Afamelanotide for Erythropoietic Protoporphyria Langendonk, Janneke G; Balwani, Manisha; Anderson, Karl E ...
The New England journal of medicine,
07/2015, Letnik:
373, Številka:
1
Journal Article
Recenzirano
In patients with erythropoietic protoporphyria, sensitivity to the sun leads to pain and compromised quality of life. In two clinical trials, one in Europe and one in the United States, a peptide ...analogue of an α-melanocyte–stimulating hormone alleviated symptoms.
Erythropoietic protoporphyria is a rare, autosomal recessive inborn error of metabolism that typically manifests in early childhood as severe painful photosensitivity. The photosensitivity results from accumulated protoporphyrin in erythroid cells and tissues because of the decreased activity of ferrochelatase, the heme biosynthetic enzyme that inserts iron into protoporphyrin to form heme.
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An X-linked form of erythropoietic protoporphyria
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that accounts for 2 to 10% of cases results from a gain of function of erythroid-specific aminolevulinic acid synthase 2.
Pathophysiologically, protoporphyrin is released from erythroid cells into the circulation, gains access to the vascular endothelium and liver, and is excreted . . .
HIV-related stigma negatively impacts HIV prevention, treatment, and care, particularly among children and adolescents in sub-Saharan Africa. Interventions that are culturally grounded and relevant ...for addressing root causes may reduce the stigma experienced by HIV-positive and HIV-affected young people. This study, to be conducted in a post-conflict, rural setting in Omoro District, Uganda, will develop and evaluate a transformative arts-based HIV-related stigma intervention rooted in local cultural knowledge to reduce stigma and improve HIV prevention and care for young people living with HIV. The intervention will be delivered to young people attending school by community Elders, with the support of teachers, through the transfer of local cultural knowledge and practices with the aim of re-establishing the important cultural and social role of Elders within a community that has suffered the loss of intergenerational transfer of cultural knowledge throughout a 25-year civil war.
A formative research phase consisting of interviews with students, teachers, and Elders will inform the intervention and provide data for study objectives. Workshops will be delivered to Elders and teachers in participating schools to build capacity for arts-based, educational workshops to be conducted with students in the classroom. The intervention will be evaluated using a stepped-wedge cluster-randomized trial. Government-funded schools in Omoro District will be randomized into three blocks, each comprised of two primary and two secondary schools (n=1800 students). Schools will be randomly assigned to a crossover sequence from control to intervention condition in 8-week intervals. A process evaluation will be implemented throughout the study to evaluate pathways between intervention development, implementation, and effects.
This study will generate comprehensive, in-depth participatory research and evaluation data to inform an effective and sustainable protocol for implementing arts-based HIV stigma interventions for young people in school settings. Findings will have widespread implications in post-conflict settings for HIV prevention, treatment, and care.
ClinicalTrials.gov NCT04946071 . Registered on 30 June 2021.
Abstract Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these ...mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegeneration and dementia, particularly by small vessel disease, is hampered by imprecise data, including the incidence and prevalence of symptomatic and clinically “silent” cerebrovascular disease, long-term outcomes (cognitive, stroke, or functional), and risk factors. New large collaborative studies with long follow-up are expensive and time consuming, yet substantial data to advance the field are available. In an initiative funded by the Joint Programme for Neurodegenerative Disease Research, 55 international experts surveyed and assessed available data, starting with European cohorts, to promote data sharing to advance understanding of how vascular disease affects brain structure and function, optimize methods for cerebrovascular disease in neurodegeneration research, and focus future research on gaps in knowledge. Here, we summarize the results and recommendations from this initiative. We identified data from over 90 studies, including over 660,000 participants, many being additional to neurodegeneration data initiatives. The enthusiastic response means that cohorts from North America, Australasia, and the Asia Pacific Region are included, creating a truly global, collaborative, data sharing platform, linked to major national dementia initiatives. Furthermore, the revised World Health Organization International Classification of Diseases version 11 should facilitate recognition of vascular-related brain damage by creating one category for all cerebrovascular disease presentations and thus accelerate identification of targets for dementia prevention.
Abstract
Background
Multisystem inflammatory syndrome in children (MIS-C) is a severe hyperinflammatory condition in persons aged <21 years associated with antecedent severe acute respiratory ...syndrome coronavirus 2 (SARS-CoV-2) infection. Our objective was to describe MIS-C cases reported to Centers for Disease Control and Prevention’s (CDC’s) national surveillance since the coronavirus disease 2019 (COVID-19) pandemic began.
Methods
We included patients meeting the MIS-C case definition with onset date from 19 February 2020 through 31 July 2021, using CDC’s MIS-C case report form, which collects information on demographics, clinical presentation, and laboratory results. Trends over time across 3 MIS-C pandemic waves were assessed using Cochran-Armitage test for categorical and Jonckheere-Terpstra test for continuous variables.
Results
Of 4901 reported cases, 4470 met inclusion criteria. Median patient age increased over time (P < .001), with a median of 9 years (interquartile range, 5–13 years) during the most recent (third) wave. Male predominance also increased (62% in third wave, P < .001). A significant (P < .001) increase in severe hematologic and gastrointestinal involvement was observed across the study period. Frequency of several cardiovascular complications (ie, cardiac dysfunction, myocarditis, and shock/vasopressor receipt) and renal failure declined (P < .001). Provision of critical care including mechanical ventilation (P < .001) and extracorporeal membrane oxygenation (ECMO; P = .046) decreased, as did duration of hospitalization and mortality (each P < .001).
Conclusions
Over the first 3 pandemic waves of MIS-C in the United States, cardiovascular complications and clinical outcomes including length of hospitalization, receipt of ECMO, and death decreased over time. These data serve as a baseline for monitoring future trends associated with SARS-CoV-2 B.1.617.2 (Delta) or other variants and increased COVID-19 vaccination among children.
In 4470 multisystem inflammatory syndrome in children (MIS-C) patients reported with onset dates from 19 February 2020 through 31 July 2021, cardiovascular complications and clinical outcomes including length of hospitalization, receipt of extracorporeal membrane oxygenation, and death decreased over time.
The number of indigenous patients with end-stage kidney disease (ESKD) is increasing in Australia, reflecting a similar trend in other countries. Because many indigenous patients live in remote ...areas, peritoneal dialysis (PD) is often preferred. Compared to non-indigenous PD patients, indigenous patients have increased complication rates but the effect of residential locations on outcomes remains unclear. The aim of this study is to examine the association between race and PD outcomes stratified by location.
Using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, all adult ESKD patients commencing PD in Australia between 1995 and 2008 were included. Patients were stratified as non-indigenous or indigenous race and were grouped according to their residential location, the latter stratified into metropolitan, regional and remote areas. Outcomes evaluated included peritonitis, technique failure, peritonitis-related and all-cause mortality.
Regional and/or remote PD patients generally have a greater risk peritonitis-related complications and/or mortality compared to metropolitan patients. However, remote indigenous PD patients had the greatest risk of all PD-related complications, including all-cause and peritonitis-related mortality.
This registry analysis demonstrates that non-metropolitan PD patients, especially remote indigenous patients, have higher complication rates, suggesting that environmental factors are important in determining PD outcomes.
During the course of the coronavirus disease 2019 (COVID-19) pandemic, reports of a new multisystem inflammatory syndrome in children (MIS-C) have been increasing in Europe and the United States ...(1-3). Clinical features in children have varied but predominantly include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 (1). Since June 2020, several case reports have described a similar syndrome in adults; this review describes in detail nine patients reported to CDC, seven from published case reports, and summarizes the findings in 11 patients described in three case series in peer-reviewed journals (4-6). These 27 patients had cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness and concurrently received positive test results for SARS-CoV-2, the virus that causes COVID-19, by polymerase chain reaction (PCR) or antibody assays indicating recent infection. Reports of these patients highlight the recognition of an illness referred to here as multisystem inflammatory syndrome in adults (MIS-A), the heterogeneity of clinical signs and symptoms, and the role for antibody testing in identifying similar cases among adults. Clinicians and health departments should consider MIS-A in adults with compatible signs and symptoms. These patients might not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection. Because of the temporal association between MIS-A and SARS-CoV-2 infections, interventions that prevent COVID-19 might prevent MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients ...enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.
Peritoneal carcinomatosis (PC) present a ubiquitous clinical conundrum in all intra-abdominal malignancies. Via functional and transcriptomic experiments of ascites-treated PC cells, we identify ...STAT3 as a key signaling pathway. Integrative analysis of publicly available databases and correlation with clinical cohorts (n = 7,359) reveal putative clinically significant activating ligands of STAT3 signaling. We further validate a 3-biomarker prognostic panel in ascites independent of clinical covariates in a prospective study (n = 149). Via single-cell sequencing experiments, we uncover that PAI-1, a key component of the prognostic biomarker panel, is largely secreted by fibroblasts and mesothelial cells. Molecular stratification of ascites using PAI-1 levels and STAT3 activation in ascites-treated cells highlight a therapeutic opportunity based on a phenomenon of paracrine addiction. These results are recapitulated in patient-derived ascites-dependent xenografts. Here, we demonstrate therapeutic proof of concept of direct ligand inhibition of a prognostic target within an enclosed biological space.
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•PAI-1 is a key STAT3 activating ligand in ascites and predicts patients' survival•Single-cell analysis identifies fibroblasts as key secretors of PAI-1 into ascites•PAI-1 and p-STAT3 molecular stratification predicts therapeutic efficacy•PAI-1 inhibition is therapeutically effective in paracrine addicted PC mouse model
Hendrikson et al. demonstrate that a phenomenon of paracrine addiction in a closed biological system can be exploited for therapy following molecular stratification in peritoneal carcinomatosis. We present proof-of-concept experiments performed in patient-derived ascites-dependent xenografts targeting PAI-1, a key ligand secreted by fibroblasts and mesothelial cells into ascites.
Aicardi-Goutières syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in ...genes encoding the 3′→5′ exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in
TREX1, RNASEH2A, RNASEH2B, and
RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an
RNASEH2A or
RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous
TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in
TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in
RNASEH2A, RNASEH2B, and
RNASEH2C were missense. We identified an
RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with
TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to
RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with
TREX1, RNASEH2A, and
RNASEH2C mutations versus 8.0%
RNASEH2B mutation–positive patients were known to have died (
P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.
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