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OBJECTIVES: Atenolol is a commonly used beta bloscker in non-pregnant women. Many providers are hesitant in prescribing atenolol in pregnancy because of a possible association with poor fetal growth. We aimed to assess the association between atenolol and the occurrence of small for gestational age neonates compared to other beta blockers, as described in the existing literature. METHODS: We used the meta-analytic method to generate a forest plot for risk ratios (RR) of small for gestational age in patients who used atenolol vs. other beta blockers. Statistical heterogeneity was assessed with the I2 statistic. RESULTS: Two studies were included, with a resultant RR of 1.94 [95â¯% confidence interval (CI) 1.60; 2.35]. A study by Duan et al. in 2018 noted the following rate of small for gestational age for each beta blocker use: 112/638 atenolol, 590/3,357 labetalol, 35/324 metoprolol, and 50/489 propranolol. A study by Tanaka et al. in 2016 noted the following rate of small for gestational age: 8/22 for propranolol, 2/12 for metoprolol, 2/6 for atenolol, 0/5 for bisoprolol. Heterogeneity (I2) was 0â¯%. CONCLUSIONS: Our results suggested an elevated risk of small for gestational age associated with atenolol use in comparison to other beta blockers, specifically labetalol, propranolol, bisoprolol, and metoprolol.
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Cases of concurrent duodenal adenocarcinoma and gastrointestinal stromal tumors (GISTs) are rare, and only a few have been reported. While some cases of other synchronous primary tumors with GIST have been reported, no shared mutations have been consistently found, creating challenges in selecting chemotherapy in cases of inoperable tumors. Here, we presented a case of a stage IIIA locally advanced/unresectable duodenal adenocarcinoma with concurrent metastatic small bowel GIST successfully being treated with combined imatinib and modified folinic acid, 5-fluorouracil, and irinotecan (mFOLFIRI) regimen.
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This article for the Highlights of 2023 Series explores recent work that suggests that targeting CD4 CAR T cells may be critical for both of these challenges.
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Linfócitos T CD4-Positivos , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Linfócitos T CD4-Positivos/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Animais , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
BACKGROUND: High levels of infant negative emotionality (NE) and low positive emotionality (PE) predict future emotional and behavioral problems. The prefrontal cortex (PFC) supports emotional regulation, with each PFC subregion specializing in specific emotional processes. Neurite orientation dispersion and density imaging estimates microstructural integrity and myelination via the neurite density index (NDI) and dispersion via the orientation dispersion index (ODI), with potential to more accurately evaluate microstructural alterations in the developing brain. Yet, no study has used these indices to examine associations between PFC microstructure and concurrent or developing infant emotionality. METHODS: We modeled PFC subregional NDI and ODI at 3 months with caregiver-reported infant NE and PE at 3 months (n = 61) and at 9 months (n = 50), using multivariable and subsequent bivariate regression models. RESULTS: The most robust statistically significant findings were positive associations among 3-month rostral anterior cingulate cortex (ACC) ODI and caudal ACC NDI and concurrent NE, a positive association between 3-month lateral orbitofrontal cortex ODI and prospective NE, and a negative association between 3-month dorsolateral PFC ODI and concurrent PE. Multivariate models also revealed that other PFC subregional microstructure measures, as well as infant and caregiver sociodemographic and clinical factors, predicted infant 3- and 9-month NE and PE. CONCLUSIONS: Greater NDI and ODI, reflecting greater microstructural complexity, in PFC regions supporting salience perception (rostral ACC), decision making (lateral orbitofrontal cortex), action selection (caudal ACC), and attentional processes (dorsolateral PFC) might result in greater integration of these subregions with other neural networks and greater attention to salient negative external cues, thus higher NE and/or lower PE. These findings provide potential infant cortical markers of future psychopathology risk.
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Microbial evolution within polymicrobial communities is a complex process. Here, we report within-species diversification within multispecies microbial communities during experimental evolution with the nematode Caenorhabditis elegans. We describe morphological diversity in the target species Chryseobacterium gleum, which developed a novel colony morphotype in a small number of replicate communities. Alternate morphotypes coexisted with original morphotypes in communities, as well as in single-species experiments using evolved isolates. We found that the original and alternate morphotypes differed in motility and in spatial expansion in the presence of C. elegans. This study provides insight into the emergence and maintenance of intraspecies diversity in the context of microbial communities.
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Caenorhabditis elegans , Chryseobacterium , Animais , Caenorhabditis elegans/genética , Chryseobacterium/genéticaRESUMO
Ageing is the greatest risk factor for a multitude of age-related diseases including sarcopenia -the loss of skeletal muscle mass and strength - which occurs at remarkable rates each year. There is an unmet need not only to understand the mechanisms that drive sarcopenia, but also to identify novel therapeutic strategies. Given the ease and affordability of husbandry, along with advances in genomics, genome editing technologies and imaging capabilities, teleost models are increasingly used for ageing and sarcopenia research. Here, we explain how teleost species such as zebrafish, African turquoise killifish and medaka recapitulate many of the classical hallmarks of sarcopenia, and discuss the various dietary, pharmacological and genetic approaches that have been used in teleosts to understand the mechanistic basis of sarcopenia.
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The house mouse (Mus musculus) is an exceptional model system, combining genetic tractability with close evolutionary affinity to humans1,2. Mouse gestation lasts only 3 weeks, during which the genome orchestrates the astonishing transformation of a single-cell zygote into a free-living pup composed of more than 500 million cells. Here, to establish a global framework for exploring mammalian development, we applied optimized single-cell combinatorial indexing3 to profile the transcriptional states of 12.4 million nuclei from 83 embryos, precisely staged at 2- to 6-hour intervals spanning late gastrulation (embryonic day 8) to birth (postnatal day 0). From these data, we annotate hundreds of cell types and explore the ontogenesis of the posterior embryo during somitogenesis and of kidney, mesenchyme, retina and early neurons. We leverage the temporal resolution and sampling depth of these whole-embryo snapshots, together with published data4-8 from earlier timepoints, to construct a rooted tree of cell-type relationships that spans the entirety of prenatal development, from zygote to birth. Throughout this tree, we systematically nominate genes encoding transcription factors and other proteins as candidate drivers of the in vivo differentiation of hundreds of cell types. Remarkably, the most marked temporal shifts in cell states are observed within one hour of birth and presumably underlie the massive physiological adaptations that must accompany the successful transition of a mammalian fetus to life outside the womb.
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Animais Recém-Nascidos , Embrião de Mamíferos , Desenvolvimento Embrionário , Gástrula , Análise de Célula Única , Imagem com Lapso de Tempo , Animais , Feminino , Camundongos , Gravidez , Animais Recém-Nascidos/embriologia , Animais Recém-Nascidos/genética , Diferenciação Celular/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Desenvolvimento Embrionário/genética , Gástrula/citologia , Gástrula/embriologia , Gastrulação/genética , Rim/citologia , Rim/embriologia , Mesoderma/citologia , Mesoderma/enzimologia , Neurônios/citologia , Neurônios/metabolismo , Retina/citologia , Retina/embriologia , Somitos/citologia , Somitos/embriologia , Fatores de Tempo , Fatores de Transcrição/genética , Transcrição Gênica , Especificidade de Órgãos/genéticaRESUMO
The ability to coordinate the hands together to act on objects where each hand does something different is known as role-differentiated bimanual manipulation (RDBM). This study investigated two motor skills that may support the development of RDBM: infants' early object skill and their early sitting skill. To evaluate these potential predictors of RDBM growth, 90 infants were examined in a lab-based longitudinal design over a 9-month period. Latent growth modeling was used to estimate RDBM growth trajectories over 9 to 14 months from infants' object and sitting skills at 6 months, controlling for infant's sex, mother's education, and family income. Higher object skill, controlling for sitting skill, was related to a higher increase in RDBM over time. Sitting did not predict infants' change in RDBM over time, controlling for object skill. The ability to manage multiple objects may support collaborative hand use by providing infants with opportunities to practice actions that will be needed later for RDBM. By comparison, sitting may free the hands in an unspecified manner for manipulation.
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Desenvolvimento Infantil , Destreza Motora , Lactente , Humanos , MãosRESUMO
A defining feature of most primates is a hand with five fingers. Spider monkeys are an exception because they have four fingers and no thumb. Despite the prevalence of reach-to-grasp research in primates, it is not known how the lack of a thumb affects reaching and grasping in spider monkeys. Drawing on patterns that have been well described in human adults, human infants, and other nonhuman primates, this study characterized prehension in Colombian spider monkeys (Ateles fusciceps rufiventris). Monkeys reached for two differently sized food objects and reaches were digitized offline for two-dimensional kinematic analysis. Grasp strategy was coded from video as preshaped when the hand was adjusted to grasp the food before contact, or not preshaped when the hand was adjusted to grasp the food after contact. Monkeys exhibited variability in reach smoothness that contrasted with the typical pattern seen in other adult primates and instead resembled the pattern observed in human infants. Monkeys anticipated the object to be grasped approximately half of the time. Reaches where the hand was preshaped to the object were smoother than reaches where the hand was adjusted to grasp after object contact. For the small object, reaches with preshaping were straighter than reaches without preshaping. Results are the first evidence of kinematic signatures for reach-to-grasp actions in spider monkeys. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Atelinae , Mãos , Animais , Humanos , Fenômenos Biomecânicos , Colômbia , Força da Mão , Desempenho Psicomotor , MovimentoRESUMO
Accumulating evidence suggests that psychological distress during pregnancy is linked to offspring risk for externalizing outcomes (e.g., reactive/aggressive behaviors, hyperactivity, and impulsivity). Effect sizes across studies have varied widely, however, due to differences in study design and methodology, including control for the confounding continuation of distress in the postnatal period. Clarifying these inconsistencies is necessary to guide the precision of prevention efforts and inform public health policies. A meta-analysis was conducted with 55 longitudinal studies to investigate the association between prenatal psychological distress (anxiety, depression, and perceived stress) and offspring externalizing behaviors. Results revealed a significant but small effect (r = .160) of prenatal distress on externalizing behaviors. The magnitude of the prenatal effect size remained largely unchanged after adjusting for postnatal distress (r = .159), implicating a unique effect of psychological distress during the prenatal period in the etiology of externalizing behaviors. Moderation tests showed that prenatal effects did not vary based on type and timing of psychological distress during pregnancy. Greater instability of distress from prenatal to postnatal periods predicted larger effects. Prenatal effects were comparable across most externalizing outcomes, consistent with the common comorbidity of externalizing spectrum disorders, although effects appeared smaller for nonaggressive rule-breaking (vs. aggressive) behaviors. Significant associations persisted across all developmental periods, appearing slightly larger in early childhood. We discuss these results in the context of developmental and psychobiological theories of externalizing behavior, offer preliminary clinical and public health implications, and highlight directions for future research including the need for longitudinal studies with more racially and socioeconomically diverse families. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Comportamento Infantil , Mães , Efeitos Tardios da Exposição Pré-Natal , Distância Psicológica , Adolescente , Pré-Escolar , Feminino , Humanos , Gravidez , Agressão , Comorbidade , Estudos Longitudinais , Mães/psicologia , CriançaRESUMO
INTRODUCTION: Gestational diabetes mellitus is the most common metabolic disorder in pregnancy, and it is associated with detrimental short- and long-term consequences to both the fetus and the mother. Some studies in the literature have found an association between the identification of fetal hyperechogenic pancreas via prenatal ultrasound and the presence of gestational diabetes mellitus. The aim of our study was to assess the association of fetal hyperechogenic pancreas with gestational diabetes mellitus using the meta-analytic method. EVIDENCE ACQUISITION: We searched electronic databases for articles describing association (or lack of) between fetal hyperechogenic pancreas and gestational diabetes mellitus. For each study, we identified patients with or without fetal hyperechogenic pancreas and with or without gestational diabetes mellitus. We then calculated risk ratios for gestational diabetes mellitus using the meta-analytic Mantel-Haenszel method with a random effect to estimate the risk ratio. EVIDENCE SYNTHESIS: We identified 286 patients in 2 studies. The risk ratio of gestational diabetes mellitus in women with fetal hyperechogenic pancreas was 3.34, P<0.0001 (95% CI, 1.56-7.17; I2=82% [95% CI 22.7-95.7%]). CONCLUSIONS: The presence of a fetal hyperechogenic pancreas was associated with gestational diabetes mellitus. We concluded that the detection of fetal pancreas echogenicity may be a promising indicator of gestational diabetes mellitus that, pending further research studies, can potentially help the clinician in making this diagnosis.
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The house mouse, Mus musculus, is an exceptional model system, combining genetic tractability with close homology to human biology. Gestation in mouse development lasts just under three weeks, a period during which its genome orchestrates the astonishing transformation of a single cell zygote into a free-living pup composed of >500 million cells. Towards a global framework for exploring mammalian development, we applied single cell combinatorial indexing (sci-*) to profile the transcriptional states of 12.4 million nuclei from 83 precisely staged embryos spanning late gastrulation (embryonic day 8 or E8) to birth (postnatal day 0 or P0), with 2-hr temporal resolution during somitogenesis, 6-hr resolution through to birth, and 20-min resolution during the immediate postpartum period. From these data (E8 to P0), we annotate dozens of trajectories and hundreds of cell types and perform deeper analyses of the unfolding of the posterior embryo during somitogenesis as well as the ontogenesis of the kidney, mesenchyme, retina, and early neurons. Finally, we leverage the depth and temporal resolution of these whole embryo snapshots, together with other published data, to construct and curate a rooted tree of cell type relationships that spans mouse development from zygote to pup. Throughout this tree, we systematically nominate sets of transcription factors (TFs) and other genes as candidate drivers of the in vivo differentiation of hundreds of mammalian cell types. Remarkably, the most dramatic shifts in transcriptional state are observed in a restricted set of cell types in the hours immediately following birth, and presumably underlie the massive changes in physiology that must accompany the successful transition of a placental mammal to extrauterine life.
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High levels of infant negative emotionality (NE) are associated with emotional and behavioral problems later in childhood. Identifying neural markers of high NE as well as low positive emotionality (PE) in infancy can provide neural markers to aid early identification of vulnerability, and inform interventions to help delay or even prevent psychiatric disorders before the manifestation of symptoms. Prefrontal cortical (PFC) subregions support the regulation of NE and PE, with each PFC subregion differentially specializing in distinct emotional regulation processes. Gray matter (GM) volume measures show good test-retest reliability, and thus have potential use as neural markers of NE and PE. Yet, while studies showed PFC GM structural abnormalities in adolescents and young adults with affective disorders, few studies examined how PFC subregional GM measures are associated with NE and PE in infancy. We aimed to identify relationships among GM in prefrontal cortical subregions at 3 months and caregiver report of infant NE and PE, covarying for infant age and gender and caregiver sociodemographic and clinical variables, in two independent samples at 3 months (Primary: n = 75; Replication sample: n = 40) and at 9 months (Primary: n = 44; Replication sample: n = 40). In the primary sample, greater 3-month medial superior frontal cortical volume was associated with higher infant 3-month NE (p < 0.05); greater 3-month ventrolateral prefrontal cortical volume predicted lower infant 9-month PE (p < 0.05), even after controlling for 3-month NE and PE. GM volume in other PFC subregions also predicted infant 3- and 9-month NE and PE, together with infant demographic factors, caregiver age, and/or caregiver affective instability and anxiety. These findings were replicated in the independent sample. To our knowledge, this is the first study to determine in primary and replication samples associations among infant PFC GM volumes and concurrent and prospective NE and PE, and identify promising, early markers of future psychopathology risk.
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Emoções , Substância Cinzenta , Adolescente , Adulto Jovem , Humanos , Lactente , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Estudos Prospectivos , Reprodutibilidade dos Testes , Emoções/fisiologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/patologia , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Elucidating the neural basis of infant positive emotionality and negative emotionality can identify biomarkers of pathophysiological risk. Our goal was to determine how functional interactions among large-scale networks supporting emotional regulation influence white matter (WM) microstructural-emotional behavior relationships in 3-month-old infants. We hypothesized that microstructural-emotional behavior relationships would be differentially mediated or suppressed by underlying resting-state functional connectivity (rsFC), particularly between default mode network and central executive network structures. METHODS: The analytic sample comprised primary caregiver-infant dyads (52 infants [42% female, mean age at scan = 15.10 weeks]), with infant neuroimaging and emotional behavior assessments conducted at 3 months. Infant WM and rsFC were assessed by diffusion-weighted imaging/tractography and resting-state magnetic resonance imaging during natural, nonsedated sleep. The Infant Behavior Questionnaire-Revised provided measures of infant positive emotionality and negative emotionality. RESULTS: After significant WM-emotional behavior relationships were observed, multimodal analyses were performed using whole-brain voxelwise mediation. Results revealed that greater cingulum bundle volume was significantly associated with lower infant positive emotionality (ß = -0.263, p = .031); however, a pattern of lower rsFC between central executive network and default mode network structures suppressed this otherwise negative relationship. Greater uncinate fasciculus volume was significantly associated with lower infant negative emotionality (ß = -0.296, p = .022); however, lower orbitofrontal cortex-amygdala rsFC suppressed this otherwise negative relationship, while greater orbitofrontal cortex-central executive network rsFC mediated this relationship. CONCLUSIONS: Functional interactions among neural networks have an important influence on WM microstructural-emotional behavior relationships in infancy. These relationships can elucidate neural mechanisms that contribute to future behavioral and emotional problems in childhood.
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Substância Branca , Humanos , Lactente , Feminino , Masculino , Substância Branca/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Imagem de Difusão por Ressonância Magnética , Redes Neurais de Computação , Vias NeuraisRESUMO
Melanoma is one of the most aggressive forms of skin cancer and is characterized by high metastatic potential. Despite improvements in early diagnosis and treatment, the mortality rate among metastatic melanoma patients continues to represent a significant clinical challenge. Therefore, it is imperative that we search for new forms of treatment. Trametes versicolor is a mushroom commonly used in Chinese traditional medicine due to its numerous beneficial properties. In the present work, we demonstrate T. versicolor fruiting body and mycelium ethanol extracts exhibit potent cytotoxic activity towards A375 (IC50 = 663.3 and 114.5 µg/mL respectively) and SK-MEL-5 (IC50 = 358.4 and 88.6 µg/mL respectively) human melanoma cell lines. Further studies revealed that T. versicolor mycelium extract induced apoptotic cell death and poly (ADP-ribose) polymerase cleavage, upregulated the expression of autophagy-associated marker LC3-II, increased the presentation of major histocompatibility complex II and expression of programmed death-ligand receptor, and inhibited cell migration in SK-MEL-5 cells. Therefore, our present findings highlight the therapeutic potential of T. versicolor mycelium extract for the treatment of melanoma and merit further study.
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Antineoplásicos , Polyporaceae , Humanos , Trametes , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , MicélioRESUMO
The gut microbiome is essential for processing complex food compounds and synthesizing nutrients that the host cannot digest or produce, respectively. New model systems are needed to study how the metabolic capacity provided by the gut microbiome impacts the nutritional status of the host, and to explore possibilities for altering host metabolic capacity via the microbiome. Here, we colonized the nematode Caenorhabditis elegans gut with cellulolytic bacteria that enabled C. elegans to utilize cellulose, an otherwise indigestible substrate, as a carbon source. Cellulolytic bacteria as a community component in the worm gut can also support additional bacterial species with specialized roles, which we demonstrate by using Lactobacillus plantarum to protect C. elegans against Salmonella enterica infection. This work shows that engineered microbiome communities can be used to endow host organisms with novel functions, such as the ability to utilize alternate nutrient sources or to better fight pathogenic bacteria.
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Microbioma Gastrointestinal , Microbiota , Animais , Caenorhabditis elegans/microbiologia , BactériasRESUMO
Adaptation of replicate microbial communities frequently produces shared trajectories of community composition and structure. However, divergent adaptation of individual community members can occur and is associated with community-level divergence. The extent to which community-based adaptation of microbes should be convergent when community members are similar but not identical is, therefore, not well-understood. In these experiments, adaptation of combinatorial minimal communities of bacteria with the model host Caenorhabditis elegans produces structurally similar communities over time, but with divergent adaptation of member taxa and differences in community-level resistance to invasion. These results indicate that community-based adaptation from taxonomically similar starting points can produce compositionally similar communities that differ in traits of member taxa and in ecological properties.
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Microbiota , Bactérias/genética , Adaptação Fisiológica , AclimataçãoRESUMO
The nematode Caenorhabditis elegans is a model system for host-microbe and host-microbiome interactions. Many studies to date use batch digests rather than individual worm samples to quantify bacterial load in this organism. Here it is argued that the large inter-individual variability seen in bacterial colonization of the C. elegans intestine is informative, and that batch digest methods discard information that is important for accurate comparison across conditions. As describing the variation inherent to these samples requires large numbers of individuals, a convenient 96-well plate protocol for disruption and colony plating of individual worms is established.
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Caenorhabditis elegans , Microbiota , Animais , Bactérias , Caenorhabditis elegans/microbiologia , Intestinos/microbiologia , Modelos BiológicosRESUMO
Hydrogen peroxide (H2O2) is a ubiquitous oxidant produced in a regulated manner by various enzymes in mammalian cells. H2O2 reversibly oxidizes thiol groups of cysteine residues to mediate intracellular signaling. While examples of H2O2-dependent signaling have been reported, the exact molecular mechanism(s) of signaling and the pathways affected are not well understood. Here, the transcriptomic response of Jurkat T cells to H2O2 was investigated to determine global effects on gene expression. With a low H2O2 concentration (10 µM) that did not induce an oxidative stress response or cell death, extensive changes in gene expression occurred after 4 h (6803 differentially expressed genes). Of the genes with a greater then 2-fold change in expression, 85% were upregulated suggesting that in a physiological setting H2O2 predominantly activates gene expression. Pathway analysis identified gene expression signatures associated with FOXO and NTRK signaling. These signatures were associated with an overlapping set of transcriptional regulators. Overall, our results provide a snapshot of gene expression changes in response to H2O2, which, along with further studies, will lead to new insights into the specific pathways that are activated in response to endogenous production of H2O2, and the molecular mechanisms of H2O2 signaling.
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Peróxido de Hidrogênio , Transdução de Sinais , Animais , Humanos , Peróxido de Hidrogênio/farmacologia , Células Jurkat , Oxidantes/farmacologia , Estresse Oxidativo , Expressão Gênica , MamíferosRESUMO
The number of older adults in the United States is projected to increase in coming years, including the number of lesbian, gay, bisexual, transgender, queer, or questioning (LGBTQ+) older adults requiring long-term care (LTC) services. We conducted an online survey of older LGBTQ+ adults living in the Southern United States between January and March of 2018 to inquire about their anticipation of discrimination in and willingness to utilize LTC services. We found that 78.6% of respondents (N = 789) anticipated discrimination in LTC. Previous experiences with discrimination, higher educational attainment, and queer/questioning sexual orientation were associated with greater expectation of discrimination. Higher anticipation of discrimination was also associated with a greater preference for utilizing LTC services offered by LGBTQ+ providers or for LGBTQ+ older adults. These findings suggest that LTC staff and researchers may be uniquely positioned to craft outreach and policies to protect LGBTQ+ LTC residents.