RESUMO
Knowledge of the anatomy of the pelvic, gonadal and renal veins is important to understand pelvic congestion syndrome (PCS) and left renal vein compression syndrome (LRCS), which is also known as the nutcracker syndrome. LRCS is related to PCS and to the presence of vulvar, vaginal and pudendal varicose veins. The diagnosis of the two syndromes is difficult, and usually achieved with CT- or phlebography. The gold standard is the intravenous pressure measurement using conventional phlebography. The definition of PCS is described as pelvic pain, aggravated in the standing position and lasting for more than 6 months. Pain in the left flank and microhaematuria is seen in patients with LRCS. Women with multiple pregnancies are at increased risk of developing varicose vein recurrences with pelvic drainage and ovarian vein reflux after crossectomy and stripping of the great saphenous vein. The therapeutic options are: conservative treatment (medroxyprogesteron) or interventional (coiling of the ovarian vein) or operative treatment (clipping of the ovarian vein). Controlled prospective trials are needed to find the best treatment.
Assuntos
Pelve/irrigação sanguínea , Insuficiência Venosa/diagnóstico , Insuficiência Venosa/terapia , Constrição Patológica/diagnóstico , Constrição Patológica/terapia , Humanos , Dor Pélvica/etiologia , Fluxo Sanguíneo Regional , Veias Renais , Síndrome , Varizes/complicações , Veias/anatomia & histologiaRESUMO
Peripheral myelin formation depends on axonal signals that tightly control proliferation and differentiation of the associated Schwann cells. Here we demonstrate that the molecular program controlling proliferation of Schwann cells switches at birth. We have analyzed the requirements for three members of the cyclin-dependent kinase (cdk) family in Schwann cells using cdk-deficient mice. Mice lacking cdk4 showed a drastic decrease in the proliferation rate of Schwann cells at postnatal days 2 and 5, but proliferation was unaffected at embryonic day 18. In contrast, ablation of cdk2 and cdk6 had no significant influence on postnatal Schwann cell proliferation. Taken together, these findings indicate that postnatal Schwann cell proliferation is uniquely controlled by cdk4. Despite the lack of the postnatal wave of Schwann cell proliferation, axons were normally myelinated in adult cdk4-deficient sciatic nerves. Following nerve injury, Schwann cells lacking cdk4 were unable to re-enter the cell cycle, while Schwann cells deficient in cdk2 or cdk6 displayed proliferation rates comparable to controls. We did not observe compensatory effects such as elevated cdk4 levels in uninjured or injured nerves of cdk2 or cdk6-deficient mice. Our data demonstrate that prenatal and postnatal Schwann cell proliferation are driven by distinct molecular cues, and that postnatal proliferation is not a prerequisite for the generation of Schwann cell numbers adequate for correct myelination.
Assuntos
Proliferação de Células , Quinase 4 Dependente de Ciclina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Bainha de Mielina/metabolismo , Células de Schwann/fisiologia , Neuropatia Ciática/enzimologia , Animais , Animais Recém-Nascidos , Bromodesoxiuridina/metabolismo , Ciclo Celular/fisiologia , Células Cultivadas , Quinase 2 Dependente de Ciclina/deficiência , Quinase 4 Dependente de Ciclina/deficiência , Quinase 6 Dependente de Ciclina/deficiência , Embrião de Mamíferos , Regulação da Expressão Gênica no Desenvolvimento/genética , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Knockout , Ratos , Degeneração Walleriana/metabolismoRESUMO
The aim of this study was to investigate whether a decrease in carnitine body stores is a risk factor for valproic acid (VPA)-associated hepatotoxicity and to explore the effects of VPA on carnitine homeostasis in mice with decreased carnitine body stores. Therefore, heterozygous juvenile visceral steatosis (jvs)(+/-) mice, an animal model with decreased carnitine stores caused by impaired renal reabsorption of carnitine, and the corresponding wild-type mice were treated with subtoxic oral doses of VPA (0.1 g/g b.wt./day) for 2 weeks. In jvs(+/-) mice, but not in wild-type mice, treatment with VPA was associated with the increased plasma activity of aspartate aminotransferase and alkaline phosphatase. Furthermore, jvs(+/-) mice revealed reduced palmitate metabolism assessed in vivo and microvesicular steatosis of the liver. The creatine kinase activity was not affected by treatment with VPA. In liver mitochondria isolated from mice that were treated with VPA, oxidative metabolism of l-glutamate, succinate, and palmitate, as well as beta-oxidation of palmitate, were decreased compared to vehicle-treated wild-type mice or jvs(+/-) mice. In comparison to vehicle-treated wild-type mice, vehicle-treated jvs(+/-) mice had decreased carnitine plasma and tissue levels. Treatment with VPA was associated with an additional decrease in carnitine plasma (wild-type mice and jvs(+/-) mice) and tissue levels (jvs(+/-) mice) and a shift of the carnitine pools toward short-chain acylcarnitines. We conclude that jvs(+/-) mice reveal a more accentuated hepatic toxicity by VPA than the corresponding wild-type mice. Therefore, decreased carnitine body stores can be regarded as a risk factor for hepatotoxicity associated with VPA.
Assuntos
Carnitina/metabolismo , Ácido Valproico/toxicidade , Animais , Carnitina/sangue , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologiaRESUMO
BACKGROUND/AIMS: Juvenile visceral steatosis (jvs-/-) mice lack the activity of the carnitine transporter OCTN2 and are dependent on carnitine substitution. The effects of carnitine deprivation on carnitine homeostasis and energy metabolism are not known in jvs-/- mice. METHODS: jvs-/- mice were studied 3, 6 and 10 days after carnitine deprivation, and compared to jvs-/- mice substituted with carnitine, wild-type (jvs+/+) and jvs+/- mice. Carnitine concentrations were assessed radioenzymatically. RESULTS: Compared to wild-type mice, carnitine-treated jvs-/- mice had decreased plasma beta-hydroxybutyrate levels and showed hepatic fat accumulation. The carnitine levels in plasma, liver and skeletal muscle were decreased by 58, 16 and 17%, respectively. After ten days of carnitine deprivation, the plasma carnitine concentration had fallen by 87% (to 2.3 mumol/l) and the tissue carnitine levels by approximately 50% compared to carnitine-treated jvs-/- mice. Carnitine deprivation was associated with a further drop in plasma beta-hydroxybutyrate and increased hepatic fat. Skeletal muscle glycogen stores decreased and lactate levels increased with carnitine deprivation, whereas tissue ATP levels were maintained. CONCLUSIONS: In jvs-/- mice, tissue carnitine stores are more resistant than carnitine plasma concentrations to carnitine deprivation. Metabolic changes (liver steatosis and loss of muscle glycogen stores) appear also early after carnitine deprivation.
Assuntos
Ácido 3-Hidroxibutírico/sangue , Carnitina/deficiência , Metabolismo Energético , Erros Inatos do Metabolismo Lipídico/metabolismo , Proteínas de Transporte de Cátions Orgânicos/deficiência , Trifosfato de Adenosina/análise , Animais , Peso Corporal , Carnitina/administração & dosagem , Carnitina/metabolismo , Carnitina/uso terapêutico , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Genótipo , Glicogênio/análise , Homeostase , Lactatos/análise , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Fígado/química , Fígado/patologia , Camundongos , Camundongos Knockout , Músculo Esquelético/química , Músculo Esquelético/patologia , Tamanho do Órgão , Proteínas de Transporte de Cátions Orgânicos/genética , Membro 5 da Família 22 de Carreadores de SolutoRESUMO
Air pollution exposure, including passenger car emissions, may cause substantial respiratory health effects and cancer death. In western countries, the majority of passenger cars are driven by gasoline fuel. Recently, new motor technologies and ethanol fuels have been introduced to the market, but potential health effects have not been thoroughly investigated. We developed and verified a coculture model composed of bronchial epithelial cells (ECs) and natural killer cells (NKs) mimicking the human airways to compare toxic effects between pure gasoline (E0) and ethanol-gasoline-blend (E85, 85% ethanol, 15% gasoline) exhaust emitted from a flexfuel gasoline car. We drove a steady state cycle, exposed ECs for 6h and added NKs. We assessed exhaust effects in ECs alone and in cocultures by RT-PCR, flow cytometry, and oxidative stress assay. We found no toxic effects after exposure to E0 or E85 compared to air controls. Comparison between E0 and E85 exposure showed a weak association for less oxidative DNA damage after E85 exposure compared to E0. Our results indicate that short-term exposure to gasoline exhaust may have no major toxic effects in ECs and NKs and that ethanol as part of fuel for gasoline cars may be favorable.
Assuntos
Poluição do Ar , Etanol/toxicidade , Gasolina/toxicidade , Emissões de Veículos/toxicidade , Poluentes Atmosféricos , Brônquios , Técnicas de Cocultura , Células Epiteliais , Humanos , Células Matadoras NaturaisRESUMO
A bursa tract diverticulum is widespread in the female part of the hermaphroditic reproductive system of stylommatophoran pulmonates. However, the ultrastructure of the diverticulum is unknown and there is only anecdotal evidence for a spermatophore-dissolving function for this organ. In the present study, we examined the ultrastructure of the diverticulum and investigated histological, histochemical, and morphometric changes at different time intervals after mating in the simultaneously hermaphroditic land snail Arianta arbustorum. The diverticulum in this species of snail is a prominent organ, consisting of a luminal columnar epithelium surrounded by a thick layer of connective tissue. During mating, the diverticulum functions as the site of spermatophore uptake. Within the lumen of the diverticulum the spermatophore wall is dissolved or at least partly broken down. The digested material is taken up by epithelial cells and accumulated in molluscan-specific cells of the connective tissue, the so-called rhogocytes. Subsequent to copulation, the total diameter of the diverticulum increases markedly, reaching a maximum size 12 h after mating, while at the same time the thicknesses of the diverticulum wall and diverticulum epithelium decrease. The length of the diverticulum shows a positive allometry and a high phenotypic variation compared to snail size, which suggests that the diverticulum is under directional sexual selection. We propose that the diverticulum in A. arbustorum has evolved in response to selection pressures imposed by divergent evolutionary interests between male and female function.
Assuntos
Evolução Biológica , Genitália Feminina/fisiologia , Genitália Feminina/ultraestrutura , Caracois Helix/fisiologia , Caracois Helix/ultraestrutura , Animais , Feminino , Masculino , Reprodução/fisiologiaRESUMO
Based on clinical and experimental studies, angiotensin II receptor blockers and angiotensin converting enzyme inhibitors have been proposed to exert acute anti-arrhythmic effects in heart failure patients. Therefore, the goal of this study was to assess acute anti-arrhythmic effects of losartan and enalaprilat in hypertrophied rat hearts during low-flow ischaemia and reperfusion. In dose-finding experiments in non-hypertrophied isolated perfused hearts, we performed dose-response curves of losartan and enalaprilat studying monophasic action potential duration at 90% repolarisation (MAPD(90%)) and ventricular fibrillation (VF) threshold. Subsequently, we determined the effects of losartan and enalaprilat (in therapeutically relevant concentrations) on ventricular tachyarrhythmias induced by low-flow ischaemia/reperfusion in hearts demonstrating left ventricular (LV) hypertrophy 70 days after aortic banding. We found that neither drug significantly affected MAPD(90%) (1 nM-1 mM) or VF threshold (1 microM losartan and 10 microM enalaprilat) in non-hypertrophied hearts. Similarly in hypertrophied hearts, neither drug significantly affected the incidence or the duration of ventricular tachyarrhythmias (ventricular tachycardia and VF) during low-flow ischaemia. However, 1 microM losartan significantly reduced the duration of ventricular tachyarrhythmias during reperfusion. In conclusion, neither losartan nor enalaprilat is acutely anti-arrhythmic in hypertrophied rat hearts during low-flow ischaemia. During reperfusion, however, losartan but not enalaprilat exerts acute anti-arrhythmic effects.
Assuntos
Antiarrítmicos/farmacologia , Enalaprilato/farmacologia , Losartan/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Taquicardia Ventricular/prevenção & controle , Fibrilação Ventricular/prevenção & controle , Potenciais de Ação , Animais , Antiarrítmicos/administração & dosagem , Relação Dose-Resposta a Droga , Enalaprilato/administração & dosagem , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hipertrofia Ventricular Esquerda/complicações , Técnicas In Vitro , Losartan/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologia , Taquicardia Ventricular/etiologia , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/fisiopatologiaRESUMO
The BM86 antigen, originally identified in Rhipicephalus (Boophilus) microplus, is the basis of the only commercialized anti-tick vaccine. The long-term goal of our study is to improve BM86 based vaccines by induction of high levels of tick gut binding antibodies that are also cross-reactive with a range of BM86 homologues expressed in other important tick species. Here we have used a BD86 derived synthetic peptide, BD86-3, to raise a series of mouse monoclonal antibodies. One of these mAbs, named 12.1, recognized BM86 homologues in immuno-histochemical analyses in four out of five tick species including R. (B.) microplus, Rhipicephalus (Boophilus) decoloratus, Hyalomma anatolicum anatolicum and Rhipicephalus appendiculatus. Our results indicate that broadly cross-reactive tick gut binding antibodies can be induced after immunization with a synthetic peptide derived from the protein BD86.
Assuntos
Anticorpos Monoclonais/imunologia , Glicoproteínas de Membrana/imunologia , Peptídeos/imunologia , Proteínas Recombinantes/imunologia , Infestações por Carrapato/prevenção & controle , Vacinas/imunologia , Sequência de Aminoácidos , Animais , Bovinos , Reações Cruzadas , Feminino , Humanos , Hibridomas , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Rhipicephalus/imunologia , Alinhamento de Sequência , Infestações por Carrapato/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Virossomais/imunologiaRESUMO
Antagonists act to restrict and negatively modulate the activity of secreted signals during progression of embryogenesis. In mouse embryos lacking the extra-cellular BMP antagonist gremlin 1 (Grem1), metanephric development is disrupted at the stage of initiating ureteric bud outgrowth. Treatment of mutant kidney rudiments in culture with recombinant gremlin 1 protein induces additional epithelial buds and restores outgrowth and branching. All epithelial buds express Wnt11, and Gdnf is significantly upregulated in the surrounding mesenchyme, indicating that epithelial-mesenchymal (e-m) feedback signalling is restored. In the wild type, Bmp4 is expressed by the mesenchyme enveloping the Wolffian duct and ureteric bud and Grem1 is upregulated in the mesenchyme around the nascent ureteric bud prior to initiation of its outgrowth. In agreement, BMP activity is reduced locally as revealed by lower levels of nuclear pSMAD protein in the mesenchyme. By contrast, in Grem1-deficient kidney rudiments, pSMAD proteins are detected in many cell nuclei in the metanephric mesenchyme, indicative of excessive BMP signal transduction. Indeed, genetic lowering of BMP4 levels in Grem1-deficient mouse embryos completely restores ureteric bud outgrowth and branching morphogenesis. The reduction of BMP4 levels in Grem1 mutant embryos enables normal progression of renal development and restores adult kidney morphology and functions. This study establishes that initiation of metanephric kidney development requires the reduction of BMP4 activity by the antagonist gremlin 1 in the mesenchyme, which in turn enables ureteric bud outgrowth and establishment of autoregulatory GDNF/WNT11 feedback signalling.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Rim/embriologia , Rim/metabolismo , Ureter/metabolismo , Proteínas Wnt/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Proteína Morfogenética Óssea 4 , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Proteínas Morfogenéticas Ósseas/genética , Núcleo Celular/metabolismo , Forma Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Rim/efeitos dos fármacos , Mesoderma/metabolismo , Camundongos , Camundongos Knockout , Morfogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Ureter/efeitos dos fármacos , Ureter/embriologiaRESUMO
The apocrine axillary glands, regarded as pheromone-producing scent glands, do not begin to function until puberty. Accordingly, sex hormones should have an impact on their activity, and the present study was designed to investigate the localization of androgen receptor (AR) and estrogen receptors (ERalpha and ERbeta) in those glands. Strong nuclear immunoreactivity for AR and ERbeta was found in the secretory epithelium. In AR especially, staining intensity was correlated with the height of the epithelium with more intense immunoreactivity in tall segments. Since the lower epithelium has been considered inactive or resting, our results suggest a correlation between steroid-receptor expression and secretory activity. Androgens are known to upregulate the cholesterol biosynthesis, and cholesterol may be used as precursor for pheromones. Accordingly, the results of this study establish a possible link between steroid hormone action and induction of pheromone production in the apocrine axillary glands.
Assuntos
Glândulas Apócrinas/metabolismo , Axila/fisiologia , Receptores de Esteroides/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Expressão Gênica/fisiologia , Humanos , Imuno-Histoquímica , Feromônios Humano/metabolismo , RNA Mensageiro/análise , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores de Esteroides/genéticaRESUMO
Hematopoietic stem cell transplantation (HSCT) is associated with significant posttransplantation gonadotoxicity. This deficit has been mainly attributed to pretransplantation conditioning, but lower sperm counts in humans also appear to be associated with graft-versus-host disease (GVHD) following allogeneic HSCT. However, the mechanisms leading to diminished spermatocyte levels during GVHD remain unknown. Here we demonstrate that injury to intratesticular cells occurs in unconditioned F1 mice following the infiltration of donor alloreactive T cells during an acute graft-versus-host reaction (GVHR). Using computer-aided quantitative microscopic morphometry we demonstrate that the nadir of Leydig cell volume density coincides with the peak of intratesticular infiltration by donor T cells. Injury to Leydig cells correlates with an intratesticular inflammatory response characterized by interferon-gamma and tumor necrosis factor-alpha production. These results demonstrate impairment of testosterone-producing Leydig cells during a local alloresponse, thus representing a mechanism that contributes to gonadal insufficiency following allogeneic HSCT.
Assuntos
Doença Enxerto-Hospedeiro/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipogonadismo/etiologia , Células Intersticiais do Testículo/patologia , Doença Aguda , Animais , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Hipogonadismo/imunologia , Hipogonadismo/patologia , Células Intersticiais do Testículo/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Espermatogênese , Linfócitos T/patologia , Testosterona/sangueRESUMO
Epithelial-mesenchymal feedback signaling is the key to diverse organogenetic processes such as limb bud development and branching morphogenesis in kidney and lung rudiments. This study establishes that the BMP antagonist gremlin (Grem1) is essential to initiate these epithelial-mesenchymal signaling interactions during limb and metanephric kidney organogenesis. A Grem1 null mutation in the mouse generated by gene targeting causes neonatal lethality because of the lack of kidneys and lung septation defects. In early limb buds, mesenchymal Grem1 is required to establish a functional apical ectodermal ridge and the epithelial-mesenchymal feedback signaling that propagates the sonic hedgehog morphogen. Furthermore, Grem1-mediated BMP antagonism is essential to induce metanephric kidney development as initiation of ureter growth, branching and establishment of RET/GDNF feedback signaling are disrupted in Grem1-deficient embryos. As a consequence, the metanephric mesenchyme is eliminated by apoptosis, in the same way as the core mesenchymal cells of the limb bud.
Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Epitélio/embriologia , Extremidades/embriologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Rim/embriologia , Mesoderma/metabolismo , Transdução de Sinais , Alelos , Animais , Animais Recém-Nascidos , Citocinas , Retroalimentação Fisiológica , Proteínas Hedgehog , Marcação In Situ das Extremidades Cortadas , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Pulmão/embriologia , Camundongos , Modelos Genéticos , Mutação , Fases de Leitura Aberta , Fatores de Tempo , Transativadores/metabolismoRESUMO
Rats with systemic carnitine deficiency induced by treatment with trimethylhydraziniumpropionate (THP) develop liver steatosis. This study aims to investigate the mechanisms leading to steatosis in THP-induced carnitine deficiency. Rats were treated with THP (20 mg/100 g) for 3 or 6 weeks and were studied after starvation for 24 h. Rats treated with THP had reduced in vivo palmitate metabolism and developed mixed liver steatosis at both time points. The hepatic carnitine pool was reduced in THP-treated rats by 65% to 75% at both time points. Liver mitochondria from THP-treated rats had increased oxidative metabolism of various substrates and of beta-oxidation at 3 weeks, but reduced activities at 6 weeks of THP treatment. Ketogenesis was not affected. The hepatic content of CoA was increased by 23% at 3 weeks and by 40% at 6 weeks in THP treated rats. The cytosolic content of long-chain acyl-CoAs was increased and the mitochondrial content decreased in hepatocytes of THP treated rats, compatible with decreased activity of carnitine palmitoyltransferase I in vivo. THP-treated rats showed hepatic peroxisomal proliferation and increased plasma VLDL triglyceride and phospholipid concentrations at both time points. A reduction in the hepatic carnitine pool is the principle mechanism leading to impaired hepatic fatty acid metabolism and liver steatosis in THP-treated rats. Cytosolic accumulation of long-chain acyl-CoAs is associated with increased plasma VLDL triglyceride, phospholipid concentrations, and peroxisomal proliferation.