 13.7, 10.0, and 12.5%, respectively. After adjusting for covariates (age, race, and current and childhood socioeconomic disadvantage), for those with both risk factors (female and 3–5 ACEs) the prevalence of MDE was 26.9%. This was 10.2% (95% CI: 1.8, 18.5%) higher than the expected prevalence based on the additive associations of the two risk factors. The adjusted prevalence of AD among females with 3–5 ACEs was 21.9%, which was 11.4% (95% CI: 4.0, 18.9%) higher than the expected prevalence. Conclusions For both MDE and AD, there was synergy between the two risk factors of exposure to ACEs and being female. Identification and treatment of MDE and AD may benefit from understanding the mechanisms involved in the synergistic interaction of gender with ACEs

Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein

BACKGROUND: Patients with antibody deficiency respond poorly to COVID-19 vaccination and are at risk of severe or prolonged infection. They are given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma to confer passive immunity against infection. Following widespread COVID-19 vaccination alongside natural exposure, we hypothesised that immunoglobulin preparations will now contain neutralising SARS-CoV-2 spike antibodies which confer protection against COVID-19 disease and may help to treat chronic infection. METHODS: We evaluated anti-SARS-CoV-2 spike antibody in a cohort of patients before and after immunoglobulin infusion. Neutralising capacity of patient samples and immunoglobulin products was assessed using in vitro pseudo-virus and live-virus neutralisation assays, the latter investigating multiple batches against current circulating omicron variants. We describe the clinical course of nine patients started on IRT during treatment of COVID-19. RESULTS: In 35 individuals with antibody deficiency established on IRT, median anti-spike antibody titre increased from 2123 to 10600 U/ml post-infusion, with corresponding increase in pseudo-virus neutralisation titres to levels comparable to healthy donors. Testing immunoglobulin products directly in the live-virus assay confirmed neutralisation, including of BQ1.1 and XBB variants, but with variation between immunoglobulin products and batches.Initiation of IRT alongside Remdesivir in patients with antibody deficiency and prolonged COVID-19 infection (median 189 days, maximum over 900 days with an ancestral viral strain) resulted in clearance of SARS-CoV-2 virus at a median of 20 days. CONCLUSIONS: Immunoglobulin preparations now contain neutralising anti-SARS-CoV-2 antibodies which are transmitted to patients and help to treat COVID-19 in individuals with failure of humoral immunity