Abstract
Background
Screening options for pancreatic ductal adenocarcinoma (PDAC) are limited. New-onset type 2 diabetes (NoD) is associated with subsequent diagnosis of PDAC in observational studies ...and may afford an opportunity for PDAC screening. We evaluated this association using a large administrative database.
Methods
Patients were identified using claims data from the OptumLabs® Data Warehouse. Adult patients with NoD diagnosis were matched 1:3 with patients without NoD using age, sex and chronic obstructive pulmonary disease (COPD) status. The event of PDAC diagnosis was compared between cohorts using the Kaplan–Meier method. Factors associated with PDAC diagnosis were evaluated with Cox’s proportional hazards modeling.
Results
We identified 640 421 patients with NoD and included 1 921 263 controls. At 3 years, significantly more PDAC events were identified in the NoD group vs control group (579 vs 505; P < 0.001). When controlling for patient factors, NoD was significantly associated with elevated risk of PDAC (HR 3.474, 95% CI 3.082–3.920, P < 0.001). Other factors significantly associated with PDAC diagnosis were increasing age, increasing age among Black patients, and COPD diagnosis (P ≤ 0.05).
Conclusions
NoD was independently associated with subsequent diagnosis of PDAC within 3 years. Future studies should evaluate the feasibility and benefit of PDAC screening in patients with NoD.
In First Amendment jurisprudence, the Supreme Court has employed two doctrines-state action and government speech-to demarcate the boundaries between the public and private spheres. Under the ...state-action doctrine, a plaintiff claiming a free-speech infringement must show some state action in order to trigger constitutional protection; the constraints of the First Amendment apply not to private persons but to the government. But when the government itself speaks, it is not constrained by the Free Speech Clause, and it need not represent all viewpoints equally. The government-speech doctrine is a defense the government raises when it is accused of violating an individual's freedom of speech or of viewpoint discrimination.
The cross talk between adipose tissue and the heart has an increasing importance for cardiac function under physiological and pathological conditions. This study characterizes the role of fat body ...lipolysis for cardiac function in Drosophila melanogaster. Perturbation of the function of the key lipolytic enzyme, brummer (bmm), an ortholog of the mammalian ATGL (adipose triglyceride lipase) exclusively in the fly's fat body, protected the heart against starvation-induced dysfunction. We further provide evidence that this protection is caused by the preservation of glycerolipid stores, resulting in a starvation-resistant maintenance of energy supply and adequate cardiac ATP synthesis. Finally, we suggest that alterations of lipolysis are tightly coupled to lipogenic processes, participating in the preservation of lipid energy substrates during starvation. Thus, we identified the inhibition of adipose tissue lipolysis and subsequent energy preservation as a protective mechanism against cardiac dysfunction during catabolic stress.
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•A cross talk between fat body and the heart regulates cardiac function in Drosophila•Knockdown of fat-body brummer lipase prevents starvation-induced cardiac dysfunction•This involves preservation of lipid stores and maintenance of cardiac energy supply•Brummer-mediated preservation of fat body lipid stores involves lipolysis and lipogenesis
Molecular Physiology; Lipidomics; Metabolomics
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•TPO inhibitors MMI and amitrole elicit similar disruptions of the thyroid hormone system.•MMI and amitrole perturb thyroid hormone dependent rat brain development via TPO ...inhibition.•MMI and amitrole reduce expression of thyroid hormone-sensitive genes in cerebral cortex.•MMI and amitrole alter motor activity of perinatally exposed rat offspring.
Disruption of the thyroid hormone system during development can impair brain development and cause irreversible damage. Some thyroid hormone system disruptors act by inhibiting the thyroperoxidase (TPO) enzyme, which is key to thyroid hormone synthesis. For the potent TPO-inhibiting drug propylthiouracil (PTU) this has been shown to result in thyroid hormone system disruption and altered brain development in animal studies. However, an outstanding question is which chemicals beside PTU can cause similar effects on brain development and to what degree thyroid hormone insufficiency must be induced to be able to measure adverse effects in rats and their offspring. To start answering these questions, we performed a perinatal exposure study in pregnant rats with two TPO-inhibitors: the drug methimazole (MMI) and the triazole herbicide amitrole. The study involved maternal exposure from gestational day 7 through to postnatal day 22, to MMI (8 and 16 mg/kg body weight/day) or amitrole (25 and 50 mg/kg body weight/day). Both MMI and amitrole reduced serum T4 concentrations in a dose-dependent manner in dams and offspring, with a strong activation of the hypothalamic-pituitary-thyroid axis. This reduction in serum T4 led to decreased thyroid hormone-mediated gene expression in the offspring’s brains and caused adverse effects on brain function, seen as hyperactivity and decreased habituation in preweaning pups. These dose-dependent effects induced by MMI and amitrole are largely the same as those observed with PTU. This demonstrates that potent TPO-inhibitors can induce effects on brain development in rats and that these effects are driven by T4 deficiency. This knowledge will aid the identification of TPO-inhibiting thyroid hormone system disruptors in a regulatory context and can serve as a starting point in search of more sensitive markers of developmental thyroid hormone system disruption.
To investigate the influence of the solid/gas density ratio
ρ
S/
ρ
F on the flow pattern in a riser reactor, a pressurized circulating fluidized bed with an inner diameter of 0.194 m and 9 m height ...was used. The experiments have been carried out from ambient conditions to a static pressure
p
abs of 5 MPa in the regime of fast fluidization and/or pneumatic conveying. With the use of glass beads (
ρ
S
=
2500 kg/m
3,
d
P
=
85 μm), density ratios
ρ
S/
ρ
F from 2094 to 41 and solids net fluxes
G
S,Net from 65 to 200 kg/m
2s (
U
G
=
0.8 to 4.5 m/s) were found. Local information about solids concentrations, solids velocities, and solids mass flows has been obtained by a capacitance probe system.
The results show a more uniform axial and radial solids distribution with increasing pressure
p
abs or decreasing density ratios
ρ
S/
ρ
F, indicating flow conditions which are different to a well known core-annulus flow structure. This flow structure is defined by a dilute upflow in the core region and a dense downflow in the annulus region which is situated immediately near the wall. In agreement, the radial profiles of axial solids mass flux show flow patterns which are untypical for fast fluidization operating conditions. The results depict a distinct wall region that covers almost half of the riser cross-sectional area. Therefore, significant solids downflow occur, pointing out massive solids backmixing even at low solid/gas density ratios
ρ
S/
ρ
F.
Finally, the obtained information is used to develop an easy correlation for the prediction of internal solids reflux in a riser reactor as a function of solids/gas density ratios
ρ
S/
ρ
F and the dimensionless superficial gas velocity
Fr
P.
The thyroperoxidase (TPO) enzyme is expressed by the thyroid follicular cells and is required for thyroid hormone synthesis. In turn, thyroid hormones are essential for brain development, thus ...inhibition of TPO in early life can have life-long consequences for brain function. If environmental chemicals with the capacity to inhibit TPO in vitro can also alter brain development in vivo through thyroid hormone dependent mechanisms, however, remains unknown. In this study we show that the in vitro TPO inhibiting pesticide amitrole alters neuronal migration and induces periventricular heterotopia; a thyroid hormone dependent brain malformation. Perinatal exposure to amitrole reduced pup serum thyroxine (T4) concentrations to less than 50% of control animals and this insufficiency led to heterotopia formation in the 16-day old pup’s brain. Two other in vitro TPO inhibitors, 2-mercaptobenzimidazole and cyanamide, caused reproductive toxicity and had only minor sporadic effects on the thyroid hormone system; consequently, they did not cause heterotopia. This is the first demonstration of an environmental chemical causing heterotopia, a brain malformation until now only reported for rodent studies with the anti-thyroid drugs propylthiouracil and methimazole. Our results highlight that certain TPO-inhibiting environmental chemicals can alter brain development through thyroid hormone dependent mechanisms. Improved understanding of the effects on the brain as well as the conditions under which chemicals can perturb brain development will be key to protect human health.
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•The pesticide amitrole causes heterotopia in brains of perinatally exposed rat pups.•First finding of thyroid hormone dependent heterotopia by environmental chemical.•Environmental chemicals with thyroperoxidase inhibitory potential can induce heterotopia.•MBI and cyanamide cause reproductive toxicity at doses below those associated with thyroid effects.
The in vitro TPO inhibiting pesticide amitrole disrupts the thyroid hormone system and causes heterotopia in brains of perinatally exposed rat pups.
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