Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of ...transplantation.
We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation.
In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs.
We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).
Intestinal microbiota may influence human physiology and disease risk due to the role it plays in mediating appropriate immune responses to harmful and innocuous antigens. Colonisation of the ...intestine in early life seems particularly important as it is the main environmental stimulus for immune system maturation. This is a dynamic process, which depends on both environmental and genetic factors. The pathogenesis of inflammatory bowel disease, such as Crohn's disease, involves genetic polymorphisms (e.g. CARD15/nucleotide-binding oligomerisation domain 2) related to an excessive inflammatory response to commensal microbiota and to its unbalanced composition. Atopic diseases have also been linked to imbalances in microbiota and to related genetic factors (e.g. TLR4 and CD14 genes), although these associations are still controversial. Research into the relationship between the genetic risk of developing celiac disease (human leukocyte antigen (HLA)-DQ2/DQ8) and the early colonisation process in infants at family risk of the disease has also reported that the HLA-DQ genotype could influence staphylococcal colonisation. Future observational studies considering both host genetics and microbiota could be critical in defining the complex host-microbe interactions and the respective role each plays in inflammatory disorders.
A major challenge in human genetics is to identify the molecular mechanisms of trait-associated and disease-associated variants. To achieve this, quantitative trait locus (QTL) mapping of genetic ...variants with intermediate molecular phenotypes such as gene expression and splicing have been widely adopted
. However, despite successes, the molecular basis for a considerable fraction of trait-associated and disease-associated variants remains unclear
. Here we show that ADAR-mediated adenosine-to-inosine RNA editing, a post-transcriptional event vital for suppressing cellular double-stranded RNA (dsRNA)-mediated innate immune interferon responses
, is an important potential mechanism underlying genetic variants associated with common inflammatory diseases. We identified and characterized 30,319 cis-RNA editing QTLs (edQTLs) across 49 human tissues. These edQTLs were significantly enriched in genome-wide association study signals for autoimmune and immune-mediated diseases. Colocalization analysis of edQTLs with disease risk loci further pinpointed key, putatively immunogenic dsRNAs formed by expected inverted repeat Alu elements as well as unexpected, highly over-represented cis-natural antisense transcripts. Furthermore, inflammatory disease risk variants, in aggregate, were associated with reduced editing of nearby dsRNAs and induced interferon responses in inflammatory diseases. This unique directional effect agrees with the established mechanism that lack of RNA editing by ADAR1 leads to the specific activation of the dsRNA sensor MDA5 and subsequent interferon responses and inflammation
. Our findings implicate cellular dsRNA editing and sensing as a previously underappreciated mechanism of common inflammatory diseases.
With the increasing incidence of thoracic tumors, radiation therapy (RT) has become an important component of comprehensive treatment. RT improves survival in many cancers, but it involves some ...inevitable complications. Radiation-induced heart disease (RIHD) is one of the most serious complications. RIHD comprises a spectrum of heart disease including cardiomyopathy, pericarditis, coronary artery disease, valvular heart disease and conduction system abnormalities. There are numerous clinical manifestations of RIHD, such as chest pain, palpitation, and dyspnea, even without obvious symptoms. Based on previous studies, the pathogenesis of RIHD is related to the production and effects of various cytokines caused by endothelial injury, inflammatory response, and oxidative stress (OS). Therefore, it is of great importance for clinicians to identify the mechanism and propose interventions for the prevention of RIHD.
The posterior cingulate cortex is a highly connected and metabolically active brain region. Recent studies suggest it has an important cognitive role, although there is no consensus about what this ...is. The region is typically discussed as having a unitary function because of a common pattern of relative deactivation observed during attentionally demanding tasks. One influential hypothesis is that the posterior cingulate cortex has a central role in supporting internally-directed cognition. It is a key node in the default mode network and shows increased activity when individuals retrieve autobiographical memories or plan for the future, as well as during unconstrained 'rest' when activity in the brain is 'free-wheeling'. However, other evidence suggests that the region is highly heterogeneous and may play a direct role in regulating the focus of attention. In addition, its activity varies with arousal state and its interactions with other brain networks may be important for conscious awareness. Understanding posterior cingulate cortex function is likely to be of clinical importance. It is well protected against ischaemic stroke, and so there is relatively little neuropsychological data about the consequences of focal lesions. However, in other conditions abnormalities in the region are clearly linked to disease. For example, amyloid deposition and reduced metabolism is seen early in Alzheimer's disease. Functional neuroimaging studies show abnormalities in a range of neurological and psychiatric disorders including Alzheimer's disease, schizophrenia, autism, depression and attention deficit hyperactivity disorder, as well as ageing. Our own work has consistently shown abnormal posterior cingulate cortex function following traumatic brain injury, which predicts attentional impairments. Here we review the anatomy and physiology of the region and how it is affected in a range of clinical conditions, before discussing its proposed functions. We synthesize key findings into a novel model of the region's function (the 'Arousal, Balance and Breadth of Attention' model). Dorsal and ventral subcomponents are functionally separated and differences in regional activity are explained by considering: (i) arousal state; (ii) whether attention is focused internally or externally; and (iii) the breadth of attentional focus. The predictions of the model can be tested within the framework of complex dynamic systems theory, and we propose that the dorsal posterior cingulate cortex influences attentional focus by 'tuning' whole-brain metastability and so adjusts how stable brain network activity is over time.
Disease transmission prediction across wildlife is crucial for risk assessment of emerging infectious diseases. Susceptibility of host species to pathogens is influenced by the geographic, ...environmental, and phylogenetic context of the specific system under study. We used machine learning to analyze how such variables influence pathogen incidence for multihost pathogen assemblages, including one of direct transmission (coronaviruses and bats) and two vector-borne systems (West Nile Virus WNV and birds, and malaria and birds). Here we show that this methodology is able to provide reliable global spatial susceptibility predictions for the studied host-pathogen systems, even when using a small amount of incidence information (i.e., Formula: see text of information in a database). We found that avian malaria was mostly affected by environmental factors and by an interaction between phylogeny and geography, and WNV susceptibility was mostly influenced by phylogeny and by the interaction between geographic and environmental distances, whereas coronavirus susceptibility was mostly affected by geography. This approach will help to direct surveillance and field efforts providing cost-effective decisions on where to invest limited resources.
ObjectivesTo examine associations between occupational exposures to rubber dust, rubber fumes and N-nitrosamines and non-cancer mortality.MethodsA cohort of 36 441 males aged 35+ years employed in ...British rubber factories was followed-up to 2015 (94% deceased). Competing risk survival analysis was used to assess risks of dying from non-cancer diseases (respiratory, urinary, cerebrovascular, circulatory and digestive diseases). Occupational exposures to rubber dust, rubber fumes, N-nitrosamines were derived based on a population-specific quantitative job-exposure matrix which in-turn was based on measurements in the EU-EXASRUB database.ResultsExposure–response associations of increased risk with increasing exposure were found for N-nitrosomorpholine with mortality from circulatory diseases (subdistribution hazard ratio (SHR) 1.17; 95% CI 1.12 to 1.23), ischaemic heart disease (IHD) (SHR 1.19; 95% CI 1.13 to 1.26), cerebrovascular disease (SHR 1.19; 95% CI 1.07 to 1.32) and exposures to N-nitrosodimethylamine with respiratory disease mortality (SHR 1.41; 95% CI 1.30 to 1.53). Increased risks for mortality from circulatory disease, IHD and digestive diseases were found with higher levels of exposures to rubber dust, rubber fumes and N-nitrosamines sum, without an exposure-dependent manner. No associations were observed between rubber dust, rubber fumes and N-nitrosamines exposures with mortality from asthma, urinary disease, bronchitis, emphysema, liver disease and some digestive diseases.ConclusionsIn a cohort of rubber factory workers with 49 years of follow-up, increased risk for mortality from circulatory, cerebrovascular, respiratory and digestive diseases were found to be associated with cumulative occupational exposures to specific agents.
Summary A previously well infant aged 9 months presented with an acute, self-limiting illness characterised by high fever and a papular eruption that started on the face. Although fever subsided ...within 3 days, the rash worsened and extended over the whole body, with some papules evolving into vesiculobullous lesions. The infant had been exposed to children with a similar illness 1 week before onset. PCR of vesicular swabs and stool samples taken on day 6 of illness showed Coxsackie virus A6. The illness resolved within 10 days of onset, although onychomadesis was seen on both big toes at follow-up 5 weeks later. Our case exemplifies the severe, atypical cases of hand, foot, and mouth disease that have been reported worldwide since 2008, and in the USA since the 2011. Atypical hand, foot, and mouth disease is caused by a new lineage of Coxsackie virus A6 and is characterised by high fever and vesiculobullous eruptions on the calves and backs of the hands. Infants with eczema might be predisposed to severe disease.
Pulmonary diseases and the heart Han, MeiLan K; McLaughlin, Vallerie V; Criner, Gerard J ...
Circulation (New York, N.Y.),
12/2007, Letnik:
116, Številka:
25
Journal Article
Recenzirano
The complex nature of interactions between the pulmonary and cardiovascular systems is becoming increasingly appreciated. Pulmonary vascular abnormalities are frequently present in patients with ...respiratory disorders, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, sarcoidosis, neuromuscular or chest wall disorders, and disorders of ventilatory control including sleep apnea syndromes and obesity hypoventilation syndrome. Pulmonary hypertension, classified as group III in the World Health Organization classification scheme for pulmonary hypertension, may result in severe right ventricular dysfunction caused by lung disease, also known as cor pulmonale. The development of cor pulmonale is generally associated with poorer prognosis and increased death. Systemic manifestations of lung disease, particularly obstructive disorders, are also particularly relevant because they are associated with increased cardiac death and impaired health status. This article will discuss the most common pulmonary diseases and disorders of ventilatory control that cause pulmonary vascular abnormalities and cor pulmonale, with particular concentration on how treatment of these diseases may affect the heart. In addition, the complex nature of cardiac and lung disease will also be explored, particularly with respect to the relationship between chronic obstructive pulmonary disease, systemic inflammation, atherosclerosis, and cardiovascular death, which is currently a very active focus of research.
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