Transforming growth factor-β regulates the growth of valve interstitial cells in vitro

Although valve interstitial cell (VIC) growth is an essential feature of injured and diseased valves, the regulation of VIC growth is poorly understood. Transforming growth factor (TGF)-β promotes VIC proliferation in early-stage wound repair; thus, herein, we tested the hypothesis that TGF-β regulates VIC proliferation under normal nonwound conditions using low-density porcine VIC monolayers. Cell numbers were counted during a 10-day period, whereas proliferation and apoptosis were quantified by bromodeoxyuridine staining and TUNEL, respectively. The extent of retinoblastoma protein phosphorylation and expression of cyclin D1, CDK 4, and p27 were compared using Western blot analysis. Adhesion was quantified using a trypsin adhesion assay, and morphological change was demonstrated by immunofluorescence localization of α-smooth muscle actin and vinculin. TGF-β-treated VICs were rhomboid; significantly decreased in number, proliferation, and retinoblastoma protein phosphorylation; and concomitantly had decreased expression of cyclin D1/CDK4 and increased expression of p27. TGF-β-treated VICs adhered better to substratum and had more vinculin plaques and α-smooth muscle actin stress fibers than did controls. Thus, the regulation of VIC growth by TGF-β is context dependent. TGF-β prevents excessive heart valve growth under normal physiological conditions while it promotes cell proliferation in the early stages of repair, when increased VICs are required.     

Transforming growth factor-β signaling in systemic sclerosis

Systemic sclerosis (SSc) is a complex, multiorgan autoimmune disease of unknown etiology. Manifestation of the disease results from an interaction of three key pathologic features including irregularities of the antigen-specific immune system and the non-specific immune system, resulting in autoantibody production, vascular endothelial activation of small blood vessels, and tissue fibrosis as a result of fibroblast dysfunction. Given the heterogeneity of clinical presentation of the disease, a lack of universal models has impeded adequate testing of potential therapies for SSc. Regardless, recent research has elucidated the roles of various ubiquitous molecular mechanisms that contribute to the clinical manifestation of the disease. Transforming growth factor β (TGF-β) has been identified as a regulator of pathological fibrogenesis in SSc. Various processes, including cell growth, apoptosis, cell differentiation, and extracellular matrix synthesis are regulated by TGF-β, a type of cytokine secreted by macrophages and many other cell types. Understanding the essential role TGF-β pathways play in the pathology of systemic sclerosis could provide a potential outlet for treatment and a better understanding of this severe disease.     

Posttraumatic growth in cancer: Reality or illusion?

Research in posttraumatic growth (PTG) among cancer patients has been triggered primarily by the inclusion of serious illnesses among the events that can lead to posttraumatic stress disorder (PTSD); increasing survival rates among cancer patients; and, attempts at encouraging a positive psychology that focuses on a patient's ability to fight adversity. The difficulties encountered in clearly defining the processes associated with this subjective feeling of growth following recovery raise doubts concerning the real or illusory nature of the phenomenon and its adaptative value. This paper explains why cancer may be different than other traumas and why PTG may interact with this ecology of circumstances in different ways. Difficulty in identifying a single stressor, the internal source of the event, cancer as a future, ongoing and chronic integration threat, and greater perceived control differences between cancer and others traumas. This review brings together the latest studies of PTG in cancer, and focuses in the debate of the real or illusory nature of the PTG and his adaptative value. The ongoing threat, uncertainty and vulnerability associated with cancer are the variables that have been related most consistently with PTG and tend to confuse the relationship between PTG and emotional well-being, too.     

Why are growth factors important in oligodendrocyte physiology?

Recent studies in chicken, rodents and transgenic mice have provided new insight on the nature of factors essential to oligodendrocyte development. Here we first review how sonic hedgehog (shh) graded signalling induces emergence of oligodendrocytes in the embryonic spinal cord from birds to man. We then discuss the way in which thyroid hormone successively signals different thyroid receptors to control fate determination, growth and differentiation in the oligodendrocyte lineage. Platelet-derived growth factor (PDGF) is a potent regulator of oligodendrocyte progenitor (OP) migration and proliferation, while insulin-like growth factor 1 (IGF-1) acts both on neurons and myelin-forming cells to promote myelination. The balance between OP proliferation and differentiation appears to be controlled by different sets of growth factors locally synthesized in the central nervous system (CNS) as well as glutamate. In experimental models of multiple sclerosis (MS), the neuregulin isoform glial growth factor 2, IGF-1 and some neurotrophins can promote remyelination after an episode of inflammatory demyelination. A future challenge is to determine how to induce multipotential neural precursors to generate migratory OP and enhance the remyelination process in the adult CNS.     

Immunoexpression of transforming growth factor β in desmoplastic ameloblastoma

Desmoplastic ameloblastoma (DA) is an unusual subtype of ameloblastoma histologically characterized by the pronounced collagenized stroma. In the present study, the immunolocalization of transforming growth factor beta (TGF-β), one of the most potent local factors for modulating extracellular matrix formation, was observed in DA in order to study its participation in the stromal desmoplasia. Seven cases of DA, including a ”hybrid” lesion, were studied together with ten cases of ordinary follicular and plexiform ameloblastomas as the control. In contrast to ordinary ameloblastomas, marked immunoexpression was observed in all DAs but one. In the ”hybrid” lesion, TGF-β was not expressed in the area of follicular ameloblastoma but in that of DA. These results show that TGF-β produced by tumor cells of DA plays a part in the desmoplastic matrix formation. Received: 22 June 1999 / Accepted: 27 September 1999     

Does growth hormone prevent aging in the healthy elderly with low serum insulin-like growth factor-I ?

Aging is associated with a gradual decline in the function of a number of endocrine glands. While there are phenotypic similarities seen in the changes of aging with some endocrine hormone deficiency states, the relationship between the decline in growth hormone (GH) secretion, and the decrease in serum insulin-like growth factor-I (IGF-I), with these body composition changes is far from clear. The decline in serum IGF-I, unlike that of thyroxine and estradiol, is not accompanied by an increase in pituitary GH secretion. The recent enthusiastic recommendation for GH 'replacement' in the aging population with low serum IGF-I remains highly controversial. The evidence is still unclear on any significant beneficial effect of such replacement in healthy fit elderly men and women. There is some early evidence of beneficial effects of such replacement in the frail elderly. There are no studies that have investigated the effect of GH on longevity in humans, but results from animal studies on caloric restriction and longevity do not suggest that GH administration will increase life span. There is still insufficient evidence that treatment with exogenous GH in the healthy elderly that attains serum IGF-I levels similar to that of young adults is beneficial or safe.     

Trend in physical growth among children in southern Iran, 1988–2003

The purpose of this paper is to describe and discuss a significant secular trend in stature, weight and mid-arm circumference (MAC) of school children of the same age (6.5–11.5 years) and sex in representative samples from primary schools of Shiraz (southern Iran) at an interval of 15 years (1988 vs 2003). Both samples include children of various socio-economic backgrounds. For both males and females of each age-class, there are significant positive secular trends in stature, weight and MAC. The results suggest that post-war born children sampled in 2003 are generally taller, heavier and larger than their peers of 15 years earlier born pre- and during the war period of Iraq against Iran. Furthermore, the 2003 sample shows less growth deficits in relation to the Center for Disease Control (CDC) reference data. The positive trend can be explained as the result of economic development and improvement of social and health indicators in the post-war Iran reconstruction period.

Résumé. Cet article a pour objet de décrire et commenter une évolution séculaire significative de la stature, du poids et de la circonférence du bras (CB) observée chez des enfants de même âge (6,5 à 11,5 ans) et de même sexe, dans des échantillons représentatifs des écoles primaires de la ville de Shiraz (sud de l’Iran) à intervalle de 15 ans (1988 et 2003). Les deux cohortes incluent des enfants de divers milieux socio-économiques. Aussi bien chez les garçons que chez les filles de chaque classe d’âge, on observe une évolution séculaire positive de la stature, du poids et de la CB. Les résultats suggèrent que les enfants examinés en 2003 et nés après la guerre entre Iraq et Iran, sont généralement plus grands et plus lourds que leurs homologues nés quinze ans plus tôt, avant ou pendant la guerre. Qui plus est, l’échantillon de 2003 présente moins de déficits de croissance en comparaison avec les données de référence NCHS. L’évolution positive peut être expliquée comme le résultat du développement économique et de l’amélioration des indicateurs sanitaires et sociaux au cours de la période de reconstruction dans l’Iran d’après guerre.

Zusammenfassung. Der Zweck dieser Untersuchung ist die Beschreibung und Diskussion eines signifikanten säkularen Trends von Körperhöhe, Gewicht und mittlerem Armumfang (mid-arm circumference, MAC) bei gleichaltrigen und gleichgeschlechtlichen Schulkindern (6,5–11,5 Jahre) aus repräsentativen Grundschul-Stichproben aus Schiras (Südiran) über einen Zeitraum von 15 Jahren (1988 bis 2003). Beide Stichproben umschließen Kinder verschiedener sozioökonomischer Herkunft. Sowohl bei Knaben als auch bei Mädchen aller Altersklassen gibt es signifikante positive säkulare Trends von Körperhöhe, Gewicht und MAC. Die Ergebnisse sprechen dafür, dass Kinder, die nach dem Krieg geboren und 2003 untersucht wurden, generell höher gewachsen, schwerer und größer sind als altersgleiche Kinder, die 15 Jahre früher und vor oder während des Krieges Irak gegen Iran geboren worden waren. Darüber hinaus zeigt die Stichprobe aus 2003 weniger Wachstumsverlust im Vergleich zu den NCHS-Referenzwerten. Der positive Trend kann als Ergebnis der ökonomischen Entwicklung und der Verbesserung von sozialen und gesundheitlichen Umständen der iranischen Aufbauphase nach dem Krieg verstanden werden.

Resumen. El propósito de este artículo es describir y discutir una tendencia secular significativa en la estatura, el peso y la circunferencia media del brazo (CMB) en escolares de la misma edad (6,5--11,5 años) y sexo, en muestras representativas de escuelas primarias de Shiraz (sur de Irán), durante un intervalo de 15 años (1988 a 2003). Ambas muestras incluyen niños de varios niveles socioeconómicos. Tanto en varones como en mujeres de cada clase de edad, hubo una evolución secular positiva en la estatura, peso y CMB. Este resultado sugiere que los niños nacidos tras la guerra y medidos en el año 2003 son en general más altos, tienen más peso y mayores anchuras que sus pares nacidos 15 años atrás, antes y durante el periodo de guerra entre Irak e Irán. Además, la muestra de 2003 muestra menos déficit de crecimiento respecto a los datos de referencia NCHS. La tendencia positiva puede explicarse como el resultado del desarrollo económico y de la mejora de los indicadores sociales y de salud en el periodo de reconstrucción de Irán tras la guerra.     

Epidermal growth factor,transforming growth factor-α, and epidermal growth factor receptor content in normal and carcinomatous gastric and colonic tissue

Summary Epidermal growth factor (EGF) and transforming growth factor- (TGF-) are polypeptides which bind to the EGF receptor (EGFr) and may play a role in cell growth and carcinogenesis. Our study investigated the content of EGF, TGF-, and EGFr in tumors of the stomach and the colon in comparison with the sourrounding mucosa. EGF was detected in half of the stomach specimens with concentrations between 1 and 9 ng/g weight irrespective of histology. In the colon no EGF was found in the tumor or normal mucosa. In the stomach normal mucosa contained higher TGF- concentrations (mean 22.4 ng/g) than the tumors (mean 11.8 ng/g), but the difference was not statistically significant because of a wide variation in mucosal values. By contrast, the colon mucosa displayed significantly higher TGF- concentrations than the tumor tissues (33 ng/g versus 12 ng/g; P < 0.01). EGFr content in the gastric mucosa was lower compared to gastric carcinoma (48 fmol/g versus 75 fmol/g) yet not significantly different. In contrast, colorectal tumor specimens disclosed significantly higher concentrations than the mucosal tissues (mean of 155 fmol/g versus 80 fmol/g; P < 0.01). In conclusion, TGF- should not be considered a tumorigenic but a physiological growth factor in the stomach and colon. An elevated EGFr content in colorectal tumors in comparison with the normal mucosa could lead to a growth advantage by an autostimulating mechanism.Abbreviations EGF epidermal growth factor - EGFr epidermal growth factor receptor - TGF- transforming growth factor - ROC receiver operating characteristic Dedicated to Prof. Dr. G. Paumgartner on the occasion of his 60th birthday     

Platelet-derived growth factor and platelet-derived growth factor receptor-α expression in the normal human thymus and thymoma

Platelet-derived growth factor (PDGF) and its receptors (PDGFRs) are strongly involved in the normal development of several organs, tumour angiogenesis and malignant progression and metastasis. Few studies concerning their expression, distribution and role in normal and pathological human thymus are available in the literature. The aim of this study has been to analyse the immunohistochemical expression of PDGF and PDGFR-α in prenatal and postnatal normal human thymus and thymomal biopsy specimens. The results demonstrated immunoreactivity to both PDGF and PDGFR-α in all specimens, but the intensity, distribution and number of positive cells were different in normal thymus and thymomas, and also among different tumour types. PDGF and PDGFR-α were weakly expressed in foetal and postnatal humans with a different distribution between cortex and medulla in both blood vessels and epithelial cells, whereas they were overexpressed in thymoma, especially in type B2 and B3, in the tumour epithelial cells. Overall, these data suggest that PDGF and PDGFR-α may be involved in the pathophysiology of the human thymus.     

Regulation of tumor growth by IFN-γ in cancer immunotherapy

Tumor immunity involves a concerted interplay between cytokines and effector cells. Extensive efforts have focused on understanding the roles of cytokines and their interactions with effector cells for the production of effective tumor immunity. One cytokine that is well recognized to play a central role in coordinating tumor immune responses is IFN-γ. IFN-γ exerts its biological effects through interaction with an IFN-γ receptor that isubiquitously expressed on nearly all cells. In this review, we discuss the positive and negative effects of IFN-γ signaling in the tumor cell on tumor growth.     

Expression and function of transforming growth factor β in melioidosis

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, is an important cause of community-acquired sepsis in Southeast Asia and northern Australia. An important controller of the immune system is the pleiotropic cytokine transforming growth factor β (TGF-β), of which Smad2 and Smad3 are the major signal transducers. In this study, we aimed to characterize TGF-β expression and function in experimental melioidosis. TGF-β expression was determined in 33 patients with culture-proven infection with B. pseudomallei and 30 healthy controls. We found that plasma TGF-β concentrations were strongly elevated during melioidosis. In line with this finding, TGF-β expression in C57BL/6 mice intranasally inoculated with B. pseudomallei was enhanced as well. To assess the role of TGF-β, we inhibited TGF-β using a selective murine TGF-β antibody. Treatment of mice with anti-TGF-β antibody resulted in decreased lung Smad2 phosphorylation. TGF-β blockade appeared to be protective: mice treated with anti-TGF-β antibody and subsequently infected with B. pseudomallei showed diminished bacterial loads. Moreover, less distant organ injury was observed in anti-TGF-β treated mice as shown by reduced blood urea nitrogen (BUN) and aspartate transaminase (AST) values. However, anti-TGF-β treatment did not have an effect on survival. In conclusion, TGF-β is upregulated during B. pseudomallei infection and plays a limited but proinflammatory role during experimental melioidosis.     

Fragrant environment with α-pinene decreases tumor growth in mice

Stress is believed to be harmful to not only mental but also physical health. However, proving a link between stress and disease is difficult. A recent study reported that an environmental enrichment reduced cancer growth via the hypothalamic-pituitary-adrenal axis and leptin. Here, we report that mice kept in a fragrant environment enriched with α-pinene show reduced melanoma growth. Tumor volume of mice under the α-pinene environment was about 40% smaller than that in the control mice. α-Pinene had no inhibitory effect on melanoma cell proliferation in vitro, suggesting that this effect was not a direct effect of α-pinene. These results suggest that the provision of a fragrant environment may be an important factor in the therapeutic approach to cancer.     

The dysregulated glomerular cell growth in Denys–Drash syndrome

While diffuse mesangial sclerosis is traditionally described as being the glomerulopathy of Denys–Drash syndrome (DDS), the podocyte proliferative lesions may be overlooked in these DDS cases. In the present study, an evolving process is extrapolated from a selected case of DDS that demonstrated glomerulopathy with conspicuous podocyte proliferation. The observation that podocytes express proliferation markers (Ki67, proliferating-cell nuclear antigen and topoisomerase II) in non-proliferative, mature-looking glomeruli suggests an initial pathogenic act to activate or to keep podocytes from quiescence. The subsequent proliferation of podocytes is in keeping with downregulation of WT1 and cyclin kinase inhibitors of p16 and p21. The emergence of cytokeratin-positive cells in glomeruli that show typical mesangial sclerosis implies elimination of podocytes and replacement with tubular and/or parietal epithelial cells. The final scene of evolving glomerulopathy displays apoptosis and expression of Fas-L and Bax in sclerotic mesangial lesions, which eventually end up with global sclerosis. This novel concept of DDS glomerulopathy implies complex molecular mechanisms involved in glomerular injury.     

Insulin-like growth factor I receptor β expression in hepatocellular carcinoma

The insulinlike growth factor signaling axis (factors I and II and their receptor) has been implicated in hepatocarcinogenesis. Previous studies on insulinlike growth factor I receptor using resected hepatocellular carcinoma generated mixed results; however, the distribution and clinical significance of insulinlike growth factor I receptor β expression in hepatocellular carcinoma in the setting of liver transplantation have not been evaluated. Immunohistochemical staining for insulinlike growth factor I receptor β was performed in 72 liver explants from patients with hepatocellular carcinoma undergoing liver transplantation. Expression of insulinlike growth factor I receptor β in hepatocytes was noted in 59.7% of tumors but only 6.9% of adjacent, nontumorous liver tissues (P < .001). Compared with subjects with tumors within Milan criteria, those who fell beyond had 3.1 times higher odds of having insulinlike growth factor I receptor β-positive tumors (95% confidence interval, 1.003-9.8). Poorly differentiated hepatocellular carcinomas had 10.3 times higher odds of insulinlike growth factor I receptor β positivity compared with well- or moderately differentiated tumors (95% confidence interval, 1.3-85.2). Subjects with nonalcoholic steatohepatitis were less likely to have insulinlike growth factor I receptor β-positive tumors (P = .015). Finally, higher arteriolar insulinlike growth factor I receptor β scores in the tumor and adjacent liver were significantly associated with insulinlike growth factor I receptor β expression in tumor cells (P = .015 and .043 for intratumoral and adjacent arterioles, respectively) in a subset of 26 randomly chosen hepatocellular carcinoma. Our results suggest that synchronized up-regulation of the insulinlike growth factor I receptor axis in tumor cells and intratumoral and adjacent arterioles could represent a mechanism of hepatocarcinogenesis and progression as manifest by poor differentiation and tumors beyond Milan criteria. Targeted therapies against insulinlike growth factor receptors may be justifiable in the treatment of hepatocellular carcinoma.     

Are sex steroids involved in the sexual growth dimorphism in Eurasian perch juveniles?

Individual growth and food intake were monitored in Eurasian perch (Perca fluviatilis L.) juveniles (13.5+/-3.4 g initial body weight) to determine whether androgens and estrogens may mediate sex-related growth differences. Fish were individually tagged with chips and implanted with cocoa butter containing 20 microg of either 17alpha-methyltestosterone (MT) or 17beta-estradiol (E(2)) per gram of fish body; controls were implanted with cocoa butter without hormones. All fish were bled at the end of the experiment for measurement of E(2) in females and testosterone (T) in males (MT was not measured) and triiodothyronine (T3) in both genders. Survival, gonadosomatic index and hepatosomatic index were not affected by steroid treatments. Relative food intake (RFI), feed efficiency (FE) and specific growth rate (SGR) were higher in females than in males in all treatments. MT treatment significantly lowered RIF, FE and SGR in both sexes, while E(2) treatment showed no significant effect on growth and feeding parameters. In contrast to E(2) and T concentrations, T3 levels were significantly and positively correlated with SGR and RFI. The results provide evidence that MT may affect sexually related growth dimorphism by decreasing food intake and FE in Eurasian perch.     

Urban–rural contrasts in the growth status of school children in Oaxaca,Mexico

Objectives:?The growth status of school children resident in an urban colonia and in a rural indigenous community in Oaxaca, southern Mexico, was considered in the context of two objectives, current status and the magnitude of urban–rural differences over a span of about 30 years. Both communities were initially surveyed in 1968 and 1972.

Materials and methods:?Height, body mass, segment lengths, skeletal breadths, limb circumferences, and subcutaneous fatness were taken on 361 rural (177 boys, 184 girls) and 339 urban (173 boys, 166 girls) school children, aged 6–13 years. Additional variables were derived.

Results:?Height and body mass were significantly greater in urban compared with rural children. Sitting height, estimated leg length and skeletal breadths on the trunk were also larger in urban than in rural school children, but only the difference in skeletal breadths was significant after age and body size were statistically controlled. Urban and rural children did not consistently differ in skeletal breadths on the extremities and limb circumferences. Subcutaneous fatness was more variable. After controlling for age and body size, rural girls had thicker skinfolds. The magnitude of the urban–rural difference in boys in 2000 was greater for body mass, BMI and triceps skinfold, and reduced for height, sitting height, leg length, and arm and estimated arm muscle circumferences compared with 1970. The magnitude of the urban–rural difference in girls was greater in 2000 than 30 years earlier for body mass, height, sitting height, leg length and BMI. Urban–rural differences for arm and arm muscle circumferences and the triceps skinfold were slightly smaller over the interval.

Conclusions:?Children resident in an urban colonia were taller and heavier than children resident in a rural indigenous community. After controlling for age and body size, urban–rural differences in skeletal breadths and limb circumferences were reduced or eliminated, but skinfold thicknesses were greater in rural girls. The magnitude of urban–rural differences in body size has decreased over approximately 30 years in boys, but has increased in girls.