Molecular probes for selective staining and imaging of protein aggregates, such as amyloid, are important to advance our understanding of the molecular mechanisms underlying protein misfolding ...diseases and also for obtaining an early and accurate clinical diagnosis of these disorders. Since normal immunohistochemical reagents, such as antibodies have shown limitation for identifying protein aggregates both in vitro and in vivo, small organic probes have been utilized as amyloid specific markers. In this review, past and recent molecular scaffolds that have been utilized for the development of small organic amyloid imaging agents are discussed.
An increase in peripheral vascular resistance at rest is not routinely observed in healthy older persons, but often associated with increased stiffness of central elastic arteries, as hallmarks of ...aging effects on the vasculature, referred to as early vascular aging (EVA). In clinical practice, the increased arterial stiffness translates into increased brachial and central systolic blood pressure and corresponding pulse pressure in subjects above 50 years of age, as well as increased carotid-femoral pulse wave velocity (c-f PWV), a marker of arterial stiffness. A c-f PWV value ≥ 10 m/s is currently defined as a threshold for increased cardiovascular risk, based on consensus statement from 2012. Prevention and treatment strategies include a healthy lifestyle and the control of risk factors via appropriate drug therapy to achieve vascular protection related to EVA. New drugs are under development for vascular protection, for example the selective Angiotensin II (AT2) receptor agonist called compound 21. One target group for early intervention could be members of risk families including subjects with early onset cardiovascular disease.
Environmental lead exposure has been associated with decreased kidney function, but evidence from large prospective cohort studies examining low exposure levels is scarce. We assessed the association ...of low levels of lead exposure with kidney function and kidney disease.
Prospective population-based cohort.
4,341 individuals aged 46 to 67 years enrolled into the Malmö Diet and Cancer Study-Cardiovascular Cohort (1991-1994) and 2,567 individuals subsequently followed up (2007-2012).
Blood lead concentrations in quartiles (Q1-Q4) at baseline.
Change in estimated glomerular filtration rate (eGFR) between the baseline and follow-up visit based on serum creatinine level alone or in combination with cystatin C level. Chronic kidney disease (CKD) incidence (185 cases) through 2013 detected using a national registry.
Multivariable-adjusted linear regression models to assess associations between lead levels and eGFRs at baseline and follow-up and change in eGFRs over time. Cox regression was used to examine associations between lead levels and CKD incidence. Validation of 100 randomly selected CKD cases showed very good agreement between registry data and medical records and laboratory data.
At baseline, 60% of study participants were women, mean age was 57 years, and median lead level was 25 (range, 1.5-258) μg/L. After a mean of 16 years of follow-up, eGFR decreased on average by 6mL/min/1.73m2 (based on creatinine) and 24mL/min/1.73m2 (based on a combined creatinine and cystatin C equation). eGFR change was higher in Q3 and Q4 of blood lead levels compared with Q1 (P for trend = 0.001). The HR for incident CKD in Q4 was 1.49 (95% CI, 1.07-2.08) compared with Q1 to Q3 combined.
Lead level measured only at baseline, moderate number of CKD cases, potential unmeasured confounding.
Low-level lead exposure was associated with decreased kidney function and incident CKD. Our findings suggest lead nephrotoxicity even at low levels of exposure.
The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to ...neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.
Abstract
We propose combining population-based register data with a nested clinical cohort to correct misclassification and unmeasured confounding through probabilistic quantification of bias. We ...have illustrated this approach by estimating the association between knee osteoarthritis and mortality. We used the Swedish Population Register to include all persons resident in the Skåne region in 2008 and assessed whether they had osteoarthritis using data from the Skåne Healthcare Register. We studied mortality through year 2017 by estimating hazard ratios. We used data from the Malmö Osteoarthritis Study (MOA), a small cohort study from Skåne, to derive bias parameters for probabilistic quantification of bias, to correct the hazard ratio estimate for differential misclassification of the knee osteoarthritis diagnosis and confounding from unmeasured obesity. We included 292,000 persons in the Skåne population and 1,419 from the MOA study. The adjusted association of knee osteoarthritis with all-cause mortality in the MOA sample had a hazard ratio of 1.10 (95% confidence interval (CI): 0.80, 1.52) and was thus inconclusive. The naive association in the Skåne population had a hazard ratio of 0.95 (95% CI: 0.93, 0.98), while the bias-corrected estimate was 1.02 (95% CI: 0.59, 1.52), suggesting high uncertainty in bias correction. Combining population-based register data with clinical cohorts provides more information than using either data source separately.
Early vascular ageing is common in patients with hypertension and increased burden of cardiovascular risk factors, often influenced by chronic inflammation. One aspect of this vascular ageing is ...arterial stiffening, as measured by increased pulse wave velocity or augmentation index and central pressure. Several studies have indicated that this process starts early in life and that arterial function and ageing properties could be programmed during foetal life or influenced by adverse growth patterns in early postnatal life. This could explain the repeated findings in observational epidemiology that an inverse association exists between birth weight, adjusted for gestational age, and systolic blood pressure elevation in childhood, adolescence and adulthood, as well as for increased cardiovascular risk. One new marker of increased pulse pressure and arterial ageing is telomere length, as regulated by telomerase enzymatic activity. Future studies will hopefully shed light on the possibilities to halt or even reverse vascular ageing, and thereby also influence telomere biology and its different expressions.
Several physicians have been nominated for the Nobel Prize in literature, but so far none of them have received it. Because physicians as women and men of letters have been a major topic of ...feuilletons, seminars and books for many years, questions arise to what extent medicine was a topic in the proposals for the Nobel Prize and in the Nobel jury evaluations: how were the nominees enacted (or not) as physicians, and why were none of them awarded? Drawing on nomination letters and evaluations by the Nobel committee for literature collected in the archive of the Swedish Academy in Stockholm, this article offers a first overview of nominated physician-author candidates. The focus is on the Austrian historian of medicine Max Neuburger (1868-1955), the German novelist Hans Carossa (1878-1956), and the German poet Gottfried Benn (1886-1956), but it also briefly takes further physician-author nominees into account such as Sigmund Freud (1856-1939) and William Somerset Maugham (1874-1965). The article is part of an interdisciplinary medical humanities project that analyses nominations and committee reports for physicians and natural scientists nominated for the Nobel Prize from 1901 to 1970.
The early life programming of adult health and disease (Developmental Origins of Adult Health and Disease; DOHaD) concept has attracted increased attention during recent years. In this review ...evidence is presented for epidemiological associations between early life factors (birth weight, prematurity) and cardiometabolic traits and risk of disease in adult life. Even if not all studies concur, the evidence in general is supporting such links. This could be due to either nature or nurture. There is evidence to state that genetic markers influencing birth weight could also be of importance for offspring hypertension or risk of coronary heart disease, this supporting the nature argument. On the other hand, several studies, both historical and experimental, have found that the change of maternal dietary intake or famine in pregnancy may cause permanent changes in offspring body composition as well as in hemodynamic regulation. Taken together, this also supports the strategy of preventive maternal and child health care, starting already during the preconception period, for lowering the risk of adult cardiometabolic disease in the affected offspring. Further studies are needed to better understand the mediating mechanisms, for example concerning arterial function, hemodynamic regulation, renal function, and neuroendocrine influences, related to the development of early vascular aging (EVA) and cardiovascular disease manifestations.
Recent studies highlight phosphorylated tau (p-tau) at threonine tau 217 (p-tau217) as a new promising plasma biomarker for pathological changes implicated in Alzheimer's disease (AD), but the ...specific brain pathological events related to the alteration in p-tau217 plasma levels are still largely unknown. Using immunostaining techniques of postmortem AD brain tissue, we show that p-tau217 is found in neurofibrillary tangles (NFTs) and neuropil threads that are also positive for p-tau181, 202, 202/205, 231, and 369/404. The p-tau217, but not the other five p-tau variants, was also prominently seen in vesicles structure positive for markers of granulovacuolar degeneration bodies and multi-vesicular bodies. Further, individuals with a high likelihood of AD showed significantly higher p-tau217 area fraction in 4 different brain areas (entorhinal cortex, inferior temporal gyrus, and superior frontal gyrus) compared to those with Primary age related tauopathy or other non-AD tauopathies. The p-tau217 area fraction correlated strongly with total amyloid-beta (Aβ) and NFT brain load when the whole group was analyzed. Finally, the mean p-tau217 area fraction correlated significantly with p-tau217 concentrations in antemortem collected plasma specifically in individuals with amyloid plaques and not in those without amyloid plaques. These studies highlight differences in cellular localization of different p-tau variants and suggest that plasma levels of p-tau217 reflect an accumulation of p-tau217 in presence of Aβ plaque load.
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