Quantitative spleen and liver volume changes predict survival of patients with primary sclerosing cholangitis.

AIM: To assess the value of quantitative spleen and liver volume changes in predicting the survival of patients with primary sclerosing cholangitis (PSC). MATERIALS AND METHODS: This institutional review board-approved single-centre study included 89 PSC patients with baseline and follow-up liver imaging studies and laboratory data between 2000 and 2018. Change in spleen, total and lobar liver volumes, and lobar-to-total liver volume ratio was compared between patients with and without adverse outcome (liver transplantation, transplant waiting list, and death). Receiver operating characteristic (ROC) and Kaplan-Meier analysis were performed to identify the volumetric threshold for prediction of outcome and show how these thresholds predict survival, respectively. A p-value of <0.05 was considered statistically significant. RESULTS: The present cohort included 53 men (60%), with mean age of 42 years at baseline. The only volumetric parameters with significant differences in change between patients with and without adverse outcome were spleen volume (p<0.001) and left-to-total liver volume ratio (L/T; p=0.025). The probability of transplant-free survival at 36 months was 59.1% versus 11.9% for patients with spleen volume change <50 ml versus ≥50 ml, respectively (AUC=0.731); and 61.3% versus 13.8% for patients with L/T change <0.04 versus ≥0.04, respectively (AUC=0.638). The patients with changes below the cut-off in both spleen volume and L/T, had a higher probability of transplant-free survival at 36 months (76.8%), compared to those with change at or below the cut-offs in one or both of these two parameters (36.7%, 15%, respectively; p=0.001). CONCLUSION: Spleen volume change and L/T change might be useful biomarkers for prediction of transplant-free survival in patients with PSC.

Immunization with homologous oxidized low density lipoprotein reduces neointimal formation after balloon injury in hypercholesterolemic rabbits.

OBJECTIVES: In this study we tested the hypothesis that immunization with homologous oxidized low density lipoprotein (oxLDL) would inhibit the neointimal response to balloon injury in hypercholesterolemic rabbits. BACKGROUND: Immunization with homologous oxLDL has been shown to markedly reduce aortic atherosclerosis in LDL receptor-deficient as well as cholesterol-fed rabbits; however, the effect of this strategy on the balloon injury-induced neointimal lesion is unknown. METHODS: New Zealand White rabbits were immunized with 280 microg of homologous native LDL (n = 5), copper-oxidized LDL (n = 5) or phosphate buffer as control (n = 5) and fed a 1% cholesterol diet. Rabbits were reimmunized after 3 weeks, and balloon injury of the right ileofemoral artery was performed 1 week later. Four weeks after balloon injury, rabbits were killed, and the neointimal lesion area was measured by computerized morphometry after perfusion fixation of the arteries. Circulating antibodies against oxLDL were measured by enzyme-linked immunosorbent assay. RESULTS: In comparison with the control animals, those immunized with oxLDL had a 58% reduction in the neointimal area (0.53 +/- 0.13 vs. 1.27 +/- 0.26 mm2; p = 0.01). The group immunized with native LDL had a 19% reduction in the neointimal area compared with the control group (p = NS). Circulating cholesterol levels and antibody titers against oxLDL were comparable in the three groups. There was a trend toward reduced immunoreactivity for T cells and oxLDL in the neointima of oxLDL-immunized animals. CONCLUSIONS: Hypercholesterolemic rabbits immunized with homologous oxLDL have a markedly reduced neointimal area after balloon injury despite severe hypercholesterolemia. Together with previous work, these data suggest that an immunization strategy (vaccination) against atherosclerosis and restenosis warrants further investigation.

Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits.

Although the existence of an immune response against modified lipoproteins in atherosclerosis has been observed in experimental animals as well as in humans, the precise pathophysiological relevance of these findings remains unclear. In this study we determined the effect of an immunization with homologous LDL and copper-oxidized LDL on the formation of atherosclerotic plaque in hypercholesterolemic rabbits. Immunizations were performed at the start of a cholesterol-rich diet and 3 weeks later. After 16 weeks, antibodies against oxidized LDL had developed in rabbits given hypercholesterolemic diet alone, but the titers were increased by twofold in rabbits immunized with oxidized LDL as well as in rabbits immunized with LDL, suggesting that the LDL had also become oxidized during the preparation and/or immunization procedure. Immunization with LDL and oxidized LDL reduced atherosclerotic lesions in the proximal aorta by 74% (P < .05) and 48% (P = NS), respectively. The cellular composition of the lesions was not affected by the immunizations. These results support the hypothesis that an immune response against modified LDL has a protective effect against the development of early atherosclerotic lesions.

Autocrine induction of DNA synthesis by mechanical injury of cultured smooth muscle cells. Potential role of FGF and PDGF.

To determine whether replication of arterial smooth muscle cells (SMCs) in response to mechanical injury would occur in the absence of serum and other cells, we created an in vitro model in which confluent, growth-arrested cultures of rat SMCs were injured by gentle pressure of a soft plastic tube and then kept in serum-free medium for up to 4 days. Replication of SMCs in and around the injury, as measured by tritiated thymidine incorporation, was noted within 24 hours and peaked at 48 hours after injury, whereas noninjured cells remained quiescent. An increased expression of platelet-derived growth factor (PDGF) A mRNA, noted 6 hours after injury, was followed by an increased PDGF AA immunoreactivity in SMCs in and around the zone of injury at 24 and 48 hours after injury. A PDGF A chain antisense oligonucleotide inhibited 87.0 +/- 4.0% (P < .005) of SMC replication in the injury zone, whereas the corresponding sense oligonucleotide reduced SMC replication by only 37.2%. An antibody to fibroblast growth factor (FGF) almost completely inhibited SMC replication in the injured zone, whereas an antibody to PDGF AA was without effect. Incubation of SMCs with FGF increased PDGF A mRNA levels in SMCs, and 5 mumol/L PDGF A antisense oligonucleotides reduced FGF-induced SMC replication by 62%. Taken together, these results demonstrate that injured rat SMCs in culture release FGF that activates DNA synthesis of neighboring SMCs both by a direct mechanism and by stimulating the production of PDGF AA.

Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits.

BACKGROUND: Several epidemiological studies have shown an inverse relation between high-density lipoprotein (HDL) cholesterol levels and coronary heart disease. Recently, observational studies have suggested a similar inverse relation between HDL and restenosis after coronary balloon angioplasty. Despite these observations, it is unclear whether this inverse relation reflects a direct vascular protective effect of HDL or apolipoprotein (apo) A-I, the major apolipoprotein component of HDL. Therefore, to determine whether HDL directly influences neointima formation, we investigated the effect of recombinant apo A-I Milano (apo A-I M), a mutant of human apo A-I with Arg-173 to Cys substitution, on intimal thickening after balloon injury in cholesterol-fed rabbits. METHODS AND RESULTS: Cholesterol feeding was initiated 18 days before injury and continued until the time of death. Eight rabbits received intravenous injections of 40 mg of apo A-I M linked to a phospholipid carrier on alternate days, beginning 5 days before and continuing for 5 days after balloon injury of femoral and iliac arteries. Eight rabbits received the carrier alone, and four received neither apo A-I M nor the carrier. Three weeks after balloon injury, apo A-I M-treated rabbits had significantly reduced intimal thickness compared with the two control groups (mean +/- SD): 0.49 +/- 0.29 versus 1.14 +/- 0.38 mm2 and 1.69 +/- 0.43 mm2, P < .002 by ANOVA). The intima-to-media ratio was also significantly reduced by apo A-I M (0.7 +/- 0.2 versus 1.5 +/- 0.5 and 2.1 +/- 0.1, P < .002 by ANOVA) compared with the two controls. The fraction of intimal lesion covered by macrophages, as identified by immunohistochemistry using macrophage-specific monoclonal antibody, was significantly less in apo A-I M-treated rabbits compared with carrier-treated animals (25.3 +/- 17% versus 59.4 +/- 12.3%, P < .005). Aortic cholesterol content, measured in an additional 10 rabbits, did not differ significantly between apo A-I M-treated animals (n = 5) and carrier-treated controls (n = 5). CONCLUSIONS: Apo A-I M significantly reduced intimal thickening and macrophage content after balloon injury in cholesterol-fed rabbits without a change in arterial total cholesterol content. Although the precise mechanism of action remains to be defined, these findings are consistent with a direct vascular effect of apo A-I, which could have potential therapeutic implications.

Effect of percutaneous transluminal coronary angioplasty on circulating endothelin levels.

Percutaneous transluminal coronary angioplasty (PTCA) is frequently associated with vasoconstriction involving large vessels as well as microcirculation, but the potential mechanisms remain poorly defined. In this study, we tested the hypothesis that endothelial disruption during PTCA is associated with an increase in circulating levels of endothelin, a potent endothelium-derived vasoconstrictor peptide. Circulating levels of endothelin and other potential vasoactive mediators such as atrial natriuretic factor, epinephrine and norepinephrine were measured immediately before and after PTCA in 23 patients with coronary artery disease. Although there was no change in the endothelin levels after angiography alone (43 +/- 5 vs 44 +/- 7 pg/ml, p = 0.5), there was a significant increase after PTCA (32 +/- 8 to 37 +/- 10 pg/ml, p < 0.005). The increase in endothelin was associated with a significant increase in atrial natriuretic factor (78 +/- 57 to 129 +/- 131 ng/ml, p = 0.01) and a decrease in epinephrine and norepinephrine levels (111 +/- 64 to 59 +/- 36 pg/ml, p = 0.005, and 1,131 +/- 500 to 811 +/- 311 pg/ml, p = 0.003, respectively). Circulating levels of endothelin did not correlate with the percent coronary stenosis before or after PTCA or the presence or absence of angiographically visible thrombus. These findings suggest that endothelial injury during PTCA may be associated with increased circulating levels of endothelin and its counter-regulatory hormone, atrial natriuretic factor, and also with a reciprocal decrease in epinephrine and norepinephrine levels. Thus, these humoral changes may modulate changes in coronary vascular tone after PTCA.

Cardiac tamponade. Pathophysiology, diagnosis, and management.

Cardiac tamponade is a clinical syndrome that results from an increased intrapericardial pressure and leads to impaired cardiocirculatory function. The spectrum of cardiac tamponade is relatively wide, ranging from an asymptomatic elevation of intrapericardial pressure recognized during objective evaluation, to extreme hemodynamic compromise in the form of severe hypotension or electromechanical dissociation, and many variations between these extremes. This article discusses the causes, pathophysiology, clinical manifestations, diagnosis, and management of cardiac tamponade.

The Northwestern University triplet study. IV. Biochemical parameters.

Umbilical arterial and venous blood gas indices of 11 triplet pregnancies were reviewed. Ten sets of triplets were delivered by cesarean section and one set was delivered vaginally. Mean 1-minute Apgar scores were significantly lower in the group of infants delivered third than in either of the other birth order groups. There were no statistically significant differences when the mean umbilical arterial or venous pH, PCO2, and base deficit were compared among any one triplet and the other two. Similarly, no significant differences were found when these parameters were compared by birth order in relation to mean 5-minute Apgar scores, mean birth weights, and mean gestational ages at delivery. Birth order did not appear to significantly influence acid-base status, although it may become significant with an increasing time in utero after delivery of the firstborn infant. Further study is necessary to investigate whether there is a critical interval of delivery whereby the infants remaining in utero become acidotic.

The Northwestern University Triplet Study. III: Neonatal outcome.

Limited data suggest that cesarean section (CS) may be the preferred method of delivery for triplets. Despite this, it is also felt that the third triplet is at great risk at delivery. We reviewed our experience of 14 triplet pregnancies at Northwestern University between 1981 and 1985. All deliveries were attended by neonatal teams in sufficient number to resuscitate each infant. Of the 14 pregnancies, two ended in previable loss. Thirty-six infants were born from 12 pregnancies of a mean gestational age of 33 weeks (28-38 weeks). The overall survival was 97.3%. Two women delivered vaginally. While the first was successful, the second resulted in vaginal delivery of the first two triplets followed by emergency CS for the third. That infant had a cord blood pH of 6.96 (BE-19), was resuscitated and survived. All 10 CS were successful. The mean cord blood gas tensions and pH were normal. In addition, Apgar scores, the requirement for mechanical ventilation or supplemental oxygen, and mortality did not differ between the first and third-born triplet. These observations suggest that CS was beneficial. Our very low mortality rate supports the concept that CS delivery and aggressive neonatal resuscitation and therapy greatly enhances survival.

The Northwestern University Triplet Study. I: Overview of the international literature.

The international literature on triplet births is surveyed. No definitive work on triplet gestations exists. The relatively few articles on this subject are divided into three categories: 1) national data; 2) local, regional or hospital series; 3) case reports. Clinical concerns, such as prematurity, low birth weight, bed rest, and tocolysis, are discussed with specific reference to literature citations.

The Northwestern University Triplet Study. II: Fourteen triplet pregnancies delivered between 1981 and 1986.

Fourteen triplet deliveries conducted between 1 January 1981 and 30 June 1986 at the principal teaching hospitals of Northwestern University Medical School are reviewed. Maternal demographic characteristics are listed, as are the obstetric outcomes, including mode of delivery, and the fetal outcome. The recent literature of triplet delivery is reviewed. The rate of triplet delivery in our study was 0.37 per 1,000 live births. About two-thirds of the pregnancies resulted from the use of fertility-inducing agents. Ultrasonic confirmation was available in all cases. The majority of women were delivered by cesarean section (85%). No consistent pattern of presentation was seen. The mean weight of all 42 infants was 1,779 g (+/- 594). Unlike-sex triplets accounted for most of the sets (77%). The mean 5-min Apgar score of all infants was 9 and had no association with the order of deliveries. The weight differences by sex regardless of birth order were clinically insignificant. Neonatal mortality was 2.3%.