Alcohol and drug use severity are independently associated with antiretroviral adherence in the current treatment era.

Substance use in people with HIV (PWH) negatively impacts antiretroviral therapy (ART) adherence. However, less is known about this in the current treatment era and the impact of specific substances or severity of substance use. We examined the associations of alcohol, marijuana, and illicit drug use (methamphetamine/crystal, cocaine/crack, illicit opioids/heroin) and their severity of use with adherence using multivariable linear regression in adult PWH in care between 2016 and 2020 at 8 sites across the US. PWH completed assessments of alcohol use severity (AUDIT-C), drug use severity (modified ASSIST), and ART adherence (visual analogue scale). Among 9400 PWH, 16% reported current hazardous alcohol use, 31% current marijuana use, and 15% current use of ≥1 illicit drugs. In multivariable analysis, current methamphetamine/crystal use, particularly common among men who had sex with men, was associated with 10.1% lower mean ART adherence (p < 0.001) and 2.6% lower adherence per 5-point higher severity of use (ASSIST score) (p < 0.001). Current and more severe use of alcohol, marijuana, and other illicit drugs were also associated with lower adherence in a dose-dependent manner. In the current HIV treatment era, individualized substance use treatment, especially for methamphetamine/crystal, and ART adherence should be prioritized.

Characterization of angiotensin II receptors in cultured adult rat cardiac fibroblasts. Coupling to signaling systems and gene expression.

Cardiac hypertrophy is largely due to cardiac fibroblast growth and increased synthesis of extracellular matrix. This study has investigated the contribution of the vasoactive hormone, angiotensin II, toward this hypertrophic process. We have demonstrated that cultures of adult rat cardiac fibroblasts express AT1 but not AT2 receptors for angiotensin II. The ability of angiotensin II to stimulate phosphoinositide catabolism and to elevate intracellular calcium concentrations in these cells was blocked by losartan, a specific AT1 receptor antagonist, but not by the AT2 receptor antagonist CGP 42112. Exposure of adult cardiac fibroblasts to angiotensin II resulted in the induction of several growth-related metabolic events including c-fos protooncogene expression and increased synthesis of DNA, RNA, and protein. Angiotensin II was also found to induce collagen type I, alpha 1 chain transcript expression in cardiac fibroblasts as well as the synthesis and secretion of collagen by these cells. The data demonstrate that angiotensin II, via AT1 receptors, can stimulate cardiac fibroblast growth and increase collagen synthesis in cardiac tissue. Thus, angiotensin II may contribute toward the development of cardiac hypertrophy in conditions of hypertension that are associated with elevated concentrations of angiotensin II.

Endothelin messenger RNA and receptors are differentially expressed in cultured human breast epithelial and stromal cells.

Paracrine regulation is implicit in the biosynthesis and secretion of milk in the breast. An important determinant for this regulation in vivo is proximate cellular location as exemplified by stromal and epithelial cells in breast tissue. Cultured human breast epithelial cells exhibited low constitutive expression of mRNA for endothelin which was enhanced 20-fold after prolactin stimulation. Human breast stromal cells did not express measurable levels of endothelin mRNA under similar conditions. In a similar differential manner, the stimulated release of immunoreactive endothelin into medium overlay was observed only for breast epithelial and not stromal cells. Specific cell-surface receptors for endothelin and biochemical responsiveness to the peptide were observed only in the stromal cells.

Differential regulation of thrombospondin-1 and fibronectin by angiotensin II receptor subtypes in cultured endothelial cells.

OBJECTIVES: Angiotensin II (ANG II) can modulate cellular proliferation in various cell types via AT(1) and AT(2) receptors. In the present study, we investigated the effect of the angiotensin AT(1) and AT(2) receptors on DNA-synthesis as well as on the expression of the extracellular matrix (ECM) components, thrombospondin-1 (TSP-1) and fibronectin (FN) in endothelial cells (EC). METHODS: The experiments were performed in microvascular EC derived from rat heart (CEC) and macrovascular EC derived from bovine aorta (BAEC). The experiments were performed in cells of the second and third passage and the expression of AT(1) and AT(2) receptors was verified by binding studies, Northern analysis or RT-PCR. Quiescent rat CEC and BAEC were stimulated to proliferate by the addition of 25 ng/ml bFGF, while ANG II (10(-7) M) and the selective ANG II receptor antagonists, Losartan (10(-5) M) and PD123177 (10(-6) M) or the AT(2) agonist, CGP42112A (10(-7) M) were added 16 h later. RESULTS: ANG II induced a dose-dependent decrease of DNA-synthesis in BAEC measured by [3H]-thymidine incorporation. This inhibitory effect of ANG II was prevented by the addition of the AT(2) receptor antagonist PD123177 (10(-6) M), demonstrating, that the inhibition of DNA synthesis is mediated by the AT(2) receptor. In the presence of Losartan, stimulation of both, CEC and BAEC, with ANG II resulted in a marked increase of TSP-1 mRNA levels, which was maximal between 3 and 6 h in rat CEC and after 9 h in BAEC. In addition, TSP-1 was clearly induced by the AT(2) agonist CGP42112A. In contrast, blockade of the AT(2) receptor by the selective AT(2) antagonist, PD123177 (10(-6) M), resulted in a pronounced down regulation of FN mRNA 9 h after the stimulation. CONCLUSIONS: The present results suggest that the ANG II receptor subtype AT(2) mediates growth inhibition in macrovascular EC similar to what has been shown before in microvascular rat EC and that AT(2) receptors mediates remodeling of the endothelial ECM by upregulation of TSP-1 expression in both macro- and micro-vascular endothelial cells.

Endothelin stimulated by angiotensin II augments contractility of spontaneously hypertensive rat resistance arteries.

In cultured endothelial cells, endothelin is produced after stimulation with angiotensin II. The effects of angiotensin II and endothelin-1 on vascular sensitivity to norepinephrine were studied in perfused rat mesenteric resistance arteries. Expression of endothelin messenger RNA (mRNA) was determined in endothelial cells obtained from the mesenteric circulation. Perfusion (5 hours) of the arteries with angiotensin II (10(-7) M) potentiated contractions in arteries with endothelium induced by norepinephrine in spontaneously hypertensive rats but not Wistar-Kyoto rats. The potentiation was inhibited by phosphoramidon and an endothelin antibody. Short-term stimulation (1 hour) with angiotensin II did not cause the potentiation. Stimulation with angiotensin I (10(-7) M; 5 hours) caused a potentiation prevented by captopril. In endothelial cells collected from the mesenteric arterial bed of spontaneously hypertensive rats, endothelin-specific mRNA was constitutively expressed, and the level of endothelin transcripts was increased by angiotensin II (10(-7) M). Threshold concentrations of exogenous endothelin-1 potentiated contractions induced by norepinephrine in arteries with and without endothelium of spontaneously hypertensive rats but not Wistar-Kyoto rats. Thus, angiotensin II stimulates the endothelial production of endothelin in situ and therapy potentiates contractions to norepinephrine in mesenteric resistance arteries of spontaneously hypertensive rats. This suggests that vascular endothelin production acts as an amplifier of the pressor effects of the renin-angiotensin system that may play an important role in hypertension.

Activation of human peripheral monocytes by angiotensin II.

This study has investigated the ability of the vasoconstrictor peptide angiotensin II to activate human peripheral blood monocytes. Activation was monitored by measuring both the release of tumor necrosis factor alpha from monocytes and their adhesion to monolayers of human endothelial cells. Angiotensin II-elicited activation of monocytes was dose-dependent (half-maximally effective concentration approximately 0.2 nM), saturable (maximally effective concentration approximately 5 nM), and sensitive to inhibition by the angiotensin type 1 receptor antagonist ZD 7155. Such direct actions imply that angiotensin II is an important candidate stimulus for the subendothelial infiltration of monocytes observed in atherogenesis and hypertension.

Effects of peptide vasoconstrictors on vessel structure.

The peptide vasoconstrictors angiotensin II and endothelin-1, originally described as being derived exclusively from the plasma renin-angiotensin system and vascular endothelium, respectively, have been demonstrated to be produced independently of these sources. Local tissue angiotensin-generating systems are well documented and endothelin production has been demonstrated for a variety of nonendothelial cells, including vascular smooth muscle cells. There is increasing evidence that these locally produced vasoconstrictor peptides may contribute to blood vessel homeostasis, as well as the development of vascular pathologic conditions. Results obtained from pharmaceutical intervention in humans and animals of these systems strongly support this hypothesis. In addition to their vasoconstrictor properties, angiotensin II and endothelin-1 act as potent biologic effectors. In vitro, both vasoconstrictor peptides appear to modulate the activity of autocrine feedback loops in vascular smooth muscle cells. The activity of these feedback loops in vivo may represent a central mechanism for regulation and phenotypic differentiation of this cell type. The most well-established autocrine feedback loops of vascular smooth muscle cells are constituted by platelet-derived growth factor and transforming growth factor-beta, both of which are influenced by the action of angiotensin II and endothelin-1. The effects of the peptide vasoconstrictors on the (auto-) regulated feedback loops are of long-term structural importance, since both vasoconstrictors (via autocrine growth modulators) may influence the composition of the extracellular matrix of vascular smooth muscle cells. This includes effects on the synthesis and secretion of thrombospondin, fibronectin, tenascin, etc. The secretion of extracellular matrix glycoproteins themselves and incorporation into extracellular matrix in vitro appear to be linked to the activity of the autocrine feedback loops: e.g., stimulation of thrombospondin mRNA results in secretion of the glycoprotein only in the concomitant presence of exogenous platelet-derived growth factor, whereas the expression of fibronectin and tenascin may be directed by transforming growth factor-beta. The influence of angiotensin II and endothelin-1 on vascular smooth muscle cell surface receptor expression may represent a secondary mode of action of these vasoconstrictor peptides. Endothelin-1, for instance, can rapidly down-regulate platelet-derived growth factor-alpha receptor mRNA and both angiotensin II and endothelin-1, via induction of transforming growth factor-beta, may interrupt the platelet-derived growth factor based autocrine feedback loop. In vivo, the highly complex interactions between local and systemic vasoconstrictor production, autoregulated feedback loops, and extracellular matrix (which also serves as a reservoir for growth and differentiation modulators) are central to vessel homeostasis.(ABSTRACT TRUNCATED AT 400 WORDS)

Biochemical and cellular identification of HLA-Bw44 subtypes.

Biochemical analysis of HLA-Bw44 antigens by two-dimensional gelelectrophoresis and one-dimensional isoelectric focusing (IEF) from serologically heterozygous and homozygous donors allows the identification of two distinct types of HLA-Bw44 molecules, designated as Bw44-I and Bw44-II. These results are in concordance with the data obtained by CML-typing where at least two types of Bw44 target cells can be distinguished clearly as well. The antigen of type I has a more acidic isoelectric point (IEP) than that of type II. The difference in IEP are not due to differences in sialic acid content.

The adhesion of glow--discharge polymers, Silastic and Parylene to implantable platinum electrodes: results of tensile pull tests after exposure to isotonic sodium chloride.

Thin organic coatings commonly are used for insulating microelectrodes and electronic packages designed for implant applications. The adherence of these coatings to the underlying substrates is a key parameter in their selection for various devices. Instron pull tests were performed on glow-discharge polymerized monomers, Parylene-N, medical-grade Silastic and various epoxies. The application of a thin coating of glow-discharge polymerized methane under a thicker Parylene-N coating improved the adhesion of the latter to the underlying substrate in isotonic sodium chloride solution and during accelerated testing conditions done by boiling.

Angiotensin-induced growth related metabolism is activated in cultured smooth muscle cells from spontaneously hypertensive rats and Wistar-Kyoto rats.

Smooth muscle cells from spontaneously hypertensive rats (SHR) proliferate in culture faster than those isolated from sex- and age-matched Wistar-Kyoto (WKY) animals. There was no difference in the kinetics of S6 kinase activation in the two cultures, but later metabolic events associated with proliferation were stimulated earlier in SHR cells than in WKY, eg, activation of ornithine decarboxylase. Both cell types elaborated an extensive extra-cellular matrix in culture composed of a different blend of connective tissue macromolecules. Matrix material from SHR cells was more stimulatory to growth of WKY cultures than their own matrices. Angiotensin stimulated the growth and synthesis of extra-cellular matrix material in SHR more than in WKY derived vascular smooth muscle cell cultures.

Nonenzymatic glycation of fibronectin impairs adhesive and proliferative properties of human vascular smooth muscle cells.

Nonenzymatic glycation of proteins is involved in the pathogenesis of diabetes vascular complications. Extracellular matrix proteins are a prominent target for nonenzymatic glycation because of their slow turnover rates. The aim of this study was to investigate the influence of human fibronectin (F) nonenzymatic glycation on adhesion and proliferation of cultured human vascular smooth muscle cells (hVSMC). Incubation of human F with 500 mmol/L D-glucose at 37 degrees C induced a time-dependent increase in fluorescence detectable at 440 nm after excitation at 363 nm. Nonenzymatic glycation did not affect binding of F itself to the plates. Adhesion of hVSMC to F increased with the increase of incubation time of the cells on the protein from 30 minutes up to 120 minutes and remained stable thereafter. Adhesion to glycated fibronectin (GF) was reduced in comparison to control F at all the different adhesion times. Adhesion of hVSMC to GF was reduced when F was exposed to glucose for 4, 9, or 28 days (P=.0417 to .0025), but not when F was exposed for 1 day. Adhesion of hVSMC to GF was reduced compared with adhesion to nonglycated F at all coating concentrations from 0.2 to 10 micrograms/mL (P=.05 to .014). Thus, nonenzymatic glycation of F impairs adhesion of hVSMC in vitro. Proliferation of hVSMC on F increased with increasing concentrations of the protein as coating agent (ANOVA:P<.0001 for both nonglycated F and GF). Proliferation with F glycated for 4, 9, and 28 days was reduced at concentrations of 1, 3, and 10 micrograms/mL as compared with proliferation with nonglycated F (P=.0253 to .0001). Proliferation on F glycated for only 1 day was not significantly reduced. When the number of hVSMC plated on control F was reduced by 25% to take into account the reduced adhesion, the number of cells that proliferated on F was still reduced. In conclusion, nonenzymatic glycation of F impairs adhesive and proliferative properties of hVSMC.

Cardiac cycle length variability in ponies at rest and during exercise.

We evaluated cardiac cycle length variability in ponies at rest and during strenuous exercise with and without premedication with atropine. In the absence of premedication, cardiac cycle length at rest was 1,112 +/- 53 ms, the individual cardiac cycle length standard deviation (SDCL) was 75 +/- 23 ms, and the individual cycle length coefficient of variation (CVCL) was 6.32 +/- 1.62. Exercise significantly decreased (P < 0.05) all three indexes (290 +/- 9 ms, 5 +/- 1 ms, and 1.65 +/- 0.20, respectively). Atropine premedication significantly reduced resting cardiac cycle length (685 +/- 46 ms), SDCL (10 +/- 2 ms), and CVCL (1.45 +/- 0.19) compared with nonpremedicated values. Cardiac cycle length was significantly decreased by exercise after atropine premedication, but no statistically significant changes occurred in SDCL or CVCL. Thus, although considerable cardiac cycle length variability exists in nonpremedicated ponies at rest, it is nearly completely abolished by strenuous exercise. The absence of significant differences between the indexes of variability during exercise without premedication, at rest after atropine, and during exercise after atropine indicates that cardiac cycle length variability in the pony is mediated primarily through activity of the parasympathetic system.

Variations on the response characteristics of oxygen electrodes.

To summarize: The works presented in this and the previous paper (2) have produced an operational model for describing the oxygen reduction process in common medical grade sterile saline media at a platinum disc shaped electrode with a fairly specific surface conditioning. This paper has illustrated some of the variations possible in electrode current responses. An important feature of these data is that they are highly consistent and repeatable and can be discussed in terms of the model. However, the question still remains: What is the aging process? Is it due to a decrease of active sites for the electrochemical reduction process, brought about by the reduction process itself, or is it a process caused by other species in the media? To answer these questions, it may be necessary to employ some of the sophisticated techniques such as angle-resolved photoelectron spectroscopy (4) and extended x-ray absorption fine structure (5), available today for the study of atomic and molecular arrangements on solid surfaces.

Factor VIII complex in canine plasma after submaximal treadmill exercise.

Exercise-induced changes in the plasma concentrations of coagulation factor VIII and von Willebrand factor were evaluated, using 8 random-source adult dogs that exercised on a treadmill for 5 to 10 minutes (mean running time = 8.3 minutes). Maximum treadmill speeds attained by the dogs were 11 to 18 km/hr, and the mean of the maximum individual speeds was 14.3 km/hr. Maximum heart rates of individual dogs during exercise were 190 to 250 beats/min with a mean of 218 beats/min (a 2.4-fold increase over the mean preexercise rate). Exercise did not induce significant increases in plasma concentrations of factor VIII coagulant activity, coagglutinin co-factor activity, or factor VIII-related antigen. Results indicated that submaximal exercise does not induce increases in plasma concentrations of coagulation factor VIII or von Willebrand factor in the dog.

Effects of halothane and isoflurane on mean arterial blood pressure, heart rate, and respiratory rate in adult Pekin ducks.

Although the cardiovascular and respiratory effects of halothane and isoflurane have been documented in a variety of common mammalian laboratory animals, they have not been investigated in birds. In this study, the effects of halothane and isoflurane anesthesia on respiratory rate, heart rate, heart rhythm, and mean arterial pressure in adult Pekin ducks were evaluated. Both anesthetics significantly increased heart rate and depressed blood pressure and respiration. Halothane induced a more profound alteration in heart rate and respiratory rate. With the ducks under halothane anesthesia, abnormal cardiac rhythms included ventricular fibrillation, ventricular bigeminy, and multifocal ventricular rhythms. Other than cardiac tachycardia, isoflurane induced no changes in cardiac rhythm.

Patent ductus arteriosus in the dog: a retrospective study of radiographic, epidemiologic, and clinical findings.

Twenty-seven cases of patent ductus arteriosus (PDA) in the dog, which were confirmed by cardiac catheterization, surgical exploration, or at necropsy, were reviewed. A machinery murmur, electrocardiographic evidence of left ventricular enlargement, and radiographic evidence of cardiomegaly with an aortic and a pulmonary artery dilatation were consistent features. Surgical repair was successful in 65% of the dogs. The postoperative radiographic and electrocardiographic changes are described. A concomitant congenital defect was present in 2 dogs. The epidemiologic features of 532 dogs identified as having PDA and submitted to the National Cancer Institute's Veterinary Medical Data Program were reviewed. Miniature and Toy Poodles, Pomeranians, and Shetland Sheepdogs were identified as being at high risk for PDA. An excess of females over males was noticed.

Effects of electrocardiograph frequency filters on P-QRS-T amplitudes of the feline electrocardiogram.

OBJECTIVE--To determine whether standard manual frequency filters in the ON and OFF settings affected P-QRS-T voltages, discover whether recorded P-QRS-T voltages vary between commercial electrocardiographs, assess effects of frequency filters on base-line artifact, and evaluate ECG frequency content by high-fidelity recordings subjected to digital filters with variable frequencies. DESIGN--Sequential 10-lead ECG were recorded in 30 cats, using 3 commercial electrocardiographs to assess effects of manual frequency filters on the P-QRS-T wave forms. Three clinically normal cats were evaluated for ECG frequency content. ANIMALS--Thirty cats (13 with hypertrophic cardiomyopathy; 4 with restrictive cardiomyopathy; 3 hyperthyroid; 1 with ventricular septal defect; 1 with aortic stenosis; and 8 with no detectable cardiovascular disease). Three additional clinically normal cats were studied for effects of frequency filters on the ECG frequency content. PROCEDURES--Ten-lead ECG were recorded on each cat by use of 3 commercial electrocardiographs sequentially. For each machine, a recording was made with manual filters ON, immediately followed by a recording with manual filters OFF. High-fidelity lead-II ECG recordings were made with filters set with their rolloff frequency at 0.1 Hz and 3.0 kHz; output voltage (0.2 mV/V) was fed to an analog-to-digital converter, then to attendant software, which sampled the signal at 6 kHz with a 12-bit sampler, and were digitally filtered at various corner frequencies. RESULTS--Voltages recorded by all 3 electrocardiographs were greatest when filters were OFF (most prominent on R- and S-wave voltages). In all recorded leads, R-wave voltage was significantly greater when filters were OFF than ON. Comparison of voltages indicated significant (P < 0.05) differences between R-wave voltages recorded in all leads with manual filters ON, but not with filters OFF. With filters ON, each electrocardiograph produced a smaller percentage of recordings with moderate to severe baseline artifact than with filters OFF. R-Wave amplitudes of high-fidelity lead-II ECG were significantly decreased with digital filters set at corner frequencies < 150 Hz. CONCLUSIONS--Significant (P < 0.05) voltage attenuation was recorded by each of the 3 commercial electrocardiographs when frequency filters were ON, compared with OFF. Comparison of waveform voltages among electrocardiographs with filters ON indicated significant variation in R-wave amplitudes in all leads. With manual filters ON, each electrocardiograph recorded a smaller percentage of recordings with baseline artifact than with filters OFF. Substantial frequency components > or = 150 Hz are present in the feline ECG waveform. Thus, filters with frequencies < 150 Hz markedly attenuate the feline R wave. CLINICAL RELEVANCE--Attenuation of feline ECG signals occurs with use of commercial electrocardiographs and varies greatly between manufacturers. This is attributable largely to internal manual frequency filters. These consequences may be important when applying standard feline reference values or when equivocal voltage measurements are recorded.

Equine laminitis of alimentary origin: an experimental model.

Acute alimentary form of laminitis was uniformly induced in 11 of 12 horses by administration of a starch and wood flour gruel and could be graded by previously established (Obel) and presently defined criteria. The experimentally induced laminitis was similar to naturally occurring laminitis, as determined on the basis of lameness severity and vital signs. Packed cell volume, leukocyte count, and total protein were significantly increased (P smaller than 0.05) at 24 and 40 hours after administration of gruel. Arterial systolic and diastolic pressures increased, central venous pressure decreased, heart rate increased, and rectal temperature increased consistently within the 56-hour experimental period. Of the 11 affected horses, 7 horses had Obel grade 3 lameness (horse moved most reluctantly and vigorously resisted attempts to lift a forefoot) at 40 hours after gruel was placed in the alimentary tract, 2 horses had Obel grade 3 lameness at 32 hours, and 2 horses had Obel grade 3 lameness at 48 hours.

Cardiac output, left ventricular ejection rate, plasma volume, and heart rate changes in equine laminitis-hypertension.

Acute laminitis-hypertension was produced experimentally by carbohydrate overloading of the gastrointestinal tract in 8 horses, and the resulting hemodynamic changes were measured. Statistically significant (P less than 0.01) increases in cardiac output, left ventricular ejection rate, heart rate, and arterial pressure were related to statistically nonsignificant changes in peripheral resistance and a delayed (Obel grade 3 plus 24 hours) decrease in plasma volume. When compared with control values, the doubling of cardiac output and left ventricular ejection rate simultaneous with little or no change in either peripheral resistance or plasma volume (16 hours after the occurrence of Obel grade 3 lameness) was suggestive of an increase in myocardial contractility. Because these pathophysiologic phenomena have important time relationships to the onset of Obel grade 3 lameness in acute laminitis, the results of this investigation are discussed in light of their relationship to clinical signs, serum electrolyte changes, plasma L-lactate alterations, and histologic deterioration of the digit.