Alzheimer's Disease (AD) is characterized by cerebral accumulation of ␤-amyloid peptides (A␤), which are proteolytically derived from ␤-amyloid precursor protein (␤APP). ␤APP metabolism is highly regulated via various signal transduction systems, e.g., several serine/threonine kinases and phosphatases. Several growth factors known to act via receptor tyrosine kinases also have been demonstrated to regulate s␤APP secretion. Among these receptors, insulin and insulin-like growth factor-1 receptors are highly expressed in brain, especially in hippocampus and cortex. Emerging evidence indicates that insulin has important functions in brain regions involved in learning and memory. Here we present evidence that insulin significantly reduces intracellular accumulation of A␤ and that it does so by accelerating ␤APP/A␤ trafficking from the transGolgi network, a major cellular site for A␤ generation, to the plasma membrane. Furthermore, insulin increases the extracellular level of A␤ both by promoting its secretion and by inhibiting its degradation via insulin-degrading enzyme. The action of insulin on ␤APP metabolism is mediated via a receptor tyrosine kinase/mitogen-activated protein (MAP) kinase kinase pathway. The results suggest cell biological and signal transduction mechanisms by which insulin modulates ␤APP and A␤ trafficking in neuronal cultures. Key words: ␤-amyloid; ␤-amyloid precursor protein; insulin; MAPK; Alzheimer's disease; diabetes mellitus; intracellular trafficking; endoplasmic reticulum; trans-Golgi network; plasma membraneNeuropathological hallmarks of Alzheimer's Disease (AD) include deposition of ␤-amyloid (A␤) plaques, neurofibrillary tangles, and neuronal cell loss in vulnerable brain regions. Plaques contain an aggregated population of heterogeneous A␤ peptides derived from ␤-amyloid precursor protein (␤APP). Full-length ␤APP undergoes proteolytic ␤-secretase and ␥-secretase activities to generate A␤40 and A␤42 peptides, the predominant A␤ variants. In addition to these amyloid-generating activities, fulllength ␤APP can undergo alternative processing by an enzymatic activity termed "␣-secretase" that cleaves within the A␤ region. This activity releases a soluble fragment (s␤APP␣) extracellularly and precludes A␤ formation. Several studies indicate that A␤ is toxic to neurons. Accumulation of A␤ peptides within the brain is believed to initiate the pathological cascade culminating in clinical AD, a hypothesis supported by the development of early-onset familial AD (FAD) within pedigrees harboring autosomal dominant gene mutations in ␤APP that lead to the excessive generation of A␤ (for review, see Selkoe, 1998). Cell biological studies have demonstrated that both A␤40 and A␤42 are produced intracellularly (Cook et al

Approximately 20% of all children in the United States live in poverty, which exists in rural, urban, and suburban areas. Thus, all child health clinicians need to be familiar with the effects of poverty on health and to understand associated, preventable, and modifiable social factors that impact health. Social determinants of health are identifiable root causes of medical problems. For children living in poverty, social determinants of health for which clinicians may play a role include the following: child maltreatment, child care and education, family financial support, physical environment, family social support, intimate partner violence, maternal depression and family mental illness, household substance abuse, firearm exposure, and parental health literacy. Children, particularly those living in poverty, exposed to adverse childhood experiences are susceptible to toxic stress and a variety of child and adult health problems, including developmental delay, asthma and heart disease. Despite the detrimental effects of social determinants on health, few child health clinicians routinely address the unmet social and psychosocial factors impacting children and their families during routine primary care visits. Clinicians need tools to screen for social determinants of health and to be familiar with available local and national resources to address these issues. These guidelines provide an overview of social determinants of health impacting children living in poverty and provide clinicians with practical screening tools and resources.

Alzheimer's disease (AD) is characterized by the age-related deposition of ␤-amyloid (A␤) 40͞42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for A␤ in the pathophysiology of AD. A␤ peptides are generated by the regulated cleavage of an Ϸ700-aa A␤ precursor protein (␤APP). Full-length ␤APP can undergo proteolytic cleavage either within the A␤ domain to generate secreted s␤APP␣ or at the N-and C-terminal domain(s) of A␤ to generate amyloidogenic A␤ peptides. Several epidemiological studies have reported that estrogen replacement therapy protects against the development of AD in postmenopausal women. We previously reported that treating cultured neurons with 17␤-estradiol reduced the secretion of A␤40͞42 peptides, suggesting that estrogen replacement therapy may protect women against the development of AD by regulating ␤APP metabolism. Increasing evidence indicates that testosterone, especially bioavailable testosterone, decreases with age in older men and in postmenopausal women. We report here that treatment with testosterone increases the secretion of the nonamyloidogenic APP fragment, s␤APP␣, and decreases the secretion of A␤ peptides from N2a cells and rat primary cerebrocortical neurons. These results raise the possibility that testosterone supplementation in elderly men may be protective in the treatment of AD. A lzheimer's disease (AD) is characterized by the deposition of senile plaques and neurofibrillary tangles in vulnerable brain regions. Senile plaques are composed of aggregated ␤-amyloid (A␤) 40͞42(43) peptides. Evidence implicates a central role for A␤ in the pathophysiology of AD (1). Epidemiological studies have reported that estrogen replacement therapy protects against the development of AD in postmenopausal women (2, 3). We previously reported that treating cultured neurons with 17␤-estradiol reduced the secretion of A␤40͞42 peptides, suggesting that estrogen replacement therapy may protect women against the development of AD by regulating A␤ precursor protein (␤APP) metabolism (4). Although it has long been established that estrogen declines during menopause in aging women, declines in testosterone in aging men, until more recently, have been more controversial. Increasing numbers of reports indicate that testosterone, especially bioavailable free testosterone, declines significantly in aging men (5, 6) and in postmenopausal women (7). Although the relative decrease in the level of testosterone in men is modest compared with those of estrogen in perimenopausal women, aging men develop clinical signs of hypogonadism, such as reduced muscle and bone mass and an increase in visceral fat. Recent studies suggest that declining testosterone levels in older men are associated with disorders similar to those associated with estrogen deficiency in postmenopausal aging women, including osteoporosis (8, 9). Testosterone supplementation in orchiectomized, aging male rats protected these animals from osteoporosis and the decrease in the rate of perios...

ImportanceSARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.ObjectiveTo develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.Design, Setting, and ParticipantsProspective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.ExposureSARS-CoV-2 infection.Main Outcomes and MeasuresPASC and 44 participant-reported symptoms (with severity thresholds).ResultsA total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.Conclusions and RelevanceA definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Clinical studies have shown that estrogen deprivation through menopause is a risk factor in both the initiation and progression of Alzheimer's disease (AD) and that estrogen replacement therapy may be protective. One of the major pathological features in the human AD brain is the senile plaque, a proteinaceous structure composed mainly of heterogeneous peptides collectively known as A-beta (Ab). In vitro studies have linked estrogen with Ab modulation, suggesting that oneway that estrogen depletion at menopause may exacerbate the features of AD is through Ab accumulation. To test this, two studies were performed on transgenic models of amyloidosis. Firstly, transgenic mice without detectable amyloid aggregates were subjected to ovariectomy and estradiol supplementation, and Ab levels were assessed. Secondly, the effects of estrogen modulation were assessed in mice at an age when plaques would be forming initially. Overall, Ab levels were higher in estrogen-deprived mice than intact mice, and this effect could be reversed through the administration of estradiol. These data suggest that, in vivo, estrogen depletion leads to the accumulation of Ab in the CNS, which can be reversed through replacement of estradiol. These results provide evidence that post-menopausal estrogen depletion may be linked to an increased risk of AD through Ab modulation.

WHAT'S KNOWN ON THIS SUBJECT: Food insecurity has been linked to childhood obesity in a number of studies. Few studies have explored potential pathways through which food insecurity is related to child weight, especially in low-income families with young infants. WHAT THIS STUDY ADDS:We found that food insecurity was related to maternal controlling feeding styles and concerns about the infants' future weight. Early obesity prevention should aim to decrease food insecurity and to reduce controlling feeding styles in families who remain food insecure. abstract OBJECTIVES: We explored the relationship between household food insecurity and maternal feeding styles, infant feeding practices, and perceptions and attitudes about infant weight in low-income mothers. METHODS: Mothers participating in the Special Supplemental FoodProgram for Women, Infants, and Children with infants aged between 2 weeks and 6 months were interviewed. By using regression analyses, the following relationships were examined between food insecurity and: (1) controlling feeding styles (restrictive and pressuring); (2) infant feeding practices, including breastfeeding, juice consumption, and adding cereal to the bottle; and (3) perceptions and attitudes about infant weight. Path analysis was used to determine if perceptions and attitudes about infant weight mediated the relationships between food insecurity and controlling feeding styles. ). This concern mediated the relationship between food insecurity and both restrictive (P = .009) and pressuring (P = .01) feeding styles. RESULTS:CONCLUSIONS: Increased concern about future overweight and controlling feeding styles represent potential mechanisms by which food insecurity could be related to obesity. Obesity prevention should aim to decrease food insecurity and to reduce controlling feeding styles in families who remain food insecure. Pediatrics 2012;130:254-261

Estrogen reduces the risk of Alzheimer's disease in post-menopausal women, ␤-amyloid (A␤) burden in animal models of Alzheimer's disease, and secretion of A␤ from neuronal cultures. The biological basis for these effects remains unknown. Here, utilizing cell-free systems derived from both neuroblastoma cells and primary neurons, we demonstrate that 17␤-estradiol (17␤-E2) stimulates formation of vesicles containing the ␤-amyloid precursor protein (␤APP) from the transGolgi network (TGN). Accelerated ␤APP trafficking precludes maximal A␤ generation within the TGN. 17␤-E2 appears to modulate TGN phospholipid levels, particularly those of phosphatidylinositol, and to recruit soluble trafficking factors, such as Rab11, to the TGN. Together, these results suggest that estrogen may exert its anti-A␤ effects by regulating ␤APP trafficking within the late secretory pathway. These results suggest a novel mechanism through which 17␤-E2 may act in estrogen-responsive tissues and illustrate how altering the kinetics of the transport of a protein can influence its metabolic fate.Reports that post-menopausal estrogen replacement therapy (ERT) 1 is clinically efficacious in delaying the onset of Alzheimer's disease (AD) (1) or improving cognition (2) in post-menopausal women have been corroborated by numerous studies (3-5). Reports questioning the validity of these retrospective studies (6) demonstrated that women with clinically defined AD have no improvement on specific cognitive tasks following short (2-15-month) trials of estrogen treatment. However, the neuroprotective effects of estrogen are hypothesized to safeguard against the development of AD and not to aid in recovering lost function. The biological mechanism(s) through which estrogen exerts its neuroprotective effects remain largely unknown; hypotheses have included modulation of basal forebrain cholinergic activity, dendritic plasticity, N-methyl-D-aspartic acid (NMDA) receptor density, and regulation of neurotrophin signaling pathways (7).ERT may slow AD progression by reducing the release of A␤, the primary constituent of amyloid plaques, into brain parenchyma. This phenomenon was first described in non-neuronal (8) and neuronal (9) cell culture. It has now received support from animal models demonstrating that ovariectomized guinea pigs (10) and transgenic mutant ␤APP/PS1-expressing mice (11) develop increased levels of parenchymal A␤ compared with intact littermates. This A␤ burden is reversible with postsurgical estrogen replacement. In addition, a recent study (12) demonstrates an inverse relationship between the levels of 17␤-E2 and A␤42, the more amyloidogenic A␤ variant, in the cerebrospinal fluid of female patients with AD. In summary, results from retrospective clinical trials, recent and on-going animal studies, and corroborating cell culture data all support the hypothesis that post-menopausal cessation of estrogen production may facilitate A␤ deposition and that the clinical efficacy of ERT may be due, in part, to a direct A␤-lowering effect.A␤ is p...

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