Antibody‐mediated rejection (AMR) is an increasingly recognized form of lung rejection. C4d deposition has been an inconsistent finding in previous reports and its role in the diagnosis has been ...controversial. We conducted a retrospective single‐center study to characterize cases of C4d‐negative probable AMR and to compare these to cases of definite (C4d‐positive) AMR. We identified 73 cases of AMR: 28 (38%) were C4d‐positive and 45 (62%) were C4d‐negative. The two groups had a similar clinical presentation, and although more patients in the C4d‐positive group had neutrophilic capillaritis (54% vs. 29%, P = .035), there was no significant difference in the presence of other histologic findings. Despite aggressive antibody‐depleting therapy, 19 of 73 (26%) patients in the overall cohort died within 30 days, but there was no significant difference in freedom from chronic lung allograft dysfunction (CLAD) or survival between the two groups. We conclude that AMR may cause allograft failure, but that the diagnosis requires a multidisciplinary approach and a high index of suspicion. C4d deposition does not appear to be a necessary criterion for the diagnosis, and although some cases may respond initially to therapy, there is a high incidence of CLAD and poor survival after AMR.
In this retrospective single‐center study, complement component 4d deposition does not appear to be a necessary criterion for the diagnosis of antibody‐mediated rejection after lung transplantation.
Marine turtles utilise terrestrial and marine habitats and several aspects of their life history are tied to environmental features that are altering due to rapid climate change. We overview the ...likely impacts of climate change on the biology of these species, which are likely centred upon the thermal ecology of this taxonomic group. Then, focusing in detail on three decades of research on the loggerhead turtle (Caretta caretta L.), we describe how much progress has been made to date and how future experimental and ecological focus should be directed. Key questions include: what are the current hatchling sex ratios from which to measure future climate-induced changes? What are wild adult sex ratios and how many males are necessary to maintain a fertile and productive population? How will climate change affect turtles in terms of their distribution?
Nemaline myopathy (NM) is the most common non-dystrophic congenital myopathy. Clinically the most important feature of NM is muscle weakness; however, the mechanisms underlying this weakness are ...poorly understood. Here, we studied the muscular phenotype of NM patients with a well-defined nebulin mutation (NM-NEB), using a multidisciplinary approach to study thin filament length regulation and muscle contractile performance. SDS–PAGE and western blotting revealed greatly reduced nebulin levels in skeletal muscle of NM-NEB patients, with the most prominent reduction at nebulin’s N-terminal end. Muscle mechanical studies indicated ∼60% reduced force generating capacity of NM-NEB muscle and a leftward-shift of the force–sarcomere length relation in NM-NEB muscle fibers. This indicates that the mechanism for the force reduction is likely to include shorter and non-uniform thin filament lengths in NM-NEB muscle compared with control muscle. Immunofluorescence confocal microscopy and electron microscopy studies indicated that average thin filament length is reduced from ∼1.3 µm in control muscle to ∼0.75 µm in NM-NEB muscle. Thus, the present study is the first to show a distinct genotype-functional phenotype correlation in patients with NM due to a nebulin mutation, and provides evidence for the notion that dysregulated thin filament length contributes to muscle weakness in NM patients with nebulin mutations. Furthermore, a striking similarity between the contractile and structural phenotypes of nebulin-deficient mouse muscle and human NM-NEB muscle was observed, indicating that the nebulin knockout model is well suited for elucidating the functional basis of muscle weakness in NM and for the development of treatment strategies.
The regularity of pulsar emissions becomes apparent once we reference the pulses' times of arrivals to the inertial rest frame of the solar system. It follows that errors in the determination of ...Earth's position with respect to the solar system barycenter can appear as a time-correlated bias in pulsar-timing residual time series, affecting the searches for low-frequency gravitational waves performed with pulsar-timing arrays. Indeed, recent array data sets yield different gravitational-wave background upper limits and detection statistics when analyzed with different solar system ephemerides. Crucially, the ephemerides do not generally provide usable error representations. In this article, we describe the motivation, construction, and application of a physical model of solar system ephemeris uncertainties, which focuses on the degrees of freedom (Jupiter's orbital elements) most relevant to gravitational-wave searches with pulsar-timing arrays. This model, BayesEphem, was used to derive ephemeris-robust results in NANOGrav's 11 yr stochastic-background search, and it provides a foundation for future searches by NANOGrav and other consortia. The analysis and simulations reported here suggest that ephemeris modeling reduces the gravitational-wave sensitivity of the 11 yr data set and that this degeneracy will vanish with improved ephemerides and with pulsar-timing data sets that extend well beyond a single Jovian orbital period.
Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is ...reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels.
Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females.
Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns.
The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight.
Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based ...in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.
The clinical significance of diaphragm weakness in critically ill patients is evident: it prolongs ventilator dependency, and increases morbidity and duration of hospital stay. To date, the nature of ...diaphragm weakness and its underlying pathophysiologic mechanisms are poorly understood.
We hypothesized that diaphragm muscle fibers of mechanically ventilated critically ill patients display atrophy and contractile weakness, and that the ubiquitin-proteasome pathway is activated in the diaphragm.
We obtained diaphragm muscle biopsies from 22 critically ill patients who received mechanical ventilation before surgery and compared these with biopsies obtained from patients during thoracic surgery for resection of a suspected early lung malignancy (control subjects). In a proof-of-concept study in a muscle-specific ring finger protein-1 (MuRF-1) knockout mouse model, we evaluated the role of the ubiquitin-proteasome pathway in the development of contractile weakness during mechanical ventilation.
Both slow- and fast-twitch diaphragm muscle fibers of critically ill patients had approximately 25% smaller cross-sectional area, and had contractile force reduced by half or more. Markers of the ubiquitin-proteasome pathway were significantly up-regulated in the diaphragm of critically ill patients. Finally, MuRF-1 knockout mice were protected against the development of diaphragm contractile weakness during mechanical ventilation.
These findings show that diaphragm muscle fibers of critically ill patients display atrophy and severe contractile weakness, and in the diaphragm of critically ill patients the ubiquitin-proteasome pathway is activated. This study provides rationale for the development of treatment strategies that target the contractility of diaphragm fibers to facilitate weaning.
•Moderate maternal prenatal distress is associated with fetal development leading to a reduction of anthropometric measures at birth.•Modest, but significant associations between maternal prenatal ...distress and altered diurnal cortisol patterns were observed.•A flattened cortisol decline across the day and higher evening cortisol were significantly associated with reduced length of gestation.•Minor changes in maternal cortisol concentrations may play a crucial role in transmitting prenatal early life stress to the fetus.•Our results highlight the importance of early recognition of moderate prenatal distress: women at risk may benefit from early interventions.
Prenatal maternal stress might be a risk for the developing fetus and may have long-lasting effects on child and adult vulnerability to somatic and psychiatric disease. Over-exposure of the unborn to excess glucocorticoids and subsequent alteration of fetal development is hypothesized to be one of the key mechanisms linking prenatal stress with negative child outcome.
In this prospective longitudinal study, mothers-to-be (n = 405) in late pregnancy (36.8 ± 1.9 weeks of gestational age) and their singleton neonates were studied. We investigated the impact of different prenatal stress indices derived from six stress variables (perceived stress, specific prenatal worries, negative life events, symptoms of depression, trait anxiety, neuroticism) and diurnal maternal saliva cortisol secretion on gestational age and anthropometric measures at birth.
Maternal prenatal distress during late gestation was associated with significant reduction in birth weight (−217 g; p = .005), birth length (−1.2 cm; p = .005) and head circumference (−0.8 cm; p = .001). Prenatal stress was modestly but significantly associated with altered diurnal cortisol pattern (flattened cortisol decline and higher evening cortisol), which in turn was significantly related to reduced length of gestation. No evidence for a profound interaction between maternal cortisol level in late pregnancy and infant’s anthropometric measures at birth (i.e., birth weight, length, head circumference) was found.
Prenatal stress is associated with flattened circadian saliva cortisol profiles and reduced infant’s anthropometric measures at birth. HPA system activity during pregnancy may be related to low gestational age. The effect of prenatal stress might be partly mediated by maternal-placental-fetal neuroendocrine mechanisms especially the dysregulation of diurnal cortisol profile.
Abstract
It is unclear why exactly gliomas show preferential occurrence in certain brain areas. Increased spiking activity around gliomas leads to faster tumour growth in animal models, while higher ...non-invasively measured brain activity is related to shorter survival in patients. However, it is unknown how regional intrinsic brain activity, as measured in healthy controls, relates to glioma occurrence. We first investigated whether gliomas occur more frequently in regions with intrinsically higher brain activity. Second, we explored whether intrinsic cortical activity at individual patients’ tumour locations relates to tumour and patient characteristics.
Across three cross-sectional cohorts, 413 patients were included. Individual tumour masks were created. Intrinsic regional brain activity was assessed through resting-state magnetoencephalography acquired in healthy controls and source-localized to 210 cortical brain regions. Brain activity was operationalized as: (i) broadband power; and (ii) offset of the aperiodic component of the power spectrum, which both reflect neuronal spiking of the underlying neuronal population. We additionally assessed (iii) the slope of the aperiodic component of the power spectrum, which is thought to reflect the neuronal excitation/inhibition ratio. First, correlation coefficients were calculated between group-level regional glioma occurrence, as obtained by concatenating tumour masks across patients, and group-averaged regional intrinsic brain activity. Second, intrinsic brain activity at specific tumour locations was calculated by overlaying patients’ individual tumour masks with regional intrinsic brain activity of the controls and was associated with tumour and patient characteristics.
As proposed, glioma preferentially occurred in brain regions characterized by higher intrinsic brain activity in controls as reflected by higher offset. Second, intrinsic brain activity at patients’ individual tumour locations differed according to glioma subtype and performance status: the most malignant isocitrate dehydrogenase-wild-type glioblastoma patients had the lowest excitation/inhibition ratio at their individual tumour locations as compared to isocitrate dehydrogenase-mutant, 1p/19q-codeleted glioma patients, while a lower excitation/inhibition ratio related to poorer Karnofsky Performance Status, particularly in codeleted glioma patients.
In conclusion, gliomas more frequently occur in cortical brain regions with intrinsically higher activity levels, suggesting that more active regions are more vulnerable to glioma development. Moreover, indices of healthy, intrinsic excitation/inhibition ratio at patients’ individual tumour locations may capture both tumour biology and patients’ performance status. These findings contribute to our understanding of the complex and bidirectional relationship between normal brain functioning and glioma growth, which is at the core of the relatively new field of ‘cancer neuroscience’.
Assessing wave energy effects on biodiversity: the Wave Hub experience Witt, M. J.; Sheehan, E. V.; Bearhop, S. ...
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
01/2012, Letnik:
370, Številka:
1959
Journal Article
Recenzirano
Odprti dostop
Marine renewable energy installations harnessing energy from wind, wave and tidal resources are likely to become a large part of the future energy mix worldwide. The potential to gather energy from ...waves has recently seen increasing interest, with pilot developments in several nations. Although technology to harness wave energy lags behind that of wind and tidal generation, it has the potential to contribute significantly to energy production. As wave energy technology matures and becomes more widespread, it is likely to result in further transformation of our coastal seas. Such changes are accompanied by uncertainty regarding their impacts on biodiversity. To date, impacts have not been assessed, as wave energy converters have yet to be fully developed. Therefore, there is a pressing need to build a framework of understanding regarding the potential impacts of these technologies, underpinned by methodologies that are transferable and scalable across sites to facilitate formal met a-analysis. We first review the potential positive and negative effects of wave energy generation, and then, with specific reference to our work at the Wave Hub (a wave energy test site in southwest England, UK), we set out the methodological approaches needed to assess possible effects of wave energy on biodiversity. We highlight the need for national and international research clusters to accelerate the implementation of wave energy, within a coherent understanding of potential effects—both positive and negative.
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