Data on the association between subclinical thyroid dysfunction and coronary heart disease (CHD) and mortality are conflicting.
To summarize prospective evidence about the relationship between ...subclinical thyroid dysfunction and CHD and mortality.
MEDLINE (1950 to January 2008) without language restrictions and reference lists of retrieved articles were searched.
Two reviewers screened and selected cohort studies that measured thyroid function and then followed persons prospectively to assess CHD or mortality.
By using a standardized protocol and forms, 2 reviewers independently abstracted and assessed studies.
Ten of 12 identified studies involved population-based cohorts that included 14 449 participants. All 10 population-based cohort studies examined risks associated with subclinical hypothyroidism (2134 CHD events and 2822 deaths), whereas only 5 examined risks associated with subclinical hyperthyroidism (1392 CHD events and 1993 deaths). In a random-effects model, the relative risk (RR) for subclinical hypothyroidism for CHD was 1.20 (95% CI, 0.97 to 1.49; P for heterogeneity = 0.14; I(2 )= 33.4%). Risk estimates were lower when higher-quality studies were pooled (RR, 1.02 to 1.08) and were higher among participants younger than 65 years (RR, 1.51 CI, 1.09 to 2.09 for studies with mean participant age <65 years and 1.05 CI, 0.90 to 1.22 for studies with mean participant age > or =65 years). The RR was 1.18 (CI, 0.98 to 1.42) for cardiovascular mortality and 1.12 (CI, 0.99 to 1.26) for total mortality. For subclinical hyperthyroidism, the RR was 1.21 (CI, 0.88 to 1.68) for CHD, 1.19 (CI, 0.81 to 1.76) for cardiovascular mortality, and 1.12 (CI, 0.89 to 1.42) for total mortality (P for heterogeneity >0.50; I(2 )= 0% for all studies).
Individual studies adjusted for different potential confounders, and 1 study provided only unadjusted data. Publication bias or selective reporting of outcomes could not be excluded.
Subclinical hypothyroidism and hyperthyroidism may be associated with a modest increased risk for CHD and mortality, with lower risk estimates when pooling higher-quality studies and larger CIs for subclinical hyperthyroidism.
Patients with mutations in AICDA, which encodes activation-induced cytidine deaminase (AID), display an impaired peripheral B cell tolerance. AID mediates class-switch recombination (CSR) and somatic ...hypermutation (SHM) in B cells, but the mechanism by which AID prevents the accumulation of autoreactive B cells in blood is unclear. Here, we analyzed B cell tolerance in AID-deficient patients, patients with autosomal dominant AID mutations (AD-AID), asymptomatic AICDA heterozygotes (AID+/-), and patients with uracil N-glycosylase (UNG) deficiency, which impairs CSR but not SHM. The low frequency of autoreactive mature naive B cells in UNG-deficient patients resembled that of healthy subjects, revealing that impaired CSR does not interfere with the peripheral B cell tolerance checkpoint. In contrast, we observed decreased frequencies of SHM in memory B cells from AD-AID patients and AID+/- subjects, who were unable to prevent the accumulation of autoreactive mature naive B cells. In addition, the individuals with AICDA mutations, but not UNG-deficient patients, displayed Tregs with defective suppressive capacity that correlated with increases in circulating T follicular helper cells and enhanced cytokine production. We conclude that SHM, but not CSR, regulates peripheral B cell tolerance through the production of mutated antibodies that clear antigens and prevent sustained interleukin secretions that interfere with Treg function.
Activation-induced cytidine deaminase (AID), the enzyme-mediating class-switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing ...autoreactive B cells. How AID mediates central B cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID+ immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B cell intrinsic AID expression mediates central B cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells.
•AID is co-expressed with RAG2 in some bone marrow immature B cells•Most AID+ immature B cells also co-expressed BCL6 like germinal center B cells•AID+ immature B cells lack anti-apoptotic MCL-1 and are deleted by apoptosis•B cell intrinsic AID expression mediates central B cell tolerance
AID is the enzyme-mediating class-switch recombination and somatic hypermutation. Meffre and colleagues demonstrate that AID inhibition in developing B cells resulted in a failure to remove autoreactive clones. Hence, B cell-intrinsic AID expression mediates central B cell tolerance potentially through RAG-coupled genotoxic activity in self-reactive immature B cells.
In Bone Tissue Engineering (BTE), autologous bone-regenerative cells are combined with a scaffold for large bone defect treatment (LBDT). Microporous, polylactic acid (PLA) scaffolds showed good ...healing results in small animals. However, transfer to large animal models is not easily achieved simply by upscaling the design. Increasing diffusion distances have a negative impact on cell survival and nutrition supply, leading to cell death and ultimately implant failure. Here, a novel scaffold architecture was designed to meet all requirements for an advanced bone substitute. Biofunctional, porous subunits in a load-bearing, compression-resistant frame structure characterize this approach. An open, macro- and microporous internal architecture (100 µm-2 mm pores) optimizes conditions for oxygen and nutrient supply to the implant's inner areas by diffusion. A prototype was 3D-printed applying Fused Filament Fabrication using PLA. After incubation with Saos-2 (Sarcoma osteogenic) cells for 14 days, cell morphology, cell distribution, cell survival (fluorescence microscopy and LDH-based cytotoxicity assay), metabolic activity (MTT test), and osteogenic gene expression were determined. The adherent cells showed colonization properties, proliferation potential, and osteogenic differentiation. The innovative design, with its porous structure, is a promising matrix for cell settlement and proliferation. The modular design allows easy upscaling and offers a solution for LBDT.
Plasmonic complementary structures are interesting model systems that combine propagating and localized surface plasmon resonances and allow the fundamental study of their hybridization. In the ...simplest form, such structures are formed by stacking arrays of nanodisks and nanoholes with matching dimensions. Here, we produce such hole-disk arrays in an experimentally easy and parallel colloidal lithography process with accurate control over vertical alignment and separation between the individual disks and holes. Importantly, our process readily enables symmetry breaking and the design of asymmetric hole-disk arrays with controlled lateral offset between each hole-disk pair. We investigate the coupling between the parental resonances of the two elements as a function of feature size and separation distance and provide a plasmon hybridization scheme to rationalize the resonances. We find that for the asymmetric hole-disk structure, a new, hybrid resonance arises as a peak in the transmission spectra, which is not found in their symmetric analogues. We demonstrate that this new resonance imparts a higher sensitivity in refractive index sensing as it features a pronounced near-field enhancement in between holes and disks. The near-field structure, paired with the accessibility of this separation region in the presented hole-disk structures, implies that this architecture should be sensitive to local changes in the refractive index at the surface of the dielectric layer separating the plasmonic elements. We demonstrate this sensitivity of the asymmetric hole-disk arrays by the detection of the binding of a silane monolayer at the walls of the dielectric silica spacer layer.
Current guidelines recommend that clinical surveillance for patients with moderate aortic stenosis (AS) and aortic valve replacement (AVR) may be considered if there is an indication for coronary ...revascularization. Recent observational studies, however, have shown that moderate AS is associated with an increased risk of cardiovascular events and mortality. Whether the increased risk of adverse events is caused by associated comorbidities, or to the underlying moderate AS itself, is incompletely understood. Similarly, which patients with moderate AS need close follow-up or could potentially benefit from early AVR is also unknown. In this review, the authors provide a comprehensive overview of the current published reports on moderate AS. They first provide an algorithm that helps to diagnose moderate AS correctly, especially when discordant grading is observed. Although the traditional focus of AS assessment has been on the valve, it is increasingly acknowledged that AS is not only a disease of the aortic valve but also of the ventricle. The authors therefore discuss how multimodality imaging can help to evaluate the left ventricular remodeling response and improve risk stratification in patients with moderate AS. Finally, they summarize current evidence on the management of moderate AS and highlight ongoing trials on AVR in moderate AS.
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•Moderate AS is associated with a high risk of adverse cardiovascular events, including death.•DSE and cardiac CT can help to improve an accurate diagnosis of moderate AS.•Multimodality imaging can help to evaluate the left ventricular remodeling response caused by the underlying moderate AS.•Randomized controlled trials are ongoing to evaluate whether AVR can improve outcomes in patients with moderate AS.
Holocene glacier fluctuations Solomina, Olga N.; Bradley, Raymond S.; Hodgson, Dominic A. ...
Quaternary science reviews,
03/2015, Letnik:
111
Journal Article
Recenzirano
Odprti dostop
A global overview of glacier advances and retreats (grouped by regions and by millennia) for the Holocene is compiled from previous studies. The reconstructions of glacier fluctuations are based on ...1) mapping and dating moraines defined by 14C, TCN, OSL, lichenometry and tree rings (discontinuous records/time series), and 2) sediments from proglacial lakes and speleothems (continuous records/time series). Using 189 continuous and discontinuous time series, the long-term trends and centennial fluctuations of glaciers were compared to trends in the recession of Northern and mountain tree lines, and with orbital, solar and volcanic studies to examine the likely forcing factors that drove the changes recorded. A general trend of increasing glacier size from the early–mid Holocene, to the late Holocene in the extra-tropical areas of the Northern Hemisphere (NH) is related to overall summer temperature, forced by orbitally-controlled insolation. The glaciers in New Zealand and in the tropical Andes also appear to follow the orbital trend, i.e., they were decreasing from the early Holocene to the present. In contrast, glacier fluctuations in some monsoonal areas of Asia and southern South America generally did not follow the orbital trends, but fluctuated at a higher frequency possibly triggered by distinct teleconnections patterns. During the Neoglacial, advances clustered at 4.4–4.2ka, 3.8–3.4ka, 3.3–2.8ka, 2.6ka, 2.3–2.1ka, 1.5–1.4ka, 1.2–1.0ka, 0.7–0.5ka, corresponding to general cooling periods in the North Atlantic. Some of these episodes coincide with multidecadal periods of low solar activity, but it is unclear what mechanism might link small changes in irradiance to widespread glacier fluctuations. Explosive volcanism may have played a role in some periods of glacier advances, such as around 1.7–1.6ka (coinciding with the Taupo volcanic eruption at 232 ± 5 CE) but the record of explosive volcanism is poorly known through the Holocene. The compilation of ages suggests that there is no single mechanism driving glacier fluctuations on a global scale. Multidecadal variations of solar and volcanic activity supported by positive feedbacks in the climate system may have played a critical role in Holocene glaciation, but further research on such linkages is needed. The rate and the global character of glacier retreat in the 20th through early 21st centuries appears unusual in the context of Holocene glaciation, though the retreating glaciers in most parts of the Northern Hemisphere are still larger today than they were in the early and/or mid-Holocene. The current retreat, however, is occurring during an interval of orbital forcing that is favorable for glacier growth and is therefore caused by a combination of factors other than orbital forcing, primarily strong anthropogenic effects. Glacier retreat will continue into future decades due to the delayed response of glaciers to climate change.
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•Northern Hemisphere mid-low latitude Holocene glaciation driven by orbital forcing.•Neoglacial advances correspond to multidecadal periods of low solar activity.•Current glacier retreat unlikely be explained only by natural forcings.
Regulatory T cells (Tregs) play an essential role in preventing autoimmunity. Mutations in the forkhead box protein 3 (FOXP3) gene, which encodes a transcription factor critical for Treg function, ...result in a severe autoimmune disorder and the production of various autoantibodies in mice and in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients. However, it is unknown whether Tregs normally suppress autoreactive B cells. To investigate a role for Tregs in maintaining human B-cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells isolated from IPEX patients. Characteristics and reactivity of antibodies expressed by new emigrant/transitional B cells from IPEX patients were similar to those from healthy donors, demonstrating that defective Treg function does not impact central B-cell tolerance. In contrast, mature naive B cells from IPEX patients often expressed autoreactive antibodies, suggesting an important role for Tregs in maintaining peripheral B-cell tolerance. T cells displayed an activated phenotype in IPEX patients, including their Treg-like cells, and showed up-regulation of CD40L, PD-1, and inducibl T-cell costimulator (ICOS), which may favor the accumulation of autoreactive mature naive B cells in these patients. Hence, our data demonstrate an essential role for Tregs in the establishment and the maintenance of peripheral B-cell tolerance in humans.
•Peripheral B-cell tolerance is defective in IPEX patients, suggesting that Tregs are involved in the maintenance of B-cell tolerance.•T cells, including Tregs, display an activated phenotype in IPEX patients that may favor the accumulation of autoreactive B cells.
In the context of sensing and transport control, nanopores play an essential role. Designing multifunctional nanopores and placing multiple surface functionalities with nanoscale precision remains ...challenging. Interface effects together with a combination of different materials are used to obtain local multifunctionalization of nanoscale pores within a model pore system prepared by colloidal templating. Silica inverse colloidal monolayers are first functionalized with a gold layer to create a hybrid porous architecture with two distinct gold nanostructures on the top surface as well as at the pore bottom. Using orthogonal silane‐ and thiol‐based chemistry together with a control of the wetting state allows individual addressing of the different locations within each pore resulting in nanoscale localized functional placement of three different functional units. Ring‐opening metathesis polymerization is used for inner silica‐pore wall functionalization. The hydrophobized pores create a Cassie–Baxter wetting state with aqueous solutions of thiols, which enables an exclusive functionalization of the outer gold structures. In a third step, an ethanolic solution able to wet the pores is used to self‐assemble a thiol‐containing initiator at the pore bottom. Subsequent controlled radical polymerization provides functionalization of the pore bottom. It is demonstrated that the combination of orthogonal surface chemistry and controlled wetting states can be used for the localized functionalization of porous materials.
A strategy to precisely graft three different functional components with nanolocal resolution into each individual pore of an inverse colloidal monolayer is demonstrated. Gold deposition on silica inverse colloidal monolayers allows using orthogonal silane and thiol chemistry in combination with control of the wetting state.
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