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ALG8 protein-truncating variants (PTVs) have previously been described in patients with polycystic liver disease and in some cases cystic kidney disease. Given a lack of well-controlled studies, we determined whether individuals heterozygous for ALG8 PTVs are at increased risk of cystic kidney disease in a large, unselected health system-based observational cohort linked to electronic health records in Pennsylvania (Geisinger-Regeneron DiscovEHR MyCode study). Out of 174,172 patients, 236 were identified with ALG8 PTVs. Using ICD-based outcomes, patients with these variants were significantly at increased risk of having any kidney/liver cyst diagnosis (Odds Ratio 2.42, 95% confidence interval: 1.53-3.85), cystic kidney disease (3.03, 1.26-7.31), and nephrolithiasis (1.89, 1.96-2.97). To confirm this finding, blinded radiology review of computed tomography and magnetic resonance imaging studies was completed in a matched cohort of 52 thirty-plus year old ALG8 PTV heterozygotes and related non-heterozygotes. ALG8 PTV heterozygotes were significantly more likely to have cystic kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%), or bilateral kidney cysts (69.2% vs. 15.4%), but not one or more liver cyst (11.5% vs. 7.7%). In publicly available UK Biobank data, ALG8 PTV heterozygotes were at significantly increased risk of ICD code N28 (other disorders of kidney/ureter) (3.85% vs. 1.33%). ALG8 PTVs were not associated with chronic kidney disease or kidney failure in the MyCode study or the UK Biobank data. Thus, PTVs in ALG8 result in increased risk of a mild cystic kidney disease phenotype.
Asunto(s)
Quistes , Hepatopatías , Enfermedades Renales Poliquísticas , Riñón Poliquístico Autosómico Dominante , Humanos , Enfermedades Renales Poliquísticas/patología , Riñón/patología , Quistes/genética , Hepatopatías/diagnóstico , Hepatopatías/epidemiología , Hepatopatías/genética , Riñón Poliquístico Autosómico Dominante/diagnóstico , Riñón Poliquístico Autosómico Dominante/epidemiología , Riñón Poliquístico Autosómico Dominante/genética , GlucosiltransferasasRESUMEN
In various infections or vaccinations of mice or humans, reports of the persistence and the requirements for restimulation of the cytotoxic mediators granzyme B (GrB) and perforin (PRF) in CD8+ T cells have yielded disparate results. In this study, we examined the kinetics of PRF and GrB mRNA and protein expression after stimulation and associated changes in cytotoxic capacity in virus-specific memory cells in detail. In patients with controlled HIV or cleared respiratory syncytial virus (RSV) or influenza virus infections, all virus-specific CD8+ T cells expressed low PRF levels without restimulation. Following stimulation, they displayed similarly delayed kinetics for lytic protein expression, with significant increases occurring by days 1 to 3 before peaking on days 4 to 6. These increases were strongly correlated with, but were not dependent upon, proliferation. Incremental changes in PRF and GrB percent expression and mean fluorescence intensity (MFI) were highly correlated with increases in HIV-specific cytotoxicity. mRNA levels in HIV-specific CD8+ T-cells exhibited delayed kinetics after stimulation as with protein expression, peaking on day 5. In contrast to GrB, PRF mRNA transcripts were little changed over 5 days of stimulation (94-fold versus 2.8-fold, respectively), consistent with posttranscriptional regulation. Changes in expression of some microRNAs, including miR-17, miR-150, and miR-155, suggested that microRNAs might play a significant role in regulation of PRF expression. Therefore, under conditions of extremely low or absent antigen levels, memory virus-specific CD8+ T cells require prolonged stimulation over days to achieve maximal lytic protein expression and cytotoxic capacity.IMPORTANCE Antigen-specific CD8+ T cells play a major role in controlling most virus infections, primarily by perforin (PRF)- and granzyme B (GrB)-mediated apoptosis. There is considerable controversy regarding whether PRF is constitutively expressed, rapidly increased similarly to a cytokine, or delayed in its expression with more prolonged stimulation in virus-specific memory CD8+ T cells. In this study, the degree of cytotoxic capacity of virus-specific memory CD8+ T cells was directly proportional to the content of lytic molecules, which required antigenic stimulation over several days for maximal levels. This appeared to be modulated by increases in GrB transcription and microRNA-mediated posttranscriptional regulation of PRF expression. Clarifying the requirements for maximal cytotoxic capacity is critical to understanding how viral clearance might be mediated by memory cells and what functions should be induced by vaccines and immunotherapies.
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Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Infecciones por VIH/inmunología , Animales , Antígenos CD8/metabolismo , Granzimas/metabolismo , VIH/metabolismo , Infecciones por VIH/metabolismo , Humanos , Cinética , Ratones , MicroARNs , Perforina , ARN Mensajero/metabolismoRESUMEN
MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
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Anomalías Múltiples/genética , Anomalías Craneofaciales/genética , Discapacidad Intelectual/genética , Trastornos del Desarrollo del Lenguaje/genética , Malformaciones del Sistema Nervioso/genética , Transactivadores/genética , Proteínas Supresoras de Tumor/genética , Anomalías Múltiples/diagnóstico por imagen , Adolescente , Arteria Basilar/anomalías , Arteria Basilar/diagnóstico por imagen , Arterias Carótidas/anomalías , Arterias Carótidas/diagnóstico por imagen , Vermis Cerebeloso/anomalías , Vermis Cerebeloso/diagnóstico por imagen , Cerebelo/anomalías , Cerebelo/diagnóstico por imagen , Niño , Preescolar , Estudios de Cohortes , Hibridación Genómica Comparativa , Anomalías Craneofaciales/diagnóstico por imagen , Femenino , Fibroblastos/metabolismo , Humanos , Imagenología Tridimensional , Lactante , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Degradación de ARNm Mediada por Codón sin Sentido , Polimicrogiria/diagnóstico por imagen , Polimicrogiria/genética , RNA-Seq , Reacción en Cadena en Tiempo Real de la Polimerasa , Síndrome , Tomografía Computarizada por Rayos X , Secuenciación del Exoma , Secuenciación Completa del GenomaRESUMEN
We specialize techniques from topological data analysis to the problem of characterizing the topological complexity (as defined in the body of the paper) of a multiclass data set. As a by-product, a topological classifier is defined that uses an open subcovering of the data set. This subcovering can be used to construct a simplicial complex whose topological features (e.g., Betti numbers) provide information about the classification problem. We use these topological constructs to study the impact of topological complexity on learning in feedforward deep neural networks (DNNs). We hypothesize that topological complexity is negatively correlated with the ability of a fully connected feedforward deep neural network to learn to classify data correctly. We evaluate our topological classification algorithm on multiple constructed and open-source data sets. We also validate our hypothesis regarding the relationship between topological complexity and learning in DNN's on multiple data sets.
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Rationale & Objective: While the use of telemedicine has increased dramatically across disciplines, patient perspectives on telemedicine related to chronic kidney disease are not well understood. We systematically reviewed qualitative studies on patients with chronic kidney disease as well as those with kidney transplant to better understand these patients' perspectives related to telemedicine. Study Design: Qualitative meta-analysis. Setting & Participants: Pre-dialysis chronic kidney disease and kidney transplant patients that used telemedicine. Selection Criteria for Studies: English language studies published in the year 2000 and beyond that investigated patient perspectives in a qualitative manner. Works that were not qualitative or did not focus on provider-patient interactive modes of telemedicine were excluded. Data Extraction: 375 articles were pulled from PubMed, Embase, and Academic Science Premier. After filtering, 8 final articles were selected. These articles were critically appraised for quality and were used in the final analysis. Analytical Approach: We used a grounded theory approach to develop a codebook to systematically review each of the selected articles through a qualitative meta-analysis of the included literature. Results: Telemedicine was seen by patients to have notable strengths as well as weaknesses. These characteristics can be organized into 4 primary themes (autonomy, logistics, privacy/confidentiality, and trust). Within each primary theme, we identified subthemes. Universally, all articles included the subtheme "fewer trips to the health care facility" as a beneficial factor of telemedicine within the primary theme "logistics." A majority (6 of 8) of the articles included positive patient perspectives on the primary theme "autonomy" in terms of telemedicine promoting the subtheme of "engagement." Patients' views on telemedicine were mixed regarding the primary themes of "privacy/confidentiality" and "trust" related to telemedicine. Limitations: Lack of provider perspectives, non-English studies, and studies published before the year 2000. Articles published after the start of data extraction were also not included. Conclusions: Telemedicine should continue to be offered to patients with chronic kidney disease and kidney transplant patients to facilitate access. Additional research should focus on ways to decrease negative factors experienced by some patients such as difficulty using the technology.
Telemedicine is the ability to do medical visits using technology such as telephone and video calls. For this study, we researched the experiences and perspectives of patients with chronic kidney disease or kidney transplant, who often require complex, coordinated care. We found 8 articles on this topic from 6 different countries and analyzed the text of these publications to see if there were any common themes across the articles. We found 4 major themes: autonomy, logistics, privacy/confidentiality, and trust. Within each of these themes, there were positive and negative connotations to telemedicine. Overall, we feel that telemedicine should continue to be available for interested patients, and more research should be done to remove barriers to telemedicine.
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Living a healthy lifestyle is one of the safest and most cost-effective ways to improve one's quality of life and prevent and/or manage chronic disease. As such, current CKD management guidelines recommend that patients adhere to a healthy diet, perform ≥150 minutes per week of physical activity, manage their body weight, abstain from tobacco use, and limit alcohol. However, there are limited studies that investigate the relationship between these lifestyle factors and the progression of CKD among people with established CKD. In this narrative review, we examine the reported frequencies of health lifestyle behavior engagement among individuals with non-dialysis-dependent CKD and the existing literature that examines the influences of diet, physical activity, weight management, alcohol consumption, and tobacco use on the progression of CKD, as measured by decline in GFR, incident ESKD, or elevated proteinuria or albuminuria in individuals with CKD. Many of the available studies are limited by length of follow-up and small sample sizes, and meta-analyses were limited because the studies were sparse and had heterogeneous classifications of behaviors and/or referent groups and of CKD progression. Further research should be done to determine optimal methods to assess behaviors to better understand the levels at which healthy lifestyle behaviors are needed to slow CKD progression, to investigate the effect of combining multiple lifestyle behaviors on important clinical outcomes in CKD, and to develop effective techniques for behavior change. Despite the lack of evidence of efficacy from large trials on the ability of lifestyle behaviors to slow CKD progression, maintaining a healthy lifestyle remains a cornerstone of CKD management given the undisputed benefits of healthy lifestyle behaviors on cardiovascular health, BP control, and survival.