4-O-卤代酰基-4′-去甲基表鬼臼毒素类似物的合成与抗肿瘤活性

为考察4′-去甲表鬼臼毒素C_4位上联结含卤素原子的酯化侧链时对化合物抗肿瘤活性的影响,设计并采用选择性酯化方法合成了9个新的4′-去甲基表鬼臼毒素酯化产物。其中标题化合物在L_(1210)白血病肿瘤细胞与KB细胞的体外生长抑制试验中普遍表现出显著的抑制活性,大部分化合物活性超过依托泊甙。而普通脂酸酯的活性较弱。     

The mechanism of action of the antiinflammatory agents dexamethasone and Auranofin in human polymorphonuclear leukocytes

Human polymorphonuclear neutrophils (PMN) were treated with the antiinflammatory agents dexamethasone or Auranofin. PMN treated with dexamethasone in a dose range of 0.25-1 microM or Auranofin, 5-15 mM, were stimulated with 10(-7)M N-formyl-methionyl-leucyl-phenylalanine (FMLP). These agents were shown to inhibit the functional responses of degranulation and superoxide production in a dose-dependent manner. Similarly, the change in electrophoretic mobility, reflecting cell surface charge, was blocked. While both agents inhibited change in the fluorescence of the calcium chelate probe chlorotetracycline (CTC), the pattern of inhibition was significantly different. Dexamethasone appeared to inhibit the CTC response during its latter phases, while Auranofin inhibited all aspects of the CTC response. Auranofin was additionally shown to significantly decrease specific binding of FMLP, as well as the number of FMLP receptors. The two agents thus appear to act by different mechanisms. Dexamethasone is shown to have an effect on membrane-bound calcium release as measured by CTC, while Auranofin interferes with receptor binding.     

Determinants of Follow-Up Participation in the Internet-Based European Influenza Surveillance Platform Influenzanet

Background

“Influenzanet” is a network of Internet-based platforms aimed at collecting real-time data for influenza surveillance in several European countries. More than 30,000 European volunteers participate every year in the study, representing one of the largest existing Internet-based multicenter cohorts. Each week during the influenza season, participants are asked to report their symptoms (if any) along with a set of additional questions.

Objective

Focusing on the first influenza season of 2011-12, when the Influenzanet system was completely harmonized within a common framework in Sweden, the United Kingdom, the Netherlands, Belgium, France, Italy, and Portugal, we investigated the propensity of users to regularly come back to the platform to provide information about their health status. Our purpose was to investigate demographic and behavioral factors associated with participation in follow-up.

Methods

By means of a multilevel analysis, we evaluated the association between regular participation during the season and sociodemographic and behavioral characteristics as measured by a background questionnaire completed by participants on registration.

Results

We found that lower participation in follow-up was associated with lower educational status (odds ratio [OR] 0.80, 95% CI 0.75-0.85), smoking (OR 0.64, 95% CI 0.59-0.70), younger age (OR ranging from 0.30, 95% CI 0.26-0.33 to 0.70, 95% CI 0.64-0.77), not being vaccinated against seasonal influenza (OR 0.77, 95% CI 0.72-0.84), and living in a household with children (OR 0.69, 95% CI 0.65-0.74). Most of these results hold when single countries are analyzed separately.

Conclusions

Given the opportunistic enrollment of self-selected volunteers in the Influenzanet study, we have investigated how sociodemographic and behavioral characteristics may be associated with follow-up participation in the Influenzanet cohort. The study described in this paper shows that, overall, the most important determinants of participation are related to education and lifestyle: smoking, lower education level, younger age, people living with children, and people who have not been vaccinated against seasonal influenza tend to have a lower participation in follow-up. Despite the cross-country variation, the main findings are similar in the different national cohorts, and indeed the results are found to be valid also when performing a single-country analysis. Differences between countries do not seem to play a crucial role in determining the factors associated with participation in follow-up.     

Candida glabrata mutants demonstrating paradoxical reduced caspofungin susceptibility but increased micafungin susceptibility

Echinocandins, including caspofungin (CSP) and micafungin (MCF), are highly active versus Candida glabrata (MIC of ≤0.06 μg/ml). True resistance (MIC of ≥1 μg/ml) is a rare event and strictly associated with mutations in β-1,3-glucan synthase gene FKS1 or FKS2. In contrast, we show here that mutants exhibiting reduced susceptibility to CSP (CRS; MICs of 0.12 to 0.5 μg/ml) are readily selected in vitro and, paradoxically, demonstrate increased susceptibility to MCF (MIS) ranging from 4- to 32-fold. CRS-MIS mutants were generated from all 10 C. glabrata strains tested and were tentatively identified within a collection of clinical isolates. Intriguingly, sequencing and gene disruption demonstrated that CRS-MIS is Fks independent.     

CE: Continuing Education ArticleMANAGEMENT OF ANAEMIA IN CHRONIC KIDNEY DISEASE

Anaemia is an almost universal issue that develops in the later stages of chronic kidney disease (CKD) primarily due to a lack of erythropoietin (EPO) and the depressed EPO response in bone marrow. This can have a profound effect on the patient's lifestyle and quality of life. Knowledge of both the psychosocial and clinical areas of CKD is imperative for healthcare professionals so that they can be at the forefront of improvements of CKD patient care.     

Inequities in Health Outcomes in Children and Adults With Type 1 Diabetes: Data From the T1D Exchange Quality Improvement Collaborative

Health care inequities among racial and ethnic groups remain prevalent. For people with type 1 diabetes who require increased medical access and care, disparities are seen in access to care and health outcomes. This article reports on a study by the T1D Exchange Quality Improvement Collaborative evaluating differences in A1C, diabetic ketoacidosis (DKA), severe hypoglycemia, and technology use among racial and ethnic groups. In a diverse cohort of nearly 20,000 children and adults with type 1 diabetes, A1C was found to differ significantly among racial and ethnic groups. Non-Hispanic Blacks had higher rates of DKA and severe hypoglycemia and the lowest rate of technology use. These results underscore the crucial need to study and overcome the barriers that lead to inequities in the care and outcomes of people with type 1 diabetes.

Health inequities among racial and ethnic groups persist in both children and adults. Individuals with chronic conditions such as type 1 diabetes require increased medical access and care. Yet, there are disparities in access to care and health outcomes (1). The incidence of type 1 diabetes is increasing in the United States across all populations, and most significantly among Hispanic youths, but despite the higher incidence, health disparities continue to worsen among specific racial and ethnic groups (2,3).Mean A1C levels were found to be higher in Hispanics and non-Hispanic Blacks with type 1 diabetes compared with non-Hispanic Whites in the largest U.S. study to date, which included ∼11,000 youths and young adults in the T1D Exchange clinic network and registry (4). Non-Hispanic Blacks and Hispanics have been reported to perform fewer blood glucose checks per day than Non-Hispanic Whites (5,6). One study evaluating A1C trajectories over time in ∼16,000 youths from Australia, Europe, and the United States found that minority groups were more likely to have increasing A1C levels over time compared with Non-Hispanic Whites, specifically in the T1D Exchange and Diabetes-Patienten-Verlaufsdokumentation registries (7).Disparities also exist in rates of acute complications such as diabetic ketoacidosis (DKA) and severe hypoglycemia, although literature in this area is more limited. One study found that Non-Hispanic Blacks were 2.5 times more likely to have at least one DKA episode in the previous 12 months compared with Non-Hispanic Whites. They were also 2.5 times more likely than Non-Hispanic Whites to have at least one severe hypoglycemic event in the previous 12 months (4). Rates of mortality in diabetes are also twice as high among Non-Hispanic Blacks compared with other racial groups (8).One area of diabetes care that has improved diabetes management is the advancement of technology, including insulin pumps and continuous glucose monitoring (CGM) systems. However, use of these advanced diabetes technologies varies by population. Both the T1D Exchange and the SEARCH for Diabetes in Youth registries reported that Non-Hispanic White youths are more likely to use an insulin pump than their Black and Hispanic counterparts (4,9,10). The T1D Exchange registry found that Non-Hispanic White youths were 1.9 times more likely than Non-Hispanic Black youths and 3.6 times more likely than Hispanic youths to use an insulin pump. This finding is particularly important because it is known that insulin pump therapy can contribute to lower A1C levels (11), and Non-Hispanic Black and Hispanic youths are more likely to have higher A1C levels (4,7). Agarwal et al. (12) recently found that insulin pump use was one variable that helped account for the difference in A1C levels between Black and White young adults with type 1 diabetes. Studies of CGM use among racial and ethnic groups are very limited. One study showed that, among youths <13 years of age, Non-Hispanic Whites were more likely than Hispanics to use CGM, but this difference was not seen in older children or adults (13).Although there have been multiple studies evaluating A1C differences among racial and ethnic groups, there are limited population studies, and none have examined inequities in acute complication rates and technology use. This study uses a dataset with a large cohort of individuals with type 1 diabetes in a real-world setting to examine racial and ethnic differences in glycemic control, acute complications rates, and technology use.