The impact of inflammation suppressor pathways on Alzheimer’s disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, ...interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mouse deficient in Il10 (APP/PS1+Il10−/−). Quantitative in silico 3D modeling revealed activated Aβ phagocytic microglia in APP/PS1+Il10−/− mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1+Il10−/− brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. In vitro knockdown of microglial Il10-Stat3 signaling endorsed Aβ phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aβ uptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated in AD patient brains. Our results suggest that “rebalancing” innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.
•Il10 deficiency promotes Alzheimer’s β-amyloid clearance in APP/PS1 mice•Il10 deficiency mitigates synaptic and cognitive deficits in APP/PS1 mice•Innate immunity is “rebalanced” in Il10 deficient APP/PS1 mouse brains•Blocking IL-10 may be therapeutically relevant for Alzheimer’s disease
In this issue, Guillot-Sestier et al. demonstrate that inhibiting IL-10 signaling, a key anti-inflammatory pathway, alters microglial activation in favor of cerebral Aβ phagocytosis. These results highlight that rebalancing cerebral innate immunity may be therapeutically relevant for Alzheimer’s disease.
Cancer cell secretion of TGF-β is a potent mechanism for immune evasion. However, little is known about how central nervous system tumors guard against immune eradication. We sought to determine the ...impact of T-cell TGF-β signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-β signaling mitigated tumor progression in the smoothened A1 (SmoA1) transgenic MB mouse. T regulatory cells were nearly abolished and antitumor immunity was mediated by CD8 cytotoxic T lymphocytes. To define the CD8 T-cell subpopulation responsible, primed CD8 T cells were adoptively transferred into tumor-bearing immunocompromised SmoA1 recipients. This led to generation of CD8 ⁺/killer cell lectin-like receptor G1 high (KLRG1 ʰⁱ)/IL-7R ˡᵒ short-lived effector cells that expressed granzyme B at the tumor. These results identify a cellular immune mechanism whereby TGF-β signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.
Recent findings have indicated the presence of a progenitor domain at the marginal zone/layer 1 of the cerebral cortex, and it has been suggested that these progenitors have neurogenic and gliogenic ...potential. However, their contribution to the histogenesis of the cortex remains poorly understood due to difficulties associated with genetically manipulating these unique cells in a population-specific manner.
We have adapted the electroporation technique to target pial surface cells for rapid genetic manipulation at postnatal day 2. In vivo data show that most of these cells proliferate and progressively differentiate into both neuronal and glial subtypes. Furthermore, these cells localize to the superficial layers of the optic tectum and cerebral cortex prior to migration away from the surface.
We provide a foundation upon which future studies can begin to elucidate the molecular controls governing neural progenitor fate, migration, differentiation, and contribution to cortical and tectal histogenesis. Furthermore, specific genetic targeting of such neural progenitor populations will likely be of future clinical interest.
To examine the surgical indications and clinical outcomes of a large cohort of patients with necrotizing pancreatitis.
Mortality after debridement for necrotizing pancreatitis continues to be ...inordinately high. The clinical experience with patients who underwent uniform surgical treatment for necrotizing pancreatitis at the Massachusetts General Hospital over a 15-year period is described.
Retrospective review of 167 patients with necrotizing pancreatitis who required intervention and were treated with single stage debridement and a closed packing technique. Particular emphasis was placed on the indication for surgery and the presence of infected necrosis. Multiple logistic regression models were used to identify predictors of mortality.
The primary preoperative indication for operation was infected necrosis (51%), but intraoperative cultures proved that 72% of the entire cohort was infected. The rate of reoperation was 12.6%, and 29.9% of patients required percutaneous interventional radiology drainage after initial debridement. Overall operative mortality was 11.4% (19/167), but higher in patients who were operated upon before 28 days (20.3% vs. 5.1%, P = 0.002). Other important predictors of mortality included organ failure > or =3 (OR = 2.4, P = 0.001), postoperative intensive care unit stay > or =6 days (OR = 15.9, P = 0.001), and female gender (OR = 5.41, P = 0.02).
Open, transperitoneal debridement followed by closed packing and drainage results in the lowest reported mortality and reoperation rates, and provides a standard for comparing other methods of treatment. A negative FNA does not reliably rule out infection. The clinical status of the patients and not proof of infection should determine the need for debridement.
Clostridium thermocellum has emerged as a leading bioenergy-relevant microbe due to its ability to solubilize cellulose into carbohydrates, mediated by multicomponent membrane-attached complexes ...termed cellulosomes. To probe microbial cellulose utilization rates, it is desirable to be able to measure the concentrations of saccharolytic enzymes and estimate the total amount of cellulosome present on a mass basis. Current cellulase determination methodologies involve labor-intensive purification procedures and only allow for indirect determination of abundance. We have developed a method using multiple reaction monitoring (MRM-MS) to simultaneously quantitate both enzymatic and structural components of the cellulosome protein complex in samples ranging in complexity from purified cellulosomes to whole cell lysates, as an alternative to a previously developed enzyme-linked immunosorbent assay (ELISA) method of cellulosome quantitation. The precision of the cellulosome mass concentration in technical replicates is better than 5% relative standard deviation for all samples, indicating high precision for determination of the mass concentration of cellulosome components.
In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic ...variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations.
We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles.
We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases.
Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (
) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with
DNA methylation and
gene expression levels.
Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated
and
.
Clostridium thermocellum has emerged as a leading bioenergy-relevant microbe due to its ability to solubilize cellulose into carbohydrates, mediated by multi-component membrane-attached complexes ...termed cellulosomes. To probe microbial cellulose utilization rates, it is desirable to be able to measure the concentrations of saccharolytic enzymes and estimate the total amount of cellulosome present on a mass basis. Current cellulase determination methodologies involve labor-intensive purification procedures and only allow for indirect determination of abundance. We have developed a method using multiple reaction monitoring (MRM-MS) to simultaneously quantitate both enzymatic and structural components of the cellulosome protein complex in samples ranging in complexity from purified cellulosomes to whole cell lysates, as an alternative to a previously-developed enzyme-linked immunosorbent assay (ELISA) method of cellulosome quantitation. The precision of the cellulosome mass concentration in technical replicates is better than 5% relative standard deviation for all samples, indicating high precision for determination of the mass concentration of cellulosome components.
RESUMEN Introducción: La anestesia regional guiada por ultrasonografía es una técnica segura y efectiva para el manejo del dolor postoperatorio. Este estudio evalúa la implementación de un protocolo ...analgésico para el reemplazo total primario de rodilla (RTPR). Métodos: Estudio observacional ambispectivo de cohortes no aleatorizado, realizado en un grupo de pacientes llevados a RTPR que recibieron infiltración de anestésico local periarticular más bloqueo del canal de aductores (IAL+BCA) como parte de un nuevo protocolo analgésico, frente a un grupo previo que recibió catéter perineural femoral más bloqueo del nervio ciático (CPF+BNC). La valoración de la intensidad del dolor se realizó utilizando la escala verbal numérica (EVN). El desenlace principal fue el dolor postoperatorio inmediato a las 24 y 48 horas. Se evaluó el cumplimiento de metas de rehabilitación física a las 48 horas como desenlace secundario. Resultados: Se analizaron 112 pacientes (67 en IAL + BCA y 45 en CPF + BNC). Ambas poblaciones fueron comparables en variables demográficas. La mediana del dolor en reposo en el primer y segundo día postoperatorios fue EVN 2/10 para ambos grupos. El promedio del dolor en movimiento en el segundo día postoperatorio fue EVN 5/10 para los pacientes con IAL + BCA y 4/10 para los pacientes con CPF + BNC, p = 0,073. El porcentaje de pacientes que cumplieron el 80 % o más de las metas de rehabilitación fue similar en ambos grupos (p = 0,201). Conclusiones: Ambas técnicas son equivalentes en el manejo analgésico postoperatorio del RTPR durante las primeras 48 horas. A pesar de que es conocido que la técnica de IAL + BCA genera menos compromiso motor del cuádriceps, esto no se reflejó en un mejor desempeño durante la rehabilitación física, posiblemente por un insuficiente control analgésico a las 48 horas.
This dissertation project addresses three observations: the degree to which researchers routinely use data collected only on survivors, ignoring that who is included in samples is pre-determined by ...non-random mortality; that historical mortality gaps between blacks and whites have generated a cumulative demographic contraction among blacks that constitute a non-trivial vanishing electorate; and that differences in infant mortality rates (IMRs) between blacks and whites strongly correlate with the party that controls the presidency. I used data from several sources including the Centers for Disease Control and Prevention, the Multiple Causes of Death, MIDUS, and the U.S. Census Bureau among others. Because researchers are always dealing with samples truncated by non-random mortality, paradigms in social research like the relationship between age and participation are partially spurious. I find that the effect that age exerts on participation is mediated by mortality rates linked to differences in SES because, as time progresses, low-SES individuals (i.e., low-level participants) die younger than high-SES individuals (i.e., high-level participants). I also set forth a model for the impact of racial mortality gaps on the total vote lost among blacks (1970-2004). Because the dead cannot vote or voice opinions, excess deaths exacerbate the imbalance of socio-political power, especially between blacks and whites, where health differences are most pronounced. I show that the total number of excess deaths among blacks is large enough to affect the outcome of presidential elections. And, finally, I investigate the fluctuations of national and black and white IMRs associated with the political party in power. Party differences in policy preferences lead to different results in many aspects of social development, of which health is no exception. Results show that a good portion of the comparative international underperformance of the U.S. for IMR as well as of persistent black-white disparities in IMR is related to variations imparted under Republican presidents between 1965 and 2010.
To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC).
The study cohort comprised 554 patients with a definite diagnosis ...of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% 95% confidence interval (CI) 1.9-3.3. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function.
The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.
PDF
