RESUMO
OBJECTIVES: To compare intensivist-diagnosed ventilator-associated pneumonia (iVAP) with four established definitions, assessing their agreement in detecting new episodes. METHODS: A multi-centric prospective study on pulmonary microbiota was carried out in patients requiring mechanical ventilation (MV). Data collected were used to compare hypothetical VAP onset according to iVAP with the study consensus criteria, the European Centre for Disease Control and Prevention definition, and two versions of the latter adjusted for leukocyte count and fever. RESULTS: In our cohort of 186 adult patients, iVAPs were 36.6% (68/186, 95% confidence interval 30.0-44.0%), with an incidence rate of 4.64/100 patient-MV-days, and median MV-day at diagnosis of 6. Forty-seven percent of patients (87/186) were identified as VAP by at least one criterion, with a median MV-day at diagnosis of 5. Agreement between intensivist judgement (iVAP/no-iVAP) and the criteria was highest for the study consensus criteria (50/87, 57.4%), but still one-third of iVAP were not identified and 9% of patients were identified as VAP contrary to intensivist diagnosis. VAP proportion differed between criteria (25.2-30.1%). CONCLUSIONS: Caution is needed when evaluating studies describing VAP incidence. Pre-agreed criteria and definitions that capture VAP's evolving nature provide greater consistency, but new clinically driven definitions are needed to align surveillance and diagnostic criteria with clinical practice.
Assuntos
Pneumonia Associada à Ventilação Mecânica , Adulto , Humanos , Pneumonia Associada à Ventilação Mecânica/diagnóstico , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Respiração Artificial/efeitos adversos , Estudos Prospectivos , Dados Preliminares , Incidência , Unidades de Terapia IntensivaRESUMO
INTRODUCTION: Severe short stature is a feature of acrodysostosis, but data on growth are sparse. Treatment with recombinant human growth hormone (rhGH) is used in some centers to increase final height, but no studies have been published so far. Our objective was to conduct a multicenter, retrospective, cohort study to investigate growth in individuals with both types of acrodysostosis, treated with rhGH or not; we used the new nomenclature to describe acrodysostosis, as this disease belongs to the large group of inactivating PTH/PTHrP signaling disorders (iPPSD); acrodysostosis refers to iPPSD4 (acrodysostosis type 1 due to PRKAR1A mutations) and iPPSD5 (acrodysostosis type 2, due to PDE4D mutations). METHODS: We present auxological data from individuals with genetically characterized iPPSD4, and participants with clinical features of iPPSD5. RESULTS: We included 20 and 17 individuals with iPPSD4 and iPPSD5, respectively. The rhGH-treated iPPSD4 patients (n = 9) were smaller at birth than those who did not receive rhGH (median - 2.2 SDS vs. - 1.7 SDS); they showed a trend to catch-up growth during rhGH therapy (median 0.5 SDS in the first year). The rhGH-treated patients (n = 5) reached a better final height compared to those who did not receive rhGH (n = 4) (median - 2.8 SDS vs. - 3.9 SDS), suggesting that rhGH is efficient to increase height in those patients. The difference in target height to final height ranged between 1.6 and 3.0 SDS for iPPSD4 not treated with rhGH (n = 4), 2.1-2.8 SDS for rhGH-treated iPPSD4 (n = 5), 0.6-5.5 SDS for iPPSD5 not treated with rhGH (n = 5) and 2.5-3.1 for rhGH-treated iPPSD5 (n = 2). CONCLUSION: Final height may be positively influenced by rhGH in patients with acrodysostosis/iPPSD. Our rhGH-treated cohort started therapy relatively late, which might explain, at least in part, the limited effect of rhGH on height.
Assuntos
Hormônio do Crescimento Humano , Recém-Nascido , Humanos , Hormônio do Crescimento Humano/uso terapêutico , Hormônio do Crescimento Humano/farmacologia , Hormônio do Crescimento/uso terapêutico , Estudos Retrospectivos , Estudos de Coortes , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/etiologia , Estatura , Proteínas Recombinantes/uso terapêuticoRESUMO
Adrenocortical carcinomas (ACCs) overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, but IGF1R/IR-targeted therapies failed in ACC patients. The cytoskeleton actin-binding protein filamin A (FLNA) impairs IR signalling in melanoma cells. Aims of this study were to test FLNA involvement in regulating IGF1R and IR responsiveness to both IGF2 and inhibitors in ACC. In ACC cells H295R and SW13 and primary cultures (1ACC, 4 adenomas) we found that IGF1R and IR interacted with FLNA, and FLNA silencing increased IGF1R and reduced IR expression, with a downstream effect of increased cell proliferation and ERK phosphorylation. In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R. Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only. In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.
Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Biomarcadores Tumorais/metabolismo , Filaminas/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Citoesqueleto de Actina/metabolismo , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Filaminas/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Imidazóis/farmacologia , Fator de Crescimento Insulin-Like II/genética , Mitógenos/farmacologia , Pirazinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais , Células Tumorais CultivadasRESUMO
In bottled wines, haze and turbidity are phenomena to be avoided. Since bentonite fining is a common process to clarify wines removing heat unstable proteins, a theoretical study on the adsorption of three Charged Model Molecules (CMMs, egg albumin, polyphenols and riboflavin) was carried out to deep comprehend this chemical phenomenon. Four bentonites were adopted and finely characterized together with the potential release of Na+ and Ca2+ cations, revealing suitable for RT albumin removal within 120 min. Better results in terms of adsorbed quantity were achieved by adopting 12%v/v EtOH/H2O solvent and by swelling bentonites for 24 h before use. With the most performing sample (Na/Ca_0.27), a comprehensive study on simultaneous adsorption of the three CMMs was performed, resulting in polyphenols adsorption increase due to their interactions with albumin. Notwithstanding the majority of albumin and riboflavin was successfully removed, ca. 40-50% of tested polyphenols was preserved.
Assuntos
Bentonita/química , Vinho/análise , Adsorção , Cálcio/química , Cálcio/metabolismo , Cromatografia Líquida de Alta Pressão , Cinética , Espectrometria de Massas , Ovalbumina/química , Polifenóis/química , Riboflavina/química , Sódio/química , Sódio/metabolismoRESUMO
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine neoplasm of the parafollicular thyroid C cells. Although somatostatin receptors are expressed by MTCs, treatment with octreotide has shown poor efficacy, whereas recently pasireotide has demonstrated antiproliferative effects in persistent postoperative MTCs. Aim of this study was to test the effects of octreotide and pasireotide on MTC cells proliferation, cell cycle proteins expression, MAPK activation, apoptosis, calcitonin secretion, migration and invasion in TT cell line as well as in primary MTC cultured cells. Our results showed that both octreotide and pasireotide reduced TT cell proliferation (-35.2 ± 12.1%, p < 0.001, and -25.3 ± 24.8%, p < 0.05, at 10-8 M, respectively), with concomitant inhibition of ERK phosphorylation and cyclin D1 expression. This cytostatic effect was accompanied by a proapoptotic action, with an increase of caspase3/7 activity of 1.5-fold. Moreover, both octreotide and pasireotide inhibited cell migration (-50.9 ± 11.3%, p < 0.01, and -40.5 ± 17%, p < 0.05, respectively) and invasion (-61.3 ± 35.1%, p < 0.05, and -49.7 ± 18%, p < 0.01, respectively). No effect was observed on calcitonin secretion. We then tried to extend these observations to primary cultures (n = 5). Octreotide and/or pasireotide were effective in reducing cells proliferation in 3 out of 5 tumors, and to induce cell apoptosis in 1 out of 3 MTCs. Both octreotide and pasireotide were able to reduce cell migration in all MTC tested. SST2, SST3 and SST5 were expressed in all MTC, with a tendency to increased expression of SST2 in RET mutated vs wild type MTCs. In agreement, inhibition of mutated RET in TT cells reduced SST2 expression. In conclusion, we demonstrated that octreotide and pasireotide inhibited cell proliferation and invasiveness in a subset of MTC, supporting their potential use in the control of tumor growth.
Assuntos
Carcinoma Neuroendócrino/patologia , Octreotida/farmacologia , Somatostatina/análogos & derivados , Neoplasias da Glândula Tireoide/patologia , Apoptose/efeitos dos fármacos , Calcitonina/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Mutação/genética , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-ret/genética , Somatostatina/metabolismo , Somatostatina/farmacologia , Células Tumorais CultivadasRESUMO
BACKGROUND: The term pseudohypoparathyroidism (PHP) describes disorders derived from resistance to the parathyroid hormone. Albright hereditary osteodystrophy (AHO) is a disorder with several physical features that can occur alone or in association with PHP. The subtype 1B, classically associated with resistance to PTH and TSH, derives from the epigenetic dysregulation of the GNAS locus. Patients showing features of AHO were described, but no explanation for such phenotypic heterogeneity is available. An AHO-like phenotype was associated with the loss of genetic information stored in chromosome 2q37, making this genomic region an interesting object of study as it could contain modifier genes involved in the development of AHO features in patients with GNAS imprinting defects. The present study aimed to screen a series of 65 patients affected with GNAS imprinting defects, with or without signs of AHO, for the presence of 2q37 deletions in order to find genes involved in the clinical variability. RESULTS: The molecular investigations performed on our cohort of patients with GNAS imprinting defects identified two overlapping terminal deletions of the long arm of chromosome 2. The smaller deletion was of approximately 3 Mb and contained 38 genes, one or more of which is potentially involved in the clinical presentation. Patients with the deletions were both affected by a combination of the most pathognomic AHO-like features, brachydactyly, cognitive impairment and/or behavioural defects. Our results support the hypothesis that additional genetic factors besides GNAS methylation defects are involved in the development of a complex phenotype in the subgroup of patients showing signs of AHO. CONCLUSIONS: For the first time, the present work describes PHP patients with hormone resistance and AHO signs simultaneously affected by GNAS imprinting defects and 2q37 deletions. Although further studies are needed to confirm the cause of these two rare molecular alterations and to identify candidate genes, this finding provides novel interesting clues for the identification of factors involved in the still unexplained clinical variability observed in PHP1B.
Assuntos
Cromograninas/genética , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Pseudo-Hipoparatireoidismo/genética , Resistência a Medicamentos , Feminino , Estudos de Associação Genética , Heterogeneidade Genética , Impressão Genômica , Humanos , Masculino , Fenótipo , Pseudo-Hipoparatireoidismo/sangue , Tireotropina/sangue , Pseudo-HipoparatireoidismoRESUMO
All tissues and organs derive from stem cells, which are undifferentiated cells able to differentiate into specialized cells and self-renewal. In mammals, there are embryonic stem cells that generate germ layers, and adult stem cells, which act as a repair system for the body and maintain the normal turnover of regenerative organs. Mesenchymal stem cells (MSCs) are nonhematopoietic adult multipotent cells, which reside in virtually all postnatal organs and tissues, and, under appropriate in vitro conditions, are capable to differentiate into osteogenic, adipogenic, chondrogenic, myogenic, and neurogenic lineages. Their commitment and differentiation depend on several interacting signaling pathways and transcription factors. Most GNAS-based disorders have the common feature of episodic de novo formation of islands of extraskeletal, qualitatively normal, bone in skin and subcutaneous fat. The tissue distribution of these lesions suggests that pathogenesis involves abnormal differentiation of MSCs and/or more committed precursor cells that are present in subcutaneous tissues. Data coming from transgenic mice support the concept that GNAS is a key factor in the regulation of lineage switching between osteoblast and adipocyte fates, and that its role may be to prevent bone formation in tissues where bone should not form. Despite the growing knowledge about the process of heterotopic ossification in rare genetic disorders, the pathophysiological mechanisms by which alterations of cAMP signaling lead to ectopic bone formation in the context of mesenchymal tissues is not fully understood.
Assuntos
Células-Tronco Adultas/metabolismo , Diferenciação Celular , Cromograninas/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Impressão Genômica , Células-Tronco Mesenquimais/metabolismo , Sistemas do Segundo Mensageiro , Células-Tronco Adultas/patologia , Animais , Cromograninas/genética , AMP Cíclico/genética , AMP Cíclico/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Células-Tronco Mesenquimais/patologiaRESUMO
Comparative studies between robotic and laparoscopic cholecystectomy (LC) focus heavily on economic considerations under the assumption of comparable clinical outcomes. Advancement of the robotic technique and the further widespread use of this approach suggest a need for newer comparison studies. 676 ICG-aided robotic cholecystectomies (ICG-aided RC) performed at the University of Illinois at Chicago (UIC) Division of General, Minimally Invasive and Robotic Surgery were compiled retrospectively. Additionally, 289 LC were similarly obtained. Data were compared to the largest single institution LC data sets from within the US and abroad. Statistically significant variations were found between UIC-RC and UIC-LC in minor biliary injuries (p = 0.049), overall open conversion (p ≤ 0.001), open conversion in the acute setting (p = 0.002), and mean blood loss (p < 0.001). UIC-RC open conversions were also significantly lower than Greenville Health System LC (p ≤ 0.001). Additionally, UIC ICG-RC resulted in the lowest percentages of major biliary injuries (0 %) and highest percentage of biliary anomalies identified (2.07 %). ICG-aided cholangiography and the technical advantages associated with the robotic platform may significantly decrease the rate of open conversion in both the acute and non-acute setting. The sample size discrepancy and the non-randomized nature of our study do not allow for drawing definitive conclusions.
Assuntos
Colecistectomia Laparoscópica/métodos , Colecistectomia/métodos , Conversão para Cirurgia Aberta/estatística & dados numéricos , Procedimentos Cirúrgicos Robóticos/métodos , Adulto , Sistema Biliar/lesões , Colecistectomia/efeitos adversos , Colecistectomia Laparoscópica/efeitos adversos , Colecistite/cirurgia , Feminino , Fluoroscopia/métodos , Humanos , Masculino , Radiografia Intervencionista/métodos , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversosRESUMO
Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, deep connective tissues and skeletal muscle. Usually, initial bone formation occurs during infancy as primary osteoma cutis (OC) then progressively extending into deep connective tissues and skeletal muscle over childhood. Most cases of POH are caused by paternally inherited inactivating mutations of GNAS gene. Maternally inherited mutations as well as epigenetic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO). During the last decade, some reports documented the existence of patients with POH showing additional features characteristic of AHO such as short stature and brachydactyly, previously thought to occur only in other GNAS-associated disorders. Thus, POH can now be considered as part of a wide spectrum of ectopic bone formation disorders caused by inactivating GNAS mutations. Here, we report genetic and epigenetic analyses of GNAS locus in 10 patients affected with POH or primary OC, further expanding the spectrum of mutations associated with this rare disease and indicating that, unlike PHP, methylation alterations at the same locus are absent or uncommon in this disorder.
Assuntos
Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Ossificação Heterotópica/diagnóstico , Ossificação Heterotópica/genética , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/genética , Adolescente , Criança , Pré-Escolar , Cromograninas , Epigênese Genética/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genéticaRESUMO
In chronic kidney disease (CKD) patients, cardiovascular (CV) morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D Receptors (VDRs) are present in several systems and tissues and VDR activation is associated to positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated to higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.
RESUMO
Pseudohypoparathyroidism-Ia and -Ib (PHP-Ia and -Ib) are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO), together with resistance to the action of different hormones that activate the Gs-coupled pathway. In PHP-Ib patients AHO is classically absent and hormone resistance is limited to PTH and TSH. This disorder is caused by GNAS methylation alterations with loss of imprinting at the exon A/B differentially methylated region (DMR) being the most consistent and recurrent defect. The familial form of the disease (AD-PHP-Ib) is typically associated with an isolated loss of imprinting at the exon A/B DMR due to microdeletions disrupting the upstream STX16 gene. In addition, deletions removing the entire NESP55 DMR, located within GNAS, associated with loss of all the maternal GNAS imprints have been identified in some AD-PHP-Ib kindreds. Conversely, most sporadic PHP-Ib cases have GNAS imprinting abnormalities that involve multiple DMRs, but the genetic lesion underlying these defects is unknown. Recently, methylation defects have been detected in a subset of patients with PHP-Ia and variable degrees of AHO, indicating a molecular overlap between the 2 forms. Imprinting defects do not seem to be associated with the severity of AHO neither with specific AHO signs. In conclusion, the latest findings on the molecular basis underlying these defects suggest the existence of a clinical and genetic/epigenetic overlap between PHP-Ia and PHP-Ib, and highlight the necessity of a new clinical classification of these disorders based on molecular findings.
Assuntos
Epigênese Genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Pseudo-Hipoparatireoidismo/classificação , Pseudo-Hipoparatireoidismo/genética , Cromograninas , Humanos , Mutação/genética , Hormônio Paratireóideo/uso terapêutico , Pseudo-Hipoparatireoidismo/tratamento farmacológico , Pseudo-Hipoparatireoidismo/fisiopatologiaRESUMO
In chronic kidney disease (CKD) patients, cardiovascular (CV) morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D Receptors (VDRs) are present in several systems and tissues and VDR activation is associated to positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated to higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.
Assuntos
Envelhecimento/efeitos dos fármacos , Receptores de Calcitriol/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Calcitriol/farmacologia , Cálcio/sangue , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Ergocalciferóis/farmacologia , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Falência Renal Crônica/complicações , Falência Renal Crônica/tratamento farmacológico , Fosfatos/sangue , Receptores de Calcitriol/efeitos dos fármacos , Calcificação Vascular/complicações , Calcificação Vascular/tratamento farmacológicoRESUMO
BACKGROUND: The aim of the present study was to evaluate the role of extracellular matrix-associated glycosaminoglycans (GAGs), connective tissue growth factor (CTGF), angiogenic vascular endothelial growth factor (VEGF) and inflammatory factors (MCP-1, CD40, IFN-γ) in the development of diabetic nephropathy in type 1 diabetes (T1DM). METHODS: Plasma and urine samples from 30 T1DM patients and 20 healthy controls were used to measure the levels of CTGF, VEGF, MCP-1, CD40 and IFN-γ by ELISA. Plasma and urine GAGs were measured using a spectrophotometric method. RESULTS: Plasma levels of GAGs, CD40 and MCP-1 and urine levels of GAGs and CTGF were significantly elevated in normoalbuminuric T1DM patients. A tendency to higher plasma VEGF levels was found in patients compared to controls. The urine/plasma GAGs ratio of T1DM patients was almost similar to that of healthy subjects (HS), whereas the urine/plasma CTGF ratio was about three times greater in diabetic patients compared to HS. CONCLUSIONS: Conclusively, increased GAGs and CTGF excretion are evident in T1DM normoalbuminuric juveniles, possibly reflecting early renal injury signs, before the initiation of albuminuria.
Assuntos
Biomarcadores , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas , Biomarcadores/sangue , Biomarcadores/urina , Antígenos CD40/sangue , Antígenos CD40/urina , Quimiocina CCL2/sangue , Quimiocina CCL2/urina , Criança , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/urina , Matriz Extracelular/química , Feminino , Glicosaminoglicanos/sangue , Glicosaminoglicanos/urina , Humanos , Interferon gama/sangue , Interferon gama/urina , Masculino , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/urinaRESUMO
BACKGROUND: Cardiopulmonary bypass (CPB) has been associated with activation and injury of endothelial cells, probably responsible for the systemic inflammatory response syndrome (SIRS) taking place in these patients. METHODS: We measured plasma concentrations of soluble P-selectin (sP-s), E-selectin (sE-s), tetranectin (TN), vonWillebrand factor (vWF) levels, and angiotensin-converting enzyme (ACE) activity in 31 adult patients undergoing elective coronary artery bypass grafting, just before and up to three days after surgery, and in 25 healthy volunteers. RESULTS: Patients showed higher plasma sP-s and sE-s and ACE concentrations, just before surgery, but significantly lower TN levels, compared with controls. During the first three postoperative days (PD), the concentration of each of the molecules followed a different and independent pattern, although in the third PD, the levels of sP-s, sE-s and ACE were higher and those of vWF and TN lower, compared with the preoperative ones. However, patients had higher sP-s (P=0.06), sE-s (P=0.07), and vWF (P=0.005), but lower TN concentrations (P=0.02) on the third PD compared with controls. CONCLUSIONS: CPB is characterised by pronounced changes in plasma sP-s, sE-s, TN, vWF levels, and ACE activity, which are associated with significant alteration in the intra- and early postoperative endothelial function observed in open heart surgery.
Assuntos
Ponte Cardiopulmonar/efeitos adversos , Ponte de Artéria Coronária , Endotélio Vascular/fisiopatologia , Síndrome de Resposta Inflamatória Sistêmica/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Lectinas Tipo C/sangue , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/sangue , Selectinas/sangue , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia , Fatores de Tempo , Fator de von Willebrand/análiseRESUMO
We determined the effect of a short-term angiotensin II signaling blockade on vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), nitric oxide (NO), and malondialdehyde (MDA) (index of lipid peroxidation) levels in the systemic circulation and on peroxynitrite generation and insulitis development in the streptozotocin (STZ) diabetic rats' pancreas. Diabetes was induced in Wistar rats by intraperitoneal STZ injection. Diabetic rats were treated for 1 week with losartan (20 mg/kg/body weight/day in the drinking water), and pancreas and blood were collected for histochemical, immunohistochemical, and biochemical studies. Diabetic rats showed greater VEGF, sICAM-1, NO, and MDA levels, a high score of insulitis, increased nitrotyrosine staining, and markedly reduced pancreatic insulin content when compared with controls. Losartan treatment suppressed the excessive NO and lipid peroxidation production systemically without restoring them to that of healthy subjects and reduced VEGF levels while leaving sICAM-1 levels unchanged. The insulitis score and nitrotyrosine staining were reduced, whereas the pancreatic islets and the beta-cell area were increased significantly in the treated group, indicating the reduction of inflammation and nitrosative stress and an early regeneration of beta-cell mass in the pancreas. Conclusively, in the STZ diabetic rat model, even a short-term losartan treatment improves oxidative and nitrosative stress systemically and locally, improving the islets' environment and accelerating beta-cell regeneration.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Antioxidantes/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Losartan/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Antioxidantes/farmacologia , Glicemia , Peso Corporal , Diabetes Mellitus Experimental/sangue , Molécula 1 de Adesão Intercelular/sangue , Losartan/farmacologia , Masculino , Malondialdeído/sangue , Nitratos/sangue , Nitratos/metabolismo , Óxido Nítrico/sangue , Pâncreas/patologia , Ratos , Ratos Wistar , Estreptozocina , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
AIMS: To evaluate the profile of pro- and anti-inflammatory cytokines in type 1 diabetes mellitus (T1DM) and the way they are connected in co-regulated networks and determine whether disease duration influences their pattern. METHODS: Plasma levels of 20 cytokines and soluble CD40 (sCD40) from 44 uncomplicated patients and 22 healthy controls (HCs) were measured using enzyme-linked immunosorbent assay (ELISA) and protein array technology. RESULTS: Patients showed significantly higher levels of sCD40, IL-1a, IL-2, IL-4, IL-5, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein (MIP)-1a, MIP-1b, regulated on activation normal T cell expressed and secreted (RANTES), matrix metalloproteinase (MMP)-9, and a trend to higher IL-6 than did HCs. RANTES and sCD40 discriminated significantly between diabetics and HCs. In patients with disease duration >6 months, cytokines were organized in two clusters mainly regulated by Th17 and Th1/Th2 cells respectively, while in those with disease duration Assuntos
Citocinas/sangue
, Diabetes Mellitus Tipo 1/sangue
, Biomarcadores/sangue
, Estudos de Casos e Controles
, Criança
, Análise por Conglomerados
, Progressão da Doença
, Feminino
, Humanos
, Masculino
, Fatores de Tempo
RESUMO
OBJECTIVES: Aberrant cAMP signaling is involved in the pathogenesis of somatotropinomas. The aim of the study was to screen acromegalic patients for the presence of variants of phosphodiesterase type 11A (PDE11A) gene, which have been recently identified in adrenocortical and testicular tumors. SUBJECTS AND METHODS: We sequenced the PDE11A gene-coding region in 78 acromegalic patients and 110 controls. Immunohistochemistry for PDE11A was performed in a subgroup of adenomas and normal pituitary samples. RESULTS: We found 15 nonsynonymous germline substitutions in 13 acromegalic patients (17%), i.e. 14 missense variants (Y727C in six, R804H in one, R867G in four, and M878V in three) and one truncating mutation (FS41X), with a prevalence only slightly higher than that observed in controls (14%). Immunohistochemistry revealed PDE11A expression higher in somatotropinomas than in normal somatotrophs, without significant difference between tumors with or without PDE11A variants, with the exception of two tumors (one with loss of heterozygosity (LOH) at the PDE11A locus and one with FS41X mutation) showing markedly reduced PDE11A staining. No significant differences in hormonal and clinical parameters between patients with or without PDE11A variants were observed, although patients with PDE11A changes showed a tendency to have a more aggressive tumor compared with patients with wild-type sequence (extrasellar extension in 69 vs 45%). CONCLUSIONS: This study first demonstrated the presence of PDE11A variants in a subset of acromegalic patients, which was only slightly more frequent than in controls. The normal expression of the enzyme in the majority of tumor tissues together with the lack of significant clinical phenotype suggests that these variants might only marginally contribute to the development of somatotropinomas.
Assuntos
Acromegalia/enzimologia , Adenoma/enzimologia , Diester Fosfórico Hidrolases/genética , Neoplasias Hipofisárias/enzimologia , 3',5'-GMP Cíclico Fosfodiesterases , Acromegalia/sangue , Acromegalia/genética , Adenoma/sangue , Adenoma/genética , Adulto , Sequência de Bases , DNA de Neoplasias/química , DNA de Neoplasias/genética , Feminino , Variação Genética , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/genética , Reação em Cadeia da Polimerase , Análise de RegressãoRESUMO
OBJECTIVE: To examine whether oxidative stress parameters were correlated with adhesion molecules derived from endothelial/platelet activation in a group of juveniles with type 1 diabetes mellitus (T1DM). SUBJECTS AND METHODS: Indicative parameters of patient oxidant/antioxidant capacity were measured and associated with P-selectin and tetranectin (TN), markers of endothelial/platelet activation, in the plasma of 45 diabetic children and adolescents and 20 healthy age-matched subjects (HS). RESULTS: Significantly, higher nitrate/nitrite (NOx) and lipid hydroperoxide (LPO) levels (p=0.049 and p=0.0011, respectively), lower glutathione peroxidase activity (GPx; p=0.038), and elevated TN and P-selectin plasma levels (p=0.0046 and p=0.042, respectively) were found in T1DM children compared with HS. Well-controlled T1DM children (HbA1c
Assuntos
Diabetes Mellitus Tipo 1/sangue , Glutationa Peroxidase/sangue , Lectinas Tipo C/sangue , Óxido Nítrico/sangue , Estresse Oxidativo/fisiologia , Selectina-P/sangue , Biomarcadores/sangue , Proteínas Sanguíneas/análise , Criança , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hemoglobinas Glicadas , Humanos , Peróxidos Lipídicos/sangue , MasculinoRESUMO
BACKGROUND: Minimally invasive surgical techniques have revolutionized the field of surgery. Telesurgical manipulators (robots) and new information technologies strive to improve upon currently available minimally invasive techniques and create new possibilities. METHODS: A retrospective review of all robotic cases at a single academic medical center from August 2000 until November 2002 was conducted. A comprehensive literature evaluation on robotic surgical technology was also performed. RESULTS: Robotic technology is safely and effectively being applied at our institution. Robotic and information technologies have improved upon minimally invasive surgical techniques and created new opportunities not attainable in open surgery. CONCLUSIONS: Robotic technology offers many benefits over traditional minimal access techniques and has been proven safe and effective. Further research is needed to better define the optimal application of this technology. Credentialing and educational requirements also need to be delineated.