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Diabetic wounds are hard-to-heal due to complex multifactorial dysregulation within the micro-environment, necessitating the development of novel regenerative approaches to stimulate healing. This study investigated whether the combined therapeutic application of two novel cellular tissue products, namely a decellularized collagen-rich amniotic membrane (AmR) and growth factor-rich umbilical cord blood serum (UCBS) could have a positive synergistic effect on long-term healing outcomes by stimulating both superficial wound closure and wound bed regeneration. Full thickness excisional wounds were induced on obese diabetic mice (B6.Cg-lepob/J, ob/ob, n = 23) and treated with either: 1) Standard wound care (control); 2) UCBS; 3) AmR or 4) UCBS + AmR. Macroscopic wound closure was assessed on days 0, 3, 7, 10 and 14 post wounding. To determine the potential impact on wound recurrence, endpoint analysis was performed to determine both the overall quality of healing histologically as well as the molecular state of the wounds on day 14 via proteomic analysis. The data demonstrated the presence of both healers and non-healers. Re-epithelization took place in the healers of all treatment groups, but underlying tissue regeneration was far more pronounced following application of the combined treatment (UCBS + AmR), suggesting improved quality of healing and potentially a reduced change of recurrence long term. In non-healers, wounds failed to heal due to excessive slough formation and a reduction in LTB4 expression, suggesting impaired antimicrobial activity. Care should thus be taken since the cellular tissue product therapy could pose an increased risk for infection in some patients.
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PURPOSE: This study sought to assess risk compensation following voluntary medical male circumcision of young school-going men. Risk compensation is defined as an inadvertent increase in sexual risk behaviors and a corresponding decrease in self-perceived risk for contracting HIV following the application of a risk reduction technology. METHODS: This study documented the sexual practices of circumcised (n = 485) and uncircumcised (n = 496) young men in 42 secondary schools at three time points (baseline and 6 and 12 months) in a sub-district of KwaZulu-Natal, South Africa. Study participants were aged from 16 to 24 years old. RESULTS: At the end of the study period, there was no significant difference between the two cohorts concerning learners' perceptions of being at risk of contracting HIV (interaction effect: b = -0.12, p = 0.40). There was also no significant difference in the number of sexual partners in the previous month (interaction effect: b = -0.23, p = 0.15). The proportion of learners who have never used a condom decreased significantly over time (time effect: b = -0.27, p = 0.01), and there was no difference between the circumcised and uncircumcised learners (interaction effect: b = -0.09, p = 0.91). CONCLUSIONS: Risk compensation, as evidenced in this study over a 1-year period, was not associated with undergoing voluntary medical male circumcision (VMMC) in our sample of young school-going men. However, it is of concern that at the end of this study, less than half of the sexually active sample in a high-HIV-prevalence community used condoms consistently in the previous month (39% for both study cohorts). The latter underscores the need to view VMMC as a potential entry point for planned HIV and sexuality education interventions targeting young men in this community.
Asunto(s)
Circuncisión Masculina/psicología , Infecciones por VIH/prevención & control , Conducta Sexual/psicología , Parejas Sexuales , Adolescente , Adulto , Circuncisión Masculina/estadística & datos numéricos , Condones/estadística & datos numéricos , Humanos , Masculino , Estudios Prospectivos , Asunción de Riesgos , Conducta Sexual/estadística & datos numéricos , Sudáfrica , Adulto JovenRESUMEN
Obesity is associated with increased morbidity and mortality from cardiovascular disease, diabetes and cancer. Although obesity is a multi-factorial heterogeneous condition, fat accumulation in visceral depots is most highly associated with these risks. Pathological glucocorticoid excess (i.e. in Cushing's syndrome) is a recognised, reversible cause of visceral fat accumulation. The aim of this study was to identify depot-specific glucocorticoid-target genes in adipocyte precursor cells (preadipocytes) using Affymetrix microarray technique. Confluent preadipocytes from subcutaneous (SC) and omental (OM) adipose tissue collected from five female patients were treated for 24 h with 100 nM cortisol (F), RNA was pooled and hybridised to the Affymetrix U133 microarray set. We identified 72 upregulated and 30 downregulated genes by F in SC cells. In OM preadipocytes, 56 genes were increased and 19 were decreased. Among the most interesting were transcription factors, markers of adipocyte differentiation and glucose metabolism, cell adhesion and growth arrest protein factors involved in G-coupled and Wnt signalling. The Affymetrix data have been confirmed by quantitative real-time PCR for ten specific genes, including HSD11B1, GR, C/EBPalpha, C/EBPbeta, IL-6, FABP4, APOD, IRS2, AGTR1 and GHR. One of the most upregulated genes in OM but not in SC cells was HSD11B1. The GR was similarly expressed and not regulated by glucocorticoids in SC and OM human preadipocytes. C/EBPalpha was expressed in SC preadipocytes and upregulated by F, but was below the detection level in OM cells. C/EBPbeta was highly expressed both in SC and in OM preadipocytes, but was not regulated by F. Our results provide insight into the genes involved in the regulation of adipocyte differentiation by cortisol, highlighting the depot specifically in human adipose tissue.
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11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adipocitos/metabolismo , Perfilación de la Expresión Génica/métodos , Glucocorticoides/metabolismo , Epiplón/citología , Grasa Subcutánea/metabolismo , Tejido Adiposo/metabolismo , Adulto , Células Cultivadas , Femenino , Humanos , Persona de Mediana Edad , Epiplón/metabolismoRESUMEN
The peroxisome proliferator activated receptor-gamma (PPARgamma) is an attractive target for therapeutic intervention, as modulation of PPARgamma-regulated pathways is potentially beneficial in a number of disease areas. This review provides an overview of what is known about the biology of PPARgamma, and an indication of what progress has been made towards drug development in several therapy areas. As well as efficacy, the safety of drugs is of course an important issue, and a substantial volume of preclinical and clinical information has already accumulated for PPARgamma agonists. Here we discuss some of the major toxicology issues with PPARgamma agonists, and give a perspective on likely issues concerning the development of PPARgamma modulators in the future.
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Diabetes Mellitus Tipo 2/fisiopatología , Hiperlipidemias/fisiopatología , Hipoglucemiantes/farmacología , Receptores Citoplasmáticos y Nucleares/fisiología , Tiazoles/farmacología , Tiazolidinedionas , Factores de Transcripción/fisiología , Proteínas de Unión al ADN , Humanos , Inflamación , Resistencia a la Insulina , Ligandos , Microcuerpos , Proteínas Nucleares , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/química , Proteínas Represoras , Factores de Transcripción/agonistas , Factores de Transcripción/química , Dedos de ZincAsunto(s)
Cromanos/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Tiazoles/administración & dosificación , Tiazolidinedionas , Anciano , Animales , Índice de Masa Corporal , Cromanos/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/uso terapéutico , Resistencia a la Insulina , Masculino , Ratones , Ratones Noqueados , Obesidad , Receptores Citoplasmáticos y Nucleares/deficiencia , Receptores Citoplasmáticos y Nucleares/fisiología , Tiazoles/uso terapéutico , Factores de Transcripción/deficiencia , Factores de Transcripción/fisiología , TroglitazonaRESUMEN
BACKGROUND: Visceral obesity is more closely associated with many deleterious metabolic sequelae than obesity per se. The identification of properties that distinguish fat cells of the omentum from adipocytes situated elsewhere in the body may lead to the development of therapeutic strategies targeting visceral obesity. We have previously demonstrated that cIAP2 mRNA is significantly overexpressed in omental (Om) compared with subcutaneous (Sc) adipocytes. This molecule is involved in the TNFalpha signalling pathway and may inhibit apoptosis. OBJECTIVE: To examine the effect of serum agents and TNFalpha upon cIAP2 mRNA expression in human primary culture preadipocytes. DESIGN: Paired omental and subcutaneous adipose tissue biopsies were obtained from 11 patients, nine female and two male, with ages ranging from 29 to 82. These were cultured in either serum containing medium or serum-free medium with or without the addition of TNFalpha for 4 h and mRNA levels analysed by quantitative reverse-transcription polymerase chain reaction. RESULTS: When human preadipocytes were cultured in a defined medium containing foetal calf serum the Om cells had a greater level of expression of cIAP2 mRNA than Sc cells from the same individual (mean 3.5-fold higher Sc>Om; P<0.01). However, when serum was removed from this media for a transitory period the level of cIAP2 mRNA decreased in the omental depot such that Sc preadipocytes had greater cIAP2 expression than their Om counterparts. Addition of TNFalpha induced a large increase in mRNA levels of cIAP2 (mean 20-fold). CONCLUSIONS: These results demonstrate that cIAP2 is expressed in a depot-specific manner in human preadipocytes and that levels of expression are regulated by serum factors and TNFalpha. Thus there may be intrinsic differences between preadipocyte cells from different adipose depots and this may play a role in the regulation of body fat distribution via the modulation of fat cell apoptosis.
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Adipocitos/efectos de los fármacos , Tejido Adiposo/anatomía & histología , Apoptosis/fisiología , Células Madre/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacología , Adipocitos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/genética , Células Cultivadas , Medios de Cultivo/farmacología , Medio de Cultivo Libre de Suero/farmacología , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Obesidad , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Madre/fisiología , VíscerasRESUMEN
Chronic exposure to toxicants is a selective pressure affecting populations and also the interactions between populations. Nonaxenic cultures of the blue-green alga Microcystis aeruginosa were used to investigate the ecological dynamics and the effect of preexposure to 2,4-dinitrophenol (DNP) on the tolerance toward subsequent DNP inputs. It was predicted that preexposure would induce an increased tolerance to further inputs. This should cause a higher population growth rate under a given DNP exposure, a broader tolerance range (the range of concentrations over which population growth can be sustained), a higher EC(50), and a lesser variability in growth rates, over the range of experimental exposure concentrations. DNP reduced Microcystis growth proportionally to exposure concentration. Light, inorganic carbon, and DNP were likely limiting factors for algal growth. Heterotrophic bacteria presumably used the dead cells and the exudate of living algae as substrates. Some unexpected effects occurred, such as an apparent increase in dissolved DNP in the medium following its initial decline and fluctuations of the bacterial population. The hypotheses were verified as concerns the effect of preexposure on tolerance. Changes were apparent in the EC(50) and in the breadth of the tolerance range. Moreover, the variability of preexposed populations, in terms of algal growth rate, over the range of exposure concentrations, was smaller than that of non-preexposed populations. Such a decrease in variability may reduce the potential of a population to resist further stresses.
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2,4-Dinitrofenol/toxicidad , Adaptación Fisiológica/efectos de los fármacos , Microcystis/efectos de los fármacos , Crecimiento Demográfico , Adaptación Fisiológica/fisiología , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos/fisiología , Microcystis/crecimiento & desarrolloRESUMEN
A hypothesis was modeled to account for complex 20-day dynamics in a culture of blue-green algae Microcystis and heterotrophic bacteria exposed to 2,4-dinitrophenol (DNP). In trials with little or no added DNP, a limiting factor (light or CO(2)) may cause algal density to fluctuate after 14 days of increase. Such factors may be unimportant at levels of DNP that restrict photosynthesis. Bacterial growth may be limited by organic substrate, and bacteria may be more resistant to DNP than blue-green algae. Hence, at intermediate levels of DNP, substrate provided by increased algal death stimulates bacterial growth more than DNP retards it, causing a bacterial peak. Sorption of DNP to cells may cause the DNP decline. Greater growth and slower DNP decline in experiments with preexposed organisms indicate lower DNP sorption affinity in preexposed cells. Bacterial assimilation of DNP-containing substrate may cause the reappearance of DNP. The model reproduced the fluctuation in algal density after growth was limited and better growth and lower DNP decline with preexposed organisms. Reappearance of DNP occurred, but was not obvious. Bacterial dynamics were least well reproduced. Changes in bacterial constants most affected output. Despite model inadequacies, probable aspects of toxicant action in nature have been revealed. Ecological relationships among populations of different species and genetic differences among individuals may have led to lower than expected toxicity, adaptation, and even growth stimulation. Responses of single species tested in isolation may be inadequate to predict toxicant impact.
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2,4-Dinitrofenol/toxicidad , Adaptación Fisiológica/efectos de los fármacos , Simulación por Computador , Microcystis/efectos de los fármacos , Modelos Biológicos , Crecimiento Demográfico , Adaptación Fisiológica/fisiología , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos/fisiología , Ecosistema , Microcystis/crecimiento & desarrollo , Sensibilidad y EspecificidadRESUMEN
Although an individual's total fat mass predicts morbidities such as coronary artery disease and diabetes, the anatomical distribution of adipose tissue is a strong and independent predictor of such adverse health outcomes. Thus, obese individuals with most of their fat stored in visceral adipose depots generally suffer greater adverse metabolic consequences than similarly overweight subjects with fat stored predominantly in subcutaneous sites. A fuller understanding of the biology of central obesity will require information regarding the genetic and environmental determinants of human fat topography and of the molecular mechanisms linking visceral adiposity to degenerative metabolic and vascular disease. Here we attempt to summarize the growing body of data relevant to these key areas and, in particular, to illustrate how recent advances in adipocyte biology are providing the basis for new pathophysiological insights.
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Tejido Adiposo/patología , Obesidad/etiología , Vísceras/patología , Citocinas/biosíntesis , Hormonas/biosíntesis , Humanos , Enfermedades Metabólicas/complicaciones , Obesidad/genética , Biosíntesis de PéptidosRESUMEN
Intraabdominal heterotopic ossification is a very uncommon disorder. We report five new cases, review the previous literature, and discuss the clinical and pathologic features of these lesions. The clinical features of the current cases and of those previously reported are remarkably similar. All patients were middle-aged to elderly men (range, 43-80 years; mean, 61 years) who had small bowel obstruction associated with heterotopic bone formation in the small bowel mesentery, often after one or more abdominal operations. In one case, an initial diagnosis of extraosseous osteosarcoma was considered. This unusual reactive process shares many of the clinical and pathologic features of myositis ossificans, as classically described in somatic soft tissues. We propose to designate this condition heterotopic mesenteric ossification.
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Obstrucción Intestinal/patología , Mesenterio/patología , Miositis Osificante/patología , Osificación Heterotópica/patología , Adulto , Anciano , Anciano de 80 o más Años , Resultado Fatal , Humanos , Obstrucción Intestinal/complicaciones , Masculino , Miositis Osificante/complicaciones , Osificación Heterotópica/complicacionesRESUMEN
Human omental adipocytes display a range of biochemical properties that distinguish them from adipocytes of subcutaneous origin. However, information about site-related gene expression in human fat cells is limited. We have previously demonstrated that leptin mRNA is markedly overexpressed in abdominal subcutaneous (SC) compared with omental (Om) adipocytes. To further investigate depot-specific differences in adipocyte gene expression, we have measured, in paired samples of isolated human adipocytes obtained from SC and Om fat depots, the expression of mRNAs encoding a number of proteins involved in the control of adipocyte metabolism. In contrast to the marked site-related expression of leptin, genes encoding lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and adipsin were not consistently differentially expressed. Of note, a highly significant inverse correlation between adipocyte PPAR-gamma expression and BMI (r = -0.7, P = 0.0005) was found. In parallel experiments, differential display was used in an attempt to identify novel and/or unexpected adipocyte genes that were expressed in a site-related manner. No transcript that was unique to one or another depot was found, but cellular inhibitor of apoptosis protein-2 (cIAP2) mRNA, which has not previously been reported in adipocytes, was expressed at higher levels in Om than SC adipocytes (Om > SC in all eight subjects; mean Om:SC ratio 1.9 +/- 0.2, P < 0.01). Because cIAP2 may be involved in the regulation of TNF-alpha signaling, this raises the possibility that depot-specific differences may exist in the regulation of adipocyte apoptosis. Thus, of the mRNAs examined to date, only leptin and cIAP2 show consistent site-related expression, suggesting that these molecules may have important roles in determining functional properties particular to individual adipose depots. Given the importance of PPAR-gamma in adipocyte development and insulin sensitivity, the inverse correlation between adipocyte PPAR-gamma mRNA levels and adiposity may represent a local regulatory mechanism restraining fat accumulation and/or may be related to the reduction of insulin sensitivity that occurs with increasing fat mass.
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Adipocitos/metabolismo , Regulación de la Expresión Génica , Apoptosis , Índice de Masa Corporal , Factor D del Complemento , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis , Leptina , Lipoproteína Lipasa/biosíntesis , Lipoproteína Lipasa/genética , Masculino , Persona de Mediana Edad , Epiplón , Reacción en Cadena de la Polimerasa , Biosíntesis de Proteínas , Proteínas/genética , ARN Mensajero/biosíntesis , Receptores Citoplasmáticos y Nucleares/biosíntesis , Receptores Citoplasmáticos y Nucleares/genética , Análisis de Regresión , Serina Endopeptidasas/biosíntesis , Serina Endopeptidasas/genética , Caracteres Sexuales , Piel , Esterol Esterasa/biosíntesis , Esterol Esterasa/genética , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Thiazolidinediones (TZDs) are a novel class of insulin-sensitizing agents used in the treatment of NIDDM and are potent agonists for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma). The thiazolidinedione BRL 49653 has been shown to promote the differentiation of the HIB-1B brown preadipocyte cell line and to increase rat interscapular brown adipose tissue (BAT) mass. Given the importance of brown fat in the control of energy metabolism in rodents, this may represent an important therapeutic effect of this class of compound. To date, however, no studies examining the effects of TZDs on human brown fat have been reported. In the present study, we have measured uncoupling protein 1 (UCP-1) mRNA, a specific marker for BAT, in isolated adipocytes and subcultured preadipocytes prepared from different adult human adipose tissue depots. Consistent with previous studies of adult human whole adipose tissue, UCP-1 mRNA was detectable in isolated human adipocytes prepared from all depots studied with a rank order of perirenal, omental, and subcutaneous. BRL 49653 treatment of subcultured human pre-adipocytes prepared from all depots resulted in increased levels of UCP-1 mRNA, compared with those of the vehicle-treated cells. When exposed to BRL 49653 for 5 days, preadipocytes from the human perirenal depot accumulated lipid, and a proportion of cells showed clear mitochondrial staining for UCP-1 protein by confocal microscopy. Thus, cells of the brown fat lineage were detectable in all human adipose depots studied, and cultured human pre-adipocytes, particularly from the perirenal depot, showed a marked increase in UCP-1 expression in response to thiazolidinediones. Given the role of brown adipocytes in the enhancement of energy expenditure, promotion of brown fat adipogenesis by thiazolidinediones could contribute to the beneficial effects of these drugs on insulin resistance in humans.
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Adipocitos/metabolismo , Proteínas Portadoras/biosíntesis , Hipoglucemiantes/farmacología , Proteínas de la Membrana/biosíntesis , Células Madre/metabolismo , Tiazoles/farmacología , Tiazolidinedionas , Adipocitos/citología , Adipocitos/efectos de los fármacos , Secuencia de Bases , Proteínas Portadoras/análisis , Proteínas Portadoras/genética , Células Cultivadas , Cartilla de ADN/análisis , Cartilla de ADN/química , Cartilla de ADN/genética , Femenino , Regulación de la Expresión Génica , Humanos , Canales Iónicos , Masculino , Proteínas de la Membrana/análisis , Proteínas de la Membrana/genética , Proteínas Mitocondriales , Reacción en Cadena de la Polimerasa , ARN Mensajero/análisis , ARN Mensajero/química , ARN Mensajero/genética , Receptores Citoplasmáticos y Nucleares/agonistas , Rosiglitazona , Células Madre/citología , Células Madre/efectos de los fármacos , Factores de Transcripción/agonistas , Proteína Desacopladora 1RESUMEN
Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse. We have previously described a women with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. Gly-->Arg483 prevents processing of proPC1 and leads to its retention in the endoplasmic reticulum (ER). A-->C+4 of the intro-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
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Ácido Aspártico Endopeptidasas/genética , Mutación , Obesidad/genética , Proproteína Convertasa 1 , Secuencia de Aminoácidos , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Células CHO , Carboxipeptidasa H , Carboxipeptidasas/metabolismo , Cricetinae , Retículo Endoplásmico/enzimología , Femenino , Técnica del Anticuerpo Fluorescente , Heterocigoto , Humanos , Ratones , Ratones Endogámicos , Microscopía Fluorescente , Datos de Secuencia Molecular , Obesidad/enzimología , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Proproteína Convertasas , Precursores de Proteínas/metabolismo , Procesamiento Proteico-Postraduccional , Empalme del ARN , ARN Mensajero/genética , TransfecciónRESUMEN
The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.
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Errores Innatos del Metabolismo/genética , Obesidad/genética , Proteínas/metabolismo , Adulto , Edad de Inicio , Animales , Composición Corporal , Células CHO , Niño , Preescolar , Consanguinidad , Cricetinae , Femenino , Mutación del Sistema de Lectura , Homocigoto , Humanos , Leptina , Masculino , Errores Innatos del Metabolismo/sangre , Ratones , Ratones Obesos , Datos de Secuencia Molecular , Obesidad/sangre , Linaje , Polimorfismo Conformacional Retorcido-Simple , Proteínas/genética , Análisis de Secuencia de ADN , TransfecciónRESUMEN
Obese subjects with excess intra-abdominal fat deposition suffer greater adverse metabolic consequences than do similarly overweight subjects with a predominantly subcutaneous distribution of adiposity. Little is known about the factors regulating the regional distribution of body fat. Leptin is a recently characterized protein secreted by adipocytes that appears to provide a long-term hormonal feedback signal regulating fat mass. No systematic evaluation of site-related differences in human adipocyte leptin expression has been reported to date. Levels of leptin mRNA were examined by quantitative reverse transcription-polymerase chain reaction in adipocytes isolated from omental and subcutaneous adipose depots of nonobese and mildly obese individuals undergoing elective surgery. In all individuals studied (n = 24), leptin mRNA levels were higher in subcutaneous than in omental adipocytes (P < 0.0001). In contrast, there were no consistent site-specific differences in the expression of glycerol-3-phosphate dehydrogenase mRNA. The subcutaneous-to-omental ratio of leptin mRNA expression was markedly higher in women (5.5 +/- 1.1-fold) than in men (1.9 +/- 0.2-fold) (P < 0.02). A significant relationship between BMI and leptin mRNA expression was demonstrable in the subcutaneous adipocytes of women (P < 0.006). Thus, leptin mRNA appears to be expressed predominantly by subcutaneous adipocytes, particularly in women. These findings suggest a possible role for leptin in the control of adipose tissue distribution and mass.
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Adipocitos/metabolismo , Tejido Adiposo/anatomía & histología , Tejido Adiposo/metabolismo , Biosíntesis de Proteínas , Caracteres Sexuales , Transcripción Genética , Abdomen , Adulto , Anciano , Femenino , Humanos , Leptina , Masculino , Persona de Mediana Edad , Obesidad/genética , Epiplón , Reacción en Cadena de la Polimerasa , ARN Mensajero/biosíntesis , Análisis de Regresión , PielRESUMEN
Activation of peroxisome proliferator-activated receptor (PPAR) gamma, a nuclear receptor highly expressed in adipocytes, induces the differentiation of murine preadipocyte cell lines. Recently, thiazolidinediones (TZDs), a novel class of insulin-sensitizing compounds effective in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) have been shown to bind to PPARgamma with high affinity. We have examined the effects of these compounds on the differentiation of human preadipocytes derived from subcutaneous (SC) and omental (Om) fat. Assessed by lipid accumulation, glycerol 3-phosphate dehydrogenase activity, and mRNA levels, subcultured preadipocytes isolated from either SC or Om depots did not differentiate in defined serum-free medium. Addition of TZDs (BRL49653 or troglitazone) or 15-deoxyDelta12,14prostaglandin J2 (a natural PPARgamma ligand) enhanced markedly the differentiation of preadipocytes from SC sites, assessed by all three criteria. The rank order of potency of these agents in inducing differentiation matched their ability to activate transcription via human PPARgamma. In contrast, preadipocytes from Om sites in the same individuals were refractory to TZDs, although PPARgamma was expressed at similar levels in both depots. The mechanism of this depot-specific TZD response is unknown. However, given the association between Om adiposity and NIDDM, the site-specific responsiveness of human preadipocytes to TZDs may be involved in the beneficial effects of these compounds on in vivo insulin sensitivity.
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Adipocitos/citología , Adipocitos/efectos de los fármacos , Cromanos/farmacología , Receptores Citoplasmáticos y Nucleares/genética , Tiazoles/farmacología , Tiazolidinedionas , Factores de Transcripción/genética , Adipocitos/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Células Cultivadas , Humanos , Ratones , Microcuerpos , Prostaglandina D2/análogos & derivados , Prostaglandina D2/farmacología , Receptores Citoplasmáticos y Nucleares/biosíntesis , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Rosiglitazona , Células Madre/citología , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Factores de Transcripción/biosíntesis , Activación Transcripcional/efectos de los fármacos , TroglitazonaRESUMEN
Two thirds of patients hospitalized to rule out acute myocardial infarction (AMI) are eventually found to have a non-AMI diagnosis, whereas 2% to 8% of patients with AMI are inappropriately discharged from the emergency department. Myoglobin has been shown to increase within 2 to 3 hours of myocardial injury. This study evaluates the usefulness of myoglobin in acute chest pain. Serial blood samples were obtained from 89 suspected AMI patients evaluated in the emergency department. Testing included creatine kinase (CK), a creatine kinase isoenzyme (CK-MB), and myoglobin. Twenty five of 89 patients (28%) had a diagnosis of AMI. The sensitivity of myoglobin for the detection of AMI was 56% at the time of admission and 100% 2 hours after admission. Thirteen of 25 AMI patients (52%) had a positive myoglobin before increases in CK or CK-MB, including one patient discharged from the emergency department. More importantly, the negative predictive value for myoglobin at the time of admission was 83% and was 100% two hours after admission. This potential for 100% predictability in excluding AMI by the use of serial myoglobin determinations will be very helpful in the correct triage of patients presenting with acute chest pain.
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Dolor en el Pecho/diagnóstico , Mioglobina/sangre , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Dolor en el Pecho/sangre , Creatina Quinasa/sangre , Servicios Médicos de Urgencia , Femenino , Humanos , Isoenzimas , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
Development of novel congenic mouse strains has allowed us to better define the location of the diabetogenic locus, Idd3, on Chromosome (Chr) 3. Congenic strains were identified by use of published and newly developed microsatellite markers, their genomes fingerprinted by a rapid, fluorescence-based approach, and their susceptibility to type 1 diabetes evaluated. The maximum interval containing Idd3 is now approximately 4 cM.
Asunto(s)
Mapeo Cromosómico , Diabetes Mellitus Tipo 1/genética , Animales , Secuencia de Bases , Cartilla de ADN , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Datos de Secuencia Molecular , Reacción en Cadena de la PolimerasaRESUMEN
A concern of ecotoxicology is to predict to which trophic levels in biocenoses bioaccumulation of compounds or of elements occurs. Transformity, a measure of the energy required to produce and maintain a component or a flow resulting from an energy transformation process, may help predict bioaccumulation potential. This notion derives from two concepts. First, common substances are more likely to be processed by the biosphere. Moreover, the uptake of rare ones from the physical environment by organisms of low trophic levels makes them less unusual to organisms of high trophic levels, which may evolve a capability of processing them. Second, transformity expresses energy relationships between parts of a system. Substances that require more energy to form or concentrate are also the more unusual. The hypothesis was formulated that there is a correlation between the rarity, complexity, and energy required for concentrating a substance, and thus its transformity, and the transformity of the trophic level to which it bioaccumulates. This hypothesis was tested for a set of elements with published data on their biogeochemistry and bioaccumulation and on energy transfers between trophic levels in ecosystems. The transformities of the elements were calculated from the energy required by the biosphere for maintaining a difference in concentration compared to its physical environment. Transformities of corresponding trophic levels were calculated from the energy driving the energy flows. There was a significant rank correlation between the transformity of elements and that of trophic levels. This may be an important generalization in ecotoxicology because it may lead to the possibility of predicting bioaccumulation tendency.