Association between Pre - diagnosis Physical Activity and Risk of Breast Cancer Recurrence – the California Teachers Study

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Healthy lifestyle and life expectancy free of cancer, cardiovascular disease, and type 2 diabetes: prospective cohort study

OBJECTIVE: To examine how a healthy lifestyle is related to life expectancy that is free from major chronic diseases. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: The Nurses' Health Study (1980-2014; n=73 196) and the Health Professionals Follow-Up Study (1986-2014; n=38 366). MAIN EXPOSURES: Five low risk lifestyle factors: never smoking, body mass index 18.5-24.9, moderate to vigorous physical activity (≥30 minutes/day), moderate alcohol intake (women: 5-15 g/day; men 5-30 g/day), and a higher diet quality score (upper 40%). MAIN OUTCOME: Life expectancy free of diabetes, cardiovascular diseases, and cancer. RESULTS: The life expectancy free of diabetes, cardiovascular diseases, and cancer at age 50 was 23.7 years (95% confidence interval 22.6 to 24.7) for women who adopted no low risk lifestyle factors, in contrast to 34.4 years (33.1 to 35.5) for women who adopted four or five low risk factors. At age 50, the life expectancy free of any of these chronic diseases was 23.5 (22.3 to 24.7) years among men who adopted no low risk lifestyle factors and 31.1 (29.5 to 32.5) years in men who adopted four or five low risk lifestyle factors. For current male smokers who smoked heavily (≥15 cigarettes/day) or obese men and women (body mass index ≥30), their disease-free life expectancies accounted for the lowest proportion (≤75%) of total life expectancy at age 50. CONCLUSION: Adherence to a healthy lifestyle at mid-life is associated with a longer life expectancy free of major chronic diseases

Non-Redundant Selector and Growth-Promoting Functions of Two Sister Genes, buttonhead and Sp1, in Drosophila Leg Development

The radically distinct morphologies of arthropod and tetrapod legs argue that these appendages do not share a common evolutionary origin. Yet, despite dramatic differences in morphology, it has been known for some time that transcription factors encoded by the Distalless (Dll)/Dlx gene family play a critical role in the development of both structures. Here we show that a second transcription factor family encoded by the Sp8 gene family, previously implicated in vertebrate limb development, also plays an early and fundamental role in arthropod leg development. By simultaneously removing the function of two Sp8 orthologs, buttonhead (btd) and Sp1, during Drosophila embryogenesis, we find that adult leg development is completely abolished. Remarkably, in the absence of these factors, transformations from ventral to dorsal appendage identities are observed, suggesting that adult dorsal fates become derepressed when ventral fates are eliminated. Further, we show that Sp1 plays a much more important role in ventral appendage specification than btd and that Sp1 lies genetically upstream of Dll. In addition to these selector-like gene functions, Sp1 and btd are also required during larval stages for the growth of the leg. Vertebrate Sp8 can rescue many of the functions of the Drosophila genes, arguing that these activities have been conserved, despite more than 500 million years of independent evolution. These observations suggest that an ancient Sp8/Dlx gene cassette was used in an early metazoan for primitive limb-like outgrowths and that this cassette was co-opted multiple times for appendage formation in multiple animal phyla

Expression of zebrafish pax6b in pancreas is regulated by two enhancers containing highly conserved cis-elements bound by PDX1, PBX and PREP factors

BACKGROUND: PAX6 is a transcription factor playing a crucial role in the development of the eye and in the differentiation of the pancreatic endocrine cells as well as of enteroendocrine cells. Studies on the mouse Pax6 gene have shown that sequences upstream from the P0 promoter are required for expression in the lens and the pancreas; but there remain discrepancies regarding the precise location of the pancreatic regulatory elements. RESULTS: Due to genome duplication in the evolution of ray-finned fishes, zebrafish has two pax6 genes, pax6a and pax6b. While both zebrafish pax6 genes are expressed in the developing eye and nervous system, only pax6b is expressed in the endocrine cells of the pancreas. To investigate the cause of this differential expression, we used a combination of in silico, in vivo and in vitro approaches. We show that the pax6b P0 promoter targets expression to endocrine pancreatic cells and also to enteroendocrine cells, retinal neurons and the telencephalon of transgenic zebrafish. Deletion analyses indicate that strong pancreatic expression of the pax6b gene relies on the combined action of two conserved regulatory enhancers, called regions A and C. By means of gel shift assays, we detected binding of the homeoproteins PDX1, PBX and PREP to several cis-elements of these regions. In constrast, regions A and C of the zebrafish pax6a gene are not active in the pancreas, this difference being attributable to sequence divergences within two cis-elements binding the pancreatic homeoprotein PDX1. CONCLUSION: Our data indicate a conserved role of enhancers A and C in the pancreatic expression of pax6b and emphasize the importance of the homeoproteins PBX and PREP cooperating with PDX1, in activating pax6b expression in endocrine pancreatic cells. This study also provides a striking example of how adaptative evolution of gene regulatory sequences upon gene duplication progressively leads to subfunctionalization of the paralogous gene pair

B-Cell Lymphoma 2 (Bcl-2) and Regulation of Apoptosis after Traumatic Brain Injury: A Clinical Perspective.

Background and Objectives: The injury burden after head trauma is exacerbated by secondary sequelae, which leads to further neuronal loss. B-cell lymphoma 2 (Bcl-2) is an anti-apoptotic protein and a key modulator of the programmed cell death (PCD) pathways. The current study evaluates the clinical evidence on Bcl-2 and neurological recovery in patients after traumatic brain injury (TBI). Materials and Methods: All studies in English were queried from the National Library of Medicine PubMed database using the following search terms: (B-cell lymphoma 2/Bcl-2/Bcl2) AND (brain injury/head injury/head trauma/traumatic brain injury) AND (human/patient/subject). There were 10 investigations conducted on Bcl-2 and apoptosis in TBI patients, of which 5 analyzed the pericontutional brain tissue obtained from surgical decompression, 4 studied Bcl-2 expression as a biomarker in the cerebrospinal fluid (CSF), and 1 was a prospective randomized trial. Results: Immunohistochemistry (IHC) in 94 adults with severe TBI showed upregulation of Bcl-2 in the pericontusional tissue. Bcl-2 was detected in 36-75% of TBI patients, while it was generally absent in the non-TBI controls, with Bcl-2 expression increased 2.9- to 17-fold in TBI patients. Terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick-end labeling (TUNEL) positivity for cell death was detected in 33-73% of TBI patients. CSF analysis in 113 TBI subjects (90 adults, 23 pediatric patients) showed upregulation of Bcl-2 that peaked on post-injury day 3 and subsequently declined after day 5. Increased Bcl-2 in the peritraumatic tissue, rising CSF Bcl-2 levels, and the variant allele of rs17759659 are associated with improved mortality and better outcomes on the Glasgow Outcome Score (GOS). Conclusions: Bcl-2 is upregulated in the pericontusional brain and CSF in the acute period after TBI. Bcl-2 has a neuroprotective role as a pro-survival protein in experimental models, and increased expression in patients can contribute to improvement in clinical outcomes. Its utility as a biomarker and therapeutic target to block neuronal apoptosis after TBI warrants further evaluation

Congenital Cytomegalovirus Infection Burden and Epidemiologic Risk Factors in Countries with Universal Screening:A Systematic Review and Meta-analysis

Importance: Congenital cytomegalovirus (cCMV) infection is the most common congenital infection and the leading acquired cause of developmental disabilities and sensorineural deafness, yet a reliable assessment of the infection burden is lacking. Objectives: To estimate the birth prevalence of cCMV in low- and middle-income countries (LMICs) and high-income countries (HICs), characterize the rate by screening methods, and delineate associated risk factors of the infection. Data Sources: MEDLINE/PubMed, Scopus, and Cochrane Database of Systematic Reviews databases were searched from January 1, 1960, to March 1, 2021, and a total of 1322 studies were identified. Study Selection: Studies that provided data on the prevalence of cCMV derived from universal screening of infants younger than 3 weeks were included. Targeted screening studies were excluded. Data Extraction and Synthesis: Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Extraction was performed independently by 3 reviewers. Quality was assessed using the Newcastle-Ottawa Scale for cohort studies. Random-effects meta-analysis was undertaken. Metaregression was conducted to evaluate the association of sociodemographic characteristics, maternal seroprevalence, population-level HIV prevalence, and screening methods with the prevalence of cCMV. Main Outcomes and Measures: Birth prevalence of cCMV ascertained through universal screening of infants younger than 3 weeks for CMV from urine, saliva, or blood samples. Results: Seventy-seven studies comprising 515646 infants met the inclusion criteria from countries representative of each World Bank income level. The estimated pooled overall prevalence of cCMV was 0.67% (95% CI, 0.54%-0.83%). The pooled birth prevalence of cCMV was 3-fold greater in LMICs (1.42%; 95% CI, 0.97%-2.08%; n = 23 studies) than in HICs (0.48%; 95% CI, 0.40%-0.59%, n = 54 studies). Screening methods with blood samples demonstrated lower rates of cCMV than urine or saliva samples (odds ratio [OR], 0.38; 95% CI, 0.23-0.66). Higher maternal CMV seroprevalence (OR, 1.19; 95% CI, 1.11-1.28), higher population-level HIV prevalence (OR, 1.22; 95% CI, 1.05-1.40), lower socioeconomic status (OR, 3.03; 95% CI, 2.05-4.47), and younger mean maternal age (OR, 0.85; 95% CI, 0.78-0.92, older age was associated with lower rates) were associated with higher rates of cCMV. Conclusions and Relevance: In this meta-analysis, LMICs appeared to incur the most significant infection burden. Lower rates of cCMV were reported by studies using only blood or serum as a screening method.. © 2021 American Medical Association. All rights reserved

Combined subtarsal contralateral transmaxillary retroeustachian and endoscopic endonasal approaches to the infrapetrous region

OBJECTIVE: The eustachian tube (ET) limits endoscopic endonasal access to the infrapetrous region. Transecting or mobilizing the ET may result in morbidities. This study presents a novel approach in which a subtarsal contralateral transmaxillary (ST-CTM) corridor is coupled with the standard endonasal approach to facilitate access behind the intact ET. METHODS: Eight cadaveric head specimens were dissected. Endoscopic endonasal approaches (EEAs) (i.e., transpterygoid and inferior transclival) were performed on one side, followed by ST-CTM and sublabial contralateral transmaxillary (SL-CTM) approaches on the opposite side, along with different ET mobilization techniques on the original side. Seven comparative groups were generated. The length of the cranial nerves, areas of exposure, and volume of surgical freedom (VSF) in the infrapetrous regions were measured and compared. RESULTS: Without ET mobilization, the combined ST-CTM/EEA approach provided greater exposure than EEA alone (mean ± SD 288.9 ± 40.66 mm2 vs 91.7 ± 49.9 mm2; p = 0.001). The VSFs at the ventral jugular foramen (JF), entrance to the petrous internal carotid artery (ICA), and lateral to the parapharyngeal ICA were also greater in ST-CTM/EEA than in EEA alone (p = 0.002, p = 0.002, and p \u3c 0.001, respectively). EEA alone, however, provided greater VSF at the hypoglossal canal (HGC) than did ST-CTM/EEA (p = 0.01). The SL-CTM approach did not increase the EEA exposure (p = 0.48). The ST-CTM/EEA approach provided greater exposure than EEA with extended inferolateral (EIL) or anterolateral (AL) ET mobilization (p = 0.001 and p = 0.02, respectively). The ST-CTM/EEA also increased the VSF lateral to the parapharyngeal ICA in comparison with EEA/EIL ET mobilization (p \u3c 0.001) but not with EEA/AL ET mobilization (p = 0.36). Finally, the VSFs at the HGC and JF were greater in EEA/AL ET mobilization than in ST-CTM/EEA without ET mobilization (p = 0.002 and p = 0.004, respectively). CONCLUSIONS: Combining the EEA with the more laterally and superiorly originating ST-CTM approach allows greater exposure of the infrapetrous and ventral JF regions while obviating the need for mobilizing the ET. The surgical freedom afforded by the combined approaches is greater than that obtained by EEA alone

A real-world study of the association between cardiovascular risk factors and depression symptom trajectory in individuals with mental illness

Background: We examined the relationship between baseline cardiovascular (CV) disease/risk factors and longitudinally-collected scores on the patient health questionnaire (PHQ-9) depression scale using an outpatient sample of individuals with mental illness (PCARES Registry, 2015–2020). Methods: Individuals with ≥2 repeated PHQ-9 assessments over one-year from the baseline PHQ-9 measurement (N = 2110) were included for trajectory modeling, with five depression symptom severity trajectory groups determined a priori (lowest, lower, middle, higher, and highest). Proportional odds models provided the association between baseline CV disease/risk factors and the odds of belonging to the more severe depression symptom trajectory group. In a sub-sample (baseline PHQ-9 score ≥10), linear-mixed effects models provided the association between baseline CV disease/risk factors and longitudinal PHQ-9 scores (N = 1118). Results: 2110 individuals included 65% females, 87% non-Hispanic white, 50% in lower and middle severity groups, with mean ± SD age: 43.0 ± 16.8 years and PHQ-9 score: 10.8 ± 7.0. Adjusting for socio-demographics and BMI [OR (95% CI)]: individuals with baseline hypertension [1.4 (1.2–1.7)], diabetes [1.3 (1.0–1.6)], dyslipidemia [1.2 (1.0–1.4)], tobacco use [2.0 (1.6–2.6)], and higher number of CV disease/risk factors (P-trend<0.0001) had significantly higher odds of more severe depression symptom trajectories; longitudinal PHQ-9 scores significantly decreased during 1-year follow-up, and the decrease was relatively lesser in individuals with hypertension or ≥1 CV disease/risk factors than those without these conditions. Limitations: Clinic-based patient sample limits generalizability of findings. Conclusions: Presence/absence of baseline CV risk factors significantly influenced longitudinal depression symptom severity among psychiatry outpatients, demonstrating the need for depression screening and surveillance among individuals with CV risk factors