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991.
In the chronic disabling disease multiple sclerosis (MS), migration of monocytes across the blood-brain barrier is a crucial step in the formation of new lesions in the central nervous system (CNS). Infiltrating monocyte-derived macrophages secrete inflammatory mediators such as oxygen radicals, which contribute to axonal demyelination and damage, resulting in neurological deficits. Flavonoids are compounds occurring naturally in food, which scavenge oxygen radicals and have antiinflammatory properties. To investigate whether they might suppress clinical symptoms in MS, we treated rats sensitized for acute and chronic experimental allergic encephalomyelitis, an experimental model of MS, with flavonoids. We demonstrated that the flavonoid luteolin substantially suppressed clinical symptoms and prevented relapse when administered either before or after disease onset. Luteolin treatment resulted in reduced inflammation and axonal damage in the CNS by preventing monocyte migration across the brain endothelium. Luteolin influenced migration by modulating the activity of Rho GTPases, signal transducers involved in transendothelial migration. Oral administration of luteolin also significantly reduced clinical symptoms.  相似文献   
992.
Activation of the cell-surface receptor Fas can lead to apoptosis in parenchymal cells in the liver, and if severe enough, result in fulminant hepatic failure and animal death. In the present study, we have examined the roles played by the Bcl-2 family members Bcl-xL and Bid in regulating this response. To do this, we have developed chemically modified 2'-O-(2-methoxy) ethyl antisense inhibitors of both Bid and Bcl-xL expression. In Balb/c mice, dosing with these antisense oligonucleotides reduced expression of the targeted mRNA by greater than 80% in the liver. This reduction was highly dependent upon oligonucleotide sequence and oligonucleotide dose. Reduction of Bcl-xL expression resulted in a potentiation of Fas-mediated apoptosis in liver and significant increase of the lethality of Fas-mediated fulminant hepatitis (p < 0.0001). In contrast, reduction of Bid expression protected the animals against Fas-mediated fulminant hepatitis and death (p < 0.0001). Simultaneous dosing of mice with Bcl-xL and Bid-targeting antisense oligonucleotides resulted in an inhibition of expression of both targeted proteins and protection of the animals from Fas-mediated apoptosis. These results demonstrate, for the first time, the role of Bcl-xL in regulating responses to proapoptotic Fas signaling in mouse liver. In addition, this is the first reported example demonstrating the ability of antisense inhibitors to reduce expression of multiple proteins in animals by simultaneous dosing.  相似文献   
993.
X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKKgamma, the regulatory subunit of the IkappaB kinase (IKK) complex. IKK normally phosphorylates the IkappaB-inhibitors of NF-kappaB at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-kappaB complexes to translocate into the nucleus where they activate their target genes. Here, we describe an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IkappaBalpha. This mutation is gain-of-function, as it enhances the inhibitory capacity of IkappaBalpha by preventing its phosphorylation and degradation, and results in impaired NF-kappaB activation. The developmental, immunologic, and infectious phenotypes associated with hypomorphic NEMO and hypermorphic IKBA mutations largely overlap and include EDA, impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta, and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily members and severe bacterial diseases. However, AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. Our report highlights both the diversity of genotypes associated with EDA-ID and the diversity of immunologic phenotypes associated with mutations in different components of the NF-kappaB signaling pathway.  相似文献   
994.

Background

The complexity and variation in ventilator associated pneumonia (VAP) definitions in paediatrics may pose threats to the reliable identification of VAP. The revision of the surveillance definition to ventilator-associated event (VAE) has been mandated in adult populations, to overcome these issues. However, the evidence for application of the definition is unknown in children.

Objectives

To review the evidence on the application of the new VAE surveillance definition in paediatric population and examine the potential challenges in clinical practice.

Review methods

A systematic approach was used to locate and synthesise the relevant paediatric literature. Studies were appraised according to epidemiological appraisal instrument (EAI) and the grades of evidence in the National Health Medical Research Council (NHMRC) guidelines.

Results

Seven studies met the inclusion criteria. Quality of study methods was above 50% on the EAI. The overall grade of evidence was assessed as C (satisfactory). The incidence of VAE in children ranged from 1.1 to 20.9 per 1000 ventilator days as a result of variations in surveillance criteria across included studies. There is little agreement between the new VAE and PNU/VAP surveillance definition in the identification of VAP. Challenges in the application of VAE surveillance were related to; the difference in modes of ventilation used in children versus adults, inconclusive criteria tailored to paediatric samples and a lack of data that support for automatic data extraction applied in paediatric studies.

Conclusion

This review demonstrated promising evidence using the new VAE surveillance definition to define the VAE in children, but the level of the evidence is low. Before the possibility of real implementation in clinical settings, challenges related to VAE paediatric specific criteria’ and the value of automated data collection need to be considered.  相似文献   
995.
996.
Richardson T  Thomas P  Ryder J  Kerr D 《Diabetes care》2005,28(6):1316-1320
OBJECTIVE: The aim of this study was to investigate the effect of caffeine (in doses equivalent to normal daily ingestion) on rates and severity of hypoglycemia in patients with long-standing type 1 diabetes to determine the relationship between caffeine, autonomic function, and hypoglycemia. RESEARCH DESIGN AND METHODS: Using a double-blinded randomized study, we investigated the effect of caffeine versus placebo in 19 patients with long-standing type 1 diabetes using continuous glucose sensing technology and simultaneous assessment of autonomic function using Holter monitoring. RESULTS: Caffeine reduced the duration of nocturnal hypoglycemia with a mean duration of 49 minutes (range 0-235) versus 132 (0-468) minutes (P = 0.035). The reduction in duration of nighttime hypoglycemia was due to a decline in the number of episodes of moderate hypoglycemia at the expense of mild hypoglycemic episodes (P = 0.04). There was no overall correlation between reduced heart rate variability (a marker of autonomic dysfunction) and hypoglycemic events (r(s) = 0.12, P = 0.62). CONCLUSIONS: Our results suggest that caffeine is associated with a significant reduction in nocturnal hypoglycemia. The reduction in nocturnal hypoglycemia was not linked to the concomitant rise in parasympathetic activity associated with caffeine.  相似文献   
997.

Background

The use of robotic platforms in performing laparoscopic Roux-en-Y gastric bypass (LRYGB) is increasing, though their safety compared with the conventional laparoscopic approach remains unclear.

Objective

The objective of this study was to evaluate perioperative data and 30-day outcomes of conventional and robot-assisted LRYGB using the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program data registry.

Setting

University health network, United States.

Methods

We reviewed all conventional and robot-assisted LRYGB cases entered between January 1 and December 31, 2016 in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program data registry. Demographic characteristics and 30-day outcomes were analyzed based on separate Mann-Whitney rank sums tests, χ2, or Fisher's exact tests as appropriate, with P ≤ .05 denoting statistical significance with no adjustment for multiple testing.

Results

Of the 39,425 patients who underwent LRYGB, 2822 were robot-assisted. The robot-assisted approach required significantly more time (138 versus 108 min, P < .0001). Rates of organ space infection, bleeding, and other significant adverse events after the conventional and robot-assisted approaches were .3% versus .5% (P?=?.13), 1.1% versus .8% (P?=?.11), and 2.3% versus 2.3% (P?=?.96), respectively. There were also no significant differences in the rates of mortality, length of stay, reoperation, or readmission between the 2 groups.

Conclusions

Robot-assisted LRYGB is an increasingly popular alternative to the conventional laparoscopic approach. According to the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database, the early safety of these 2 techniques is equal, although the robotic approach requires more operative time.  相似文献   
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