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The right ventricle (RV) and pulmonary arterial (PA) tree are inextricably linked, continually transferring energy back and forth in a process known as RV-PA coupling. Healthy organisms maintain this relationship in optimal balance by modulating RV contractility, pulmonary vascular resistance, and compliance to sustain RV-PA coupling through life's many physiologic challenges. Early in states of adaptation to cardiovascular disease-for example, in diastolic heart failure-RV-PA coupling is maintained via a multitude of cellular and mechanical transformations. However, with disease progression, these compensatory mechanisms fail and become maladaptive, leading to the often-fatal state of "uncoupling." Noninvasive imaging modalities, including echocardiography, magnetic resonance imaging, and computed tomography, allow us deeper insight into the state of coupling for an individual patient, providing for prognostication and potential intervention before uncoupling occurs. In this review, we discuss the physiologic foundations of RV-PA coupling, elaborate on the imaging techniques to qualify and quantify it, and correlate these fundamental principles with clinical scenarios in health and disease. © 2022 American Physiological Society. Compr Physiol 12: 1-26, 2022.

Background Since the initial description in the 1980s, our understanding of the diversity of pulmonary arterial hypertension (PAH) has continued to evolve. In this study, we report the characteristics of patients seen in an academic medical center for PAH from August 2020 through November 2021 and contrast those with nationally reported data from the United States Pulmonary Hypertension Scientific Registry (USPHSR). Study Design Investigators at the University of Utah Pulmonary Hypertension Program prospectively enrolled adult patients diagnosed with WHO Group 1 PAH, who were evaluated between August 2020 and November 2021 in a program-specific registry. Patient exposure and health histories were collected through structured interviews and questionnaires, along with clinical data and medication use. A total of 242 patients were enrolled in the University of Utah Pulmonary Hypertension Registry (UUPHR). Results Of the 242 enrolled patients, the most common etiology was associated PAH (APAH), accounting for 71.1% of the population. The second largest etiology was idiopathic PAH (IPAH) at 26.4%. The remaining patients were distributed between familial PAH (FPAH), pulmonary veno-occlusive disease (PVOD), and others. Of the total population classified as APAH, 39% of cases were noted as secondary to connective tissue disease (CTD) and 33% as toxin-induced. These represented 28% and 24% of the total population, respectively. Conclusions In this US-based accredited academic medical center, the etiology of PAH in our patient population contrasts with national registry data. In the UUPHR, APAH, specifically CTD-PAH and toxin-associated PAH, accounts for the majority of patients with PAH. This contrasts with IPAH, which nationally is the most reported cause of PAH. Differences in our population may reflect the regional variation of the referral site, but it is noteworthy for its contrast with historically reported phenotypes.

Diabetic ketoacidosis (DKA) is a common condition, with wide variation in admission location and clinical practice. We aimed to decrease intensive care unit (ICU) admission for DKA by implementing a standardized, electronic health record-driven clinical care pathway that used subcutaneous insulin, rather than a continuous insulin infusion, for patients with nonsevere DKA. This is a retrospective, observational preintervention to postintervention study of 214 hospital admissions for DKA that evaluated the effect of our intervention on clinical, safety, and cost outcomes. The primary outcome was ICU admission, which decreased from 67.0% to 41.7% (p < .001). Diabetes nurse educator consultation increased from 45.3% to 63.9% (p = .006), and 30-day Emergency Department (ED) return visit decreased from 12.3% to 2.8% (p = .008). Time to initiation of basal insulin increased from 18.19 ± 1.25 hours to 22.47 ± 1.76 hours (p = .05) and reopening of the anion gap increased from 4.7% to 13.9% (p = .02). No changes in ED length of stay (LOS), hospital LOS, hypoglycemia, treatment-induced hypokalemia, 30-day hospital readmission, or inpatient mortality were observed. The implementation of a standardized DKA care pathway using subcutaneous insulin for nonsevere DKA resulted in decreased ICU use and increased diabetes education, without affecting patient safety.

IntroductionHuman amniotic fluid (hAF) has been shown to reduce inflammation in multiple experimental models. hAF has previously been approved by the US Food and Drug Administration (FDA) as a human cellular and tissue product for tissue injury for human administration, and used safely in thousands of patients as a therapeutic treatment for diverse conditions. Given the profound inflammatory response observed in patients with COVID-19, and the successful completion of 10-patient pilot study of intravenous hAF, we present a trial design for a larger clinical trial of intravenous hAF for the treatment of COVID-19.Methods and analysisThis paper describes the methodology of a phase I/II randomised, double-blinded, placebo-controlled clinical trial to determine the safety and feasibility of using acellular sterile filtered amniotic fluid as a treatment for patients with COVID-19. Primary outcome will be the change in C-reactive protein. Secondary outcomes include safety, biomarker inflammatory levels and clinically relevant outcomes at 30 days, including mortality, ventilator-free days and hospital and intensive care unit length of stay. Exploratory outcomes of health-related quality-of-life patient-reported outcomes will be collected. Hospitalised patients with laboratory-confirmed COVID-19 will be recruited.Ethics and disseminationThis study was approved by the University of Utah Institutional Review Board (IRB_0013292), approved by the US FDA under Investigational New Drug (No 23369) and is registered on ClinicalTrials.gov. Results will be disseminated via peer-reviewed publications and conference presentations.Trial registration numberNCT04497389; Pre-results.

COVID‐19 causes severe disease with poor outcomes. We tested the hypothesis that early SARS‐CoV‐2 viral infection disrupts innate immune responses. These changes may be important for understanding subsequent clinical outcomes. We obtained residual nasopharyngeal swab samples from individuals who requested COVID‐19 testing for symptoms at drive‐through COVID‐19 clinical testing sites operated by the University of Utah. We applied multiplex immunoassays, real‐time polymerase chain reaction assays and quantitative proteomics to 20 virus‐positive and 20 virus‐negative samples. ACE‐2 transcripts increased with infection (OR =17.4, 95% CI [CI] =4.78–63.8) and increasing viral N1 protein transcript load (OR =1.16, CI =1.10–1.23). Transcripts for two interferons (IFN) were elevated, IFN‐λ1 (OR =71, CI =7.07–713) and IFN‐λ2 (OR =40.2, CI =3.86–419), and closely associated with viral N1 transcripts (OR =1.35, CI =1.23–1.49 and OR =1.33 CI =1.20–1.47, respectively). Only transcripts for IP‐10 were increased among systemic inflammatory cytokines that we examined (OR =131, CI =1.01–2620). We found widespread discrepancies between transcription and translation. IFN proteins were unchanged or decreased in infected samples (IFN‐γ OR =0.90 CI =0.33–0.79, IFN‐λ2,3 OR =0.60 CI =0.48–0.74) suggesting viral‐induced shut‐off of host antiviral protein responses. However, proteins for IP‐10 (OR =3.74 CI =2.07–6.77) and several interferon‐stimulated genes (ISG) increased with viral load (BST‐1 OR =25.1, CI =3.33–188; IFIT1 OR =19.5, CI =4.25–89.2; IFIT3 OR =245, CI =15–4020; MX‐1 OR =3.33, CI =1.44–7.70). Older age was associated with substantial modifications of some effects. Ambulatory symptomatic patients had an innate immune response with SARS‐CoV‐2 infection characterized by elevated IFN, proinflammatory cytokine and ISG transcripts, but there is evidence of a viral‐induced host shut‐off of antiviral responses. Our findings may characterize the disrupted immune landscape common in patients with early disease., SARS‐CoV‐2 disrupts the innate immune landscape. Interferon‐lambda transcripts are increased but protein production may be blocked by viral shut‐off. However, key interferon‐stimulated antiviral genes are transcribed and translated.

To examine innate immune responses in early SARS-CoV-2 infection that may change clinical outcomes, we compared nasopharyngeal swab data from 20 virus-positive and 20 virus-negative individuals. Multiple innate immune-related and ACE-2 transcripts increased with infection and were strongly associated with increasing viral load. We found widespread discrepancies between transcription and translation. Interferon proteins were unchanged or decreased in infected samples suggesting virally-induced shut-off of host anti-viral protein responses. However, IP-10 and several interferon-stimulated gene proteins increased with viral load. Older age was associated with modifications of some effects. Our findings may characterize the disrupted immune landscape of early disease.

Background Evidence supports streamlined approaches for inpatients with community-acquired pneumonia (CAP) including early transition to oral antibiotics and shorter therapy. Uptake of these approaches is variable, and the best approaches to local implementation of infection-specific guidelines are unknown. Our objective was to evaluate the impact of a clinical decision support (CDS) tool linked with a clinical pathway on CAP care. Methods This is a retrospective, observational pre–post intervention study of inpatients with pneumonia admitted to a single academic medical center. Interventions were introduced in 3 sequential 6-month phases; Phase 1: education alone; Phase 2: education and a CDS-driven CAP pathway coupled with active antimicrobial stewardship and provider feedback; and Phase 3: education and a CDS-driven CAP pathway without active stewardship. The 12 months preceding the intervention were used as a baseline. Primary outcomes were length of intravenous antibiotic therapy and total length of antibiotic therapy. Clinical, process, and cost outcomes were also measured. Results The study included 1021 visits. Phase 2 was associated with significantly lower length of intravenous and total antibiotic therapy, higher procalcitonin lab utilization, and a 20% cost reduction compared with baseline. Phase 3 was associated with significantly lower length of intravenous antibiotic therapy and higher procalcitonin lab utilization compared with baseline. Conclusions A CDS-driven CAP pathway supplemented by active antimicrobial stewardship review led to the most robust improvements in antibiotic use and decreased costs with similar clinical outcomes.

Purpose of Review This review focuses on the therapeutic management and individualized approach to Group 1 pulmonary arterial hypertension (PAH), utilizing Food and Drug Administration-approved PAH-specific therapies and various interventional and surgical options for PAH. Recent Findings The paradigm for the optimal management of PAH has shifted in recent years. Upfront combination therapy with an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor is now widely accepted as standard of care. In addition, there is increasing emphasis on starting prostanoids early in order to delay time to clinical worsening. However, less is known regarding which prostanoid agent to initiate and the optimum time to do so. In order to facilitate shared decision-making, there is an increasing need for decision tools based on guidelines and collective clinical experiences to navigate between pharmacologic and interventional treatments, as well as explore innovative, therapeutic pathways for PAH. Summary The management of PAH has become increasingly complex. With a growing number of PAH-specific therapies, intimate knowledge of the therapeutics and the potential barriers to adherence are integral to providing optimal care for this high-risk patient population. While current PAH-specific therapies largely mediate their effects through pulmonary vasodilation, ongoing research efforts are focused on ways to disrupt the mechanisms leading to pulmonary vascular remodeling. By targeting aberrations identified in the metabolism and proliferative state of pulmonary vascular cells, novel PAH treatment pathways may be just on the horizon.

Dyspnea is defined by the American Thoracic Society as a “subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.”1 It is a common nonspecific symptom in patients presenting to both primary care and subspecialty medical providers. Dyspnea can be the presenting complaint for a large variety of disease processes and as a result, patients see several specialists for upwards of 2 years prior to formal diagnoses (Table 1).2–4 For example, nearly 90% of people with pulmonary arterial hypertension (PAH) present with dyspnea on exertion,5 but distinguishing between dyspnea caused by PAH from dyspnea caused by other cardiac or pulmonary disease—or a whole host of other conditions—is challenging. In this review, we will discuss the diagnostic approach to patients presenting with chronic dyspnea of inexact etiology.

Purpose The ratio of right ventricular end-diastolic diameter (EDD) to left ventricular EDD (RV/LV) is a measure predictive of right ventricular failure. We hypothesized that an increase in RV/LV would be associated with poor prognosis in severe sepsis and septic shock. Materials and methods This is a retrospective chart review of patients with severe sepsis and septic shock admitted to a medical intensive care unit (ICU) at a single tertiary care hospital. Patients were identified by ICD-9 codes: 995.92 for severe sepsis and 785.52 for septic shock; and had to have an echocardiogram within 48 h of ICU admission. Increased RV/LV was defined as RV/LV ≥ 0.9. Left and right-sided chamber dimensions were measured according to American Society of Echocardiography guidelines. Results We included 146 consecutive ICU patients admitted with septic shock (72) or severe sepsis (74). There was no significant difference in ICU mortality in patients with RV/LV ≥ 0.9 versus RV/LV Conclusions An increased RV/LV does not predict mortality in severe sepsis or septic shock.

Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patient's functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.

New, sophisticated tools are being used to advance our knowledge of PAH and facilitate individualised treatment based on phenotypeshttp://ow.ly/qP6h30ocllp

Amyloidosis involves extravascular deposition of fibrillar proteins within tissues and organs. Primary light chain amyloidosis represents the most common form of systemic amyloidosis involving deposition of monoclonal immunoglobulin light chains. Although pulmonary amyloid deposition is common in primary amyloidosis, clinically significant pulmonary amyloidosis is uncommon, and elevated pulmonary artery pressures are rarely observed in the absence of other underlying etiologies for pulmonary hypertension, such as elevated filling pressures secondary to cardiac amyloid. In this case report, we present a patient with primary light chain amyloidosis and pulmonary arterial hypertension in the setting of pulmonary vascular and right ventricular myocardial amyloid deposition.

According to Dr Seuss, “Sometimes the questions are complicated and the answers are simple.” However, when practitioners are asked if anticoagulation is beneficial in pulmonary arterial hypertension (PAH), it is the question that is simple and the answer that is quite complicated. The histology of PAH is characterized by plexiform lesions, vasoconstriction, medial hypertrophy, intimal hyperplasia, perivascular inflammation, and thrombotic lesions within the pulmonary vasculature. The aetiology of these pathologic lesions remains unclear but has been associated with drug exposures, genetic mutations, and other systemic diseases including cirrhosis, HIV, and collagen vascular diseases. Despite the diverse risk factors for the development of PAH, the therapeutic options currently available have focused on pulmonary vasodilation and improvement in right ventricular function. Randomized controlled trials (RCTs) of antiinflammatory and antiproliferative agents have failed to show clinical benefit or decrease the vascular remodelling seen in PAH. Although pulmonary vasodilators have contributed to an improved prognosis in PAH, 1-year mortality rates remain considerable at 7%-17%. Additionally, mortality differs between phenotypes of PAH, and most particularly is worse in scleroderma-associated PAH. In this setting, efforts to define optimum pharmacotherapy in PAH and individualize therapy based on clinical phenotype are important tasks facing PAH providers. One potential therapeutic approach that has remained somewhat controversial is the use of warfarin and anticoagulation in PAH. In 1992, Rich and colleagues found survival was significantly better in patients given anticoagulation when concurrent therapies with calcium channel blockers were examined. Although these patients were not randomized nor was anticoagulation the primary intervention

Pulmonary hypertension (PH) in clinical practice is most commonly secondary to chronic cardiac or pulmonary disease. PH secondary to left heart disease, Group 2 PH, can result from heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, valvular heart disease, among others. PH secondary to hypoxic pulmonary disease, classified as Group 3 PH, is most often associated with chronic obstructive pulmonary disease, interstitial lung disease, obesity hypoventilation syndrome and obstructive sleep apnea. In this chapter we will discuss the epidemiology, cellular mechanisms, clinical diagnosis and evaluation, management and outcomes of Group 2 and Group 3 PH. Also highlighted are overlap syndromes, that may have characteristics of Group 1, 2 and 3 PH. These syndromes include Systemic Sclerosis, Lymphangioleiomyomatosis, Pulmonary Langerhans Cells Histiocytosis and Sarcoidosis.

A 19-year-old girl with a history of pulmonary arterial hypertension secondary to patent ductus arteriosus (PDA) presented in respiratory failure after blood transfusion for severe menorrhagia. The patient had been raised previously in a rural mountain community that did not engage in medical care. She had been experiencing cyanosis and syncope for 2 years before emancipating herself from her family. One year before this admission, she was seen by a physician for the first time and underwent an echocardiogram, which showed a PDA and right ventricular enlargement. Right heart catheterization demonstrated severe pulmonary arterial hypertension with a mean pulmonary artery pressure of 68 mm Hg and a pulmonary capillary wedge pressure of 8 mm Hg. Cardiac output was 4 L/min. The patient was started on sildenafil 20 mg 3 times a day and bosentan 125 mg twice a day, and her exercise tolerance improved, with resolution of her syncopal episodes. In the week before admission, the patient developed progressive menorrhagia and presented to an outside hospital where she required blood transfusions. After transfusion, the patient developed respiratory …

A 50-year-old woman who gardens regularly with rotting bark mulch presented with exertional dyspnea, diffusion impairment, and radiographic abnormalities (centrilobular nodules, tree-in-bud and ground glass opacities, calcified mediastinal and hilar lymph nodes) on a computed tomogram. Moderate lymphocytosis was noted on bronchoalveolar lavage. Surgical biopsy of her lung revealed granulomatous changes, and biopsies grew Phanerochaete chrysosporium, a fungus that causes white rot in tree bark. She was treated with voriconazole and instructed to avoid gardening, which led to radiographic and symptomatic improvement. She had recurrence of symptoms when she started doing yard work again. P. chrysosporium has been demonstrated to cause hypersensitivity pneumonitis in animal models. This case is the first documented report of P. chrysosporium associated with granulomatous lung disease in a human.

The importance of the right ventricle (RV) in pulmonary arterial hypertension (PAH) has been gaining increased recognition. This has included a reconceptualization of the RV as part of an RV–pulmonary circulation interrelated unit and the observation that RV function is a major determinant of prognosis in PAH. Noninvasive imaging of RV size and function is critical to the longitudinal management of patients with PAH, and continued understanding of the pathophysiology of pulmonary vascular disease relies on the response of the RV to pulmonary vascular remodeling. Echocardiography, in particular the newer echocardiographic measurements and techniques, allows easy, readily accessible means to assess and follow RV size and function.

Chronic alveolar hypoxia is the major cause of pulmonary hypertension. The cellular mechanisms involved in hypoxia- induced pulmonary arterial remodeling are still poorly understood. Mitogen-activated protein kinase (MAPK) is a key enzyme in the signaling pathway leading to cellular growth and proliferation. The purpose of this investigation was to determine the roles that MAPKs, specifically Jun-N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), and p38 kinase, play in the hypoxia-induced pulmonary arterial remodeling. Rats were exposed to normobaric hypoxia (10% O(2)) for 1, 3, 7, or 14 d. Hypoxia caused significant remodeling in the pulmonary artery characterized by thickening of pulmonary arterial wall and increases in tissue mass and total RNA. JNK, ERK, and p38 kinase tyrosine phosphorylations and their activities were significantly increased by hypoxia. JNK activation peaked at Day 1 and ERK/p38 kinase activation peaked after 7 d of hypoxia. The results from immunohistochemistry show that hypoxia increased phospho-MAPK staining in both large and small intrapulmonary arteries. Hypoxia also upregulated vascular endothelial growth factor messenger RNA (mRNA) and platelet-derived growth factor receptor mRNA levels in pulmonary artery with a time course correlated to the activation of ERK and p38 kinase. The gene expressions of c-jun, c-fos, and egr-1, known as downstream effectors of MAPK, were also investigated. Hypoxia upregulated egr-1 mRNA but downregulated c-jun and c-fos mRNAs. These data suggest that hypoxia-induced activation of JNK is an early response to hypoxic stress and that activation of ERK and p38 kinase appears to be associated with hypoxia-induced pulmonary arterial remodeling.

In 460 B.C., Hippocrates described a syndrome of thickened skin. It wasn’t until 1752 that this condition was described in more detail by Carlo Curzio. The term “scleroderma” was first used by Giovambattista Fantonetti in 1836. There was little interest in this disease again until the mid-late 1900’s and now it is a clearly defined disease with ongoing research into pathophysiology and treatment options. Scleroderma is broken down into three main categories: localized, systemic and sine. The first, localized sclerosis is limited to the skin. It has deep and extensive involvement of the skin but spares any internal organ involvement. Systemic Scleroderma (SSc) is divided into limited and diffuse based on the extent of skin involvement. Limited cutaneous (lcSSc) can involve the forearms, hands, legs, feet and face. Diffuse cutaneous (dcSSc) can involve any body area. Both will involve internal organs, differentiating them from the localized form. The last major category, Sine (ssSSc), is rare and involves only internal organs, sparing the skin.

Pruritus is a common symptom in systemic sclerosis (SSc), an autoimmune disease which causes fibrosis and vasculopathy in skin, lung, and gastrointestinal tract (GIT). Unfortunately, pruritus has limited treatment options in this disease. Pilot trials of low-dose naltrexone hydrochloride (LDN) for pruritus, pain, and quality of life (QOL) in other GIT diseases have been successful. In this case series we report three patients that had significant improvement in pruritus and total GIT symptoms as measured by the 10-point faces scale and the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA SCTC GIT 2.0) questionnaire. This small case series suggests LDN may be an effective, highly tolerable, and inexpensive treatment for pruritus and GIT symptoms in SSc.

The role of the vascular microenvironment in the pathogenesis Systemic Sclerosis (SSc) is appreciated clinically as Raynaud's syndrome with capillary nail bed change. This manifestation of vasculopathy is used diagnostically in both limited and diffuse cutaneous subsets of SSc, and is thought to precede fibrosis. The degree of subsequent fibrosis may also be determined by the vascular microenvironment. This paper describes why the vascular microenvironment might determine the degree of end-organ damage that occurs in SSc, with a focus on vascular cell senescence, endothelial progenitor cells (EPC) including multipotential mesenchymal stem cells (MSC), pericytes, and angiogenic monocytes. An explanation of the role of EPC, pericytes, and angiogenic monocytes is important to an understanding of SSc pathogenesis. An evolving understanding of the vascular microenvironment in SSc may allow directed treatment.

Hydrogen peroxide (H(2)O(2)) has recently been shown to have a dual effect on cell growth by stimulating proliferation and triggering apoptosis. Apoptosis induced by H(2)O(2) is a direct consequence of oxidant injury, while the proliferative response to H(2)O(2) is thought to be a protective mechanism against oxidant injury. Signaling of the H(2)O(2)-induced proliferative effect has been proposed to occur via the activation of mitogen-activated protein kinase (MAPK) and increase in expression of transcription factors. In the present study, H(2)O(2)-induced mitogenic signaling in aortic smooth muscle cells (ASMC) was investigated with a specific focus on the roles of tyrosine kinase and tyrosine phosphatase in the regulation of the H(2)O(2)-stimulated egr-1, fra-1, and c-jun transcription. The results show that H(2)O(2)-induced increases in egr-1, fra-1, and c-jun mRNA levels, as measured by Northern blot analysis, are time and dose dependent with the peak of the response within 2 h. Tyrosine kinase inhibitors (genistein, amino-genistein, and tyrphostin 51) significantly attenuated H(2)O(2)-induced expression of these genes and a tyrosine phosphatase inhibitor (perox-vanadate) stimulated their expression. H(2)O(2) stimulated tyrosine kinase activities and caused protein tyrosine phosphorylation, which was blocked by tyrphostin 51. H(2)O(2) also caused tyrosine phosphorylation of platelet derived growth factor (PDGF) receptor. These data show that H(2)O(2) increases egr-1, fra-1, and c-jun mRNA levels in vascular smooth muscle cells, and the increase in expression of these genes is mediated by activation of tyrosine kinase. Our data also provide evidence that the H(2)O(2)-induced mitogenic response is, in part, mediated through the receptor tyrosine kinase, PDGF receptor.