Health-related quality of life in adolescents with inflammatory bowel disease depends on disease activity and psychiatric comorbidity.

Adolescent patients with inflammatory bowel disease (IBD) show an increased risk for behavioral and emotional dysfunction. Health-related quality of life (HRQoL) is influenced by medical illnesses, as well as by psychiatric disorders, but for adolescents with IBD, the extent to which HRQoL is influenced by these two factors is unclear. For 47 adolescent IBD patients, we analyzed disease activity, HRQoL and whether or not a psychiatric disorder was present. Disease activity was estimated using pediatric Ulcerative Colitis Activity Index and pediatric Crohn's Disease Activity Index. The IMPACT-III and the EQ-5D were used to measure HRQoL and QoL, respectively. In addition, patient and parent diagnostic interviews were performed. 55.3 % patients fulfilled DSM-IV criteria for one or more psychiatric disorders. In all patients, psychiatric comorbidity together with disease activity contributed to a reduction in quality of life. Adolescents with IBD are at a high risk for clinically relevant emotional or behavioral problems resulting in significantly lower HRQoL. We conclude that accessible, optimally structured psychotherapeutic and/or psychiatric help is needed in adolescent patients with IBD.

Human immunodeficiency virus associated tuberculosis more often due to recent infection than reactivation of latent infection.

BACKGROUND: It is unclear whether human immunodeficiency virus (HIV) increases the risk of tuberculosis (TB) mainly through reactivation or following recent Mycobacterium tuberculosis (re)infection. Within a DNA fingerprint-defined cluster of TB cases, reactivation cases are assumed to be the source of infection for subsequent secondary cases. As HIV-positive TB cases are less likely to be source cases, equal or higher clustering in HIV-positives would suggest that HIV mainly increases the risk of TB following recent infection. METHODS: A systematic review was conducted to identify all studies on TB clustering and HIV infection in HIV-endemic populations. Available individual patient data from eligible studies were pooled to analyse the association between clustering and HIV. RESULTS: Of seven eligible studies, six contributed individual patient data on 2116 patients. Clustering was as, or more, likely in the HIV-positive population, both overall (summary OR 1.26, 95%CI 1.0-1.5), and within age groups (OR 1.50, 95%CI 0.9-2.3; OR 1.00, 95%CI 0.8-1.3 and OR 2.57, 95%CI 1.4-5.7) for ages 15-25, 26-50 and >50 years, respectively. CONCLUSIONS: Our results suggest that HIV infection mainly increases the risk of TB following recent M. tuberculosis transmission, and that TB control measures in HIV-endemic settings should therefore focus on controlling M. tuberculosis transmission rather than treating individuals with latent M. tuberculosis infection.

An early increase in gamma glutamyltranspeptidase and low aspartate aminotransferase peak values are associated with superior outcomes after orthotopic liver transplantation.

BACKGROUND: Prediction of prognosis after liver transplantation (OLT) remains difficult. The present study determines if standard laboratory parameters measured within the first week after OLT correlate with outcome. PATIENTS AND METHODS: Laboratory parameters measured within the first weak after OLT of 328 patients were grouped either graft loss or death within 90 days after (group 1: graft loss; group 2: death; group 3: neither graft loss nor death within 90 days). RESULTS: Peak AST and ALT were significantly lower in group 3 (1867 and 1252 U/L) than in group 1 (4474 and 2077 U/L) or 2 (3121 and 1865 U/L). Bilirubin was significantly lower and gamma-GT significantly higher in group 3 compared to groups 1 and 2. In multivariate analysis, high AST peaks were independently associated with death or graft loss within 90 days. An increase in gamma-GT and low bilirubin early after transplantation were found to be independently associated with superior outcome. DISCUSSION: Unexpectedly, a disproportionate rise in gamma-GT was associated with graft and patient survival of more than 90 days. This might be explained by regeneration phenomena in the liver indicative of a well functioning graft.

Recurrent acute liver failure and mitochondriopathy in a case of Wolcott-Rallison syndrome.

A 10-year-old Arabic boy of consanguineous parents has suffered eight episodes of acute liver failure with haemolysis triggered by intercurrent febrile illnesses. The first crisis occurred at 9 months of age, after which diabetes mellitus developed. By the age of 6 years, short stature, mild myopathy and later skeletal epiphyseal dysplasia also became evident. His psychosocial development and educational achievements have remained within normal limits. While there were no clear biochemical indicators of a mitochondrial disorder, an almost complete deficiency of complex I of the respiratory chain was demonstrated in liver but not in fibroblast or muscle samples. Molecular analysis of the eukaryotic translation initiation factor 2alpha kinase gene (EIF2AK3) demonstrated a homozygous mutation, compatible with a diagnosis of Wolcott-Rallison syndrome (WRS). This patient's course adds a new perspective to the presentation of WRS caused by mutations in the EIF2AK3 gene linking it to mitochondrial disorders: recoverable and recurrent acute liver failure. The findings also illustrate the diagnostic difficulty of mitochondrial disease as it cannot be excluded by muscle or skin biopsy in patients presenting with liver disease. The case also further complicates the decision-making process for liver transplantation in cases of acute liver failure in the context of a possible mitochondrial disorder. Such patients may be more likely to recover spontaneously if a mitochondrial disorder underlies the liver failure, yet without neurological features liver transplantation remains an option.

Successful arterial thrombolysis and percutaneous transluminal angioplasty for early hepatic artery thrombosis after split liver transplantation in a four-month-old baby.

Early HAT is the most frequent and severe vascular complication following liver transplantation. It is one of the major causes of graft failure and mortality. Endovascular thrombolytic treatment in patients with thrombotic complications after liver transplantation is an attractive alternative to open surgery as lower morbidity and mortality rates are reported for it. PTA following transcatheter thrombolysis has been successfully used to treat HAT in adults. To the best of our knowledge, there have not been any reports of a successful transcatheter thrombolysis using interventional radiological techniques in a patient only four months old. The present report describes the successful endovascular emergency treatment of a HAT three days after DD split liver transplantation.

Indications for pediatric liver transplantation. Data from the Heidelberg pediatric liver transplantation program.

Nowadays liver transplantation is an established treatment for children with end-stage liver disease with very good 1- and 5-year survival. This has been achieved through constant improvement of surgical techniques, new immunosuppressive drugs and clinical management. Indications for liver transplantation in infants and children include acute liver failure (ALF), chronic liver failure with pruritus, complications of cholestasis and failure to thrive. In young children, the most common liver disease leading to transplantation is biliary atresia. Biliary atresia accounts for at least 50 percent of all liver transplants in children and is characterized by the failure of the bile ducts to develop normally and drain bile from the liver. Several models to assess prognosis of liver disease have been developed. In acute liver failure leukocyte count, bilirubin, International Normalized Ratio (INR) and age have a strong correlation with outcome. In chronic liver failure, PELD (Pediatric end-stage liver disease) Score and the occurrence of complications of liver disease are important prognostic tools. Since the start of our own paediatric liver transplantation program at the University of Heidelberg in 2003, already 15 Children between 5 months and 14 years have been transplanted. Indications and outcome of these patients are reviewed in this paper.

Conservative treatment of infantile hypertrophic pyloric stenosis with intravenous atropine sulfate does not replace pyloromyotomy.

Pyloromyotomy as described by Weber and Ramstedt has been the standard therapy for infantile hypertrophic pyloric stenosis since the 1960's and conservative therapy has been abandoned. The objective of this study was to test the effectiveness of systemic atropine applied intravenously for 7 days as a conservative therapeutic strategy and as an alternative to primary operation. Forty-two consecutive term infants with infantile hypertrophic pyloric stenosis were enrolled in the study over a period of 5 years. After confirmation of the diagnosis they all received intravenous atropine at a dose of 0.04 mg/(kg day) and increased by 0.01 mg/(kg day) up to 0.12 mg/(kg day), given as 6-8 single doses per/day. Nine pairs of parents requested that their child should be operated before completing the 7 days of medical therapy. Surgery was necessary in 8 of the remaining 33 infants (24,.2%) who did not improve after 7 days of conservative treatment. Successful treatment with i.v. atropine sulfate was achieved only in 25/33 term infants at an average maximal dose of 0.11 mg/(kg day), without any major side effects. Intravenous atropine sulfate has been considered as a potential alternative therapeutic strategy in the treatment of infantile hypertrophic pyloric stenosis. Clinical improvement however was often not seen before the 6th or 7th day of intravenous treatment. A success rate for the conservative approach of only 75% at day 7 in our study does not favour atropine therapy, in view of success rates above 95% with surgical repair.

Transmission dynamics of tuberculosis in a high-incidence country: prospective analysis by PCR DNA fingerprinting.

We have prospectively analyzed the DNA fingerprints of Mycobacterium tuberculosis strains from a random sample of patients with newly diagnosed tuberculosis in Windhoek, Namibia. Strains from 263 smear-positive patients in whom tuberculosis was diagnosed during 1 year were evaluated, and the results were correlated with selected epidemiological and clinical data. A total of 163 different IS6110 fingerprint patterns were observed among the 263 isolates. Isolates from a high percentage of patients (47%) were found in 29 separate clusters, with a cluster defined as isolates with 100% matching patterns. The largest cluster included isolates from 39 patients. One predominant strain of M. tuberculosis caused 15% of cases of smear-positive pulmonary tuberculosis in Windhoek. That strain was also prevalent in the north of the country, suggesting that in contrast to other African countries with isolates with high levels of diversity in their DNA fingerprint patterns, only a restricted number of different strains significantly contribute to the tuberculosis problem in Namibia.

Heat shock proteins delivered with a virus vector can protect cardiac cells against apoptosis as well as against thermal or hypoxic stress.

Over expression of heat shock proteins (hsps) by transfection of plasmid constructs in vitro and in transgenic animals in vivo can protect primary cardiac cells from subsequent exposure to severe thermal or hypoxic stress. Here we show that such protection can also be achieved by over-expressing the hsps using herpes simplex virus (HSV) vectors capable of efficient gene delivery in vivo. Moreover, the convenience and high efficiency of this system has allowed us to show, for the first time, that over-expression of hsp27 or hsp70 can protect cardiac cells against three different apoptosis-inducing stimuli as well as against thermal or hypoxic stress whereas hsp56 has no protective effect. The potential therapeutic use of inducing the over-expression of specific hsps in cardiac cells in vivo using pharmacological or gene therapy procedures is discussed.

Preoperative diagnosis of Mycobacterium avium lymphadenitis in two immunocompetent children by polymerase chain reaction of gastric aspirates.

BACKGROUND: Analysis of gastric aspirates is a routine procedure for detection of Mycobacterium tuberculosis in pediatric pulmonary tuberculosis. However, identification of nontuberculous mycobacteria in gastric aspirates of immunocompetent children is not thought to be clinically significant. METHODS: A PCR method was devised for the detection of M. avium in clinical specimens. The method is based on the amplification of a M. avium-specific DNA fragment present in the 3'-end of the repetitive element IS1245. Surgically removed lymphatic tissue was analyzed prospectively by microscopy, culture and PCR in 13 children admitted to our hospital with suspected mycobacterial lymphadenitis. In 4 of these children 1 to 4 gastric aspirates were obtained before surgical treatment and submitted to the same analysis. RESULTS: We report the detection of M. avium in the gastric aspirates of two children with cervical lymphadenitis before surgical intervention by a novel PCR method. The subsequently surgically removed lymph nodes were also positive by PCR and culture. In one child cultures of both sources grew M. avium. The isolates could be identified as the same strain by DNA fingerprinting. The PCR assay was almost twice as sensitive as culture in detecting M. avium. CONCLUSIONS: Our findings suggest the possibility for noninvasive diagnosis of cervical lymphadenitis caused by nontuberculous mycobacteria before surgery. In addition detection of M. avium in gastric aspirates without evidence of fistula formation provides new insights into the pathogenesis of mycobacterial infection and disease in immunocompetent children.

Immediate postnatal rat heart development modified by abdominal aortic banding: analysis of gene expression.

Proliferative growth of the ventricular myocyte (cardiomyocyte) is primarily limited to embryonic, fetal and very early neonatal periods of heart development. In contrast, cardiomyocyte maturation, as evidenced by cellular hypertrophy, is a long-term process that can occupy the bulk of the life-span of the mature organism. As the newborn myocyte undergoes a 'transition' from proliferative to hypertrophic growth, ventricular remodeling of the non-myocyte compartment is characterized by increased extracellular matrix (ECM) formation and coronary capillary angiogenesis. A role for ventricular-derived growth factors (GFs) in these inter-related processes are examined in an animal model of altered heart development produced by neonatal aortic banding. The suprarenal abdominal aorta of five day old rat pups were banded (B), sham operated (S), or untreated (C) and ventricular tissue (left ventricular free wall and septum) obtained at 7-, 14-, and 21-days post-intervention. Using Northern blot RNA hybridizations, expression of growth factors (GFs) and/or GF-receptors (GFR's) temporally associated with heart development were evaluated. Transcript levels for TGF-beta 1, IGF-II, and their associated cell surface receptors were increased in B animals. Concomitant changes in extracellular matrix (ECM) genes (as evaluated by Collagens Type I, III, and IV) were also increased in B animals. In addition, transcript levels for the vascular morphogenesis and remodeling-related protein SPARC (Secreted Protein, Acidic and Rich in Cysteine) was also elevated in the B animals. In several instances, S animals demonstrated changes in steady state transcript levels for genes which may influence myocyte maturation during the postnatal period. This suggests that normal autocrine/paracrine growth regulatory stimuli and responses can be modified (by surgical intervention and/or abdominal aortic banding) and these perturbations in gene expression may be related to previously documented changes in myocyte cell number, vascular composition, and ventricular architecture of the banded, neonatal heart. Future studies using this model will provide an opportunity to evaluate and possibly identify the stimuli and signal transduction machinery that regulate the final phases of myocyte proliferation, stimulate capillary formation and ECM deposition, and orchestrate the transition to hypertrophic growth during heart development.

Expression of cardiac muscle markers in rat myocyte cell lines.

Recently developed rat heart myocyte cell lines have afforded us the opportunity to evaluate the expression of several transcription factors associated with early cardiac development. These factors include, but are not limited to, Nkx-2.5/Csx, MEF-2C and MLP (Muscle LIM Protein). These factors have been shown to be temporally expressed in pre-cardiac mesenchyme coincident with the earliest stages of heart development. Using the BWEM and CLEM myocyte cell lines as models of the embryonic, committed cardiomyocyte, we have evaluated the basal expression levels of these three genes over multiple passages. Both cell lines express these genes, with MEF-2C being the most abundant based on Northern blot hybridization analyses. Interestingly, as these cells increased their passage number, there was a corresponding increase in their basal expression levels. To evaluate potential 'downstream' effectors of these genes, we examined the basal expression levels of two cardiac-specific genes cTNC and MLC-2v. Transcript levels for both of these contractile filament genes were elevated with passage, suggestive of a inductive process mediated by one or all these three transcription factors. Promoter analysis of MLC-2v expression in the CLEM line shows that this increase is transcriptionally-mediated and the lines retain the necessary regulatory factors to maintain and control the transcription of this gene. Analysis of the dynamics of the regulatory role(s) that these three transcription factors play in cardiac development can now be evaluated in a homogeneous, cell culture system.

In utero exposure to ethanol alters mRNA for insulin-like growth factors and insulin-like growth factor-binding proteins in placenta and lung of fetal rats.

Insulin-like growth factors I and II (IGF-I and IGF-II) play a role in regulating fetal growth and development. Their actions in target tissues are modulated in part by binding to IGF binding proteins 1 and 2 (IGFBP-1 and IGFBP-2). In this study, we examined the effect of fetal exposure to alcohol IGF-I and on IGF-II and IGFBP-1 and IGFBP-2 mRNA in placenta and fetal lung tissue. Timed-pregnant Sprague-Dawley dams were fed a diet consisting of 35% ethanol-derived calories [alcohol-fed (AF)], an Isocaloric diet with sucrose substituted for alcohol (pair-fed; PF), or ad libitum rat chow (CF). Alcohol feeding began on gestational age (G) 14. At G20, dams were killed, and we examined placenta and fetal lung for the steady-state levels of mRNA for IGF-1 and IGF-II and for IGFBP-1 and IGFBP-2. In all dams, body weight increased throughout gestation, and there were no differences between the three groups. At G20, the mean weight for the fetuses from the AF group was lower (p < 0.001) than the fetuses from the CF and PF groups. Steady-state mRNA levels were detected in fetal lung and in placentas by Northern-blot hybridization analysis and semiquantitated by slot-blot hybridization analysis. Multiple transcripts for IGF-I and IGF-II, 1.8 kb species for IG-FBP-1 and 1.6 kb species for IGFBP-2 were detected from total RNA isolated from the fetal lung and placenta, Slot-blot hydridization analysis of fetal lung RNA showed that IGF-I mRNA was significantly increased (p < 0.001) in AF males and females by 4.0 +/- 0.28-fold and by 3.25 +/- 0.2-fold, respectively. IGF-II transcript levels were not affected. IGFBP-1 and IGFBP-2 were increased in AF males, whereas only IGFBP-2 was increased in AF females. In the placenta, there was a significant increase in IGFBP-1 and IGFBP-2 transcripts [(p < 0.001) 1.75 +/- 0.5-fold and 3 +/- 0.53-fold increase, respectively]. No differences between the groups in serum levels of IGFBP-1 or -2 were detected when measured by Western-blot analysis. The increased gene expression for IGFBPs within fetal lung and placenta may decrease bioavailability of locally synthesized, IGFs that may contribute to the fetal growth retardation observed in this model system.

Human thymic epithelial cells produce TGF-beta 3 and express TGF-beta receptors.

TGF-beta affects proliferation, differentiation and maturation of T cells; however, the effect of TGF-beta on thymic stromal cells has not been characterized. To better understand the role of TGF-beta in T cell development, we determined whether TGF-beta is present in the human thymus, and identified stromal cells that express TGF-beta receptors and respond to TGF-beta. We demonstrate that primary cultured human thymic epithelial cells (TEC) express TGF-beta 1, TGF-beta 2 and TGF-beta 3, as well as TGF-beta type I receptor (T beta RI) (ALK-5) and TGF-beta type II receptor (T beta RII) transcripts. In vitro, epidermal growth factor (EGF) increases transcript levels of TGF-beta 1, TGF-beta 3 and T beta RII, suggesting that EGF may modulate TGF-beta responses in TEC; however, TGF-beta 2 and T beta RI transcript levels were not affected. We also detect TGF-beta 3 and T beta RII protein in association with keratin-positive TEC in vitro and in vivo. TEC culture supernatants contain TGF-beta 3 as detected by Western blots and, upon heat and acid activation, display growth inhibitory activity on the CCL-64 cells that is neutralized by anti-TGF-beta mAb treatment. We further demonstrate that TGF-beta 1 increases leukemia inhibitory factor transcript levels in TEC, indicating that TEC express functional TGF-beta receptors. Thus, we have shown in the human thymus that TEC produce TGF-beta 3 and express T beta RI and T beta RII. The data suggest that TGF-beta is present in the human thymus and may indirectly affect T cell development by regulating TEC cytokine production.

Stimulation of a Ca(2+)-calmodulin-activated histone 3 arginine kinase in quiescent rat heart endothelial cells compared to actively dividing cells.

A Ca(2+)-calmodulin-activated histone 3 kinase was partially purified from nuclear extracts of dividing and quiescent rat heart endothelial cells. The histone 3 phosphorylating activity was 20-100-fold higher in quiescent than in dividing cells. Base hydrolysis followed by amino acid analysis revealed that histone 3 was phosphorylated on arginine. Further investigations were conducted to determine whether phosphorylation of histone 3 also occurred in vivo. Cells were incubated for 3 h in a phosphate-free medium supplemented with [32P]phosphoric acid. It was observed that the nuclear content of arginine-phosphorylated histone 3 was considerably higher in quiescent than in dividing rat heart endothelial cells. The histone 3 arginine kinase is a component of a complex containing a Ca(2+)-dependent calmodulin-binding protein of apparent molecular mass of 85 kDa. Using polyclonal antibodies to an 85-kDa protein, also the major Ca(2+)-dependent calmodulin-binding component of the histone 3 arginine kinase from calf thymus, an immunoreactive protein of identical apparent molecular mass was found to be present in equal amounts both in dividing and quiescent cells. We propose that the 85-kDa protein is either the histone 3 arginine kinase or one of its subunits and that phosphorylation of histone 3 is involved with cell cycle exit in eukaryotes.

Characterization of the gap junction protein, connexin45.

Connexin45 is a gap junction protein which forms channels with unique characteristics. RNA blots demonstrated that connexin45 is expressed in a number of cell lines including WB, SK Hep1, BHK, A7r5, CLEM, and BWEM cells. Connexin45 was further studied in BWEM cells using specific affinity-purified antibodies directed against a synthetic peptide representing amino acids 285-298 of its sequence. Immunofluorescence experiments demonstrated that the BWEM cells expressed both connexin43 and connexin45 and that these connexins colocalized. Connexin45 polypeptide, immunoprecipitated from BWEM cells metabolically labeled with [35S]-methionine, consisted of a predominant 48 kD polypeptide. Connexin45 and connexin43 contained radioactive phosphate when immunoprecipitated from BWEM cells metabolically labeled with [32P]-orthophosphoric acid. This phosphate label was removed from connexin45 by alkaline phosphatase digestion. Treatment of BWEM cells with the tumor promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibited intercellular passage of microinjected Lucifer yellow. While TPA treatment induced phosphorylation of connexin43 in these cells, it reduced the expression of connexin45. Furthermore, the connexin45 expressed after TPA treatment was not phosphorylated. These results suggest that treatments which alter protein phosphorylation may regulate connexin43 and connexin45 in BWEM cells by different mechanisms.

Coordinate TGF-beta receptor gene expression during rat heart development.

Transforming growth factor-beta (TGF-beta) has been implicated to participate in heart development. The receptors which transduce the signal(s) mediated by TGF-beta ligand binding have only recently been cloned. One of the most prominent effects of TGF-beta is inhibition of cell proliferation, a process that is tightly regulated during heart development. Using the developing rat ventricle as a model system, we have determined the steady state expression patterns for the Type I, II, and III TGF-beta receptors (TGF-beta Rs). Using RNA isolated from ventricular chambers on day 18 of gestation through the ninth postnatal week of age, we detected a modest increase in expression levels for Type I and Type III TGF-beta Rs. In contrast, steady state transcript levels for the Type II TGF-beta R showed a profound developmental increase from nearly undetectable levels at the fetal ages examined to high levels during the first postnatal week of age. Immunoelectron microscopic localization of Type II TGF-beta R confirmed that the 3-week-old ventricular myocyte, as well as nonmyocytes, contained immunoreactive material. Immunoreactivity was found at both the cell surface as well as intracellular compartment. Regional variations (right ventricle, left ventricle, or septum) in the expression pattern of several markers of heart development, but not the TGF-beta R's, were found in RNA obtained from 3-week-old postnatal animals. These data suggest that "downstream" effectors of TGF-beta-mediated stimulation are modulated in a developmental, regional-specific manner in the neonatal/mature myocardium by the level of bioactive TGF-beta.

Coordinate gene expression during neonatal rat heart development. A possible role for the myocyte in extracellular matrix biogenesis and capillary angiogenesis.

OBJECTIVE: Neonatal heart development is a period of active extracellular matrix deposition and capillary angiogenesis which follows the cessation of ventricular myocyte proliferation. The aim was to determine whether coordinate expression of growth factors by the ventricular myocyte could function to inhibit myocyte proliferation directly as well as indirectly by paracrine stimulation of non-myocyte extracellular matrix deposition and capillary angiogenesis. METHODS: Immunohistochemistry and northern blot hybridisations were performed on ventricular samples from fetal to mature animals of the spontaneously hypertensive (SHR) and normotensive control Wistar Kyoto (WKY) strains. RESULTS: Ventricular expression of types I, III, and IV collagen genes reached their "maximum" within the first 2-3 postnatal weeks and then rapidly declined. Expression of TGF beta 3 and SPARC were found to precede and accompany the changes in extracellular matrix gene expression during this same developmental period. TGF beta 3 was immunolocalised to fetal cardiomyocytes with very limited expression in neonatal/adult non-myocytes. Associated with the neonatal expression of TGF beta variants, transcripts for the type 2 IGF receptor gradually declined over the first three postnatal weeks. Myocyte TGF beta gene expression, latent TGF beta release, and paracrine mechanisms of action could be facilitated by residual type 2 IGF receptor expression to help mediate stimulation of non-myocyte extracellular matrix synthesis and deposition. CONCLUSIONS: Expression of select growth factors, growth factor receptors, and components of the extracellular matrix appear to be highly coordinated during ventricular remodelling which occurs during neonatal heart development. A paradigm is presented which integrates the expression patterns of various myocyte derived stimuli and their postulated impact on formation of the structural components of the neonatal heart by modulation of myocyte and non-myocyte cell types.