Background
This study aims to estimate the association between radon and site‐specific cancer mortality among a large contemporary cohort of male uranium miners.
Methods
Annual occupational radon ...exposure was estimated based on a worker's duration of underground mining in a year and estimates of potential alpha energy of radon progeny in their location of work. Cancer mortality over the period 1977‐1992 was ascertained for a cohort of 16 434 male underground uranium miners employed in the Czech Republic between 1946 and 1992. Poisson regression was used to estimate relationships between cumulative radiation exposure (in working level months WLM) and site‐specific cancer mortality.
Results
Radon is positively associated with lung cancer mortality (excess relative rate ERR per 100 WLM = 0.2; 95% confidence interval CI: 0.10, 0.37). The best fit of the dose‐response relationship between radon and lung cancer mortality was linear and estimates of radon‐lung cancer associations varied by windows of time‐since‐exposure. Positive associations between radon and several types of cancer other than lung cancer were identified, notably chronic lymphocytic leukemia (CLL) (ERR/100 WLM = 0.24; 95% CI: not determined ND, 5.10) and extrathoracic cancer (ERR/100 WLM = 0.12; 95% CI: ND, 0.69). We observed no associations between radon and stomach cancer, nor between radon and several hematopoietic cancer subtypes.
Conclusions
This study confirms the established radon‐lung cancer association and suggests that radon may also be associated with other types of cancer mortality. Further investigations of extrathoracic and CLL cancer, with the aim of obtaining more precise estimates, are warranted to understand associations between radon and cancers other than lung.
RAC1 is a highly conserved Rho GTPase critical for many cellular and developmental processes. De novo missense RAC1 variants cause a highly variable neurodevelopmental disorder. Some of these ...variants have previously been shown to have a dominant negative effect. Most previously reported patients with this disorder have either severe microcephaly or severe macrocephaly. Here, we describe eight patients with pathogenic missense RAC1 variants affecting residues between Q61 and R68 within the switch II region of RAC1. These patients display variable combinations of developmental delay, intellectual disability, brain anomalies such as polymicrogyria and cardiovascular defects with normocephaly or relatively milder micro- or macrocephaly. Pulldown assays, NIH3T3 fibroblast spreading assays and staining for activated PAK1/2/3 and WAVE2 suggest that these variants increase RAC1 activity and over-activate downstream signalling targets. Axons of neurons isolated from Drosophila embryos expressing the most common of the activating variants are significantly shorter, with an increased density of filopodial protrusions. In vivo, these embryos exhibit frequent defects in axonal organization. Class IV dendritic arborization neurons expressing this variant exhibit a significant reduction in the total area of the dendritic arbour, increased branching and failure of self-avoidance. RNAi knock down of the WAVE regulatory complex component Cyfip significantly rescues these morphological defects. These results establish that activating substitutions affecting residues Q61-R68 within the switch II region of RAC1 cause a developmental syndrome. Our findings reveal that these variants cause altered downstream signalling, resulting in abnormal neuronal morphology and reveal the WAVE regulatory complex/Arp2/3 pathway as a possible therapeutic target for activating RAC1 variants. These insights also have the potential to inform the mechanism and therapy for other disorders caused by variants in genes encoding other Rho GTPases, their regulators and downstream effectors.
Fetal conditions associated with placental insufficiency and intrauterine growth restriction (IUGR) chronically elevate plasma norepinephrine (NE) concentrations. Our objective was to evaluate the ...effects of chronically elevated NE on insulin-stimulated glucose metabolism in normally grown, non-IUGR fetal sheep, which are independent of other IUGR-related reductions in nutrients and oxygen availability. After surgical placement of catheters, near-term fetuses received either a saline (control) or NE intravenous infusion with controlled euglycemia. In NE fetuses, plasma NE concentrations were 5.5-fold greater than controls, and fetal euglycemia was maintained with a maternal insulin infusion. Insulin secretion was blunted in NE fetuses during an intravenous glucose tolerance test. Weight-specific fluxes for glucose were measured during a euinsulinemic-euglycemic clamp (EEC) and a hyperinsulinemic-euglycemic clamp (HEC). Plasma glucose and insulin concentrations were not different between groups within each clamp, but insulin concentrations increased 10-fold between the EEC and the HEC. During the EEC, rates of glucose uptake (umbilical uptake + exogenous infusion) and glucose utilization were 47% and 35% lower (
< 0.05) in NE fetuses compared with controls. During the HEC, rates of glucose uptake were 28% lower (
< 0.05) in NE fetuses than controls. Glucose production was undetectable in either group, and glucose oxidation was unaffected by the NE infusion. These findings indicate that chronic exposure to high plasma NE concentrations lowers rates of net glucose uptake in the fetus without affecting glucose oxidation rates or initiating endogenous glucose production. Lower fetal glucose uptake was independent of insulin, which indicates insulin resistance as a consequence of chronically elevated NE.
Key points
Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin ...sensitivity.
Although whole‐body glucose clearance is normal, 1‐month‐old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation.
Impaired glucose‐stimulated insulin secretion in IUGR lambs is due to lower intra‐islet insulin availability and not from glucose sensing.
We investigated adrenergic receptor (ADR) β2 desensitization by administering oral ADRβ modifiers for the first month after birth to activate ADRβ2 and antagonize ADRβ1/3. In IUGR lambs ADRβ2 activation increased whole‐body glucose utilization rates and insulin sensitivity but had no effect on isolated islet or myocyte deficiencies.
IUGR establishes risk for developing diabetes. In IUGR lambs we identified disparities in key aspects of glucose‐stimulated insulin secretion and insulin‐stimulated glucose oxidation, providing new insights into potential mechanisms for this risk.
Placental insufficiency causes intrauterine growth restriction (IUGR) and disturbances in glucose homeostasis with associated β adrenergic receptor (ADRβ) desensitization. Our objectives were to measure insulin‐sensitive glucose metabolism in neonatal lambs with IUGR and to determine whether daily treatment with ADRβ2 agonist and ADRβ1/β3 antagonists for 1 month normalizes their glucose metabolism. Growth, glucose‐stimulated insulin secretion (GSIS) and glucose utilization rates (GURs) were measured in control lambs, IUGR lambs and IUGR lambs treated with adrenergic receptor modifiers: clenbuterol atenolol and SR59230A (IUGR‐AR). In IUGR lambs, islet insulin content and GSIS were less than in controls; however, insulin sensitivity and whole‐body GUR were not different from controls. Of importance, ADRβ2 stimulation with β1/β3 inhibition increases both insulin sensitivity and whole‐body glucose utilization in IUGR lambs. In IUGR and IUGR‐AR lambs, hindlimb GURs were greater but fractional glucose oxidation rates and ex vivo skeletal muscle glucose oxidation rates were lower than controls. Glucose transporter 4 (GLUT4) was lower in IUGR and IUGR‐AR skeletal muscle than in controls but GLUT1 was greater in IUGR‐AR. ADRβ2, insulin receptor, glycogen content and citrate synthase activity were similar among groups. In IUGR and IUGR‐AR lambs heart rates were greater, which was independent of cardiac ADRβ1 activation. We conclude that targeted ADRβ2 stimulation improved whole‐body insulin sensitivity but minimally affected defects in GSIS and skeletal muscle glucose oxidation. We show that risk factors for developing diabetes are independent of postnatal catch‐up growth in IUGR lambs as early as 1 month of age and are inherent to the islets and myocytes.
Key points
Previous studies in fetuses with intrauterine growth restriction (IUGR) have shown that adrenergic dysregulation was associated with low insulin concentrations and greater insulin sensitivity.
Although whole‐body glucose clearance is normal, 1‐month‐old lambs with IUGR at birth have higher rates of hindlimb glucose uptake, which may compensate for myocyte deficiencies in glucose oxidation.
Impaired glucose‐stimulated insulin secretion in IUGR lambs is due to lower intra‐islet insulin availability and not from glucose sensing.
We investigated adrenergic receptor (ADR) β2 desensitization by administering oral ADRβ modifiers for the first month after birth to activate ADRβ2 and antagonize ADRβ1/3. In IUGR lambs ADRβ2 activation increased whole‐body glucose utilization rates and insulin sensitivity but had no effect on isolated islet or myocyte deficiencies.
IUGR establishes risk for developing diabetes. In IUGR lambs we identified disparities in key aspects of glucose‐stimulated insulin secretion and insulin‐stimulated glucose oxidation, providing new insights into potential mechanisms for this risk.
Prior studies have shown that parent and adolescent cortisol are associated across days and that this covariation may be adolescent‐driven. This study extends this literature by (a) testing whether ...parents' cognitive interference (i.e., distracting and ruminative thoughts potentially due to worry) mediates the linkages between adolescent and next‐day parent cortisol and (b) whether these linkages were moderated by parent gender or warmth. Daily diary data, including bedtime cortisol, were collected on two samples of employees and their adolescent‐aged children (N = 318 dyads, Myouth age = 13.18 years, 74% mothers). We tested mediation with autoregressive cross‐lagged models. Moderated mediation by parent gender was found in our bedtime cortisol models. Higher adolescent bedtime cortisol levels were associated with higher next‐day levels of mothers' cognitive interference. In turn, higher levels of mothers' cognitive interference were linked to higher mothers' same‐day bedtime cortisol levels. These linkages were not significant for fathers. Cognitive interference did not mediate the associations between child and parent area under the curve or cortisol awakening response. No moderation was evident for parental warmth. Results suggest that mothers' cognitions play a key role in the transmission of elevated bedtime cortisol levels from adolescents to their mothers.
Erythropoietin (EPO) is a hormone that induces red blood cell production. In its recombinant form, EPO is the one of most prescribed drugs to treat anemia, including that arising in cancer patients. ...In randomized trials, EPO administration to cancer patients has been associated with decreased survival. Here, we investigated the impact of EPO modulation on tumorigenesis. Using genetically engineered mouse models of breast cancer, we found that EPO promoted tumorigenesis by activating JAK/STAT signaling in breast tumor-initiating cells (TICs) and promoted TIC self renewal. We determined that EPO was induced by hypoxia in breast cancer cell lines, but not in human mammary epithelial cells. Additionally, we demonstrated that high levels of endogenous EPO gene expression correlated with shortened relapse-free survival and that pharmacologic JAK2 inhibition was synergistic with chemotherapy for tumor growth inhibition in vivo. These data define an active role for endogenous EPO in breast cancer progression and breast TIC self-renewal and reveal a potential application of EPO pathway inhibition in breast cancer therapy.
Chronic pain is a common and costly experience. Cognitive behavioral therapies (CBT) are efficacious for an array of chronic pain conditions. However, the literature is based primarily on urban ...(white) samples. It is unknown whether CBT works in low-socioeconomic status (SES) minority and nonminority groups. To address this question, we conducted a randomized controlled trial within a low-SES, rural chronic pain population. Specifically, we examined the feasibility, tolerability, acceptability, and efficacy of group CBT compared with a group education intervention (EDU). We hypothesized that although both interventions would elicit short- and long-term improvement across pain-related outcomes, the cognitively-focused CBT protocol would uniquely influence pain catastrophizing. Mixed design analyses of variance were conducted on the sample of eligible participants who did not commence treatment (N=26), the intention-to-treat sample (ITT; N=83), and the completer sample (N=61). Factors associated with treatment completion were examined. Results indicated significantly more drop-outs occurred in CBT. ITT analyses showed that participants in both conditions reported significant improvement across pain-related outcomes, and a nonsignificant trend was found for depressed mood to improve more in CBT than EDU. Results of the completer analyses produced a similar pattern of findings; however, CBT produced greater gains on cognitive and affect variables than EDU. Treatment gains were maintained at 6-month follow-up (N=54). Clinical significance of the findings and the number of treatment responders is reported. Overall, these findings indicate that CBT and EDU are viable treatment options in low-SES minority and nonminority groups. Further research should target disseminating and sustaining psychosocial treatment options within underserved populations.
Recent decline of sea ice habitat has coincided with increased use of land by polar bears (Ursus maritimus) from the southern Beaufort Sea (SB), which may alter the risks of exposure to pathogens and ...contaminants. We assayed blood samples from SB polar bears to assess prior exposure to the pathogens Brucella spp., Toxoplasma gondii, Coxiella burnetii, Francisella tularensis, and Neospora caninum, estimate concentrations of persistent organic pollutants (POPs), and evaluate risk factors associated with exposure to pathogens and POPs. We found that seroprevalence of Brucella spp. and T. gondii antibodies likely increased through time, and provide the first evidence of exposure of polar bears to C. burnetii, N. caninum, and F. tularensis. Additionally, the odds of exposure to T. gondii were greater for bears that used land than for bears that remained on the sea ice during summer and fall, while mean concentrations of the POP chlordane (ΣCHL) were lower for land-based bears. Changes in polar bear behavior brought about by climate-induced modifications to the Arctic marine ecosystem may increase exposure risk to certain pathogens and alter contaminant exposure pathways.
Patients with classic hydroa vacciniforme–like lymphoproliferative disorder (HVLPD) typically have high levels of Epstein-Barr virus (EBV) DNA in T cells and/or natural killer (NK) cells in blood and ...skin lesions induced by sun exposure that are infiltrated with EBV-infected lymphocytes. HVLPD is very rare in the United States and Europe but more common in Asia and South America. The disease can progress to a systemic form that may result in fatal lymphoma. We report our 11-year experience with 16 HVLPD patients from the United States and England and found that whites were less likely to develop systemic EBV disease (1/10) than nonwhites (5/6). All (10/10) of the white patients were generally in good health at last follow-up, while two-thirds (4/6) of the nonwhite patients required hematopoietic stem cell transplantation. Nonwhite patients had later age of onset of HVLPD than white patients (median age, 8 vs 5 years) and higher levels of EBV DNA (median, 1 515 000 vs 250 000 copies/ml) and more often had low numbers of NK cells (83% vs 50% of patients) and T-cell clones in the blood (83% vs 30% of patients). RNA-sequencing analysis of an HVLPD skin lesion in a white patient compared with his normal skin showed increased expression of interferon-γ and chemokines that attract T cells and NK cells. Thus, white patients with HVLPD were less likely to have systemic disease with EBV and had a much better prognosis than nonwhite patients. This trial was registered at www.clinicaltrials.gov as #NCT00369421 and #NCT00032513.
•White patients with HVLPD more often had earlier-onset disease, lower EBV DNA, and normal numbers of NK cells in the blood than nonwhites.•White patients with HVLPD were less likely to develop systemic disease or require hematopoietic stem cell transplant than nonwhites.
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