Obstructive sleep apnea and dementia: A role to play?

A growing number of studies, in animal models and humans, have highlighted the link between sleep and Alzheimer's disease (AD) pathophysiology. Among sleep disorders, obstructive sleep apnea (OSA) appears to be a potentially interesting comorbidity, as it is highly prevalent in the middle-aged and elderly population, often associated with some cognitive impairment, associated with an increased risk of developing cognitive decline and dementia including AD, and indeed treatable. The association between OSA and cognition varies according to the studies, but OSA is more frequent in older people with AD than those who are cognitively normal. People with OSA suffer from daytime sleepiness, impaired cognitive function and an increased risk of developing mild cognitive impairment, dementia and AD than those without OSA. Finally, the literature suggests a link between OSA and AD biomarkers. Whether screening and treating OSA could have positive impact on the levels of AD biomarkers and slow or even prevent incident dementia remain to be investigated. It therefore seems essential to understand the role of OSA in the pathophysiology of AD, as there is still no effective treatment to slow or halt its progression. At present, treating the risk factors that can promote the development and/or worsening of AD represents a promising strategy for delaying or even thwarting the onset of symptoms.

Nonconvulsive status epilepticus in the elderly.

There is a higher incidence of status epilepticus in the older adult population that commonly presents as nonconvulsive status epilepticus (NCSE). NCSE most often corresponds to prolonged focal seizures with impaired consciousness with three main clinical presentations: i) an unexplained acute confusional state, ii) subtle eye, motor or behavioral signs or mood changes and iii) typical temporal or frontal seizures with impaired consciousness. Focal seizures without impaired consciousness or de novo absence status of late onset may also be met. The identified risk factors for NCSE onset are: a precession by a generalized tonic-clonic seizure, a known history of epilepsy, female gender, and an acute symptomatic cause or a known brain injury (especially a stroke sequelae). Diagnosis in this population may be difficult, as the clinical presentation is often not very suggestive (stupor, confusion, even coma), and requires an unrestricted use of EEG with an EEG diagnosis based on the EEG with now accepted criteria (so-called Salzburg EEG criteria). The treatment is based first on the injection of benzodiazepines and in the second line on intravenous or oral or gastric tube administration of antiepileptic drugs. It is not recommended to resort to an intubation-ventilation (except necessary to treat respiratory distress, multi-organ failure…). Prognosis is poor with about 30% mortality.

Cerebrovascular Accident Rate Is Different Between Centrifugal and Axial-Flow Pumps, but Survival and Driveline Infection Rates Are Similar.

OBJECTIVES: We analyzed the outcome of patients with implantable left ventricular assist devices (LVADs) at the University of Tokyo Hospital to compare those with centrifugal pumps (CE group: Duraheart and Evaheart) and those with axial-flow pumps (AX group: Heartmate II and Jarvik 2000). METHODS: A total of 68 patients who underwent implantation of LVADs (Duraheart: n = 15; Evaheart: n = 23; Heartmate II: n = 22; Jarvik 2000: n = 8) as a bridge to transplantation at our institution from May 2011 to April 2015 were retrospectively reviewed. All patients were followed through December 2015. RESULTS: The mean follow-up time of the CE group was 1.95 ± 0.92 year (total 74.1 patient-years) and that of the AX group was 1.56 ± 0.56 year (total 46.8 patient-years). Whether the patients underwent centrifugal or axial-flow pump implantations was not associated with survival or driveline infection according to log-rank test (1-year survival rate: 89% vs 100% [P = .221]; 1-year freedom rate: 40% vs 43% [P = .952]). The rates of freedom from cerebrovascular accident (CVA) at 1 year after LVAD implantation in the CE and AX groups were 70% and 96%, respectively (P < .001). The CE group showed a higher frequency of CVA (0.472 vs 0.021 event per patient-year). CONCLUSIONS: Our findings indicate that overall survival and driveline infection rates are similar between centrifugal and axial-flow pumps, but they suggest that patients with centrifugal pumps are more likely to develop CVAs than those with axial-flow pumps.

Association of the Number of HLA-DR Mismatches With Early Post-transplant Acute Cellular Rejection Among Heart Transplantation Recipients: A Cohort Study in Japanese Population.

BACKGROUND: Although many risk factors are reported about graft rejection after heart transplantation (HTx), the effect of HLA mismatch (MM) still remains unknown, especially in the Japanese population. The aim of the present study was to investigate the influence of HLA MM on graft rejection among HTx recipients in Japan. METHODS: We retrospectively investigated the association of the number of HLA MM including class I (A, B) and class II (DR) (for each locus MM: 0 to 2, total MM: 0 to 6) and the incidence of moderate to severe acute cellular rejection (ACR) confirmed by endomyocardial biopsy (International Society for Heart and Lung Transplantation grade ≥ 3A/2R) within 1 year after HTx. RESULTS: Between 2007 and 2014, we had 49 HTx cases in our institute. After excluding those with insufficient data and positive donor-specific antigen, finally 35 patients were enrolled. Moderate to severe ACR was observed in 16 (45.7%) patients. The number of HLA-DR MM was significantly associated with the development of ACR (ACR+: 1.50 ± 0.63, ACR-: 1.11 ± 0.46, P = .029). From univariate analysis, DR MM = 2 was the only independent risk factor for ACR episodes (P = .017). The frequency of ACR within 1 year was significantly higher in those with DR MM = 2 (DR MM = 0 to 1: 0.3 ± 0.47, DR MM = 2: 1.17 ± 1.34 times, P = .007). CONCLUSIONS: The number of HLA-DR MMs was associated with the development and recurrence of ACR episodes among HTx recipients within 1 year after transplantation in Japanese population.

[Obstructive sleep apnea syndrome: a cause of cognitive disorders in the elderly?]. / Le syndrome d'apnées obstructives du sommeil : une cause de troubles cognitifs chez les personnes âgées ?

Obstructive sleep apnea syndrome is a chronic disease characterized by repeated upper airway obstructions during sleep, resulting in fragmented sleep with arousals, nocturnal intermittent hypoxemia and diurnal dysfunctions. Despite its high prevalence in elderly, sleep apnea syndrome seems to be underestimated and difficult to be recognized because of the lack of clinical symptoms specificity in this population. Among the numerous consequences of the obstructive sleep apnea syndrome, cognitive impairment prevails on the attention, executive functions and memory. Neuroimaging studies in human and experimental models allowed to highlight neural correlates of these cognitive dysfunctions in obstructive sleep apnea syndrome. The obstructive sleep apnea syndrome with cognitive impairment shares some features with Alzheimer's disease, involving genetic predisposition ApoE4, hippocampus and synaptic plasticity abnormalities. In this context, the question arises whether obstructive sleep apnea syndrome is a possible etiological or aggravating factor of cognitive decline in elderly with mild cognitive impairment or Alzheimer's disease. Although there are conflicting results in studies evaluating therapeutic efficiency of continuous positive air pressure, obstructive sleep apnea syndrome seems nevertheless as a correctable factor, at least for its impact on some cognitive consequences. Looking for sleep apnea syndrome in elderly with cognitive decline should be considered in a global, diagnosis and therapeutic management.

Improved survival in patients with continuous-flow ventricular assist device for bridge to heart transplantation.

BACKGROUND: Contemporary continuous-flow ventricular assist devices (CFVADs) have greatly improved patient survival for indications of bridge to transplantation (BTT) and destination therapy. In Japan, CFVAD is limited for BTT use. The waiting period for heart transplantation (HT) is long owing to donor shortage. We examined the results of CFVAD for BTT indication. METHODS: Eighty-nine VAD treatments were performed among subjects whose preimplantation condition was profile 1 (n = 49) or profile 2 or 3 (n = 40). The device was the paracorporeal pulsatile Nipro VAD (n = 67) or CFVAD (n = 22). All CFVAD patients were profile 2 or 3. RESULTS: The median assist period was 529 days (Nipro VAD, 530; CFVAD, 528). Twenty-six patients were on the device for >2 years. Actuarial survival was 81.6%, 69.5%, and 61.1% at 1, 3, and 5 years. Survival in profile 1 was significantly worse than in profile 2 or 3. Survival of CFVAD patients was superior to that of paracorporeal VAD. Six-month mortality rate of 20% in cases before 2009 (n = 60) was dramatically improved to 3% among those after 2010 (n = 29). All patients with CFVAD were alive and discharged home. 26 patients were transplanted, 7 had been weaned from VAD and 27 were on a device. The rate of events requiring hospital admission was 0.98 per patient-year in CFVAD patients. CONCLUSIONS: Contemporary CFVADs have enabled advanced heart failure patients to await HT safely with an improved quality of life. The advent of CFVAD has also shifted their preimplantation condition to a less sick status. CFVADs were the safest, most reliable circulatory support devices for long-term waiting periods for the BTT indications.

Effects of bosentan on nondigital ulcers in patients with systemic sclerosis.

BACKGROUND: Bosentan is an oral dual endothelin receptor antagonist, which has been shown to be efficacious for preventing new digital ulcers in patients with systemic sclerosis (SSc) in two high-quality randomized controlled trials. However, its efficacy for nondigital ulcers in SSc remains unknown. OBJECTIVES: To evaluate the efficacy of bosentan on nondigital ulcers in patients with SSc. METHODS: Bosentan was administered to five patients with SSc with pulmonary arterial hypertension, who also had nondigital ulcers refractory to conventional treatments. The efficacy of bosentan on nondigital ulcers and its association with clinical features of ulcers were analysed. RESULTS: The nondigital ulcers refractory to conventional treatments were significantly improved by the administration of bosentan in cases surrounded with severe cyanosis. In contrast, nondigital ulcers without cyanosis were still refractory to bosentan therapy. CONCLUSIONS: Bosentan may be efficacious for accelerating the healing of nondigital ulcers with severe cyanosis, suggesting that nondigital ulcers caused by severely impaired peripheral circulation are highly responsive to this treatment.

Measurement of short-chain fatty acids in human faeces using high-performance liquid chromatography: specimen stability.

BACKGROUND: Short-chain fatty acids such as lactic acid produced by the intestinal bacterial flora have various physiological actions involved in health, and it is important to determine the concentrations of faecal short-chain fatty acids and evaluate their relationship with large intestinal diseases. In this study, we evaluated the highly selective and sensitive simultaneous measurement of both volatile and non-volatile short-chain fatty acid hydrazides using high-performance liquid chromatography (HPLC). MATERIALS AND METHODS: Faeces treated with ethanol were used as analytic samples. Short-chain fatty acids were measured as fatty acid hydrazides by HPLC. RESULTS: For 12 types of short-chain fatty acid, the results regarding linearity, recovery tests and reproducibility were favourable. Faeces treated with ethanol could be stored at room temperature. DISCUSSION: The stability of short-chain fatty acids in faeces at room temperature was statistically analysed. Faeces stored without treatment with ethanol showed increases/decreases in the concentrations of short-chain fatty acids, which may be due to assimilation by intestinal bacteria. However, specimen in 70% ethanol and stored in room temperature exhibited no substantial changes in concentrations of short-chain fatty acids up to seven days.

Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy.

Physiological and pathological cardiac hypertrophy have directionally opposite changes in transcription of thyroid hormone (TH)-responsive genes, including alpha- and beta-myosin heavy chain (MyHC) and sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), and TH treatment can reverse molecular and functional abnormalities in pathological hypertrophy, such as pressure overload. These findings suggest relative hypothyroidism in pathological hypertrophy, but serum levels of TH are usually normal. We studied the regulation of TH receptors (TRs) beta1, alpha1, and alpha2 in pathological and physiological rat cardiac hypertrophy models with hypothyroid- and hyperthyroid-like changes in the TH target genes, alpha- and beta-MyHC and SERCA. All 3 TR subtypes in myocytes were downregulated in 2 hypertrophy models with a hypothyroid-like mRNA phenotype, phenylephrine in culture and pressure overload in vivo. Myocyte TRbeta1 was upregulated in models with a hyperthyroid-like phenotype, TH (triiodothyronine, T3), in culture and exercise in vivo. In myocyte culture, TR overexpression, or excess T3, reversed the effects of phenylephrine on TH-responsive mRNAs and promoters. In addition, TR cotransfection and treatment with the TRbeta1-selective agonist GC-1 suggested different functional coupling of the TR isoforms, TRbeta1 to transcription of beta-MyHC, SERCA, and TRbeta1, and TRalpha1 to alpha-MyHC transcription and increased myocyte size. We conclude that TR isoforms have distinct regulation and function in rat cardiac myocytes. Changes in myocyte TR levels can explain in part the characteristic molecular phenotypes in physiological and pathological cardiac hypertrophy.

Prognostic factors for survival and bladder recurrence in transitional cell carcinoma of the upper urinary tract.

BACKGROUND: Prognostic factors for survival in transitional cell carcinoma of the upper urinary tract have been extensively evaluated, but detailed analyses of patterns of bladder recurrence after surgery have been rare. METHODS: The outcome and tumor recurrence of 93 patients with transitional cell carcinoma of the upper urinary tract surgically treated between 1975 and 1999 were reviewed, retrospectively. Disease-specific survival by pathologic stage and grade were analyzed by the Kaplan-Meier METHOD: Prognostic factors for survival and bladder recurrence were examined by univariate and multivariate analysis. RESULTS: The 5-year disease-specific survival rates of the patients with pTa, T1 and T2 were 92.9%, 100% and 88.9%, respectively. However, that of the pT3 patients was 61.9% and the median survival of the pT4 cases was only 7 months. Bladder recurrence was seen in 40 cases and recurrences occurred within 1 year in 32 of these patients. The stage and grade of metachronous bladder tumors usually resembled those of primary tumors, but invasive recurrences were seen in 19% of recurrent cases with primary pTa, pT1 tumors. The significant prognostic factor for survival was pathologic stage (pT3, pT4), but no significant variables were detected for bladder recurrence by multivariate analysis. CONCLUSIONS: The prognosis of pT3, pT4 patients is poor and effective systemic adjuvant therapy is necessary. Invasive bladder recurrence occurred in 19% of patients with superficial primary tumors. As no significant prognostic variables for bladder recurrence were identified, careful follow up for bladder recurrence is important even if the primary tumors are non-invasive.

Cloning of hypoxia-inducible factor 1alpha cDNA from chick embryonic ventricular myocytes.

Hypoxia-inducible factor 1 (HIF-1) is composed of HIF-1alpha and arylhydrocarbon nuclear receptor translocator (ARNT), which belong to the basic-helix-loop-helix-Per/ARNT/Sim (bHLH-PAS) family of transcription factors. HIF plays key roles in oxygen homeostasis and embryonic cardiovascular development. In this study, we have cloned cDNAs encoding the chick HIF-1alpha from cultured embryonic ventricular myocytes (CEVM) and then examined its expression in various embryonic tissues. The deduced amino acid sequence of the chick HIF-1alpha cDNA showed 79% identity with that of the human HIF-1alpha cDNA. In contrast, sequence homology between the chick HIF-1alpha and endothelial PAS protein 1 (EPAS1), another member of the bHLH-PAS proteins, was only low (49%). HIF-1alpha mRNA was expressed abundantly in CEVM, but scarcely in the liver, which was quite different from expression pattern of EPAS1 mRNA. These data suggest that HIF-1alpha may be involved in embryonic cardiovascular development. HIF-1alpha and EPAS1 may play distinct roles during developmental stages.

Signaling pathways responsible for fetal gene induction in the failing human heart: evidence for altered thyroid hormone receptor gene expression.

BACKGROUND: We have previously demonstrated that changes in myosin heavy chain (MHC) isoforms that occur in failing human hearts resemble the pattern produced in rodent myocardium in response to hypothyroidism. Because thyroid hormone status is usually within normal limits in these patients, we hypothesized that failing/hypertrophied human myocardium might have a defect in thyroid hormone signaling due to alterations in expression of thyroid hormone receptors (TRs). METHODS AND RESULTS: To examine this hypothesis, we used RNase protection assay to measure mRNA levels of TRs in failing left ventricles that exhibited a fetal pattern of gene expression, ie, decreased expression of alpha-MHC with increased beta-MHC expression compared with left ventricles from age-matched controls. We detected expression of TR-alpha(1), -alpha(2), and -beta(1) isoforms in human left ventricles. In failing left ventricles, TR-alpha(1) was downregulated, whereas TR-alpha(2), a splice variant that does not bind thyroid hormone but inhibits responses to liganded TRs, was increased. Expression levels of TR-beta(1) did not differ significantly between the 2 groups. According to linear regression analysis, expression levels of TR-alpha(1) and -alpha(2) were positively and negatively correlated with those of alpha-MHC, respectively. CONCLUSIONS: We conclude that decreases in TR-alpha(1) and increases in TR-alpha(2) may lead to local attenuation of thyroid hormone signaling in the failing human heart and that the resulting tissue-specific hypothyroidism is a candidate for the molecular mechanism that induces fetal gene expression in the failing human ventricle.

Ets-1 is involved in transcriptional regulation of the chick inducible nitric oxide synthase gene in embryonic ventricular myocytes.

In order to elucidate roles of Ets family of transcription factors in transcriptional activation of inducible nitric oxide synthase (iNOS) genes, we analyzed the chick iNOS gene expression in cultured chick embryonic ventricular myocytes (CEVM). Deletional analysis and site-directed mutagenesis demonstrated that both the Ets/PEA3 site (-221 to -216 bp) and the kappaB site (-101 to -93 bp) of the 5'-flanking region of the chick iNOS gene were involved in the maximal activation of the lipopolysaccharide (LPS)-induced expression of the reporter (luciferase) gene, although the proximal kappaB site played the more essential role. Electrophoretic mobility shift assay revealed that LPS augmented the nuclear protein bindings to the Ets/PEA3 as well as kappaB motifs. Ets-1, one of the Ets proteins, was suggested to be bound to the Ets/PEA3 oligonucleotide. By Northern blot analysis, LPS was shown to induce iNOS mRNA in CEVM, along with a preceding increase in the levels of c-ets-1 mRNA. Ets-1 may be involved in the iNOS gene transcription in CEVM, presumably through interacting with the NF-kappaB.

Quantum effects on liquid dynamics as evidenced by the presence of well-defined collective excitations in liquid para-hydrogen

The origin of the well-defined collective excitations found in liquid para-H2 by recent experiments is investigated. The persistence of their relatively long lifetimes down to microscopic scales is well accounted for by calculations carried out by means of path-integral-centroid molecular dynamics. In contrast only overdamped excitations are found in calculations carried within the classical limit. The results provide fully quantitative evidence of quantum effects on the dynamics of a simple liquid.

Expression of genes encoding vascular endothelial growth factor and its Flk-1 receptor in the chick embryonic heart.

Vascular endothelial growth factor (VEGF) is known to play an essential role in embryonic vascular development. The heart is one of the main organs that produce VEGF, but it is still unknown how expression of VEGF gene is regulated in embryonic cardiac myocytes. Thus, we cloned cDNAs encoding VEGF and its receptor (a KDR/flk-1 or Quek1 homologue) from cultured 10-day-old chick embryonic ventricular myocytes (CEVM). Reverse transcription-polymerase chain reaction revealed that the chick VEGF mRNAs consisted of at least four different species corresponding to the isoforms of 190, 166, 146 and 122 amino acids. In the embryonic heart and CEVM, the isoforms of 166 and 122 amino acids were dominant. Northern blot analysis detected an abundance of VEGF mRNA in both the embryonic heart and CEVM, even at the basal state. The levels of VEGF mRNA in CEVM were significantly augmented by forskolin (100 microM), or phorbol 12-myristate, 13-acetate (200 nM) in a time-dependent manner in CEVM. In contrast, the basal levels of VEGF mRNA were attenuated by genistein (100 microM), but not by H89 (100 microM) or bisindolylmaleimide (75 microM). Northern blot analysis also detected the chick flk-1 mRNA in abundance in the embryonic heart, and to a much lesser extent in CEVM. The expression levels of VEGF and flk-1 mRNA species were continuously high in the 6, 8 and 10-day-old chick embryonic hearts. In the 10-day-old embryonic hearts, in situ hybridization confirmed that mRNA encoding VEGF was mainly expressed in ventricular myocytes. In contrast, the flk-1 mRNA was detected in the microvascular endothelial cells, and to a lesser extent in the ventricular myocytes. These data suggest that VEGF is produced in embryonic ventricular myocytes, even at the basal state, and that the levels of VEGF mRNA may be differently regulated by various protein kinases. VEGF produced by the chick embryonic heart may play important roles in embryonic cardiovascular development by acting on surrounding endothelial cells and, possibly, on ventricular myocytes themselves.

[Clinical evaluation of low dose glucocorticoid therapy for hormone-refractory prostate cancer].

Fifteen cases with hormone-refractory metastatic carcinoma of the prostate were treated by the combination therapy of LH-RH analogue and low-dose glucocorticoid. Prior treatments of the patients were composed of maximum androgen blockade (MAB) therapy (14 cases) and bilateral orichiectomy (1 case). Nine of 15 cases underwent estramustine based treatment or anti-cancer chemotherapy as the second-line therapy. As a glucocorticoid (steroid) therapy, 1.5 or 2.0 mg of dexamethasone or 10 mg of predonisolone were given for a median period of nine months. Clinical responses were evaluated by the determination of serum PSA, EOD score and QOL scales. PSA responses were classified as CR, PR and PD according to the following categories; CR : PSA level decreased to less than 2 ng/ml, PR : PSA level decreased to less than half values of pretreatment level, PD: 20% or more increased to pretreatment level. PSA responses (CR + PR) were observed in eight of 15 patients for a median period of six months. Responses are seemed to be correlated with the Gleason scores. No apparent improvement on EOD scores by bone scintigraphy was seen, however, definite improvement of bone pain was identified in eight of 11 cases. The steroid therapy was considered as one of the useful treatment choice for patients with hormone-refractory prostate cancer.

Lipopolysaccharide augments expression and secretion of vascular endothelial growth factor in rat ventricular myocytes.

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is highly expressed in the myocardium under various stimuli including hypoxia and ischemia. On the other hand, lipopolysaccharide (LPS) causes systemic inflammatory response syndrome (SIRS), which consists of systemic pathophysiological changes related to vascular hyperpermeability. To test the hypothesis that VEGF is one of the important mediators of SIRS, we examined effects of LPS on the VEGF expression and secretion in cultured neonatal rat ventricular myocytes. LPS (10 microg/ml) rapidly (within 1 h) augmented the levels of VEGF mRNA in these cells. Pharmacological inhibition of nucleic factor-kappaB or tyrosine kinases did not affect the LPS-induced augmentation of VEGF mRNA expression, while these treatments markedly suppressed the up-regulation of inducible nitric oxide synthase (iNOS) expression by LPS. The VEGF concentrations in the conditioned media were also significantly increased by the LPS treatment of 6 h. In conclusion, LPS augments VEGF expression and secretion in rat ventricular myocytes, suggesting that VEGF may be involved in pathogenesis of SIRS. LPS may induce VEGF mRNA through the signaling pathways that are distinct from those responsible for the iNOS induction.

Platelet-derived growth factor induces cellular growth in cultured chick ventricular myocytes.

OBJECTIVES: Platelet-derived growth factor (PDGF) stimulates growth in various types of cells, but little is known about its effect on cardiac myocytes. Therefore, we examined whether PDGF had a direct effect on cardiac myocytes and investigated their intracellular signaling pathways. METHODS: A primary culture of chick embryonic (Hamburger and Hamilton stage 36) ventricular myocytes was prepared. Cellular growth was estimated by 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide assay and 5-bromo-2'-deoxyuridine incorporation assay. The number of PDGF binding sites was measured by binding assay. Induction of c-fos mRNA was analyzed by Northern blot analysis. The binding activity of activator protein (AP)-1 was examined by electrophoretic mobility shift assay. The activation of mitogen-activated protein kinase (MAPK) and signal transducers and activators of transcription (STATs) was analyzed by Western blot analysis, immunoprecipitation, and immunocytochemistry. Furthermore, intracellular Ca2+ concentration ([Ca2+]i) was measured with indo-1 and L-type Ca(2+)- channel current (ICa) was recorded with the patch clamp technique. RESULTS: PDGF-AB and -BB, but not PDGF-AA, increased viable cell number (5 ng/ml of PDGF-AA, -AB, -BB: 101 +/- 4%, 115* +/- 4%, 122* +/- 4%, respectively, n = 4, *P < 0.05) and DNA synthesis (104 +/- 11%, 202* +/- 18%, 295* +/- 25%, respectively, n = 4, *P < 0.05). Scatchard analysis demonstrated that the maximal number of PDGF-AA, -AB, -BB binding sites was 5 +/- 1, 63 +/- 12, 126 +/- 24 fmol/10(6) cells, respectively. PDGF-BB provoked induction of c-fos mRNA and increases in binding activity to the AP-1 site. PDGF-BB also induced tyrosine phosphorylation and nuclear translocation of MAPK. The c-fos induction, the increased AP-1 binding activity and the acceleration of DNA synthesis were all attenuated by genistein (100 microM) or MAPK kinase inhibitor (10 or 50 microM PD98059). Interestingly, protein kinase C inhibitor (250 nM calphostin C) attenuated the increases of AP-1 binding activity to some extent, but did not inhibit the c-fos induction at all. The phosphorylation states of STATs were not significantly affected by PDGF-BB. PDGF-BB did not alter [Ca2+]i or ICa. CONCLUSIONS: We conclude that PDGF can exert direct effects on embryonic cardiac myocytes and induce their growth. MAPK cascade may play an important role in the PDGF-induced embryonic myocardial growth.