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Growth mixture modeling (GMM) identified latent groups based on treatment outcome trajectories of headache disability measures in patients in headache subspecialty treatment clinics. Using a longitudinal design, 219 patients in headache subspecialty clinics in 4 large cities throughout Ohio provided data on their headache disability at pretreatment and 3 follow-up assessments. GMM identified 3 treatment outcome trajectory groups: (1) patients who initiated treatment with elevated disability levels and who reported statistically significant reductions in headache disability (high-disability improvers; 11%); (2) patients who initiated treatment with elevated disability but who reported no reductions in disability (high-disability nonimprovers; 34%); and (3) patients who initiated treatment with moderate disability and who reported statistically significant reductions in headache disability (moderate-disability improvers; 55%). Based on the final multinomial logistic regression model, a dichotomized treatment appointment attendance variable was a statistically significant predictor for differentiating high-disability improvers from high-disability nonimprovers. Three-fourths of patients who initiated treatment with elevated disability levels did not report reductions in disability after 5 months of treatment with new preventive pharmacotherapies. Preventive headache agents may be most efficacious for patients with moderate levels of disability and for patients with high disability levels who attend all treatment appointments. [ABSTRACT FROM AUTHOR]

Introduction: The COVID-19 pandemic has led to the rapid and widespread adoption of telehealth services. Telehealth may aid in bridging gaps in access to care. The specific impact of telehealth on opioid use disorder (OUD) and its treatment remains uncertain. Methods: A retrospective review of commercial insurance claim records within the United States was conducted to investigate the association between the COVID-19 pandemic and changes in the rates of(a) OUD treatments with and without telehealth support and (b) prescriptions for medications for opioid use disorder (MOUD) with and without telehealth support among individuals diagnosed with OUD. Results: In a study population of 1,340,506 individuals, OUD diagnosis rates were 5 per 1,000 in-person and 1 per 1,000 via telehealth. COVID-19 decreased in-person OUD diagnoses by 0.89 per 1,000, while telehealth diagnoses increased by 0.83 per 1,000. In-person MOUD treatment rates increased by 0.07 per 1,000 during COVID-19, while telehealth rates remained low. The onset of COVID-19 saw a 1.13 per 1,000 higher increase in telehealth-supported MOUD treatment compared to solely in-person treatment. Conclusions: A retrospective review of commercial insurance claim records within the United States was conducted to investigate the association between the COVID-19 pandemic and changes in the rates of (a) OUD treatments with and without telehealth support and (b) prescriptions for MOUD with and without telehealth support among individuals diagnosed with OUD.

Objective: Healthy Families America (HFA) is an evidence-based home visiting program that provides parenting education with the overall goal of preventing child maltreatment and optimizing child development. This study compares the health care utilization and vaccination of infants enrolled in HFA with similar infants not in the program., Methods: From January 2014 to December 2020, 604 children served statewide by HFA in Arkansas were identified in vital statistics and administrative medical claims records. Using propensity score matching, infants in HFA were matched with nonprogram control infants based on family demographics and birth characteristics. Double propensity-score adjustment method and generalized linear models were used to estimate program effects., Results: In the first year after birth hospital discharge and compared to a propensity score matched cohort of infants not enrolled, those enrolled in HFA had significantly greater use of the emergency department overall (incidence rate ratios (IRR) = 1.24 [95% confidence interval (CI) = 1.07-1.43], P = .004) and for less complex conditions (IRR = 1.22 [95% CI = 1.04-1.44], P = .01), more outpatient medical appointments for child wellness (IRR = 1.09 [95% CI = 1.03-1.15], P = .003), illness (IRR = 1.17 [95% CI = 1.07-1.29], P = .001), and speech and language therapies (IRR = 2.86 [95% CI = 1.18-6.93], P = .02), and more medical visits during which vaccinations were provided (IRR = 1.09 [95% CI = 1.04-1.15], P = .002)., Conclusions: Findings from the current study suggest that HFA supports increased health care utilization and visits in which vaccinations occurred during the first year of life., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose. The funder did not participate in the work., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: The American Academy of Pediatrics recommends all pediatricians to be ready to implement trauma-informed care, including the mitigation of impacts of Adverse Childhood Experiences (ACEs) through screening and identification of at-risk population. Reliable survey tools and knowledge of the consequences of ACEs are needed., Objective: This study examines the healthcare utilization and diagnoses captured in insurance claims in association with the number of ACEs recorded by the Family Map Inventories (FMI). The FMI offers a comprehensive family assessment, which includes child ACEs (FMI-ACEs) using prospective, proxy risk indicators., Participants and Setting: Low-income families (N = 1647) with children aged three to five years who completed the FMI were linked to their insurance records., Methods: Multivariable logistic and generalized linear regression models were fitted to explore the association between the number of ACEs (FMI-ACEs scores) and healthcare utilization and health outcomes., Results: Children were exposed at rates of 32.4 % to zero, 31.7 % to one, 19.7 % to two, and 16.3 % to three or more ACEs. The FMI-ACEs scores were associated with greater use of non-preventive outpatient visits, filled prescriptions, and overall use of healthcare. Incidences of adjustment disorders were 4 times and attention-deficit conducts were 2 times higher among children with the highest FMI-ACEs scores than those with zero FMI-ACEs., Conclusions: This study marks the first effort to conduct insurance claims data review to ascertain association between a survey measure of ACEs and health utilization and diagnosed conditions. The association of ACEs risk screening and healthcare utilization and diagnoses was observed., Competing Interests: Declaration of competing interest Leanne Whiteside-Mansell and UAMS have a financial interest in a technology discussed in this publication. These financial interests have been reviewed and approved in accordance with the UAMS conflict of interest policies., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The benefits of exercise involve skeletal muscle redox state alterations of nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD). We determined the fiber-specific effects of acute exercise on the skeletal muscle redox state in healthy adults. Muscle biopsies were obtained from 19 participants (11 M, 8 F; 26 ± 4 yr) at baseline (fasted) and 30 min and 3 h after treadmill exercise at 80% maximal oxygen consumption (V̇o 2max ). Muscle samples were probed for autofluorescence of NADH (excitation at 340-360 nm) and oxidized flavoproteins (Fp; excitation at 440-470 nm) and subsequently, fiber typed to quantify the redox signatures of individual muscle fibers. Redox state was calculated as the oxidation-to-reduction redox ratio: Fp/(Fp + NADH). At baseline, pair-wise comparisons revealed that the redox ratio of myosin heavy chain (MHC) I fibers was 7.2% higher than MHC IIa ( P = 0.023, 95% CI: 5.2, 9.2%) and the redox ratio of MHC IIa was 8.0% higher than MHC IIx ( P = 0.035, 95% CI: 6.8, 9.2%). MHC I fibers also displayed greater NADH intensity than MHC IIx ( P = 0.007) and greater Fp intensity than both MHC IIa ( P = 0.019) and MHC IIx ( P < 0.0001). Fp intensities increased in all fiber types (main effect, P = 0.039) but redox ratios did not change (main effect, P = 0.483) 30 min after exercise. The change in redox ratio was positively correlated with capillary density in MHC I (rho = 0.762, P = 0.037), MHC IIa fibers (rho = 0.881, P = 0.007), and modestly in MHC IIx fibers (rho = 0. 771, P = 0.103). These findings support the use of redox autofluorescence to interrogate skeletal muscle metabolism. NEW & NOTEWORTHY This study is the first to use autofluorescent imaging to describe differential redox states within human skeletal muscle fiber types with exercise. Our findings highlight an easy and efficacious technique for assessing skeletal muscle redox in humans.

Alzheimer's disease (AD) is an age-related disorder that results in progressive cognitive impairment and memory loss. Deposition of amyloid β (Aβ) peptides in senile plaques is a hallmark of AD. γ-secretase produces Aβ peptides, mostly as the soluble Aβ40 with fewer insoluble Aβ42 peptides. Rare, early-onset AD (EOAD) occurs in individuals under 60 years of age. Most EOAD cases are due to unknown genetic causes, but a subset is due to mutations in the genes encoding the amyloid precursor protein that is processed into Aβ peptides or the presenilins (PS1 and PS2) that process APP. PS1 interacts with the epsilon isoform of glial fibrillary acidic protein (GFAPɛ), a protein found in the subventricular zone of the brain. We have found that GFAPɛ interacts with the telomere protection factor RAP1 (TERF2IP). RAP1 can also interact with PS1 alone or with GFAPɛ in vitro. Our data show that the nuclear protein RAP1 has an extratelomeric role in the cytoplasm through its interactions with GFAPɛ and PS1. GFAPɛ coprecipitated with RAP1 from human cell extracts. RAP1, GFAPɛ, and PS1 all colocalized in human SH-SY5Y cells. Using a genetic model of the γ-secretase complex in Saccharomyces cerevisiae, RAP1 increased γ-secretase activity, and this was potentiated by GFAPɛ. Our studies are the first to connect RAP1 with an age-related disorder., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Genetics Society of America.)

Purpose: The Following Baby Back Home (FBBH) visiting program, which is provided by nurse and social worker teams, supports families of low-birthweight preterm infants after discharge from a neonatal intensive care unit. Enrollment in the FBBH program has been documented to reduce the likelihood of infant death. In this study, we conducted a cost-benefit analysis of the FBBH program., Design and Methods: Infants enrolled in the FBBH program (N = 416) were identified through administrative records. Infants in the FBBH program were propensity score matched with comparison infants to estimate the difference in healthcare costs in the first year of life., Results: Infants enrolled in the FBBH program incurred similar medical care costs compared to a comparison group. Avoided deaths, program costs, healthcare costs resulted in net economic benefits of the FBBH program to avoid infant death estimate at $83,020, cost per life saved at $3080, and benefit-to-cost ratio at 27.95., Conclusions: The FBBH program's net economic benefits from avoided deaths suggest a substantial return on investment of resources, yielding benefits in excess of program and healthcare costs., Practice Implications: It is economically beneficial to provide home visiting services to families of low-birthweight babies by a team comprised of a registered nurse and social worker., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lipid metabolism is profoundly dysregulated in amyotrophic lateral sclerosis (ALS), yet the lipid composition of the white matter, where the myelinated axons of motor neurons are located, remains uncharacterised. We aimed to comprehensively characterise how myelin is altered in ALS by assessing its lipid and protein composition. We isolated white matter from the motor cortex from post-mortem tissue of ALS patients (n = 8 sporadic ALS cases and n = 6 familial ALS cases) and age- and sex-matched controls (n = 8) and conducted targeted lipidomic analyses, qPCR for gene expression of relevant lipid metabolising enzymes and Western blotting for myelin proteins. We also quantified myelin density by using spectral confocal reflectance microscopy (SCoRe). Whilst myelin protein composition was similar in ALS and control tissue, both the lipid levels and the expression of their corresponding enzymes were dysregulated, highlighting altered lipid metabolism in the white matter as well as a likely change in myelin composition. Altered myelin composition could contribute to motor neuron dysfunction, and this highlights how oligodendrocytes may play a critical role in ALS pathogenesis.

Introduction: The COVID-19 pandemic has prompted a shift in health care delivery and compelled a heavier reliance on telehealth. The objective of this study was to determine if differences in coverage policies by payer type resulted in differential telehealth use during the first 3 months of the COVID-19 pandemic. In this population-based cohort study of low-income Arkansans, Medicaid beneficiaries enrolled in the traditional Primary Care Case Management (PCCM) program were compared with Medicaid beneficiaries covered through premium assistance in private Qualified Health Plans (QHPs). Methods: A retrospective review was conducted of insurance claims records from June 1, 2019, to June 30, 2020, for synchronous telehealth and mobile health (m-health) visits, as well as other forms of telehealth. To establish the baseline equivalence of enrollees in the two groups, propensity score matching design was used on demographic and geographic characteristics, Charlson Comorbidity Index, broadband availability, and prior service utilization. Results: Compared with enrollees in the PCCM program, Medicaid expansion enrollees in QHPs had higher odds of having had at least one telehealth visit (adjusted odds ratio [aOR] = 1.35, 95% confidence interval [CI]: 1.29-1.42) during the early phase of the COVID-19 pandemic. Categorizing utilizations by domain, QHP enrollees were more likely to use synchronous telehealth (aOR = 1.31; 95% CI: 1.25-1.37) and m-health (aOR = 5.91; 95% CI: 4.25-8.21). A higher proportion of QHP enrollees also had at least one mental or behavioral health telehealth session (aOR = 1.13; 95% CI: 1.07-1.19). Conclusions: Our study demonstrated that within low-income populations, payer type was associated with inequitable access to telehealth during the early phase of the COVID-19 pandemic.

Background and Objectives: The Following Baby Back Home (FBBH) home visiting program supports families of high-risk low birth weight preterm infants after discharge from a hospital NICU. This study compares the health care use, immunization, and infant mortality rate of low birth weight preterm infants enrolled in FBBH with similar infants not in the program., Methods: From January 2013 to December 2017, 498 children enrolled in FBBH were identified in Arkansas vital statistics records and the Arkansas All-Payer Claims Database. Infants in FBBH were matched with children in a control group on the basis of demographics and medical conditions of the infant. Generalized linear mixed models with double propensity-score adjustment were used to estimate program effects., Results: In the first year after discharge and compared with a propensity-score matched cohort of control infants, those enrolled in FBBH were significantly more likely to have higher numbers of medical appointments and more compliant immunization history. The odds of dying in the first year of life for control infants was 4.4 times (95% confidence interval: 1.2-20.7) higher than those managed in the program., Conclusions: A goal of the FBBH home visiting program is to work with parents to educate and support them as they care for their medically fragile infants. We conclude that education and support was instrumental in the infant health care use and outcome differences we observed during the first year of life., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Light is the key regulator of circadian clock, the time-keeping system synchronizing organism physiology and behavior with environmental day and night conditions. In its natural habitat, the strictly subterranean naked mole-rat (Heterocephalus glaber) has lived in a light-free environment for millennia. We questioned if this species retains a circadian clock and if the patterns of this clock and concomitant rhythms differed in liver tissue from mice and naked mole-rats. As expected, in mice, the various circadian clock genes peaked at different times of the day; the Period gene (Per) group peaked in the evening, whereas Brain and Muscle ARNT-like1 (Bmal1) gene peaked in the morning; this phase shift is considered to be fundamental for circadian clock function. In sharp contrast, in the naked mole-rat both Per1 and Per2, as well as Bmal1, peaked at the same time in the morning-around ZT2-suggesting the organization of the molecular circadian oscillator was different. Moreover, gene expression rhythms associated with glucose metabolism and mTOR signaling also differed between the species. Although the activity of mTORC1 was lower, while that of mTORC2 was higher in naked mole-rat livers compared to mice, unlike that of mice where the expression profiles of glucose metabolism genes were not synchronized, these were highly synchronized in naked mole-rats and likely linked to their use of feeding times at zeitgebers., (© 2021 Federation of American Societies for Experimental Biology.)

The goal of the current study was to determine the role of maternal diet in the perinatal period on the health and survival of the offspring. AKR/J mice, a model described to be susceptible to leukemia development, was used where females were maintained on either standard diet (SD), high sucrose diet, Western diet, or calorie restriction (CR) as they were mated with SD-fed males. Body weights, pregnancy rates, litter size, and litter survival were used as markers of successful pregnancy and pup health. Data indicated that maternal diet had significant effects on litter size, early pup survival, and early pup body weights. As pups matured, the makeup of their respective maternal diet was a predictor of adult metabolic health and survival. Overall, these results suggest that perinatal maternal diet is an important determinant of the health and survival of the offspring and that these effects continue well into adulthood, strongly correlating with lifespan.

Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in C. elegans the overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo . Humanin transgenic mice have many phenotypes that overlap with the worm phenotypes and, similar to exogenous humanin treatment, have increased protection against toxic insults. Treating middle-aged mice twice weekly with the potent humanin analogue HNG, humanin improves metabolic healthspan parameters and reduces inflammatory markers. In multiple species, humanin levels generally decline with age, but here we show that levels are surprisingly stable in the naked mole-rat, a model of negligible senescence. Furthermore, in children of centenarians, who are more likely to become centenarians themselves, circulating humanin levels are much greater than age-matched control subjects. Further linking humanin to healthspan, we observe that humanin levels are decreased in human diseases such as Alzheimer's disease and MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes). Together, these studies are the first to demonstrate that humanin is linked to improved healthspan and increased lifespan.

The naked mole-rat is a subterranean rodent, approximately the size of a mouse, renowned for its exceptional longevity (>30 years) and remarkable resistance to cancer. To explore putative mechanisms underlying the cancer resistance of the naked mole-rat, we investigated the regulation and function of the most commonly mutated tumor suppressor, TP53, in the naked mole-rat. We found that the p53 protein in naked mole-rat embryonic fibroblasts (NEFs) exhibits a half-life more than ten times in excess of the protein's characterized half-life in mouse and human embryonic fibroblasts. We determined that the long half-life of the naked mole-rat p53 protein reflects protein-extrinsic regulation. Relative to mouse and human p53, a larger proportion of naked mole-rat p53 protein is constitutively localized in the nucleus prior to DNA damage. Nevertheless, DNA damage is sufficient to induce activation of canonical p53 target genes in NEFs. Despite the uniquely long half-life and unprecedented basal nuclear localization of p53 in NEFs, naked mole-rat p53 retains its canonical tumor suppressive activity. Together, these findings suggest that the unique stabilization and regulation of the p53 protein may contribute to the naked mole-rat's remarkable resistance to cancer.

Single substances within complex vertebrate chemical signals could be physiologically or behaviourally active. However, the vast diversity in chemical structure, physical properties and molecular size of semiochemicals makes identifying pheromonally active compounds no easy task. Here, we identified two volatile cyclic dipeptides, cyclo(L-Leu-L-Pro) and cyclo(L-Pro-L-Pro), from the complex mixture of a chemical signal in terrestrial vertebrates (lizard genus Sceloporus), synthesised one of them and investigated their biological activity in male intra-specific communication. In a series of behavioural trials, lizards performed more chemosensory behaviour (tongue flicks, lip smacks and substrate lickings) when presented with the synthesised cyclo(L-Pro-L-Pro) chemical blend, compared to the controls, the cyclo(L-Leu-L-Pro) blend, or a combined blend with both cyclic dipeptides. The results suggest a potential semiochemical role of cyclo(L-Pro-L-Pro) and a modulating effect of cyclo(L-Leu-L-Pro) that may depend on the relative concentration of both compounds in the chemical signal. In addition, our results stress how minor compounds in complex mixtures can produce a meaningful behavioural response, how small differences in structural design are crucial for biological activity, and highlight the need for more studies to determine the complete functional landscape of biologically relevant compounds.

Pedomorphy, maintenance of juvenile traits throughout life, is most pronounced in extraordinarily long-lived naked mole-rats. Many of these traits (e.g., slow growth rates, low hormone levels, and delayed sexual maturity) are shared with spontaneously mutated, long-lived dwarf mice. Although some youthful traits likely evolved as adaptations to subterranean habitats (e.g., thermolability), the nature of these intrinsic pedomorphic features may also contribute to their prolonged youthfulness, longevity, and healthspan.

The original version of this article unfortunately contained an error.

Mouse-sized naked mole-rats (Heterocephalus glaber), unlike other mammals, do not conform to Gompertzian laws of age-related mortality; adults show no age-related change in mortality risk. Moreover, we observe negligible hallmarks of aging with well-maintained physiological and molecular functions, commonly altered with age in other species. We questioned whether naked mole-rats, living an order of magnitude longer than laboratory mice, exhibit different plasma metabolite profiles, which could then highlight novel mechanisms or targets involved in disease and longevity. Using a comprehensive, unbiased metabolomics screen, we observe striking inter-species differences in amino acid, peptide, and lipid metabolites. Low circulating levels of specific amino acids, particularly those linked to the methionine pathway, resemble those observed during the fasting period at late torpor in hibernating ground squirrels and those seen in longer-lived methionine-restricted rats. These data also concur with metabolome reports on long-lived mutant mice, including the Ames dwarf mice and calorically restricted mice, as well as fruit flies, and even show similarities to circulating metabolite differences observed in young human adults when compared to older humans. During evolution, some of these beneficial nutrient/stress response pathways may have been positively selected in the naked mole-rat. These observations suggest that interventions that modify the aging metabolomic profile to a more youthful one may enable people to lead healthier and longer lives.

Background: Gadolinium-based contrast agents (GBCAs) have been used for magnetic resonance (MR) imaging over the last three decades. Recent reports demonstrated gadolinium retention in patients' brains following intravenous administration. Since gadolinium is a highly toxic heavy metal, there is a potential for adverse effects from prolonged retention or deposition, particularly in children. For this reason, the Society (SPR) for Pediatric Radiology Quality and Safety committee conducted a survey to evaluate the current status of GBCAs usage among pediatric radiologists., Objective: To assess the usage of GBCAs among SPR members., Materials and Methods: An online 15-question survey was distributed to SPR members. Survey questions pertained to the type of GBCAs used, protocoling workflow, requirement of renal function or pregnancy tests, and various clinical indications for contrast-enhanced MRI examinations., Results: A total of 163 survey responses were compiled (11.1% of survey invitations), the majority of these from academic institutions in the United States. Ninety-four percent reported that MR studies are always or usually protocoled by pediatric radiologists. The most common GBCA utilized by survey respondents were Eovist (60.7%), Ablavar (45.4%), Gadovist (38.7%), Magnevist (34.4%) and Dotarem (32.5%). For several clinical indications, survey responses regarding GBCA administration were concordant with American College of Radiology (ACR) Appropriateness Criteria, including seizures, headache and osteomyelitis. For other indications, including growth hormone deficiency and suspected vascular ring, survey responses revealed potential overutilization of GBCAs when compared to ACR recommendations., Conclusion: Survey results demonstrate that GBCAs are administered judiciously in children, yet there is an opportunity to improve their utilization with the goal of reducing potential future adverse effects.

Animals have evolved to survive, and even thrive, in different environments. Genetic adaptations may have indirectly created phenotypes that also resulted in a longer lifespan. One example of this phenomenon is the preternaturally long-lived naked mole-rat. This strictly subterranean rodent tolerates hypoxia, hypercapnia, and soil-based toxins. Naked mole-rats also exhibit pronounced resistance to cancer and an attenuated decline of many physiological characteristics that often decline as mammals age. Elucidating mechanisms that give rise to their unique phenotypes will lead to better understanding of subterranean ecophysiology and biology of aging. Comparative genomics could be a useful tool in this regard. Since the publication of a naked mole-rat genome assembly in 2011, analyses of genomic and transcriptomic data have enabled a clearer understanding of mole-rat evolutionary history and suggested molecular pathways (e.g., NRF2-signaling activation and DNA damage repair mechanisms) that may explain the extraordinarily longevity and unique health traits of this species. However, careful scrutiny and re-analysis suggest that some identified features result from incorrect or imprecise annotation and assembly of the naked mole-rat genome: in addition, some of these conclusions (e.g., genes involved in cancer resistance and hairlessness) are rejected when the analysis includes additional, more closely related species. We describe how the combination of better study design, improved genomic sequencing techniques, and new bioinformatic and data analytical tools will improve comparative genomics and ultimately bridge the gap between traditional model and nonmodel organisms.

Aging is the greatest risk factor for developing neurodegenerative diseases, which are associated with diminished neurotransmission as well as neuronal structure and function. However, several traits seemingly evolved to avert or delay age-related deterioration in the brain of the longest-lived rodent, the naked mole-rat (NMR). The NMR remarkably also exhibits negligible senescence, maintaining an extended healthspan for ~75 % of its life span. Using a proteomic approach, statistically significant changes with age in expression and/or phosphorylation levels of proteins associated with neurite outgrowth and neurotransmission were identified in the brain of the NMR and include: cofilin-1; collapsin response mediator protein 2; actin depolymerizing factor; spectrin alpha chain; septin-7; syntaxin-binding protein 1; synapsin-2 isoform IIB; and dynamin 1. We hypothesize that such changes may contribute to the extended lifespan and healthspan of the NMR.

Methionine restriction is a widely reported intervention for increasing life span in several model organisms. Low circulating levels of methionine are evident in the long-lived naked mole-rat, suggesting that it naturally presents with a life-extending phenotype akin to that observed in methionine-restricted animals. Similarly, long-lived dwarf mice also appear to have altered methionine metabolism. The mechanisms underlying methionine-restriction effects on life-span extension, however, remain unknown, as do their potential connections with caloric restriction, another well-established intervention for prolonging life span. Paradoxically, methionine is enriched in proteins expressed in mitochondria and may itself serve an important role in the detoxification of reactive oxygen species and may thereby contribute to delayed aging. Collectively, we highlight the evidence that modulation of the methionine metabolic network can extend life span-from yeast to humans-and explore the evidence that sulfur amino acids and the concomitant transsulfuration pathway play a privileged role in this regard. However, systematic studies in single organisms (particularly those that exhibit extreme longevity) are still required to distinguish the fundamental principles concerning the role of methionine and other amino acids in regulating life span., (© 2016 New York Academy of Sciences.)

Biological diversity among mammals is remarkable. Mammalian body weights range seven orders of magnitude and lifespans differ more than 100-fold among species. While genetic, dietary, and pharmacological interventions can be used to modulate these traits in model organisms, it is unknown how they are determined by natural selection. By profiling metabolites in brain, heart, kidney, and liver tissues of 26 mammalian species representing ten taxonomical orders, we report metabolite patterns characteristic of organs, lineages, and species longevity. Our data suggest different rates of metabolite divergence across organs and reveal patterns representing organ-specific functions and lineage-specific physiologies. We identified metabolites that correlated with species lifespan, some of which were previously implicated in longevity control. We also compared the results with metabolite changes in five long-lived mouse models and observed some similar patterns. Overall, this study describes adjustments of the mammalian metabolome according to lifespan, phylogeny, and organ and lineage specialization., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The preternaturally long-lived naked mole-rat, like other long-lived species and experimental models of extended longevity, is resistant to both endogenous (e.g., reactive oxygen species) and environmental stressors and also resists age-related diseases such as cancer, cardiovascular disease, and neurodegeneration. The mechanisms behind the universal resilience of longer-lived organisms to stress, however, remain elusive. We hypothesize that this resilience is linked to the activity of a highly conserved transcription factor, nuclear factor erythroid 2-related factor (Nrf2). Nrf2 regulates the transcription of several hundred cytoprotective molecules, including antioxidants, detoxicants, and molecular chaperones (heat shock proteins). Nrf2 itself is tightly regulated by mechanisms that either promote its activity or increase its degradation. We used a comparative approach and examined Nrf2-signaling activity in naked mole-rats and nine other rodent species with varying maximum lifespan potential (MLSP). We found that constitutive Nrf2-signaling activity was positively correlated (P = 0.0285) with MLSP and that this activity was also manifested in high levels of downstream gene expression and activity. Surprisingly, we found that species longevity was not linked to the protein levels of Nrf2 itself, but rather showed a significant (P < 0.01) negative relationship with the regulators Kelch-like ECH-Associated Protein 1 (Keap1) and β-transducin repeat-containing protein (βTrCP), which target Nrf2 for degradation. These findings highlight the use of a comparative biology approach for the identification of evolved mechanisms that contribute to health span, aging, and longevity.

Significance: The oxidative stress theory of aging has been the most widely accepted theory of aging providing insights into why we age and die for over 50 years, despite mounting evidence from a multitude of species indicating that there is no direct relationship between reactive oxygen species (ROS) and longevity. Here we explore how different species, including the longest lived rodent, the naked mole-rat, have defied the most predominant aging theory., Recent Advances: In the case of extremely long-lived naked mole-rat, levels of ROS production are found to be similar to mice, antioxidant defenses unexceptional, and even under constitutive conditions, naked mole-rats combine a pro-oxidant intracellular milieu with high, steady state levels of oxidative damage. Clearly, naked mole-rats can tolerate this level of oxidative stress and must have mechanisms in place to prevent its translation into potentially lethal diseases., Critical Issues: In addition to the naked mole-rat, other species from across the phylogenetic spectrum and even certain mouse strains do not support this theory. Moreover, overexpressing or knocking down antioxidant levels alters levels of oxidative damage and even cancer incidence, but does not modulate lifespan., Future Directions: Perhaps, it is not oxidative stress that modulates healthspan and longevity, but other cytoprotective mechanisms that allow animals to deal with high levels of oxidative damage and stress, and nevertheless live long, relatively healthy lifespans. Studying these mechanisms in uniquely long-lived species, like the naked mole-rat, may help us tease out the key contributors to aging and longevity.

Background: Written and video approaches to donor education have been shown to enhance donation attitudes and intentions to give blood, particularly when the information provides specific coping suggestions for donation-related concerns. This study extends this work by comparing Web-based approaches to donor preparation among donors and nondonors., Study Design and Methods: Young adults (62% female; mean [±SD] age, 19.3 [±1.5] years; mean [range] number of prior blood donations, 1.1 [0-26]; 60% nondonors) were randomly assigned to view 1) a study Web site designed to address common blood donor concerns and suggest specific coping strategies (n = 238), 2) a standard blood center Web site (n = 233), or 3) a control Web site where participants viewed videos of their choice (n = 202). Measures of donation attitude, anxiety, confidence, intention, anticipated regret, and moral norm were completed before and after the intervention., Results: Among nondonors, the study Web site produced greater changes in donation attitude, confidence, intention, and anticipated regret relative to both the standard and the control Web sites, but only differed significantly from the control Web site for moral norm and anxiety. Among donors, the study Web site produced greater changes in donation confidence and anticipated regret relative to both the standard and the control Web sites, but only differed significantly from the control Web site for donation attitude, anxiety, intention, and moral norm., Conclusion: Web-based donor preparation materials may provide a cost-effective way to enhance donation intentions and encourage donation behavior., (© 2012 American Association of Blood Banks.)

The daughter cyst sign is a specific indicator of an uncomplicated ovarian cyst and pathologically represents a stimulated ovarian follicle. This finding must be differentiated from an ectopic pregnancy in a patient who has the potential to become pregnant. We report an uncomplicated ovarian cyst in a 3-year-old female with McCune-Albright syndrome and precocious puberty mimicking an ectopic pregnancy.

Emerging research has shown that subtle factors during pregnancy and gestation can influence long-term health in offspring. In an attempt to be proactive, we set out to explore whether a nonpharmacological intervention, perinatal exercise, might improve offspring health. Female mice were separated into sedentary or exercise cohorts, with the exercise cohort having voluntary access to a running wheel prior to mating and during pregnancy and nursing. Offspring were weaned, and analyses were performed on the mature offspring that did not have access to running wheels during any portion of their lives. Perinatal exercise caused improved glucose disposal following an oral glucose challenge in both female and male adult offspring (P < 0.05 for both). Blood glucose concentrations were reduced to lower values in response to an intraperitoneal insulin tolerance test for both female and male adult offspring of parents with access to running wheels (P < 0.05 and P < 0.01, respectively). Male offspring from exercised dams showed increased percent lean mass and decreased fat mass percent compared with male offspring from sedentary dams (P < 0.01 for both), but these parameters were unchanged in female offspring. These data suggest that short-term maternal voluntary exercise prior to and during healthy pregnancy and nursing can enhance long-term glucose homeostasis in offspring.

Objective: Concern over the rise of vaccine preventable diseases (VPD) coupled with the increasing popularity of homeschooling makes understanding the attitudes and behaviors of homeschoolers regarding immunizations a critical area of investigation. This study was a pilot to investigate the immunization attitudes of homeschooling parents and the vaccination status of their children., Methods: In the spring of 2010, online surveys were sent to a convenience sample of 707 homeschooling parents in Western Pennsylvania with children ages 0-18 years of age. Information was collected on demographic characteristics, vaccination status of children, and attitudes toward vaccination., Results: Surveys were returned by 18 percent of respondents, representing 396 homeschooled children. Demographic characteristics mirrored national homeschooling trends. The majority (95%) surveyed felt that education about vaccines was important. Thirty-eight percent of families had fully vaccinated children while 56% reported partial vaccination and 6% said children had received no vaccines. Respondents who fully vaccinated their children were more likely to agree that vaccinating according to the American Academy of Pediatrics was a good idea (OR: 4.8 [95% CI: 2.0-11.7]) and were more likely to comply with the recommendations of their health care provider (OR: 8.3 [95% CI: 3.6-19.1]). Respondents who vaccinated their children were more likely to believe that vaccines are safe (OR: 7.6 [95% CI: 1.0-56.2]). Beliefs about autism, thimerosal and learning disabilities did not vary significantly with vaccination status in regression analysis., Conclusions: While specific factors influencing vaccination practices were not identified, this study demonstrated that recommendations of physicians and the AAP do not significantly influence homeschooling vaccination practices in the pilot population. Given the results of this pilot study, more research is called for, particularly a larger study with public school controls., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We report a case of a newborn with cholestasis that was diagnosed as nonsyndromic Alagille syndrome. The main feature of the disease is a paucity of biliary ducts. There are two known types of the disease: the syndromic type which is associated with other congenital defects and the nonsyndromic type without other anomalies detected at birth. We describe the case and discuss its clinical and radiologic findings. We also discuss the various etiologies of cholestasis that are included in the differential diagnosis.

Background: Studies comparing similar-sized species with disparate longevity may elucidate novel mechanisms that abrogate aging and prolong good health. We focus on the longest living rodent, the naked mole-rat. This mouse-sized mammal lives ~8 times longer than do mice and, despite high levels of oxidative damage evident at a young age, it is not only very resistant to spontaneous neoplasia but also shows minimal decline in age-associated physiological traits., Objectives: We assess the current status of stress resistance and longevity, focusing in particular on the molecular and cellular responses to cytotoxins and other stressors between the short-lived laboratory mouse and the naked mole-rat., Results: Like other experimental animal models of lifespan extension, naked mole-rat fibroblasts are extremely tolerant of a broad spectrum of cytotoxins including heat, heavy metals, DNA-damaging agents and xenobiotics, showing LD(50) values between 2- and 20-fold greater than those of fibroblasts of shorter-lived mice. Our new data reveal that naked mole-rat fibroblasts stop proliferating even at low doses of toxin whereas those mouse fibroblasts that survive treatment rapidly re-enter the cell cycle and may proliferate with DNA damage. Naked mole-rat fibroblasts also show significantly higher constitutive levels of both p53 and Nrf2 protein levels and activity, and this increases even further in response to toxins., Conclusion: Enhanced cell signaling via p53 and Nrf2 protects cells against proliferating with damage, augments clearance of damaged proteins and organelles and facilitates the maintenance of both genomic and protein integrity. These pathways collectively regulate a myriad of mechanisms which may contribute to the attenuated aging profile and sustained healthspan of the naked mole-rat. Understanding how these are regulated may be also integral to sustaining positive human healthspan well into old age and may elucidate novel therapeutics for delaying the onset and progression of physiological declines that characterize the aging process., (Copyright © 2012 S. Karger AG, Basel.)

Reactive oxygen species (ROS), by-products of aerobic metabolism, cause oxidative damage to cells and tissue and not surprisingly many theories have arisen to link ROS-induced oxidative stress to aging and health. While studies clearly link ROS to a plethora of divergent diseases, their role in aging is still debatable. Genetic knock-down manipulations of antioxidants alter the levels of accrued oxidative damage, however, the resultant effect of increased oxidative stress on lifespan are equivocal. Similarly the impact of elevating antioxidant levels through transgenic manipulations yield inconsistent effects on longevity. Furthermore, comparative data from a wide range of endotherms with disparate longevity remain inconclusive. Many long-living species such as birds, bats and mole-rats exhibit high-levels of oxidative damage, evident already at young ages. Clearly, neither the amount of ROS per se nor the sensitivity in neutralizing ROS are as important as whether or not the accrued oxidative stress leads to oxidative-damage-linked age-associated diseases. In this review we examine the literature on ROS, its relation to disease and the lessons gleaned from a comparative approach based upon species with widely divergent responses. We specifically focus on the longest lived rodent, the naked mole-rat, which maintains good health and provides novel insights into the paradox of maintaining both an extended healthspan and lifespan despite high oxidative stress from a young age.

Clear cell renal sarcoma is a rare tumor and comprises 4% of primary pediatric malignant renal tumors. It is known as an aggressive tumor with poor prognosis. Clinically and radiographically, it resembles Wilms tumor. We present a case of a child with an abdominal mass that was diagnosed as clear cell sarcoma of her right kidney.

Although aging is a ubiquitous process that prevails in all organisms, the mechanisms governing both the rate of decline in functionality and the age of onset remain elusive. A profound constitutively upregulated cytoprotective response is commonly observed in naturally long-lived species and experimental models of extensions to lifespan (e.g., genetically-altered and/or experimentally manipulated organisms), as indicated by enhanced resistance to stress and upregulated downstream components of the cytoprotective nuclear factor erythroid 2-related factor 2 (Nrf2)-signaling pathway. The transcription factor Nrf2 is constitutively expressed in all tissues, although levels may vary among organs, with the key detoxification organs (kidney and liver) exhibiting highest levels. Nrf2 may be further induced by cellular stressors including endogenous reactive-oxygen species or exogenous electrophiles. The Nrf2-signaling pathway mediates multiple avenues of cytoprotection by activating the transcription of more than 200 genes that are crucial in the metabolism of drugs and toxins, protection against oxidative stress and inflammation, as well as playing an integral role in stability of proteins and in the removal of damaged proteins via proteasomal degradation or autophagy. Nrf2 interacts with other important cell regulators such as tumor suppressor protein 53 (p53) and nuclear factor-kappa beta (NF-κB) and through their combined interactions is the guardian of healthspan, protecting against many age-related diseases including cancer and neurodegeneration. We hypothesize that this signaling pathway plays a critical role in the determination of species longevity and that this pathway may indeed be the master regulator of the aging process.

Acute myeloid leukemia (AML) is also referred to non-lymphocytic leukemia in the literature. It comprises about 15% of the childhood leukemia. There are multiple subtypes of AML from M0-M7 with approximately 45% of the cases being M0-M2 and the remaining subtypes being rare. The definitive diagnosis relies on bone marrow biopsy showing bone marrow infiltration with leukemic cells. We describe a rare radiographic presentation of myelodysplastic syndrome (MDS) transformed to AML in an 8 month old boy who presented with a orbital wall fracture, periosteal reaction, and mixed lytic and sclerotic lesions.

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

Caloric restriction (CR) is the most potent intervention known to both protect against carcinogenesis and extend lifespan in laboratory animals. A variety of anticarcinogens and CR mimetics induce and activate the NF-E2-related factor 2 (Nrf2) pathway. Nrf2, in turn, induces a number of antioxidative and carcinogen-detoxifying enzymes. Thus, Nrf2 offers a promising target for anticarcinogenesis and antiaging interventions. We used Nrf2-disrupted (KO) mice to examine its role on the biological effects of CR. Here, we show that Nrf2 is responsible for most of the anticarcinogenic effects of CR, but is dispensable for increased insulin sensitivity and lifespan extension. Nrf2-deficient mice developed tumors more readily in response to carcinogen exposure than did WT mice, and CR was ineffective in suppressing tumors in the KO mice. However, CR extended lifespan and increased insulin sensitivity similarly in KO and WT mice. These findings identify a molecular pathway that dissociates the prolongevity and anticarcinogenic effects of CR.

Calcium sulfate (CS) is one of the oldest bone graft materials still in use. Its main limitations are poor handling characteristics, poor mechanical properties, and a resorption rate that is too fast for some applications. The present study investigated the effect of viscous polymers, such as carboxymethylcellulose (CMC) and hyaluronan (HY), on the handling characteristics, mechanical properties, and degradation behavior of CS. CMC and HY were added to CS at concentrations from 1-10 wt%. Addition of CMC to CS at more than 4 wt% produced a putty-like material and decreased the density of the composite, while also increasing flexural and compressive strength at higher loadings. Incorporation of CMC produced a concentration-dependent increase in water absorption and degradation rate. At an equivalent loading, HY-containing CS composites showed better compressive strength than CS with CMC. Overall, addition of CMC or HY to CS resulted in composite materials with better handling characteristics and improved mechanical properties after set, however the degradation rate of the augmented materials was increased. These properties suggest that the enhanced CS materials may be useful in certain clinical situations, such as filling non-uniform bone defects and situations that require mechanical integrity of the bone graft substitute during implantation.

Repetitive-sequence-based PCR (rep-PCR) is useful for generating DNA fingerprints of diverse bacterial and fungal species. Rep-PCR amplicon fingerprints represent genomic segments lying between repetitive sequences. A commercial system that electrophoretically separates rep-PCR amplicons on microfluidic chips, and provides computer-generated readouts of results has been adapted for use with Mycobacterium species. The ability of this system to type M. tuberculosis and M. avium complex (MAC) isolates was evaluated. M. tuberculosis strains (n = 56) were typed by spoligotyping with rep-PCR as a high-resolution adjunct. Results were compared with those generated by a standard approach of spoligotyping with IS6110-targeted restriction fragment length polymorphism (IS6110-RFLP) as the high-resolution adjunct. The sample included 11 epidemiologically and genotypically linked outbreak isolates and a population-based sample of 45 isolates from recent immigrants to Seattle, Wash., from the African Horn countries of Somalia, Eritrea, and Ethiopia. Twenty isolates exhibited unique spoligotypes and were not analyzed further. Of the 36 outbreak and African Horn isolates with nonunique spoligotypes, 23 fell into four clusters identified by IS6110-RFLP and rep-PCR, with 97% concordance observed between the two methods. Both approaches revealed extensive strain heterogeneity within the African Horn sample, consistent with a predominant pattern of reactivation of latent infections in this immigrant population. Rep-PCR exhibited 89% concordance with IS1245-RFLP typing of 28 M. avium subspecies avium strains. For M. tuberculosis as well as M. avium subspecies avium, the discriminative power of rep-PCR equaled or exceeded that of RFLP. Rep-PCR also generated DNA fingerprints from M. intracellulare (n = 8) and MAC(x) (n = 2) strains. It shows promise as a fast, unified method for high-throughput genotypic fingerprinting of multiple Mycobacterium species.

The Greek language has shaped and formed the lexicon of modern medicine. Although medical terminology may seem complex and difficult to master, the clarity and functionality of this language owe a great debt to the tongue of the classical Greeks.

The tuberculosis (TB) vaccine bacille Calmette-Guérin (BCG) is a live attenuated organism, but the mutation responsible for its attenuation has never been defined. Recent genetic studies identified a single DNA region of difference, RD1, which is absent in all BCG strains and present in all Mycobacterium tuberculosis (MTB) strains. The 9 open-reading frames predicted within this 9.5-kb region are of unknown function, although they include the TB-specific immunodominant antigens ESAT-6 and CFP-10. In this study, RD1 was deleted from MTB strain H37Rv, and virulence of H37Rv:DeltaRD1 was assessed after infections of the human macrophage-like cell line THP-1, human peripheral blood monocyte-derived macrophages, and C57BL/6 mice. In each of these systems, the H37Rv:DeltaRD1 strain was strikingly less virulent than MTB and was very similar to BCG controls. Therefore, it was concluded that genes within or controlled by RD1 are essential for MTB virulence and that loss of RD1 was important in BCG attenuation.