Translational research : the journal of laboratory and clinical medicine
-
Review
Risk Factors for Clonal Hematopoiesis of Indeterminate Potential and Mosaic Chromosomal Alterations.
Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) of the autosomes, X, and Y chromosomes are aging-related somatic mutations detectable in peripheral blood. The presence of these acquired mutations predisposes otherwise healthy adults to increased risk of several chronic aging-related conditions including hematologic cancers, atherosclerotic cardiovascular diseases, other inflammatory conditions, and mortality. While the public health impact and disease associations of these blood-derived somatic mutations continue to expand, the inherited, behavioral/lifestyle, environmental risk factors and comorbid conditions that influence their occurrence and progression have been less well characterized. ⋯ Some loci, such as TERT, ATM, TP53, CHEK2, and TCL1A, have overlapping associations with different types of CHIP, mCAs, and cancer predisposition. Various environmental or co-morbid contexts associated with presence or expansion of specific CHIP or mCA mutations are beginning to be elucidated, such as cigarette smoking, diet, cancer chemotherapy, particulate matter, and premature menopause. Further characterization of the germline genetic and environmental correlates of CHIP/mCAs may inform our ability to modify their progression and ultimately reduce the risk and burden of chronic diseases associated with these clonal somatic phenomena.
-
A second mild traumatic brain injury (mTBI) sustained prior to neuropathological recovery can lead to exacerbated effects. Without objective indicators of this neuropathology, individuals may return to activities at risk of mTBI when their brain is still vulnerable. With axonal injury recognized as a neuropathological hallmark of mTBI, we hypothesized that serum levels of neurofilament light (NfL), a highly sensitive biomarker of axonal injury, may be predictive of vulnerability to worse outcomes in the event of a second mTBI. ⋯ Importantly, this potentiation phenomenon remained even when limiting analyses to rats with longer inter-injury intervals, providing evidence that vulnerability to re-injury may not be exclusively dependent on inter-injury interval. Finally, NfL levels correlated with, and were predictive of, the severity of neurological signs following the second mTBI. These findings provide evidence that measurement of NfL during mTBI recovery may be reflective of the vulnerability to a second mTBI, and as such may have utility to assist return to sport, duty and work decisions.
-
Vertical transmission of Chikungunya virus (CHIKV) has been reported in humans, but the transmission routes have not been completely understood, and experimental animal models are needed to enable detailed investigation of the transmission and pathogenesis of congenital infections. The intertwining of immune response and virus components at the gestation/breastfeeding interfaces between mother and fetus/newborn may have effects during the offspring development. An experimental model of CHIKV was established by infecting pregnant BALB/c female mice that enabled confirmation that dams inoculated up to the 10th gestational day transmit CHIKV transplacentally to approximately 8.4% of the fetuses, resulting in severe teratogenic effects. ⋯ CHIKV RNA and proteins were also detected in breast milk retrieved from the stomachs of recently fed newborns. The experimental results were also complemented by the finding of CHIKV RNA in 6% of colostrum samples from healthy lactating women in a CHIKV-endemic area. Breastfeeding induces immune protection to challenge with CHIKV in mice.
-
While natriuretic peptides (NPs) are primarily known for their renal and cardiovascular actions, NPs stimulate lipolysis in adipocytes and induce a thermogenic program in white adipose tissue (WAT) that resembles brown fat. The biologic effects of NPs are negatively regulated by the NP clearance receptor (NPRC), which binds and degrades NPs. Knockout (KO) of NPRC protects against diet induced obesity and improves insulin sensitivity in obese mice. ⋯ These beneficial effects were accompanied by a decrease in infiltrating macrophages in adipose tissue, and reduced expression of inflammatory markers in both serum and WAT. These data suggest that inhibiting NP clearance may be an effective pharmacologic approach to promote weight loss and enhance insulin sensitivity in type 2 diabetes. Optimizing the therapeutic approach may lead to useful therapies for obesity and type 2 diabetes.
-
Alzheimer's disease (AD) is the most common cause of dementia and is characterized by progressive neurodegeneration and cognitive decline. Understanding the pathophysiology underlying AD is paramount for the management of individuals at risk of and suffering from AD. The vascular hypothesis stipulates a relationship between cardiovascular disease and AD-related changes although the nature of this relationship remains unknown. ⋯ Cerebral small vessel disease such as cerebral amyloid angiopathy, characterized by the aggregation of Aß in the vessel wall, is highly prevalent in vascular dementia and AD patients. Current data is unclear whether cardiovascular disease causes, precipitates, amplifies, precedes, or simply coincides with AD. Targeted imaging tools to quantitatively evaluate the intracranial vasculature and longitudinal studies in individuals at risk for or in the early stages of the AD continuum could be critical in disentangling this complex relationship between vascular disease and AD.