Objectives The aim of the study was to determine whether longitudinal left ventricular (LV) function provides prognostic information in a large cohort of patients with systemic light-chain (AL) ...amyloidosis. Background AL amyloidosis is associated with a high incidence of cardiovascular events. Reduced myocardial longitudinal function is one of the hallmarks of myocardial involvement in this rare disease. Methods Two hundred six consecutive patients with biopsy-proven AL amyloidosis were investigated in this prospective observational study. Echocardiographic imaging parameters, mean tissue Doppler-derived longitudinal strain (LS), and two-dimensional global longitudinal strain (2D-GLS) of the LV, cardiac serological biomarkers, and comprehensive clinical disease characteristics were assessed. The primary endpoint was all-cause mortality or heart transplantation. Results After a median follow-up of 1207 days, LS and 2D-GLS were significant predictors of survival in AL amyloidosis. The cutoff values discriminating survivors from nonsurvivors were −10.65% for LS and −11.78% for 2D-GLS. In a multivariable echocardiographic Cox model, only diastolic dysfunction and 2D-GLS remained as independent predictors of survival. In comprehensive clinical models, 2D-GLS (p < 0.0001), diastolic dysfunction (p < 0.01), the pathologic free light chains (p < 0.05), cardiac troponin-T (cTnT) (p < 0.01), and the Karnofsky index (p < 0.001) remained as independent predictors. 2D-GLS delineated a superior prognostic value compared with that derived from pathologic free light chains or cTnT in patients evaluated before firstline chemotherapy (n = 113; p < 0.0001), and remained the only independent predictor besides the Karnofsky index in subjects with preserved LV ejection fraction (≥50%; n = 127; p < 0.01). LS and 2D-GLS both offered significant incremental information (p < 0.001) for the assessment of outcome compared with clinical variables (age, Karnofsky index, and New York Heart Association functional class) and serological biomarkers. Conclusions In the largest serial investigation reported so far, reduced LV longitudinal function served as an independent predictor of survival in AL amyloidosis and offered incremental information beyond standard clinical and serological parameters.
Mosquitoes have a wide range of digestive enzymes that enable them to utilize requisite blood and sugar meals for survival and reproduction. Sugar meals, typically derived from plant sources, are ...critical to maintain energy in both male and female mosquitoes, whereas blood meals are taken only by females to complete oogenesis. Enzymes involved in sugar digestion have been the subject of study for decades but have been limited to a relatively narrow range of mosquito species. The southern house mosquito,
Culex quinquefasciatus
, is of public health importance and seldom considered in these types of studies outside of topics related to
Bacillus sphaericus
, a biocontrol agent that requires interaction with a specific gut-associated α-glucosidase. Here we sought to describe the nature of α-glucosidases and unexplored β-glucosidases that may aid
Cx
.
quinquefasciatus
larvae in acquiring nutrients from cellulosic sources in their aquatic habitats. Consistent with our hypothesis, we found both α- and β-glucosidase activity in larvae. Interestingly, β-glucosidase activity all but disappeared at the pupal stage and remained low in adults, while α-glucosidase activity remained in the pupal stage and then exceeded larval activity by approximately 1.5-fold. The expression patterns of the putative α- and β-glucosidase genes chosen did not consistently align with observed enzyme activities. When the α-glucosidase inhibitor acarbose was administered to adults, mortality was seen especially in males but also in females after two days of exposure and key energetic storage molecules, glycogen and lipids, were significantly lower than controls. In contrast, administering the β-glucosidase inhibitor conduritol β-epoxide to larvae did not produce mortality even at the highest soluble concentration. Here we provide insights into the importance of α- and β-glucosidases on the survival of
Cx
.
quinquefasciatus
in their three mobile life stages.
More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene
The canonical function of the
gene product, pRB, is to repress the E2F transcription ...factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus AAV) that expresses Cre recombinase and sgRNAs targeting
, and
into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to
SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.
The aim of this study was to determine the value of extracellular volume fraction (ECV) for the non-invasive assessment of diffuse myocardial fibrosis (MF) in different stages of systolic left ...ventricular (LV) dysfunction in dilated cardiomyopathy (DCM) in comparison with endomyocardial biopsy.
Non-invasive ECV assessment using cardiovascular magnetic resonance (CMR) T1 mapping reflects diffuse MF in patients with severe DCM, but earlier stages of DCM with mild LV functional impairment have not been investigated yet.
Forty-five subjects with mild functional impairment and LV dilation 'early DCM', ejection fraction (EF) 45-55%, 29 with LV dysfunction and volume dilatation ('DCM', EF <45%) and 56 healthy volunteers (controls) underwent standard CMR imaging, late gadolinium enhancement (LGE) and T1 mapping for the calculation of ECV. The collagen volume fraction (CVF) was quantified histologically from endomyocardial biopsies of 24 DCM patients out of the study cohort.
The ECV between 'early DCM' (25 ± 4%), 'DCM' (27 ± 4%), and controls (23 ± 3; P < 0.05 for all) differed significantly. There was a weak inverse correlation between ECV and EF (r = -0.35; P < 0.01). A strong correlation between ECV and CVF could be detected (r = 0.85; P = 0.01). The cut-off value for ECV to differentiate between healthy myocardium and DCM was 26% (specificity 91.1%, sensitivity 62.1%, area under the curve 0.8, P < 0.0001). ECV is already elevated at early stages of functional impairment, whereby an overlap between early DCM and controls is present. But 31% of the early DCM patients had an ECV fraction above the mean ±2 SD ECV of controls.
ECV measurement with CMR reflects myocardial collagen content in DCM. Therefore, CMR-based assessment of ECV may have the potential to serve as a non-invasive tool for the quantification of diffuse MF in order to monitor therapy response and aid risk stratification in different stages of DCM.
Context.
The origin of the
γ
-ray emission of the blazar
Mrk 421
is still a matter of debate.
Aims.
We used 5.5 years of unbiased observing campaign data, obtained using the FACT telescope and the
...Fermi
-LAT detector at TeV and GeV energies, the longest and densest so far, together with contemporaneous multi-wavelength observations, to characterise the variability of
Mrk 421
and to constrain the underlying physical mechanisms.
Methods.
We studied and correlated light curves obtained by ten different instruments and found two significant results.
Results.
The TeV and X-ray light curves are very well correlated with a lag of < 0.6 days. The GeV and radio (15 Ghz band) light curves are widely and strongly correlated. Variations of the GeV light curve lead those in the radio.
Conclusions.
Lepto-hadronic and purely hadronic models in the frame of shock acceleration predict proton acceleration or cooling timescales that are ruled out by the short variability timescales and delays observed in Mrk 421. Instead the observations match the predictions of leptonic models.
Objectives The extent of adverse myocardial remodeling contributes essentially to the prognosis after myocardial infarction (MI). In this study we investigated whether inhibition of “mammalian target ...of rapamycin” (mTOR) attenuates left ventricular (LV) remodeling after MI. Background Therapeutic strategies to inhibit remodeling are currently limited to inhibition of neurohumoral activation. The mTOR-dependent signaling mechanisms are centrally involved in remodeling processes and provide new therapeutic opportunities. Methods Everolimus (RAD) treatment was initiated on the day after or 3 days after induction of myocardial infarction (MI) in rats. Results After 28 days, RAD-treated animals had reduced post-MI remodeling, with improved LV function and smaller LV end-diastolic diameters (8.9 ± 0.3 mm vs. 11.4 ± 0.2 mm, p < 0.05), end-diastolic volumes (304 ± 30 μl vs. 414 ± 16 μl, p < 0.05), and cardiac myocyte size (−40% vs. vehicle, p < 0.05). Infarct size was significantly reduced compared with vehicle-treated animals. The mTOR inhibition increased autophagy and concomitantly decreased proteasome activity in the border zone of the infarcted myocardium. Measurement of autophagic flux demonstrated that RAD did not decrease autophagosome clearance. When RAD treatment was initiated 3 days after MI, adverse remodeling was still attenuated and increased autophagy was still present. Sustained improvement of LV function was observed 3 months after MI, even when RAD treatment was discontinued after 1 month. Conclusions Inhibition of mTOR is a potential therapeutic strategy to limit infarct size and to attenuate adverse LV remodeling after MI.
Management options for newly diagnosed vestibular schwannoma (VS) include observation, surgery, or radiation. There are no randomized trials to guide management of patients with VS. This article is a ...short review of the role of stereotactic radiosurgery in management of newly diagnosed VS.
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•Twisting of structural elements of bone can be found across multiple scales.•3D imaging and analysis supports original observations by Pettigrew and Thompson.•Self-similarity in the ...form of the twist is a hallmark of bone structure.•Consideration of twisting/spiraling in bone may enhance understanding of function.
Structural hierarchy of bone – observed across multiple scales and in three dimensions (3D) – is essential to its mechanical performance. While the mineralized extracellular matrix of bone consists predominantly of carbonate-substituted hydroxyapatite, type I collagen fibrils, water, and noncollagenous organic constituents (mainly proteins and small proteoglycans), it is largely the 3D arrangement of these inorganic and organic constituents at each length scale that endow bone with its exceptional mechanical properties. Focusing on recent volumetric imaging studies of bone at each of these scales – from the level of individual mineralized collagen fibrils to that of whole bones – this graphical review builds upon and re-emphasizes the original work of James Bell Pettigrew and D’Arcy Thompson who first described the ubiquity of spiral structure in Nature. Here we illustrate and discuss the omnipresence of twisted, curved, sinusoidal, coiled, spiraling, and braided motifs in bone in at least nine of its twelve hierarchical levels – a visualization undertaking that has not been possible until recently with advances in 3D imaging technologies (previous 2D imaging does not provide this information). From this perspective, we hypothesize that the twisting motif occurring across each hierarchical level of bone is directly linked to enhancement of function, rather than being simply an energetically favorable way to assemble mineralized matrix components. We propose that attentive consideration of twists in bone and the skeleton at different scales will likely develop, and will enhance our understanding of structure–function relationships in bone.
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