Reduced exposure to daytime sunlight and increased exposure to electrical lighting at night leads to late circadian and sleep timing 1–3. We have previously shown that exposure to a natural summer ...14 hr 40 min:9 hr 20 min light-dark cycle entrains the human circadian clock to solar time, such that the internal biological night begins near sunset and ends near sunrise 1. Here we show that the beginning of the biological night and sleep occur earlier after a week’s exposure to a natural winter 9 hr 20 min:14 hr 40 min light-dark cycle as compared to the modern electrical lighting environment. Further, we find that the human circadian clock is sensitive to seasonal changes in the natural light-dark cycle, showing an expansion of the biological night in winter compared to summer, akin to that seen in non-humans 4–8. We also show that circadian and sleep timing occur earlier after spending a weekend camping in a summer 14 hr 39 min:9 hr 21 min natural light-dark cycle compared to a typical weekend in the modern environment. Weekend exposure to natural light was sufficient to achieve ∼69% of the shift in circadian timing we previously reported after a week’s exposure to natural light 1. These findings provide evidence that the human circadian clock adapts to seasonal changes in the natural light-dark cycle and is timed later in the modern environment in both winter and summer. Further, we demonstrate that earlier circadian timing can be rapidly achieved through natural light exposure during a weekend spent camping.
•Living in the modern electrical lighting environment delays the human circadian clock•The human circadian clock adapts to seasonal changes in the natural light-dark cycle•A weekend camping trip prevented the typical weekend circadian and sleep delay
Late sleep timing is associated with health problems. Stothard et al. show that the human circadian clock is timed later in modern society, especially after the weekend, compared to natural light-dark cycles. Further, the clock responds to seasonal natural light-dark cycle changes and is rapidly shifted earlier by weekend camping.
The importance of uptake transporters in determining drug disposition is increasingly appreciated. While the focus of regulatory agencies worldwide has been on the hepatic organic anion transporting ...polypeptides (OATPs)—1B1 and—1B3, there is another isoform of the OATP sub-family, OATP2B1, which should be considered equally relevant. Unlike the other members of the OATP sub-family, OATP2B1 is expressed in multiple organs in humans, including in the intestine and the liver. Similar to other OATPs, OATP2B1 mediates the hepatic and intestinal uptake of many drugs and endogenous compounds. The importance of OATP2B1 in the disposition of many drugs is highlighted by the growing recognition of its role in significant in vivo drug-drug or food-drug interactions. The dramatic changes in drug exposure attributable to inhibition of OATP2B1 highlight the importance of developing a better understanding of the clinical role of OATP2B1. This review aims to provide a thorough summary of the current understanding of the pharmacogenetics, regulation, expression and abundance of OATP2B1 in humans, as well as its clinical relevance in drug-drug and food-drug interactions.
Objective To estimate the percentage reduction in incidence of dementia that would be obtained if specific risk factors were eliminated.Design Prospective seven year cohort study.Setting General ...population, Montpellier, France.Participants 1433 people aged over 65 with a mean baseline age of 72.5 (SD 5.1) years.Main outcome measures Diagnosis of mild cognitive impairment or dementia established by a standardised neurological examination.Results Cox models were constructed to derive hazard ratios and determine confounding and interaction effects for potentially modifiable risk factors for dementia. Mean percentage population attributable fractions were calculated with 95% confidence intervals derived from bootstrapping for seven year incidence of mild cognitive impairment or dementia. The final model retained crystallised intelligence (population attributable fraction 18.11%, 95% confidence interval 10.91% to 25.42%), depression (10.31%, 3.66% to 17.17%), fruit and vegetable consumption (6.46%, 0.15% to 13.06%), diabetes (4.88%, 1.87% to 7.98%), and apolipoprotein E ε4 allele (7.11%, 2.44% to 11.98%).Conclusions Increasing crystallised intelligence and fruit and vegetable consumption and eliminating depression and diabetes are likely to have the biggest impact on reducing the incidence of dementia, outweighing even the effect of removing the principal known genetic risk factor. Although causal relations cannot be concluded with certainty, the study suggests priorities that may inform public health programmes.
The regulation of the brain-derived neurotrophic factor (BDNF) is important for depression pathophysiology and epigenetic regulation of the BDNF gene may be involved. This study investigated whether ...BDNF methylation is a marker of depression. One thousand and twenty-four participants were recruited as part of a longitudinal study of psychiatric disorders in general population elderly (age ⩾ 65). Clinical levels of depression were assessed using the Mini International Neuropsychiatric Interview for the diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorder IV criteria, and the Centre for Epidemiologic Studies Depression Scale (CES-D) for assessment of moderate to severe depressive symptoms. Buccal DNA methylation at the two most widely studied BDNF promoters, I and IV, was investigated using the Sequenom MassARRAY platform that allows high-throughput investigation of methylation at individual CpG sites within defined genomic regions. In multivariate linear regression analyses adjusted for a range of participant characteristics including antidepressant use, depression at baseline, as well as chronic late-life depression over the 12-year follow-up, were associated with overall higher BDNF methylation levels, with two sites showing significant associations (promoter I, Δ mean = 0.4%, P = 0.0002; promoter IV, Δ mean = 5.4%, P = 0.021). Three single-nucleotide polymorphisms (rs6265, rs7103411 and rs908867) were also found to modify the association between depression and promoter I methylation. As one of the largest epigenetic studies of depression, and the first investigating BDNF methylation in buccal tissue, our findings highlight the potential for buccal BDNF methylation to be a biomarker of depression.
Late-life depression Ritchie, K
European psychiatry,
November 2014, Letnik:
29, Številka:
8
Journal Article
Recenzirano
Late-life depression is highly heterogeneous in clinical presentation, and is also commonly resistant to treatment. While some cases are a continuation of the chronic course of illness beginning in ...early adulthood, a large number of persons will have a first episode of depression in later life following alife-time of relatively good mental health. While incident cases of major depression tend to decrease with age, the number of persons with clinically significant depressive symptomatology rises. À distinction has often been made between early-onset and late-onset depression, however, there is no conclusive evidence to suggest these are distinct clinical entities. On the other hand observations from a fifteen year prospective population study of psychiatric disorder in the elderly (the ESPRIT Study) supports the alternative idea that depression may be divided into sub-types according to postulated aetiology; for example depression with a strong genetic component, related to hormonal changes, the consequence of trauma; the result of cerebrovascular insult. Exposure to these putative causes may be more common at different points in the life span, thus suggesting age-differences. Our research further suggests that even cases of depression appearing for the first time in late-life, may be initially triggered by risk factors occurring decades before. Our findings suggest, for example, that childhood events may lead to changes in the biology of stress management, which continue throughout life, increasing vulnerability to depression and persisting even after effective treatment of symptoms. Together these observations suggest it may be more meaningful to classify depression in the elderly according to probable principle precipitating factors rather than age.
In biology, molecular linkages at, within, and beneath cell interfaces arise mainly from weak noncovalent interactions. These bonds will fail under any level of pulling force if held for sufficient ...time. Thus, when tested with ultrasensitive force probes, we expect cohesive material strength and strength of adhesion at interfaces to be time- and loading rate-dependent properties. To examine what can be learned from measurements of bond strength, we have extended Kramers' theory for reaction kinetics in liquids to bond dissociation under force and tested the predictions by smart Monte Carlo (Brownian dynamics) simulations of bond rupture. By definition, bond strength is the force that produces the most frequent failure in repeated tests of breakage, i.e., the peak in the distribution of rupture forces. As verified by the simulations, theory shows that bond strength progresses through three dynamic regimes of loading rate. First, bond strength emerges at a critical rate of loading (> or = 0) at which spontaneous dissociation is just frequent enough to keep the distribution peak at zero force. In the slow-loading regime immediately above the critical rate, strength grows as a weak power of loading rate and reflects initial coupling of force to the bonding potential. At higher rates, there is crossover to a fast regime in which strength continues to increase as the logarithm of the loading rate over many decades independent of the type of attraction. Finally, at ultrafast loading rates approaching the domain of molecular dynamics simulations, the bonding potential is quickly overwhelmed by the rapidly increasing force, so that only naked frictional drag on the structure remains to retard separation. Hence, to expose the energy landscape that governs bond strength, molecular adhesion forces must be examined over an enormous span of time scales. However, a significant gap exists between the time domain of force measurements in the laboratory and the extremely fast scale of molecular motions. Using results from a simulation of biotin-avidin bonds (Izrailev, S., S. Stepaniants, M. Balsera, Y. Oono, and K. Schulten. 1997. Molecular dynamics study of unbinding of the avidin-biotin complex. Biophys. J., this issue), we describe how Brownian dynamics can help bridge the gap between molecular dynamics and probe tests.
Objective
To determine whether premature menopause (≤40 years) can have long‐lasting effects on later‐life cognition and investigate whether this association varies depending on the type of menopause ...and use of hormone treatment (HT).
Design
Population‐based cohort study.
Setting
The French Three‐City Study.
Population
Four thousand eight hundred and sixty‐eight women aged at least 65 years.
Methods
Multivariable‐adjusted logistic regression models were used to determine the association between age at menopause, type of menopause (surgical, natural), and the use of menopausal HT and later‐life cognitive function.
Main outcome measures
Performance on a cognitive test battery (at baseline and over 7 years) and clinical dementia diagnosis.
Results
Menopause at or before the age of 40 years, both premature bilateral ovariectomy and premature ovarian failure (non‐surgical loss of ovarian function), was associated with worse verbal fluency (OR 1.56, 95%CI 1.12–1.87, P = 0.004) and visual memory (OR 1.39, 95%CI 1.09–1.77, P = 0.007) in later life. HT at the time of premature menopause appeared beneficial for later‐life visual memory but increased the risk of poor verbal fluency. Type of menopause was not significantly associated with cognitive function. Premature menopause was associated with a 30% increased risk of decline in psychomotor speed and global cognitive function over 7 years.
Conclusion
Both premature surgical menopause and premature ovarian failure were associated with long‐term negative effects on cognitive function, which are not entirely offset by menopausal HT. In terms of surgical menopause, these results suggest that the potential long‐term effects on cognitive function should form part of the risk/benefit ratio when considering ovariectomy in younger women.
Scholars of development have learned a great deal about what economic
institutions do, but much less about the origins of such arrangements.
This article introduces and assesses a new political ...explanation for the
origins of “developmental states”—organizational
complexes in which expert and coherent bureaucratic agencies collaborate
with organized private sectors to spur national economic transformation.
Conventional wisdom holds that developmental states in South Korea,
Taiwan, and Singapore result from “state autonomy,” especially
from popular pressures. We argue that these states' impressive
capacities actually emerged from the challenges of delivering side
payments to restive popular sectors under conditions of extreme
geopolitical insecurity and severe resource constraints. Such an
interactive condition of “systemic vulnerability” never
confronted ruling elites in Indonesia, Malaysia, the Philippines, or
Thailand—allowing them to uphold political coalitions, and hence to
retain power, with much less ambitious state-building efforts.Authors listed alphabetically. We are grateful
to the following for helpful comments: Cliff Carrubba, Eric Hershberg,
Dave Kang, Stephan Haggard, Linda Lim, Greg Noble, Kristen Nordhaug, John
Ravenhill, Eric Reinhardt, Dani Reiter, Tom Remington, Michael Ross, Randy
Strahan, Judith Tendler, and two anonymous reviewers. Special thanks to
David Waldner, whose book inspired this article and who graciously
provided important insights.
Regulatory approval documents contain valuable information, often not published, to assess the drug-drug interaction (DDI) profile of newly marketed drugs. This analysis aimed to systematically ...review all drug metabolism, transport, pharmacokinetics, and DDI data available in the new drug applications and biologic license applications approved by the U.S. Food and Drug Administration in 2014, using the University of Washington Drug Interaction Database, and to highlight the significant findings. Among the 30 new drug applications and 11 biologic license applications reviewed, 35 new molecular entities (NMEs) were well characterized with regard to drug metabolism, transport, and/or organ impairment and were fully analyzed in this review. In vitro, a majority of the NMEs were found to be substrates or inhibitors/inducers of at least one drug metabolizing enzyme or transporter. In vivo, when NMEs were considered as victim drugs, 16 NMEs had at least one in vivo DDI study with a clinically significant change in exposure (area under the time-plasma concentration curve or Cmax ratio ≥2 or ≤0.5), with 6 NMEs shown to be sensitive substrates of cytochrome P450 enzymes (area under the time-plasma concentration curve ratio ≥5 when coadministered with potent inhibitors): paritaprevir and naloxegol (CYP3A), eliglustat (CYP2D6), dasabuvir (CYP2C8), and tasimelteon and pirfenidone (CYP1A2). As perpetrators, seven NMEs showed clinically significant inhibition involving both enzymes and transporters, although no clinically significant induction was observed. Physiologically based pharmacokinetic modeling and pharmacogenetics studies were used for six and four NMEs, respectively, to optimize dosing recommendations in special populations and/or multiple impairment situations. In addition, the pharmacokinetic evaluations in patients with hepatic or renal impairment provided useful quantitative information to support drug administration in these fragile populations.
PDF
