Role of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels.

Dyslipidemia is a main driver of cardiovascular diseases. The ability of macrophages to scavenge excess lipids implicate them as mediators in this process and understanding the mechanisms underlying macrophage lipid metabolism is key to the development of new treatments. Here, we investigated how adipose tissue macrophages regulate post-prandial cholesterol transport. Single-cell RNA sequencing and protected bone marrow chimeras demonstrated that ingestion of lipids led to specific transcriptional activation of a population of resident macrophages expressing Lyve1, Tim4, and ABCA1. Blocking the phosphatidylserine receptor Tim4 inhibited lysosomal activation and the release of post-prandial high density lipoprotein cholesterol following a high fat meal. Both effects were recapitulated by chloroquine, an inhibitor of lysosomal function. Moreover, clodronate-mediated cell-depletion implicated Tim4+ resident adipose tissue macrophages in this process. Thus, these data indicate that Tim4 is a key regulator of post-prandial cholesterol transport and adipose tissue macrophage function and may represent a novel pathway to treat dyslipidemia.

Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation.

Transduction of the vascular endothelium by adeno-associated virus (AAV) vectors would have broad appeal for gene therapy. However, levels of transduction by AAV serotype-2 are low, an observation linked to deficiencies in endothelial cell binding, sequestration of virions in the extracellular matrix and/or virion degradation by the proteasome. Strategies to improve transduction of endothelial cells include AAV-2 capsid targeting using small peptides isolated by phage display or the use of alternate serotypes. Previously, we have shown that AAV serotypes-3 through -6 transduce endothelial cells with poor efficiency. Recently, AAV serotypes-7 and -8 have been shown to mediate efficient transduction of the skeletal muscle and liver, respectively, although their infectivity profile for vascular cells has not been addressed. Here, we show that AAV-7 and -8 also transduce endothelial cells with poor efficiency and the levels of transgene expression are markedly enhanced by inhibition of the proteasome. In both cases proteasome blockade enhances the nuclear translocation of virions. We further show that this is vascular cell-type selective since transduction of smooth muscle cells is not sensitive to proteasome inhibition. Analysis in intact blood vessels corroborated these findings and suggests that proteasome degradation is a common limiting factor for endothelial cell transduction by AAV vectors.

Analysis of the wideband external pulse: an application of graphical methods.

This paper demonstrates the power of statistical graphics in gleaning information from very large medical data sets. In the case of the particular data set described here (the wideband external pulse signal) little was known about the shape of the signal and the relationship of that shape to the characteristics of the related physical system, the cardiovascular system. Previous numerical statistical analyses of the data were unfruitful in finding the important relationships which were easily discovered through the appropriately designed graphics. The paper also describes the process of designing graphics to help in discovering the important relationships in the data.

An enzyme-linked immunosorbent assay (ELISA) for measurement of antibodies against equine herpesvirus 2 in equine sera.

An indirect enzyme-linked immunosorbent assay (ELISA) was developed for the detection of antibodies against equine herpesvirus type 2 (EHV-2) in equine sera. The optimal conditions of antigen concentration, and serum and conjugate dilutions were established by chequerboard titrations. When the standard ELISA test was used for titration of test sera, it was found to give titres approximately 1500 times higher than those obtained in the virus neutralization (VN) test, and a correlation coefficient of 0.815 was obtained between these two tests on 42 equine sera. All the positive serum samples by the VN were also positive by the ELISA, and one negative serum in the former test was found to be positive in the latter. Under field conditions, the test also detected increases in antibody titres against EHV-2 in 13 out of 14 foals soon after these animals excreted the virus.

A quantitative analysis of the effects of activity and time of day on the diurnal variations of blood pressure.

The effects of activity and time of day on blood pressure (BP) were analyzed in 461 patients with untreated hypertension who wore a noninvasive portable BP recorder which took readings every 15 minutes for 24 hours. Patients recorded activity and location in a diary. The data were analyzed separately for two groups of patients: the 190 who stayed at home and the 271 who went to work. The effects of 16 different activities on BP were estimated by relating the BP to the associated activity and to the individual's clinic BP. Blood pressure was higher at work than at home, but the increment of BP for individual activities was similar in the two locations. The overall effect of activities on BP variability was computed using a one-way analysis of covariance model. For the patients who went to work this model accounted for 40% of the observed variation (R2) for systolic and 39% for diastolic BP. A similar model using time of day instead of activity accounted for 33% of variability in both systolic and diastolic BP. Combining activity and time of day was little better than activity alone (41% for both). After allowing for the effects of activity on BP, where sleep is one of the activities, there was no significant diurnal variation of BP. We conclude that there is no important circadian rhythm of BP which is independent of activity.

Behavioral determinants of 24-hour blood pressure patterns in borderline hypertension.

Borderline hypertension is a heterogeneous condition; only a minority of patients will progress to fixed essential hypertension or suffer cardiovascular damage. Ambulatory blood pressure monitoring can detect the subgroup of borderlines with sustained blood pressure elevation outside the office setting and can also provide a measure of blood pressure variability. Patients in the former group may be at greatest risk for cardiovascular complications while the latter have been theorized to be at risk for progression to fixed hypertension. Evidence we have gathered utilizing ambulatory monitoring does not support the contention that there is a subgroup of borderline hypertensives with excessive blood pressure variability in natural settings. Such recordings have been of benefit in identifying patients with excessive pressor responses to office visits. Future studies employing ambulatory monitoring may be useful in the detection of clinically important subgroups of borderline hypertension.