ACE inhibitors, angiotensin receptor blockers and endothelial injury in COVID-19.

BACKGROUND: COVID-19 is caused by the coronavirus SARS-CoV-2, which uses angiotensin-converting enzyme 2 (ACE-2) as a receptor for cellular entry. It is theorized that ACE inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) may increase vulnerability to SARS-CoV-2 by upregulating ACE-2 expression, but ACE-I/ARB discontinuation is associated with clinical deterioration. OBJECTIVE: To determine whether ACE-I and ARB use is associated with acute kidney injury (AKI), macrovascular thrombosis and in-hospital mortality. METHODS: A retrospective, single-centre study of 558 hospital inpatients with confirmed COVID-19 admitted from 1 March to 30 April 2020, followed up until 24 May 2020. AKI and macrovascular thrombosis were primary end-points, and in-hospital mortality was a secondary end-point. RESULTS: AKI occurred in 126 (23.1%) patients, 34 (6.1%) developed macrovascular thrombi, and 200 (35.9%) died. Overlap propensity score-weighted analysis showed no significant effect of ACE-I/ARB use on the risk of occurrence of the specified end-points. On exploratory analysis, severe chronic kidney disease (CKD) increases odds of macrovascular thrombi (OR: 8.237, 95% CI: 1.689-40.181, P = 0.009). The risk of AKI increased with advancing age (OR: 1.028, 95% CI: 1.011-1.044, P = 0.001) and diabetes (OR: 1.675, 95% CI: 1.065-2.633, P = 0.025). Immunosuppression was associated with lower risk of AKI (OR: 0.160, 95% CI: 0.029-0.886, P = 0.036). Advancing age, dependence on care, male gender and eGFR < 60 mL min-1 /1.73 m2 increased odds of in-hospital mortality. CONCLUSION: We did not identify an association between ACE-I/ARB use and AKI, macrovascular thrombi or mortality. This supports the recommendations of the European and American Societies of Cardiology that ACE-Is and ARBs should not be discontinued during the COVID-19 pandemic.

Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis.

Pulmonary arteries of patients with severe pulmonary hypertension (SPH) presenting in an idiopathic form (primary PH-PPH) or associated with congenital heart malformations or collagen vascular diseases show plexiform lesions. It is postulated that in lungs with SPH, endothelial cells in plexiform lesions express genes encoding for proteins involved in angiogenesis, in particular, vascular endothelial growth factor (VEGF) and those involved in VEGF receptor-2 (VEGFR-2) signalling. On immunohistochemistry and in situ hybridization, endothelial cells in the plexiform lesions expressed VEGF mRNA and protein and overexpressed the mRNA and protein of VEGFR-2, and the transcription factor subunits HIF-1alpha and HIF-1beta of hypoxia inducible factor, which are responsible for the hypoxia-dependent induction of VEGF. When compared with normal lungs, SPH lungs showed decreased expression of the kinases PI3 kinase and src, which, together with Akt, relay the signal transduction downstream of VEGFR-2. Because markers of angiogenesis are expressed in plexiform lesions in SPH, it is proposed that these lesions may form by a process of disordered angiogenesis.

Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling.

Prostacyclin (PGI(2)) reduces pulmonary vascular resistance and attenuates vascular smooth muscle cell proliferation through signal transduction following ligand binding to its receptor. Because patients with severe pulmonary hypertension have a reduced PGI(2) receptor (PGI-R) expression in the remodeled pulmonary arterial smooth muscle, we hypothesized that pulmonary vascular remodeling may be modified PGI-R dependently. To test this hypothesis, PGI-R knockout (KO) and wild-type (WT) mice were subjected to a simulated altitude of 17,000 ft or Denver altitude for 3 wk, and right ventricular pressure and lung histology were assessed. The PGI-R KO mice developed more severe pulmonary hypertension and vascular remodeling after chronic hypoxic exposure when compared to the WT mice. Our results indicate that PGI(2) and its receptor play an important role in the regulation of hypoxia-induced pulmonary vascular remodeling, and that the absence of a functional receptor worsens pulmonary hypertension.

Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis.

Primary pulmonary hypertension (PPH) is a disease of unknown etiology characterized by lumen-obliterating endothelial cell proliferation and vascular smooth muscle hypertrophy of the small precapillary pulmonary arteries. Because the vascular lesions are homogeneously distributed throughout the entire lung, we propose that a tissue fragment of the lung is representative of the whole lung. RNA extracted from the fragments is likely to provide meaningful information regarding the changes in gene expression pattern in PPH when compared with structurally normal lung tissue. We hypothesize that the lung tissue gene expression pattern of patients with PPH has a characteristic profile when compared with the gene expression pattern of structurally normal lungs and that this characteristic gene expression profile provides new insights into the pathobiology of PPH. Using oligonucleotide microarray technology, we characterized the expression pattern in the lung tissue obtained from 6 patients with primary pulmonary hypertension (PPH)-including 2 patients with the familial form of PPH (FPPH)-and from 6 patients with histologically normal lungs. For the data analysis, gene clusters were generated and the gene expression pattern differences between PPH and normal lung tissue and between PPH and FPPH lung tissue were compared. All PPH lung tissue samples showed a decreased expression of genes encoding several kinases and phosphatases, whereas several oncogenes and genes coding for ion channel proteins were upregulated in their expression. Importantly, we could distinguish by pattern comparison between sporadic PPH and FPPH, because alterations in the expression of transforming growth factor-beta receptor III, bone morphogenic protein 2, mitogen-activated protein kinase kinase 5, RACK 1, apolipoprotein C-III, and the gene encoding the laminin receptor 1 were only found in the samples from patients with sporadic PPH, but not in FPPH samples. We conclude that the microarray gene expression technique is a new and useful molecular tool that provides novel information pertinent to a better characterization and understanding of the pathobiology of the distinct clinical phenotypes of pulmonary hypertension.

Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension.

Our understanding of the pathobiology of severe pulmonary hypertension, usually a fatal disease, has been hampered by the lack of information of its natural history. We have demonstrated that, in human severe pulmonary hypertension, the precapillary pulmonary arteries show occlusion by proliferated endothelial cells. Vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR-2) are involved in proper maintenance, differentiation, and function of endothelial cells. We demonstrate here that VEGFR-2 blockade with SU5416 in combination with chronic hypobaric hypoxia causes severe pulmonary hypertension associated with precapillary arterial occlusion by proliferating endothelial cells. Prior to and concomitant with the development of severe pulmonary hypertension, lungs of chronically hypoxic SU5416-treated rats show significant pulmonary endothelial cell death, as demonstrated by activated caspase 3 immunostaining and TUNEL. The broad caspase inhibitor Z-Asp-CH2-DCB prevents the development of intravascular pulmonary endothelial cell growth and severe pulmonary hypertension caused by the combination of SU5416 and chronic hypoxia.

Glass-forming tendency in the system water-dimethyl sulfoxide.

The glass-forming tendency on cooling and the stability of the wholly amorphous state on warming have been previously reported for many cryoprotective solutions. However, unlike the other solutions, those of dimethyl sulfoxide (Me(2)SO) have not been studied on cooling. In this paper, the glass-forming tendency of Me(2)SO aqueous solutions has been measured for solutions containing 40, 43, 45, and 47.5% (w/w) Me(2)SO. At a concentration of 45% (w/w), the glass-forming tendency decreases in the following order: levo-2, 3-butanediol, 1,3-butanediol, 1,2-propanediol, 1,2,3-butanetriol, dimethyl sulfoxide, dimethylformamide, diethylformamide, 1, 4-butanediol, ethylene glycol, glycerol, 1,3-propanediol. New measurements have also been made on warming the Me(2)SO solutions.

Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension.

Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway leading to prostacyclin (PGI2) production. Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels, but the importance of this deficiency for lung vascular remodeling remains unclear. We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension. To study this hypothesis, transgenic mice were created with selective pulmonary PGIS overexpression using a construct of the 3.7-kb human surfactant protein-C (SP-C) promoter and the rat PGIS cDNA. Transgenic mice (Tg+) and nontransgenic littermates (Tg-) were subjected to a simulated altitude of 17,000 ft for 5 weeks, and right ventricular systolic pressure (RVSP) was measured. Histology was performed on the lungs. The Tg+ mice produced 2-fold more pulmonary 6-keto prostaglandin F1alpha (PGF1alpha) levels than did Tg- mice. After exposure to chronic hypobaric hypoxia, Tg+ mice have lower RVSP than do Tg- mice. Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg+ mice in comparison with vessel wall hypertrophy in the Tg- mice. These studies demonstrate that Tg+ mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia. We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia. This has important implications for the pathogenesis and treatment of severe pulmonary hypertension.

Fetal coronary and cerebral blood flow in acute fetomaternal hemorrhage.

A fetal heart rate tracing with absent variation and a sinusoidal pattern led to the diagnosis of acute fetomaternal hemorrhage at 29 + 2 weeks' gestation. The middle cerebral artery had increased peak blood flow velocity with reversed end-diastolic flow. Fetal coronary arteries visualized by color-coded and pulsed wave Doppler sonography showed slight decrease of time-averaged maximum velocities after oxygen administration, while cerebral flows remained unchanged. After administration of 50 ml blood (pre-transfusion hematocrit < 11%) the middle cerebral artery flow normalized and coronary artery velocities decreased further until coronary blood flow could no longer be visualized within 30 min of the transfusion (post-transfusion hematocrit 27%). Evidence of successful fetal resuscitation also included normalization of the fetal heart rate tracing and resumption of fetal activity (biophysical profile score 8/10). This was also observed after a second transfusion of 38 ml blood. Deterioration from repeated fetomaternal hemorrhage led to delivery of a severely anemic neonate (cord hematocrit 7%) by Cesarean section. Postnatally, a single seizure, moderate severity respiratory distress syndrome and grade III intraventricular hemorrhage were noted. Increased peak blood flow velocity with reversed end-diastolic flow may be observed in the middle cerebral artery of fetuses with acute anemia. Correction of this phenomenon with transfusion suggests that hypovolemia and low blood viscosity are major contributing factors. Furthermore, decreasing coronary artery blood flow velocities with supplemental oxygen and blood replacement confirm functional autoregulation of the fetal coronary circulation. Observation of these acute flow changes during fetal surveillance warrants investigation for a potentially serious underlying condition.

Second trimester abortion using prostaglandin E2 suppositories with or without intracervical Laminaria japonica: a randomized study.

OBJECTIVE: To compare the abortifacient efficacy of vaginal prostaglandin (PG) E2 suppositories with and without pretreatment with intracervical PGE2 gel and Laminaria japonica. METHODS: One hundred seventy-five women between 16 and 20 weeks' gestation requesting abortion were divided randomly into three groups. Forty-one received PGE2 vaginal suppositories alone to induce abortion, 72 had Laminaria placed 24 hours before vaginal PGE2, and 62 were given intracervical 0.5 mg PGE2 gel plus Laminaria 24 hours before vaginal PGE2. Maternal demographic characteristics, induction to delivery time, number of suppositories required, and complications were analyzed. RESULTS: The mean maternal age, gravidity, parity, race, and gestational age were similar among groups. Ninety-five percent of all women delivered within 24 hours. The induction to delivery time was significantly longer in the PGE2-only women (mean +/- standard deviation 689+/-319 minutes) compared with that of those receiving PGE2 plus Laminaria (487+/-321 minutes) and PGE2 plus Laminaria plus gel (547 +/-374 minutes, P = .01). There was a statistically significant difference in the number of suppositories needed to complete the abortion process. The PGE2-only group required more suppositories (median three, range 1-8) compared with PGE2 plus Laminaria (median 3, range 1-3) and PGE2 plus Laminaria plus gel (median 2.5, range 1-9; P = .001). Patients in the PGE2 plus Laminaria plus gel group reported more pain associated with placement (median pain score 4, range 0-10) compared with PGE2 plus Laminaria (median 2, range 0-9; P = .003). There was a lower incidence of febrile episodes in the PGE2-only group (29%) compared with PGE2 plus Laminaria (68%) and PGE2 plus Laminaria plus gel (54%, P = .002). CONCLUSION: Placement of Laminaria japonica 24 hours before PGE2 vaginal suppository-induced abortion resulted in a significantly shorter induction-to-delivery time, and pretreatment with Laminaria japonica decreased the number of suppositories required to complete abortion. Pretreatment with intracervical PGE2 gel increased pain associated with Laminaria placement and did not improve the efficacy of the procedure.

Impact of zidovudine use on risk and risk factors for perinatal transmission of HIV. Perinatal AIDS Collaborative Transmission Studies.

OBJECTIVES: To evaluate the impact of perinatal zidovudine use on the risk of perinatal transmission of HIV and to determine risk factors for transmission among women using perinatal zidovudine. DESIGN: Prospective cohort study of 1533 children born to HIV-infected women between 1985 and 1995 in four US cities. METHODS: The association of potential risk factors with perinatal HIV transmission was assessed with univariate and multivariate statistics. RESULTS: The overall transmission risk was 18% [95% confidence interval (CI), 16-21]. Factors associated with transmission included membrane rupture > 4 h before delivery [relative risk (RR), 2.1; 95% CI, 1.6-2.7], gestational age < 37 weeks (RR, 1.8; 95% CI, 1.4-2.2), maternal CD4+ lymphocyte count < 500 x 10(6) cells/l (RR, 1.7; 95% CI, 1.3-2.2), birthweight < 2500 g (RR, 1.7; 95% CI, 1.3-2.1), and antenatal and neonatal zidovudine use (RR, 0.6; 95% CI, 0.4-0.9). For infants exposed to zidovudine antenatally and neonatally, the transmission risk was 13% overall but was significantly lower following shorter duration of membrane rupture (7%) and term delivery (9%). The transmission risk declined from 22% before 1992 to 11% in 1995 (P < 0.001) in association with increasing zidovudine use and changes in other risk factors. CONCLUSIONS: Perinatal HIV transmission risk has declined with increasing perinatal zidovudine use and changes in other factors. Further reduction in transmission for women taking zidovudine may be possible by reducing the incidence of other potentially modifiable risk factors, such as long duration of membrane rupture and prematurity.

Activated eosinophils elicit substance P release from cultured dorsal root ganglion neurons.

This study was performed to test the hypothesis that activated eosinophils or their secretory products can directly stimulate sensory neurons to release their neuropeptides. Neurons derived from neonatal rat dorsal root ganglia (DRG), which synthesize and store sensory neuropeptides, were placed in primary cell culture and were exposed to eosinophils or their bioactive mediators. The resultant release of substance P (SP) was measured by enzyme-linked immunosorbent assay and was expressed as a percent (mean +/- SE) of total neuronal SP content. Eosinophils were isolated from human volunteers with a history of allergic rhinitis and/or mild asthma and were activated by incubation with cytochalasin B (5 micrograms/ml) and N-formyl-methionyl-leucyl-phenylalanine (FMLP, 1 microM). Activated eosinophils [6 x 10(6)/ml, suspended in Hanks' buffered salt solution (HBSS)] applied to cultured DRG neurons for 30 min increased basal SP release 2.4-fold compared with HBSS-exposed neurons (activated eosinophils 11.10 +/- 2.48% vs. HBSS 4.59 +/- 0.99%; P = 0.002), whereas neither nonactivated eosinophils nor cytochalasin B and FMLP in HBSS influenced SP release. Additional cultured DRG neurons were exposed to soluble products made by eosinophils. Compared with SP release under control conditions (2.37 +/- 0.34%), major basic protein (MBP) increased release in a concentration-related fashion (e.g., 3 microM MBP: 6.23 +/- 0.67%, P = 0.006 vs. control), whereas neither eosinophil cationic protein (3 microM), eosinophil-derived neurotoxin (3 microM), leukotriene D4 (500 nM), platelet-activating factor (100 nM), nor H2O2 (100 microM) affected SP release. These studies demonstrate that activated eosinophils can stimulate cultured DRG neurons directly and suggest that MBP may be the responsible mediator.

Toxoplasmosis and parvovirus B19.

Pregnant women might well improve their chances for a successful pregnancy outcome by following the advice of W. C. Fields: avoid contact with small children and animals whenever possible. Failing widespread acceptance of this philosophy, management of T. gondii and parvovirus B19 infections continues to be a challenge for the foreseeable future.

Structure and expression of a smooth muscle cell-specific gene, SM22 alpha.

SM22 alpha is expressed exclusively in smooth muscle-containing tissues of adult animals and is one of the earliest markers of differentiated smooth muscle cells (SMCs). To examine the molecular mechanisms that regulate SMC-specific gene expression, we have isolated and structurally characterized the murine SM22 alpha gene. SM22 alpha is a 6.2-kilobase single copy gene composed of five exons. SM22 alpha mRNA is expressed at high levels in the aorta, uterus, lung, and intestine, and in primary cultures of rat aortic SMCs, and the SMC line, A7r5. In contrast to genes encoding SMC contractile proteins, SM22 alpha gene expression is not decreased in proliferating SMCs. Transient transfection experiments demonstrated that 441 base pairs of SM22 alpha 5'-flanking sequence was necessary and sufficient to program high level transcription of a luciferase reporter gene in both primary rat aortic SMCs and A7r5 cells. DNA sequence analyses revealed that the 441-base pair promoter contains two CArG/SRF boxes, a CACC box, and one potential MEF-2 binding site, cis-acting elements which are each important regulators of striated muscle transcription. Taken together, these studies have identified the murine SM22 alpha promoter as an excellent model system for studies of developmentally regulated, lineage-specific gene expression in SMCs.

Proliferation of guinea pig tracheal epithelial cells in coculture with rat dorsal root ganglion neural cells.

Neuropeptides secreted by sensory afferent nerves in airways may modulate growth of airway epithelial cells. To determine whether airway sensory C-fiber nerves secrete neuropeptides that stimulate airway epithelial cell proliferation, we measured S-phase traversal in guinea pig tracheal epithelial (GPTE) cells after coculture with rat dorsal root ganglion (DRG) cells. GPTE cells were grown in subconfluent culture on collagen-coated filters for 2 days. DRG cells were harvested from newborn rat pups and grown in primary culture for 7-10 days in separate wells. GPTE and DRG cells then were cocultured for 48 h, and 10 mM bromodeoxyuridine (BrdU), a thymidine analogue, was added in the final 24 h. Control GPTE cells were grown under similar conditions but without DRG cells. Coculture with DRG cells stimulated GPTE cell traversal of S phase. BrdU labeling in cocultured GPTE cells was 42.8 +/- 5.8 compared with 18.1 +/- 7.2% in control GPTE cells (P < 0.001, n = 6). Coculture in the presence of either the neurokinin (NK)1 receptor antagonists LY-297911 or CP-99,994, the NK2 receptor antagonist SR-48,968, or the calcitonin gene-related peptide (CGRP) receptor antagonist hCGRP-(8-37) (10(-7) M of each) during coculture attenuated proliferation of GPTE cells. Treatment with all three antagonists together during coculture decreased BrdU labeling to 2.4 +/- 0.9% of labeled cells vs. 8.5 +/- 0.5% of labeled cells during coculture without antagonists (n = 4, P < 0.02). DRG cells in coculture secreted substantial concentrations of CGRP [71.0 +/- 11.3 (+/- SE) pmol/ml], substance P (1.26 +/- 0.35 pmol/ml), and neurokinin A (0.45 +/- 0.10 pmol/ml) (n = 19 for each).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertonicity, but not hypothermia, elicits substance P release from rat C-fiber neurons in primary culture.

Isocapnic dry gas hyperventilation provokes hyperpnea-induced bronchoconstriction in guinea pigs by releasing tachykinins from airway sensory C-fiber neurons. It is unknown whether dry gas hyperpnea directly stimulates C-fibers to release tachykinins, or whether this physical stimulus initiates a mediator cascade that indirectly stimulates C-fiber tachykinin release. We tested the hypotheses that mucosal hypothermia and/or hyperosmolarity--physical consequences of airway heat and water loss imposed by dry gas hyperpnea--can directly stimulate C-fiber tachykinin release. Neurons isolated from neonatal rat dorsal root ganglia were maintained in primary culture for 1 wk. Cells were then exposed for 30 min at 37 degrees C to graded concentrations of NaCl, mannitol, sucrose, or glycerol (0-600 mOsm) added to isotonic medium, or to isotonic medium at 25 degrees C without or with 462 mOsm mannitol added. Fractional release of substance P (SP) was calculated from supernatant and intracellular SP contents following exposure. Hyperosmolar solutions containing excess NaCl, mannitol, or sucrose all increased fractional SP release equivalently, in an osmolarity-dependent fashion. In marked contrast, hypothermia had no effect on fractional SP release under isotonic or hypertonic conditions. Thus, hyperosmolarity, but not hypothermia, can directly stimulate tachykinin release from cultured rat sensory C-fibers. The lack of effect of glycerol, a solute which quickly crosses cell membranes, suggests that neuronal volume change represents the physical stimulus transduced by C-fibers during hyperosmolar exposure.

Ontogeny of dry gas hyperpnea-induced bronchoconstriction in guinea pigs.

Adolescent guinea pigs (AGPs) demonstrate dry gas hyperpnea-induced bronchoconstriction (HIB) that shares key features with HIB in humans with asthma. The airways of immature animals exhibit enhanced reactivity to diverse types of stimulation. We tested whether dry gas HIB is also increased in newborn guinea pigs (NGPs). We quantified HIB as the fractional increase of respiratory system resistance (Rrs) over baseline (BL) in five 4- to 7-day-old NGPs after 10 min of hyperpnea, as well as changes in Rrs elicited by intravenous methacholine or capsaicin, and compared these responses with those of AGPs. During hyperpnea, analogous stimuli were delivered by mechanically imposing hyperpnea at 3.0, 4.5, and 6.0 times quiet eucapnic minute ventilation (VE). In AGPs, hyperpnea caused significant bronchoconstriction that increased with VE; peak fractional increase of Rrs was 7.6 +/- 2.0 times BL. In contrast, hyperpnea caused insignificant bronchoconstriction in NGPs (1.4 +/- 0.2 times BL after the largest VE; P < 0.05 vs. AGP). Responses elicited by methacholine (10(-10)-10(-7) mol/kg) or capsaicin (0.01-10.0 microgram/kg) were similar in NGPs and AGPs. In AGPs, hyperpnea suppressed HIB until posthyperpnea. To determine whether the reduced HIB of NGPs was caused by enhanced suppression, NGPs and AGPs were administered acetylcholine (10(-10)-10(-7) mol/kg i.v.) during BL eucapnic ventilation and during eucapnic hyperpnea with warm humidified gas. Responses to acetylcholine were suppressed in AGPs and NGPs to a similar degree. We conclude that HIB is markedly diminished shortly after birth in guinea pigs and that it increases substantially during maturation.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of eicosanoids in hyperpnea-induced airway responses in guinea pigs.

Guinea pigs mechanically hyperventilated with dry gas exhibit hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH). Tachykinins released from airway C-fiber neurons are the central mediators of guinea pig HIB but play only a contributory role in HIBVH. Recent studies suggest that eicosanoid mediators can provoke bronchoconstriction and bronchovascular hyperpermeability, are released by dry gas hyperpnea, and can themselves elicit or modulate tachykinin release. We therefore hypothesized that eicosanoids may participate in HIB and/or HIBVH. To test these hypotheses, we analyzed respiratory system resistance changes and Evans blue-labeled albumin extravasation into the airways of 60 tracheostomized and mechanically ventilated guinea pigs. Animals were subjected to 10 min of isocapnic dry gas hyperpnea or to quiet breathing of humidified gas and received as pretreatment either piroxicam, a cyclooxygenase (CO) inhibitor; A-63162, a 5-lipoxygenase (5-LO) inhibitor; BW-755c, a combined CO and 5-LO inhibitor; ICI-198,615, a leukotriene D4 receptor antagonist; or no drug. HIB was substantially (50-80%) reduced by each of the four eicosanoid-modulating drugs. In contrast, HIBVH was reduced only by BW-755c, and this effect occurred only within the extrapulmonary airways (42% reduction). These data indicate that both CO and 5-LO products, including leukotriene D4, participate in the pathogenesis of HIB but that, like tachykinins, they play only a small contributory role in HIBVH. Together with our previous demonstration that sensory neuropeptide release is critical for the occurrence of HIB, we conclude that the roles of eicosanoids and tachykinins in guinea pig HIB are interdependent.

Codeine and the breastfed neonate.

Codeine is an analgesic commonly used to relieve pain in the early post partum. Its metabolite, morphine, is probably responsible for its effectiveness in this use. However, morphine may also cause neonatal apnea. We studied free codeine and morphine levels in breastmilk of 17 samples from seven mothers and neonatal plasma of 24 samples from 11 healthy, term neonates. Levels were determined by radioimmunoassay. Milk codeine levels ranged from 33.8 to 314 ng/ml 20 to 240 minutes after codeine; morphine levels ranged from 1.9 to 20.5 ng/ml. Infant plasma samples one to four hours after feeding had codeine levels ranging from < 0.8 to 4.5 ng/ml; morphine ranged from < 0.5 to 2.2 ng/ml. Low infant plasma levels are secondary to low excretion into milk and the small amounts of milk available in the first few days. Moderate codeine use during this time (< or = four 60 mg doses) is probably safe.

Interactions of human immunodeficiency virus infection and pregnancy.

OBJECTIVE: To assess the influence of human immunodeficiency virus (HIV) infection on pregnancy outcome and the effect of pregnancy on the short-term course of HIV infection. METHODS: Pregnant women with identified risk factors for HIV infection but without AIDS were tested serologically for HIV antibodies. Seropositive women were compared to seronegative patients with similar risk factors and demographic characteristics at enrollment, at delivery, and 6-8 weeks postpartum. One hundred one seropositive and 97 seronegative subjects were evaluated for symptoms or physical manifestations of HIV infection; evidence of immune dysfunction; historical, physical, or laboratory evidence of related infections; and maternal and neonatal outcome. Both groups were compared to the entire obstetric population delivering at the University of Maryland Hospital during 1 year. RESULTS: There was a significant reduction in reported risk behaviors in both groups during pregnancy as compared to the period before pregnancy (P < .001). The majority of women in both groups were asymptomatic, but seropositive women were more likely to have a history or physical evidence of condylomata (13 versus 4%; P < .05) and higher temperatures on admission to the labor suite (98.6 +/- 1.0 versus 98.3 +/- 0.8F; P = .02). Seropositive women were not at greater risk for antepartum medical complications. Only one woman developed an AIDS-defining opportunistic infection. Although hematologic indices in seropositive women were abnormal, these did not progress over the course of pregnancy. At delivery, seropositive women were more likely to receive antibiotics (25 versus 10%; P = .006) and less likely to have an episiotomy (25 versus 40%; P = .03), but obstetric outcome was unaffected. Neonatal status was independent of antibody status. CONCLUSION: Our findings support a growing body of evidence that pregnancy has no discernible effect on the early progression of HIV disease in asymptomatic women, and infection does not influence perinatal outcome.

Tachykinin receptor antagonists inhibit hyperpnea-induced bronchoconstriction in guinea pigs.

We tested the hypothesis that hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH) are mediated through stimulation of NK-1 and NK-2 receptors in guinea pigs. We first established the efficacy and selectivity of (+/-) CP-96,345 (3 mg/kg i.v.) and of SR-48,968 (300 micrograms/kg i.v.) as NK-1 and NK-2 antagonists, respectively. (+/-) CP-96,345 substantially attenuated bronchoconstriction and systemic vascular leak caused by administration of Sar9,Met(O2)11-Substance P (a specific NK-1 agonist), but had no effect upon bronchoconstriction induced by selective NK-2 stimulation with Nle10-Neurokinin A[4-10]. Conversely, SR-48,968 antagonized the bronchoconstrictor response to Nle10-NKA[4-10], right-shifting the dose-response curve by 2 log units, but had no effect on Sar9, Met(O2)11-SP-induced bronchoconstriction. Anesthetized, tracheostomized, opened-chest male Hartley guinea pigs were pretreated with (+/-) CP-96,345 (3 mg/kg i.v.), SR-48,968 (300 micrograms/kg i.v.), or their respective vehicles, and Evans blue dye (30 mg/kg i.v.) to label circulating albumin. 10 min isocapnic dry gas hyperpnea (12 ml/kg, 150 breaths/min) provoked HIB and HIBVH in vehicle-treated animals. (+/-) CP-96,345 reduced the magnitude of HIB by one-half (peak posthyperpnea RL 7.8 +/- 1.9 [SE] times prehyperpnea baseline versus 16.1 +/- 2.6, vehicle-treated; P < or = 0.0001, ANOVA); SR-48,968 blocked HIB more completely (peak posthyperpnea RL 5.1 +/- 1.7 [SE] times prehyperpnea baseline versus 19.3 +/- 2.8, vehicle-treated; P < 0.0001, ANOVA). Neither drug reduced HIBVH. We conclude that dry gas hyperpnea causes bronchoconstriction in guinea pigs through activation of tachykinin receptors. The differential effects of neurokinin receptor blockade on HIB and HIBVH demonstrate that hyperpnea-induced airflow obstruction is not primarily a consequence of hyperpnea-induced bronchovascular leak.