Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to ...decreases in tissue function and regenerative capacity
. Changes to DNA methylation patterns over time form the basis of ageing clocks
, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity
. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.
Recent global warming is acting across marine, freshwater, and terrestrial ecosystems to favor species adapted to warmer conditions and/or reduce the abundance of cold-adapted organisms (i.e., ...“thermophilization” of communities). Lack of community responses to increased temperature, however, has also been reported for several taxa and regions, suggesting that “climatic lags” may be frequent. Here we show that microclimatic effects brought about by forest canopy closure can buffer biotic responses to macroclimate warming, thus explaining an apparent climatic lag. Using data from 1,409 vegetation plots in European and North American temperate forests, each surveyed at least twice over an interval of 12–67 y, we document significant thermophilization of ground-layer plant communities. These changes reflect concurrent declines in species adapted to cooler conditions and increases in species adapted to warmer conditions. However, thermophilization, particularly the increase of warm-adapted species, is attenuated in forests whose canopies have become denser, probably reflecting cooler growing-season ground temperatures via increased shading. As standing stocks of trees have increased in many temperate forests in recent decades, local microclimatic effects may commonly be moderating the impacts of macroclimate warming on forest understories. Conversely, increases in harvesting woody biomass—e.g., for bioenergy—may open forest canopies and accelerate thermophilization of temperate forest biodiversity.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained incapacitating illness that may affect up to 4 million people in the United States alone. There are no validated ...laboratory tests for diagnosis or management despite global efforts to find biomarkers of disease. We considered the possibility that inability to identify such biomarkers reflected variations in diagnostic criteria and laboratory methods as well as the timing of sample collection during the course of the illness. Accordingly, we leveraged two large, multicenter cohort studies of ME/CFS to assess the relationship of immune signatures with diagnosis, illness duration, and other clinical variables. Controls were frequency-matched on key variables known to affect immune status, including season of sampling and geographic site, in addition to age and sex. We report here distinct alterations in plasma immune signatures early in the course of ME/CFS (
= 52) relative to healthy controls (
= 348) that are not present in subjects with longer duration of illness (
= 246). Analyses based on disease duration revealed that early ME/CFS cases had a prominent activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks. We found a stronger correlation of cytokine alterations with illness duration than with measures of illness severity, suggesting that the immunopathology of ME/CFS is not static. These findings have critical implications for discovery of interventional strategies and early diagnosis of ME/CFS.
Diabetes mellitus type 1 and type 2 are diseases characterized by impaired regulation of blood glucose due to decreased insulin production and insulin resistance, respectively. Management of diabetes ...mellitus often requires injection of exogenous insulin. Continuous subcutaneous insulin infusion (CSII or insulin pump) is a diabetes treatment modality utilizing a device to aid in regulation of glycemic control. Malfunctions in device components can have rare fatal consequences. Described in this report are six fatalities due to one such malfunction, the failure of plastic cannulas of CSII devices to penetrate the skin and deliver insulin, resulting in fatal diabetic ketoacidosis (DKA). The cases derive from four different death investigation systems. For each case, scene and autopsy findings are presented, as well as selected toxicology and histology findings. These cases illustrate the importance of careful examination of CSII devices in death investigations and introduce a discussion on discrepant manner of death classifications.
False killer whales (Pseudorca crassidens) are large delphinids typically found in deep water far offshore. However, in the Hawaiian Archipelago, there are 2 resident island-associated populations of ...false killer whales, one in the waters around the main Hawaiian Islands (MHI) and one in the waters around the Northwestern Hawaiian Islands (NWHI). We use mitochondrial DNA (mtDNA) control region sequences and genotypes from 16 nuclear DNA (nucDNA) microsatellite loci from 206 individuals to examine levels of differentiation among the 2 island-associated populations and offshore animals from the central and eastern North Pacific. Both mtDNA and nucDNA exhibit highly significant differentiation between populations, confirming limited gene flow in both sexes. The mtDNA haplotypes exhibit a strong pattern of phylogeographic concordance, with island-associated populations sharing 3 closely related haplotypes not found elsewhere in the Pacific. However, nucDNA data suggest that NWHI animals are at least as differentiated from MHI animals as they are from offshore animals. The patterns of differentiation revealed by the 2 marker types suggest that the island-associated false killer whale populations likely share a common colonization history, but have limited contemporary gene flow.
Fentanyl induces pharmacological effects and abuse liability comparable to other prescription opioids and heroin. A surge in fentanyl-related fatalities has been periodically reported throughout the ...USA. The University of Florida Forensic Toxicology Laboratory observed a significant increase in fentanyl-related deaths starting in mid-2014. The present report evaluated toxicological findings, demographics of the decedents and circumstances of death in the postmortem cases that were submitted to the laboratory for toxicological analysis from July 2014 to January 2015 and that were tested for fentanyl in biological specimens. The cases originated from 6 of the 24 Florida Medical Examiner Districts, with the majority from District 12 (Desoto, Manatee and Sarasota counties). The specimens were analyzed for fentanyl by gas chromatography–mass spectrometry; the limit of detection (LOD) was 0.62 ng/mL and the limit of quantification (LOQ) was 2.5 ng/mL. During the 7-month period, the laboratory tested 143 postmortem cases for fentanyl and 50% had quantifiable fentanyl in postmortem blood. Fentanyl concentrations ranged from 2.5 to 68 ng/mL (n = 66; median: 9.8 ng/mL); six cases were positive for fentanyl >LOD but <LOQ. The majority of the cases (85%) had indications of possible drug abuse with heroin use being the most often suspected. Concurrent detection of 6-acetylmorphine, morphine and cocaine along with other opioids and benzodiazepines was common. Of the 59 deaths from District 12, the cause of death was accidental drug intoxication with fentanyl as a sole or contributing factor for 57 cases (two non-drug intoxication deaths). The median age of the 57 decedents was 35 (range: 19–63) years. Males represented 87% of the deaths and 96% were Whites. Most of the decedents (n = 53) had no prescription for fentanyl. Considering fentanyl's high potency and abuse liability, the recent rise in fentanyl-related deaths is a serious public health concern and signifies the urgent need to establish prevention and treatment efforts.
Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase,
and the binding of angiogenic growth factors to heparan sulfate. ...This agent showed potent inhibition of placental blood vessel
angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study.
Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive
days bimonthly (part 1) or weekly (part 2).
Results: Forty-two patients median age, 53 years (range, 19-78 years); median performance status, 1 with a range of advanced solid
tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia
and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin
time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient
variability was moderate. Both AUC and C max correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point
can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth
factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was
maintained for >50 months, and 9 patients had stable disease for ≥6 months.
Conclusion: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well
tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.
This report describes seven deaths caused by angioedema of the tongue related to angiotensin converting enzyme (ACE) inhibitors. These seven cases were received in our office between 1998 and 2000. ...In that time frame we performed approximately 2000 autopsies. The cases involved African-American men and women, aged 51 to 65 years, all of whom had been prescribed an ACE inhibitor for the treatment of hypertensive heart disease. In each case, the external examination revealed markedly swollen tongues. The autopsies confirmed massive tongue swelling due to angioedema, and some patients also had swelling of the lips, pharynx, and larynx. Toxicologic analyses on postmortem blood samples were negative for ethanol and drugs of abuse. Although oral and pharyngeal swelling related to angioedema is well known in the clinical literature, its fatal potential has rarely been described.
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