Relationship between haemodynamics and morphology in pulmonary hypertension. A quantitative intravascular ultrasound study

BACKGROUND: Intravascular ultrasound imaging of the pulmonary arteries has been demonstrated to be a reliable method of quantifying vessel diameter, luminal area and pulsatility. Simultaneous measurement of flow velocity and its response to vasodilators allows the relationship between morphology and functional compromise to be studied, especially endothelial dysfunction. METHODS: In 51 patients (mean age = 49.8 +/- 12.6 years, 17 female) we performed right heart catheterization and simultaneous intravascular ultrasound of pulmonary artery branches. The patients were divided in two groups: group 1 with normal pulmonary artery pressure and pulmonary vascular resistance, and group 2 with pulmonary hypertension (peak pulmonary artery pressure > 30 mmHg and/or mean pulmonary artery pressure > 20 mmHg). Vessel wall and lumen were studied using a 2.9 F intravascular ultrasound catheter with a 30 MHz phased array transducer. Measurement of blood flow velocity was accomplished by a Doppler flow wire (0.018 inch). The maximal flow change during acetylcholine infusion (adjusted to 10(-6); 10(-5), and 10(-4) M concentration in the blood vessel) was measured. RESULTS: There were no significant differences between groups 1 and 2 with respect to age (48.5 +/- 14.3 years vs 50.3 +/- 12.3 years; P = ns), gender (4 female/8 male vs 13 female/26 male; P = ns), luminal area of the vessel segment in which the intravascular ultrasound measurements were obtained (11.8 +/- 6.1 mm2 vs 16.7 +/- 14.3 mm2; P = ns), internal diameter (3.9 +/- 1.2 mm vs 4.2 +/- 1.7 mm; P = ns), and external diameter (6.1 +/- 1.3 mm vs 6.9 +/- 2.1 mm; P = ns). Cross-sectional images of the pulmonary artery wall demonstrated a single ring with high echodensity with a thin inner layer regarded as intima in group 1. In contrast, the majority of patients (n = 35/39) in group 2 demonstrated a thickening of the intimal layer and/or a disturbance of layering of the echogenic arterial wall. The relative wall thickness was higher in group 2 than in group 1 (22.5 +/- 10.4% vs 15.3 +/- 6.5%; P < 0.05). There were no significant correlations between pulmonary artery pressure and wall thickness pulmonary artery pressure and area change in the cardiac cycle, acetylcholine-dependent increase in pulmonary flow and morphological changes in the vessel wall. CONCLUSION: We conclude that intravascular ultrasound is capable of detecting morphological changes in the pulmonary vessel wall in pulmonary hypertension and that vessel wall hypertrophy of small pulmonary segment arteries, as detected by intravascular ultrasound, is not predictive of functional vasodilatory response of resistance vessels of the same vessel area.     

Immunostimulatory DNA: sequence-dependent production of potentially harmful or useful cytokines

Certain bacterial immunostimulatory (i.s.) DNA sequences containing unmethylated CpG motifs stimulate antigen-presenting cells (APC) to express a full complement of costimulatory molecules and to produce cytokines including interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha. While IL-12 is key to their T helper cell (Th)1-promoting adjuvant activity, secretion of toxic levels of TNF-alpha is harmful in that it promotes toxic shock. Given the beneficial as well as harmful consequences of i.s. DNA, we investigated the possibility of identifying DNA sequences, i.e. CpG oligodeoxynucleotides (ODN) which differentially activate IL-12 versus TNF-alpha cytokine production in APC. Here, we describe an i.s. DNA sequence with these characteristics. While its potential to induce IL-12 is preserved, its ability to trigger TNF-alpha release is strongly curtailed both in vitro and in vivo. I.s. DNA could be segregated into lethal and non-lethal in a mouse toxic shock model. The non-toxic i.s. DNA was useful as an adjuvant, thus allowing cytotoxic T cell responses to the soluble protein ovalbumin and conferring a resistant Th 1 phenotype to BALB/c mice lethally infected with Leishmania major. This i.s. CpG motif may thus be prototypic for a useful immunostimulating DNA sequence that lacks harmful side effects.     

Regulation of V(D)J recombination activator protein RAG-2 by phosphorylation

Antigen receptor genes are assembled by site-specific DNA rearrangement. The recombination activator genes RAG-1 and RAG-2 are essential for this process, termed V(D)J rearrangement. The activity and stability of the RAG-2 protein have now been shown to be regulated by phosphorylation. In fibroblasts RAG-2 was phosphorylated predominantly at two serine residues, one of which affected RAG-2 activity in vivo. The threonine at residue 490 was phosphorylated by p34cdc2 kinase in vitro; phosphorylation at this site in vivo was associated with rapid degradation of RAG-2. Instability was transferred to chimeric proteins by a 90-residue portion of RAG-2. Mutation of the p34cdc2 phosphorylation site of the tumor suppressor protein p53 conferred a similar phenotype, suggesting that this association between phosphorylation and degradation is a general mechanism.     

The lack of long-term detrimental effects on liver allografts caused by donor-specific anti-HLA antibodies

Recent reports indicate a higher incidence of both acute and chronic liver allograft rejection when, at the time of transplantation, the recipients serum contains donor-specific anti-HLA antibodies. From 9/89 to 5/91, 133 liver allografts were performed at our institution. Thirteen liver recipients had donor-specific IgG anti-HLA antibodies (complement-fixing) at the time of transplantation. In eleven patients, antibodies reacted to donor class I antigens while in 1 patient the donor-specific antibody had class II reactivity. Twelve patients have been followed for a minimum of 12 months (median 18 months, range 28-12 months). No hyperacute rejection was seen in any of the cases and four patients had acute rejections. Thus far only one of the twelve patients has biopsy evidence suggestive of chronic liver injury. The remaining have normal liver enzymes and bilirubin. Three of these twelve patients died (one from a myocardial infarction and the others from sepsis) accounting for a one-year graft survival of 75%. There was no significant statistical difference in the one-year graft survival in those recipients without donor-specific antibodies (i.e., 80.5%). In eight of the twelve patients, pretransplant preformed antibody level (PRA) was > 50%. In six of the thirteen patients donor-specific antibody was present at dilutions greater than 1:64. As previously reported, the donor-specific antibody disappeared from the serum posttransplant within hours and did not reappear. In vitro studies demonstrated no factor in portal or hepatic artery blood that could inhibit rabbit complement mediated lysis of anti-HLA antibodies. We conclude that it is not a contraindication to do liver transplants in the presence of donor-specific anti-HLA antibodies.     

Role of nitric oxide in the regulation of the hepatic microcirculation in vivo

BACKGROUND/AIMS: Nitric oxide (NO) is an important mediator in the regulation of vascular tone. However, no data exist on the physiological role of NO in the regulation of the hepatic microcirculation. This study was designed to evaluate the role of NO in the hepatic microcirculation in vivo under physiological conditions. METHODS: The hepatic microcirculation was investigated in anesthetized rats by intravital fluorescence microscopy after injection of fluorescein-isothiocyanate-labeled erythrocytes. Following assessment of baseline sinusoidal perfusion, animals were randomly treated with L-NMMA (n=6), L-arginine (n=6), nitroprusside sodium (NPS, n=5) or a comparable volume of NaCl (n=4). Drugs were given through a portal vein catheter at three doses (Dx), each followed by intravital microscopy. L-NMMA was given: 5 mg/kg (D1), 25 mg/kg (D2), 50 mg/kg (D3); L-arginine 30 mg/kg (D1), 150 mg/kg (D2), 300 mg/kg (D3); and NPS continuously 80 microg x kg(-1) x h(-1). RESULTS: L-NMMA induced a significant increase of mean arterial blood pressure (MAP) (114 vs. 129 mm Hg; p<0.05). In contrast, MAP of NPS-treated animals decreased (107 vs. 91 mm Hg; p<0.01) whereas MAP of animals receiving L-arginine did not significantly differ. Sinusoidal blood flow revealed dose-dependent changes: L-NMMA significantly decreased perfusion of sinusoids (D1: 65%, D2: 57%, D3: 50% of baseline, p<0.05). Injection of L-arginine increased the sinusoidal flow even with the lowest dose (D1: 137%, D2: 133%, D3: 123%, p<0.05). Continuous infusion of NPS had little effect on sinusoidal blood flow at the first and second times of microscopy but sinusoidal blood flow was significantly increased at the third time (D1: 103%, D2: 106%, D3: 122%). CONCLUSIONS: Inhibition of NOS results in a dose-dependent disturbance of the hepatic microcirculation despite significantly increased MAP, whereas L-arginine increases the sinusoidal blood flow. The results indicate an important role for NO in the regulatory mechanisms of hepatic sinusoidal perfusion under physiological conditions.     

Determinants of genital human papillomavirus infection among cytologically normal women attending the University of New Mexico student health center

OBJECTIVES: To confirm the risk factors for genital human papillomavirus (HPV) infection. GOAL OF THIS STUDY: To investigate risk factors for HPV detection apart from the correlated risk factors for cervical neoplasia. STUDY DESIGN: Cervical human papillomavirus (HPV) DNA was assessed in 357 cytologically normal women attending the University of New Mexico student health center. Cervical swab samples were obtained for HPV DNA detection and typing using a PCR-based DNA amplification system. Possible determinants of cervical HPV were examined including age, ethnicity, history of sexually transmitted disease, oral contraceptive use, smoking, age at first intercourse, lifetime number of sex partners, marital status, and history of pregnancy. RESULTS: A 44.3% overall prevalence of cervical HPV was observed. On univariate analysis, factors associated with increasing HPV prevalence included higher lifetime number of sex partners and single marital status. After adjustment for potential confounding variables, we found that HPV prevalence increased with higher lifetime number of sexual partners. CONCLUSION: These findings, along with those from the companion reports in this issue of the journal, support the sexual route of transmission of the virus.