Application of intrawell testing of RCRA groundwater monitoring data when no upgradient well exists.

A statistical quality control approach to detect changes in groundwater quality from a regulated waste unit is described. The approach applies the combined Shewhart-CUSUM control chart methodology for intrawell comparison of analyte concentrations over time and does not require an upgradient well. A case study from the U.S. Department of Energy's Hanford Site is used for illustration purposes. This method is broadly applicable in groundwater monitoring programs where there is no clearly defined upgradient location, the groundwater flow rate is exceptionally slow, or where a high degree of spatial variability exists in parameter concentrations. This study also indicates that the use of the Data Quality Objectives (DQO) process can assist in designing an efficient and cost-effective groundwater monitoring plan to achieve the optimum goal of both low false positive and low false negative rates (high power).

Boston HAPPENS Program: a model of health care for HIV-positive, homeless, and at-risk youth. Human immunodeficiency virus (HIV) Adolescent Provider and Peer Education Network for Services.

The Boston HAPPENS [Human immunodeficiency virus (HIV) Adolescent Provider and Peer Education Network for Services] Program is a project supported by Special Projects of National Significance (SPNS) Program, HIV/AIDS Bureau, Health Resources and Services Administration, which provides a network of care for homeless, at-risk, and HIV-positive youth (ages 12-24 years), involving eight agencies. The program has provided services to 1301 youth, including 46 who are HIV-positive. Boston HAPPENS provides a citywide network of culturally and developmentally appropriate adolescent-specific care, including: (a) outreach and risk-reduction counseling through professional and adult-supervised peer staff, (b) access to appropriate HIV counseling and testing support services, (c) life management counseling (mental health intake and visits as part of health care and at times of crisis), (d) health status screening and services needs assessment, (e) client-focused, comprehensive, multidisciplinary care and support, (f) follow-up and outreach to ensure continuing care, and (g) integrated care and communication among providers in the metropolitan Boston area. This innovative network of youth-specific care offers a continuum from street outreach to referral and HIV specialty care that crosses institutional barriers.

Flow characteristics of peripherally inserted central catheters.

PURPOSE: Clinical applications of peripherally inserted central catheters (PICCs) are limited by the relatively small lumina and long lengths of these devices. Quantitative analysis of the flow capabilities of a variety of PICCs was performed to aid in deciding which patients should have a PICC and in selecting the appropriate catheter. MATERIALS AND METHODS: Sixteen different PICCs from six manufacturers were infused at flow rates of 25-270 mL/h. Infusions were performed with distilled water, normal saline, total parenteral nutrition solution, intralipids, and blood. Flow versus pressure curves were generated for each PICC and infusate. Additional catheter data recorded included the working length, outer diameter (OD), and inner diameter (ID) of the PICCs. RESULTS: Because of the thin wall construction of polyurethane catheters, PICCs made from polyurethane showed much better flow rates than silicone PICCs of a comparable OD. The measured ODs of the PICCs were 4-6 F, whereas the IDs ranged from 0.012 to 0.032 inch. Because of the small ID of some PICCs, infusing blood or intralipids is not practical. CONCLUSION: There is significant variability in the flow capabilities of available PICCs. Many of the PICCs require pressures greater than those that can be generated by commercially available infusion pumps. Matching PICC characteristics to the desired application will avoid many of the clinical problems currently encountered with PICCs.

Small cell carcinoma as the cause for a nondiagnostic V/Q lung scan.

Pulmonary thromboembolism (PTE) is a common cause of morbidity and mortality in an emergency department patient population. The advent of ventilation/perfusion (V/Q) lung scanning and the more recent publication of well- controlled analysis of results, such as the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) data, have provided the clinician with effective diagnostic algorithms to use in suggestive cases. However, there are disorders other than PTE, such as bronchogenic carcinoma, that can cause characteristic abnormalities in V/Q scanning. One such case is described in this report.

Pulmonary capillaritis and alveolar hemorrhage associated with the antiphospholipid antibody syndrome.

Pulmonary hemorrhage due to small vessel vasculitis is a well recognized complication of many autoimmune and collagen vascular disorders. The antiphospholipid antibody syndrome (APS) is a disorder associated with hypercoagulability, thrombocytopenia, and thromboembolic phenomena. Pulmonary manifestations include pulmonary embolism, pulmonary hypertension, and respiratory failure associated with diffuse pulmonary infiltrates. We describe a patient with the APS syndrome, without systemic lupus erythematosus, who developed pulmonary hemorrhage due to pulmonary capillaritis with evidence of perivascular immune complex deposition.

Blood and bronchoalveolar lavage endothelin-1 levels in nocturnal asthma.

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that was recently shown to exhibit bronchoconstrictive properties in vitro. In asthmatic patients, the expression of ET-1 peptide was also shown to be increased in endobronchial biopsies. Thus, we postulated that ET-1 could be higher in subjects with nocturnal asthma. Bronchoalveolar lavage (BAL) fluid levels of ET-1 were measured in 10 subjects with nocturnal asthma and 6 normal volunteers at 0400 h (nighttime groups) and in an additional 7 subjects with nocturnal asthma and 6 control subjects at 1600 h (daytime groups). ET-1 levels were significantly lower in the nighttime asthmatic group (median 39.3 pg/mg protein, 7.3 to 44.0 IQ) than in the nighttime control group (median 77.4 pg/mg protein, 46.8 to 121.9 IQ; p = 0.01) or the daytime asthmatic group (median 56.8 pg/mg protein, 51.6 to 97.4 IQ; p = 0.04). ET-1 levels did not differ significantly between the daytime asthmatic and the daytime control groups or between control groups. Additionally, the overnight reduction in lung function was significantly correlated with lower BAL ET-1 levels (r = 0.57, p = 0.05). These results suggest that ET-1 plays a role in the overnight worsening of asthma and perhaps is more tightly tissue bound, resulting in lower levels of BAL fluid.

Invertebrate cytokines. III: Invertebrate interleukin-1-like molecules stimulate phagocytosis by tunicate and echinoderm cells.

Phagocytosis is the predominant defense mechanism of invertebrates. Here we show that phagocytosis by echinoderm bladder amoebocytes and tunicate granular amoebocytes can be enhanced by invertebrate interleukin-1-like molecules. As little as 5 ng/ml of invertebrate interleukin-1 produced a significant stimulation of echinoderm and tunicate amoebocyte phagocytosis. Stimulation of phagocytosis by echinoderm interleukin-1-like molecules was inhibited by antisera to vertebrate interleukin-1. Invertebrate interleukin-1 also acted as an opsonin when preincubated with erythrocytes or yeast. In addition, the cellular mechanisms of invertebrate phagocytosis were studied using pharmacologic agents to inhibit echinoderm amoebocyte phagocytosis. The energy requirements and involvement of cellular cytoskeletal elements in phagocytosis by bladder amoebocytes were similar to those of mammalian macrophages. These results demonstrate a role for interleukin-1 in invertebrate host defense mechanisms.

Endothelin-1 increases the pulmonary microvascular pressure and causes pulmonary edema in salt solution but not blood-perfused rat lungs.

Endothelin-1 (ET-1) is a potent vasoactive peptide that has been reported to cause lung edema. This study tested if the edemagenic effect of ET-1 is due to preferential venoconstriction and, if so, whether the site of resistance is similar with salt solution (PSS) and more physiologic blood perfusate. ET-1 caused concentration-dependent contraction of pulmonary arterial and venous rings, with an EC50 of 1.3 nM in artery and 0.6 nM in vein (p less than 0.05). In PSS-perfused lungs, 5 nM ET-1 caused a 7.0 +/- 0.8 torr pressor response that was associated with a 5.0 +/- 0.3 torr increase in microvascular pressure and a 530 +/- 20 mg increase in lung weight within 10 min. In contrast, KCl-treated lungs had an equivalent pressor response (7.4 +/- 1.1 torr), yet the microvascular pressure increased by only 2.5 +/- 0.4 torr (p less than 0.05 from ET-1) and the lung weight was unchanged. Meclofenamate did not prevent the effect of ET-1 on microvascular pressure or lung weight. In blood-perfused lungs, ET-1 caused a 7.3 +/- 0.1 torr pressor response but only a 2.0 +/- 0.5 torr increase in microvascular pressure and no increase in lung weight. ET-1 had no effect on permeability either of cultured endothelial cell monolayers or in the pulmonary microvasculature in vivo. We conclude that the edemagenic effect of ET-1 in PSS-perfused lungs is mediated through venoconstriction and an increase in microvascular pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased lung endothelin-1 production in rats with idiopathic pulmonary hypertension.

The role of endogenous circulating or locally produced endothelin-1 (ET-1) in pulmonary hypertensive states is unknown. To investigate this we measured ET-1 levels and preproendothelin-1 (prepro-ET-1) mRNA expression at various ages in control Sprague-Dawley (SDR) rats and in fawn-hooded rats (FHR), a strain which develops idiopathic pulmonary hypertension. Although serum ET-1 levels were similar in SDR and FHR, we found twofold increases in FHR whole lung homogenate ET-1 levels by radioimmunoassay. Coexisting threefold increases in preproET-1 mRNA expression were found in FHR lungs by densitometric analysis of Northern blots and by filter hybridization, suggesting the increase in lung ET-1 was due to enhanced intrapulmonary production of the peptide. To test whether the increase in lung preproET-1 mRNA was primary or secondary to established pulmonary hypertension, we compared preproET-1 mRNA expression prior to development of pulmonary hypertension in fetal (19 day gestation) and neonatal (5 day old) FHR and SDR. Despite similar right ventricular size in SDR and FHR, preproET-1 mRNA was already elevated in neonatal FHR lungs. Furthermore, we found no increase in lung preproET-1 mRNA or ET-1 levels in adult SDR with an equivalent degree of pulmonary hypertension due to chronic hypoxia, implying that the increases in ET-1 production in FHR were not a common consequence of all pulmonary hypertensive states. The functional significance of these observations remains unclear but raises the possibility of a role for ET-1 in the pathophysiology of pulmonary hypertension in the FHR.

Factors influencing the idiopathic development of pulmonary hypertension in the fawn hooded rat.

Fawn hooded rats (FHR), a strain of rat with a hereditary bleeding tendency due to a genetic defect in platelet aggregation, have recently been found to develop pulmonary hypertension. However, whether the pulmonary hypertension in FHR has a genetic basis or simply reflects the influence of extrinsic factors known to increase pulmonary artery pressure in other rat strains has not been fully evaluated. To further examine the structural and hemodynamic changes of pulmonary hypertension in FHR, and to investigate the extent to which alveolar hypoxia may have promoted these abnormalities, hemodynamic and morphometric measurements were made in FHR (4 to 24 wk) and compared with age-matched Sprague-Dawley (SDR) control rats. Increases in mean pulmonary artery pressure, total pulmonary resistance, and right ventricular enlargement were present in both male and female FHR and were evident at an early age (4 wk). Morphometric analysis of barium gelatin-infused lungs revealed marked pulmonary vascular remodelling in FHR characterized as extension of muscle into more peripheral pulmonary vessels, medial hypertrophy of proximal vessels, and reduced number of barium-filled arteries. The increases in pulmonary artery pressure in FHR were not due to the influence of more severe hypoxia, hypoventilation, or polycythemia, as blood gas tension and hematocrit were similar in FHR and SDR. Moreover, we found that pulmonary hypertension could be transmitted to backcross and second filial generation offspring arising from selective matings between FHR and control Wistar Kyoto rats, confirming the heritable basis for pulmonary hypertension in the FHR.

Late disassembly of a modular acetabular component. A case report.

Disassembly of metal-backed acetabular components used for total hip arthroplasty is becoming more common in both preassembled and modular designs. This complication is usually associated with a dislocation of the femoral component or other radiographic evidence of dissociation. A case of late disassembly of the acetabular component without dislocation or radiographic evidence is presented. The authors believe this complication should be considered, along with infection and aseptic loosening, in all cases of late development of pain following total hip arthroplasty.

Paradoxical constriction to platelets by arteries from rats with pulmonary hypertension.

We recently described the early appearance of pulmonary hypertension in the fawn-hooded rat (FHR), an animal with platelet storage pool disease also known to develop systemic hypertension at later ages. Since mediators released from aggregating platelets influence vascular tone, we hypothesized that platelet-mediated pulmonary vascular responses in FHR may be abnormal and potentially linked to the mechanism of pulmonary hypertension. To test this we examined reactivity of isolated pulmonary arteries (PA) and thoracic aortas (Ao) from young FHR with moderately severe pulmonary hypertension but normal systemic pressures. These vessels were compared with PA and Ao from control Sprague-Dawley rat (SDR). Aggregating platelets (1,000-40,000 platelets/mm3) from FHR caused dilation of SDR PA and Ao but constriction of FHR PA and Ao. Qualitatively similar responses were also observed with platelets isolated from SDR implying that abnormal responses were not simply due to the storage pool deficiency in FHR. Response to the platelet-derived endothelium-dependent vasodilator ADP was markedly impaired in FHR PA and mildly impaired in FHR Ao. Endothelium-dependent dilation to acetylcholine, but not to A23187, was mildly impaired in FHR PA while responses to both dilators were normal in FHR Ao. Endothelium-independent dilation to sodium nitroprusside was normal in both FHR PA and Ao. Constrictor sensitivity to serotonin, but not to the thromboxane A2 mimetic U-46619, was increased in FHR PA while responses to both constrictors were normal in FHR Ao. In summary, PAs from FHR with spontaneous pulmonary hypertension exhibit paradoxical constriction to both normal and storage pool deficient platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Pentoxifylline lessens the endotoxin-induced increase in albumin clearance across pulmonary artery endothelial monolayers with and without neutrophils.

Pentoxifylline, a methylxanthine with phosphodiesterase inhibitor activity, attenuates endotoxin-induced pulmonary vascular protein leak and decreases lung neutrophil accumulation in vivo. In vitro, pentoxifylline decreases neutrophil activation as measured by superoxide release and phagocytosis of latex beads. To test the hypothesis that the beneficial effect of pentoxifylline may be via a direct effect on the endothelial cells as well as via prevention of neutrophil activation, we incubated bovine pulmonary artery endothelial cell monolayers with endotoxin and pentoxifylline in the presence or absence of human neutrophils. Albumin clearance across the monolayers was used as an index of endothelial permeability. Endotoxin (1.0 micrograms/ml) increased albumin clearance in a dose- and time-dependent fashion (207.5 +/- 25%, P less than 0.05). Co-incubation with neutrophils enhanced this effect. Pentoxifylline significantly attenuated the endotoxin-induced increase in albumin clearance both with and without neutrophils, and lessened endotoxin-induced cell lysis (chromium release) and morphologic changes. Because increased endothelial cyclic adenosine monophosphate (cAMP) levels may decrease protein permeability and pentoxifylline increases cAMP in neutrophils, we measured cAMP levels in endothelial cells. Incubation with pentoxifylline failed to raise cAMP levels in endothelial cells, in contrast to incubation with aminophylline. In conclusion, pentoxifylline attenuates endotoxin-induced increase in albumin clearance across endothelial monolayers both in the presence and absence of neutrophils. These results suggest that part of the protective effect of pentoxifylline may be mediated via effects on endothelium. Furthermore, this pentoxifylline-mediated endothelial barrier effect appears to be independent of an effect on cAMP.

Effects of inhibitors of EDRF and EDHF on vasoreactivity of perfused rat lungs.

Recent studies indicate that the endothelium of isolated rat pulmonary arteries releases two different factors, endothelium-derived relaxing factor (EDRF) and hyperpolarizing factor (EDHF), which participate in histamine- and acetylcholine-induced relaxation. There is evidence for EDRF vasoreactivity in perfused lungs, but a role for EDHF, which hyperpolarizes vascular smooth muscle by activating membrane K+ channels, has not been reported. We used the inhibitors of EDRF, 20 microM hemoglobin, 200 microM NG-mono-methyl-L-arginine, and 2 mM L-canavanine, the nonselective blocker of K+ channels, 10 mM tetraethylammonium (TEA), and the inhibitor of ATP-sensitive K+ channels, 20 microM glibenclamide, to compare the roles of EDRF and EDHF in the vasoregulation of meclofenamate-treated, salt solution-perfused rat lungs. The three EDRF inhibitors had little or no effect on baseline perfusion pressure, but each potentiated the peak pressor response to airway hypoxia. Neither of them inhibited the pulmonary vasodilation to 5 microM histamine. TEA, but not glibenclamide, increased baseline pressure and potentiated the peak hypoxic response. Both K+ channel blockers, but not the EDRF inhibitors, also prolonged the hypoxic response by reducing the rate of spontaneous vasodilation. TEA, but not glibenclamide, inhibited histamine vasodilation. These results suggest roles for both EDRF and EDHF in the control of rat pulmonary vascular reactivity. EDRF is apparently not responsible for the low vascular tone of the normoxic lung and does not mediate the vasodilation to histamine, but it does modulate the hypoxic pressor response. The exact role of EDHF is uncertain, but it may also modulate hypoxic vasoconstriction and mediate at least part of the histamine vasodilation.

Protein kinase C activation allows pulmonary artery smooth muscle cells to proliferate to hypoxia.

Pulmonary artery (PA) smooth muscle cell (SMC) proliferation occurs with hypoxic pulmonary hypertension in vivo. However, proliferation of cultured PA SMC to hypoxia has not been demonstrated, and thus the mechanism by which these cells respond to hypoxia is unknown. Because protein kinase C (PKC) plays a role in intracellular transduction of proliferative signals, we asked whether PKC activation 1) causes proliferation of bovine PA SMC and 2) is important in PA SMC proliferative response to hypoxia. By measuring [3H]thymidine incorporation and cell counts, we found that quiescent PA SMC from four different cows proliferated with the PKC activator, phorbol 12-myristate 13-acetate (PMA), in a concentration-dependent manner. The proliferation was blocked with a PKC inhibitor, dihydrosphingosine, or by downregulating SMC PKC. We tested whether "priming" PA SMC by PKC activation was required for in vitro SMC proliferative response to hypoxia. Each SMC population was treated with PMA and then exposed for 24 h to 20, 10, 7, 3 or 0% O2. These cells proliferated with hypoxia reaching a peak response at 3% O2. The magnitude of the response to PMA and hypoxia was different for each cell population tested. No hypoxic proliferation occurred in control cells (no PMA). Dihydrosphingosine blocked the hypoxic response to the same extent that it inhibited the initial PMA conditioning stimulus. PKC-downregulated PA SMC did not proliferate to PMA or to subsequent hypoxia. The hypoxic response was not due to a reduction in O2 radical-mediated antiproliferative effect; rather, the PMA-primed cells seemed to "acquire" the ability to directly sense hypoxia and proliferate. In summary, PKC activation caused proliferation of PA SMC in vitro and allowed an additional proliferative response to hypoxia. Activation of PKC may be a requisite step for PA SMC to respond directly to hypoxia.

Serum endothelin-1 concentrations and cold provocation in primary Raynaud's phenomenon.

To determine whether the vasoconstriction in Raynaud's phenomenon is associated with raised concentrations of the endothelium-derived vasoconstrictor endothelin (ET-1), responses to cold pressor testing were examined in 7 subjects with primary Raynaud's phenomenon and in 7 control subjects. Baseline serum ET-1 levels (pg/ml), as measured by radioimmunoassay, were three times higher in Raynaud's subjects (5.3 [SEM 1.7] pg/ml) than in controls (1.7 [0.3]). With progressive local cooling digital arterial pulsatility, as measured by plethysmography, fell earlier and to a greater extent in Raynaud's subjects than in controls, with a half-maximum decrement in pulsatility occurring at 27 [2.6] degrees C and 18 [0.5] degrees C, respectively. Temperature reduction sufficient to cause loss of pulsatility in the Raynaud's subjects produced increases in ET-1 concentrations in both groups that were greater in Raynaud's (10.3 [4.4] pg/ml) than in control subjects (2.7 [0.9] pg/ml). Serum ET-1 in the contralateral arm rose in parallel to but to a lesser extent than that in the cold-challenged arm. Increases in ET-1 concentrations were temporally related to loss of pulsatility but followed the onset of symptoms. Thus the increased basal and stimulated serum endothelin concentrations in Raynaud's disease are associated with the enhanced, prolonged vasospasm of this disorder.

Uptake and metabolism of endothelin in the isolated perfused rat lung.

The uptake and metabolism of endothelin was studied in the isolated perfused rat lung. 125I-Labeled endothelin (4 x 10(-12) M) was rapidly removed from the lung perfusate. More than 90% of the label was removed by 5 min, and only 4-5% remained in the perfusate after 30 min. In the presence of 10(-9) or 5 x 10(-9) M unlabeled endothelin added 6 min before 125I-labeled endothelin, the radiolabel was more slowly removed, so that after 30 min 19 or 73% of the label, respectively, remained in the perfusate. Although a high level of unlabeled endothelin in the perfusate reduced the uptake of 125I-labeled endothelin, it did not displace radiolabel previously taken up by the lung. Analysis of radiolabel composition showed that endothelin metabolism was less than 15% in both the lung and the perfusate after 30 min of lung perfusion. Autoradiography of the lung indicated that the radiolabel was located primarily within the alveolar wall. These results suggest that circulating endothelin is readily but finitely taken up in the pulmonary microvasculature where it is avidly bound but slowly metabolized.

Endothelin 1 causes pulmonary vasodilation in rats.

Endothelin 1 (ET-1), a peptide produced by endothelial cells, causes transient dilation of some systemic vascular beds. To test whether low concentrations of ET-1 could also dilate the pulmonary vascular bed, we examined its effects in isolated blood- and salt solution-perfused rat lungs and in conscious catheterized rats. In blood-perfused lungs undergoing hypoxic (3% O2) vasoconstriction, repeated additions of 0.5 nM ET-1 to the perfusate elicited transient partial vasodilations. The higher concentration of 5 nM caused a larger transient vasodilation followed by vasoconstriction. In nine conscious rats exposed to 8% O2, intravenous ET-1 (0.2 nmol/kg) reversed the hypoxic pressor response by 63 +/- 8% without affecting cardiac output. In eight salt solution-perfused lungs vasoconstricted with 25 mM KCl, 0.5 nM ET-1 caused a maximum vasodilation of 35 +/- 3% with a half-life of 10.7 +/- 1.1 min. The vasodilation was not inhibited by blockers of cyclooxygenase (3.1 microM meclofenamate), platelet-activating factor receptors (10 microM Web 2086), histamine H1 receptors (50 microM chlorpheniramine), or endothelium-derived relaxing factor activity (10 microM hemoglobin and 50 microM methylene blue). However, it was reduced by approximately 50% with the K+ channel blockers, tetraethylammonium chloride (10 mM) and glybenclamide (10 microM), and the inhibitor of Na(+)-K+ pumping, ouabain (0.1 mM). These results indicate that ET-1 is a potent dilator of the pulmonary vascular bed of the rat and that the mechanism of dilation may involve activation of ATP-sensitive K+ channels and membrane hyperpolarization.

Insulin-like growth factor I and protein kinase C activation stimulate pulmonary artery smooth muscle cell proliferation through separate but synergistic pathways.

Smooth muscle cell (SMC) hyperplasia is an important component of vascular remodeling in chronic hypoxic pulmonary hypertension. The mechanisms underlying SMC proliferation in the remodeling process are poorly understood, but may involve insulin-like growth factor I (IGF-I). This study investigates the potential proliferative effects of IGF-I on SMC cultured from the pulmonary arteries (PA) of neonatal calves. We hypothesized that IGF-I stimulates PA SMC proliferation through a protein kinase C (PKC)-independent pathway, but that PKC activation would augment this proliferative response. Incorporation of 3H-thymidine was used as an index of cellular proliferation, and was correlated with subsequent changes in cell counts. Under serum-free conditions, IGF-I (100 ng/ml) induced a 6-fold increase in thymidine incorporation by quiescent PA SMC. This stimulation was not blocked by dihydrosphingosine, an inhibitor of PKC activation. Phorbol myristate acetate (PMA) (1 nM), a membrane-permeable PKC activator, induced a 12-fold increase in thymidine incorporation which was 70% inhibited by dihydrosphingosine. Co-incubation with IGF-I and PMA caused a 60-fold increase in thymidine incorporation, which was 30% inhibited by dihydrosphingosine. This synergistic increase in thymidine incorporation was associated with a subsequent significant increase in cell number. PKC-downregulated cells (1,000 nM PMA x 30 hr) proliferated in response to IGF-I but not PMA, and did not demonstrate synergism with the combination of IGF-I and PMA. The threshold concentrations of IGF-I and PMA for synergism were approximately 1 ng/ml and 1 pM, respectively. We conclude that IGF-I stimulates neonatal PA SMC proliferation via a PKC-independent pathway, and that trace amounts of PKC activators are capable of synergistically augmenting this response. We speculate that the synergistic stimulation of SMC proliferation by IGF-I and PKC activators may play an important role in hypertensive pulmonary vascular remodeling.