RESUMO
PURPOSE: To compare organ specific cancer incidence risks for standard and complex external beam radiotherapy (including cone beam CT verification) following breast conservation surgery for early breast cancer. METHOD: Doses from breast radiotherapy and kilovoltage cone beam CT (CBCT) exposures were obtained from thermoluminescent dosimeter measurements in an anthropomorphic phantom in which the positions of radiosensitive organs were delineated. Five treatment deliveries were investigated: (i) conventional tangential field whole breast radiotherapy (WBRT), (ii) noncoplanar conformal delivery applicable to accelerated partial beast irradiation (APBI), (iii) two-volume simultaneous integrated boost (SIB) treatment, (iv) forward planned three-volume SIB, and (v) inverse-planned three volume SIB. Conformal and intensity modulated radiotherapy methods were used to plan the complex treatments. Techniques spanned the range from simple methods appropriate for patient cohorts with a low cancer recurrence risk to complex plans relevant to cohorts with high recurrence risk. Delineated organs at risk included brain, salivary glands, thyroid, contralateral breast, left and right lung, esophagus, stomach, liver, colon, and bladder. Biological Effects of Ionizing Radiation (BEIR) VII cancer incidence models were applied to the measured mean organ doses to determine lifetime attributable risk (LAR) for ages at exposure from 35 to 80 yr according to radiotherapy techniques, and included dose from the CBCT imaging. RESULTS: All LAR decreased with age at exposure and were lowest for brain, thyroid, liver, and bladder (<0.1%). There was little dependence of LAR on radiotherapy technique for these organs and for colon and stomach. LAR values for the lungs for the three SIB techniques were two to three times those from WBRT and APBI. Uncertainties in the LAR models outweigh any differences in lung LAR between the SIB methods. Constraints in the planning of the SIB methods ensured that contralateral breast doses and LAR were comparable to WBRT, despite their added complexity. The smaller irradiated volume of the ABPI plan contributed to a halving of LAR for contralateral breast compared with the other plan types. Daily image guided radiotherapy (IGRT) for a left breast protocol using kilovoltage CBCT contributed <10% to LAR for the majority of organs, and did not exceed 22% of total organ dose. CONCLUSIONS: Phantom measurements and calculations of LAR from the BEIR VII models predict that complex breast radiotherapy techniques do not increase the theoretical risk of second cancer incidence for organs distant from the treated breast, or the contralateral breast where appropriate plan constraints are applied. Complex SIB treatments are predicted to increase the risk of second cancer incidence in the lungs compared to standard whole breast radiotherapy; this is outweighed by the threefold reduction in 5 yr local recurrence risk for patients of high risk of recurrence, and young age, from the use of radiotherapy. APBI may have a favorable impact on risk of second cancer in the contralateral breast and lung for older patients at low risk of recurrence. Intensive use of IGRT increased the estimated values of LAR but these are dominated by the effect of the dose from the radiotherapy, and any increase in LAR from IGRT is much lower than the models' uncertainties.
Assuntos
Neoplasias da Mama/radioterapia , Modelos Biológicos , Neoplasias Induzidas por Radiação/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Tomografia Computadorizada de Feixe Cônico , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/diagnóstico por imagem , Segunda Neoplasia Primária/diagnóstico por imagem , Especificidade de Órgãos , Imagens de Fantasmas , Dosagem Radioterapêutica , Medição de Risco , Fatores de TempoRESUMO
Control of human cytomegalovirus (HCMV) infection during the posttransplant period was investigated in 134 solid-organ transplant recipients by monitoring in parallel virologic and immunologic parameters for at least 1 year of follow-up. Virologic monitoring was achieved by determining HCMV DNAemia with real-time PCR, using the threshold of 300 000 DNA copies/mL blood as a cutoff for starting preemptive therapy. Immunologic monitoring included measurement of HCMV-specific CD4+ and CD8+ T cells by cytokine flow cytometry, using HCMV-infected dendritic cells as a stimulus. HCMV infection was diagnosed in 110 (82%) and required treatment in 49 (36%) patients. At 12 months after transplantation 'protective' immunity (≥0.4 CD4+ and CD8+ HCMV-specific T cells/µL blood) was achieved in 115/129 (89%) patients. During the entire study period, 122 patients reconstituting HCMV-specific CD4+ and CD8+ T-cell immunity at 60 days posttransplant onward were able to control HCMV infection, except for one patient who developed HCMV disease because of a rejection episode. Patients reconstituting HCMV-specific CD8+ only did not control HCMV infection. In conclusion, the presence of both HCMV-specific CD4+ and CD8+ T cells ≥ 0.4/µL blood appears to be protective against HCMV disease. This result does not apply to patients undergoing antirejection treatment, or reconstituting HCMV-specific CD8+ T cells only.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/diagnóstico , DNA Viral/sangue , Transplante de Coração/efeitos adversos , Transplante de Rim/efeitos adversos , Transplante de Pulmão/efeitos adversos , Adulto , Idoso , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Citomegalovirus/genética , Citomegalovirus/imunologia , Infecções por Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , Células Dendríticas/virologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Carga ViralRESUMO
AIMS: To report oncologic and functional outcomes in terms of tumor control and toxicity of carbon ion radiotherapy (CIRT) in reirradiation setting for recurrent salivary gland tumors at CNAO. METHODS: From November 2013 to September 2016, 51 consecutive patients with inoperable recurrent salivary gland tumors were retreated with CIRT in the frame of the phase II protocol CNAO S14/2012C for recurrent head and neck tumors. RESULTS: Majority of pts (74.5%) had adenoid cystic carcinoma, mainly rcT4a (51%) and rcT4b (37%). Median dose of prior photon based radiotherapy was 60 Gy. Median dose of CIRT was 60 Gy [RBE] at a mean of 3 Gy [RBE] per fraction. During reirradiation, 19 patients (37.3%) experienced grade G1 toxicity, 19 pts (37.3%) had G2 and 2 pts (3.9%) had G3. Median follow up time was 19 months. Twenty one (41.2%) patients had stable disease and 30 (58.8%) tumor progression at the time of last follow up. Furthermore, 9 (18%) patients had G1 late toxicity, 19 (37%) had G2 and 9 (17. 5%) had G3. Using the Kaplan Meier method, progression free survival (actuarial) at one and two years were 71.7% and 52.2% respectively. Estimated overall survival (actuarial) at one and two years were 90.2% and 64%, respectively. CONCLUSIONS: CIRT is a good option for retreatment of inoperable recurrent salivary gland tumors with acceptable rates of acute and late toxicity. Longer follow up time is needed to assess the effectiveness of CIRT in reirradiation setting of salivary gland tumors.
Assuntos
Carcinoma Adenoide Cístico , Neoplasias de Cabeça e Pescoço , Radioterapia com Íons Pesados , Reirradiação , Neoplasias das Glândulas Salivares , Carcinoma Adenoide Cístico/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Recidiva Local de Neoplasia/radioterapia , Dosagem Radioterapêutica , Neoplasias das Glândulas Salivares/radioterapiaRESUMO
Ivabradine, a heart rate reducing agent, protects the vascular system by unidentified mechanisms. We sought to determine the effects of the treatment with ivabradine, started before plaque formation, on early transcriptional changes and endothelium lesions in regions of aorta subjected to disturbed blood flow. Six week-old apolipoprotein E-deficient (ApoE-/-) mice, fed a low-fat diet, were treated with ivabradine to determine the effect on transcriptional changes (2-and 4-week treatment) and on lesions formation (19-week treatment) in the endothelium of the aortic arch. Microarrays analysis (60k probes) of endothelium-enriched RNA was carried out to detect changes in gene expression induced by treatment. Endothelium damage was assessed by en-face immunofluorescence staining for vascular endothelial (VE) cadherin. According to microarray analysis, 930 transcripts were affected by the treatment. We found downregulation of pro-apoptotic and pro-inflammatory genes, the majority of which are nuclear factor-κB (NF-κB)-and/or angiotensin II-regulated genes, and upregulation of anti-inflammatory genes. Many shear stress-responsive genes were affected by the treatment and the MAPK, Notch signalling and sterol metabolic processes were among the most significantly affected pathways. Consistently, we observed increased levels of Hes5, a Notch target gene, together with a reduction of endothelium damage, in the lower aortic arch of treated- compared with untreated- mice. We concluded that an early treatment with ivabradine protected the endothelium of the aortic arch of ApoE-/- mice. Activation of the Notch signalling could be part of the mechanism underlying this protection.
Assuntos
Aterosclerose/genética , Benzazepinas/farmacologia , Fármacos Cardiovasculares/farmacologia , Endotélio Vascular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Aterosclerose/fisiopatologia , Benzazepinas/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Ivabradina , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Notch/metabolismo , Transcriptoma/efeitos dos fármacosRESUMO
It is widely acknowledged that mitochondria are highly active structures that rapidly respond to cellular and environmental perturbations by changing their shape, number, and distribution. Mitochondrial remodeling is a key component of diverse biological processes, ranging from cell cycle progression to autophagy. In this chapter, we describe different methodologies for the morphological study of the mitochondrial network. Instructions are given for the preparation of samples for fluorescent microscopy, based on genetically encoded strategies or the employment of synthetic fluorescent dyes. We also propose detailed protocols to analyze mitochondrial morphometric parameters from both three-dimensional and bidimensional datasets. Finally, we describe a protocol for the visualization and quantification of mitochondrial structures through electron microscopy.
Assuntos
Autofagia , Microscopia Confocal/métodos , Microscopia Eletrônica/métodos , Mitocôndrias/ultraestrutura , Mitofagia , Imagem Óptica/métodos , Animais , Corantes Fluorescentes/análise , Proteínas de Fluorescência Verde/análise , Humanos , Mitocôndrias/metabolismoRESUMO
Mitochondria, the organelles that function as the powerhouse of the cell, have been increasingly linked to the pathogenesis of many neurological disorders, including multiple sclerosis (MS). MS is a chronic inflammatory demyelinating disease of the central nervous system (CNS) and a leading cause of neurological disability in young adults in the western world. Its etiology remains unknown, and while the inflammatory component of MS has been heavily investigated and targeted for therapeutic intervention, the failure of remyelination and the process of axonal degeneration are still poorly understood. Recent studies suggest a role of mitochondrial dysfunction in the neurodegenerative aspects of MS. This review is focused on mitochondrial functions under physiological conditions and the consequences of mitochondrial alterations in various CNS disorders. Moreover, we summarize recent findings linking mitochondrial dysfunction to MS and discuss novel therapeutic strategies targeting mitochondria-related pathways as well as emerging experimental approaches for modeling mitochondrial disease.
Assuntos
Mitocôndrias/metabolismo , Esclerose Múltipla/genética , Animais , Modelos Animais de Doenças , Humanos , Modelos Biológicos , Terapia de Alvo Molecular , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Degeneração Neural/patologiaRESUMO
Following the identification of two clinical isolates of vancomycin-resistant enterococci (VRE) from intensive care unit (ICU) patients, a surveillance programme detected that six of eight ICU patients were colonised by VRE. Standard epidemic control measures were instituted in the ICU. During a 16-month period, 13 (2.5%) of 509 ICU patients had VRE-positive swabs upon admission, and 43 (8.7%) of 496 VRE-negative patients were colonised by VRE in the ICU. Patients who acquired VRE in the ICU had a longer ICU stay (p < 0.0001). No other statistically significant differences were demonstrated. Two patients had documented infection (infection/colonisation index, 3.6%; overall VRE infection frequency, 0.4%), but both recovered and were discharged. VRE colonisation did not increase the mortality rate. Automated ribotyping identified three clusters containing, respectively, the first 52 Enterococcus faecium isolates, two Enterococcus faecalis isolates, and two further isolates of E. faecium. Multilocus sequence typing demonstrated that two E. faecium isolates representative of the two ribotypes belonged to sequence types 78 and 18, and that these two isolates belonged to the epidemic lineage C1, which includes isolates with a wide circulation in northern Italy. The outbreak was controlled by continuous implementation of the infection control programme, and by the opening of a new unit with an improved structural design and hand-washing facilities.
Assuntos
Infecção Hospitalar/epidemiologia , Surtos de Doenças , Enterococcus/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/epidemiologia , Unidades de Terapia Intensiva , Resistência a Vancomicina , Adulto , Idoso , Análise por Conglomerados , Infecção Hospitalar/microbiologia , DNA Bacteriano/química , DNA Bacteriano/genética , Enterococcus/classificação , Enterococcus/genética , Enterococcus/isolamento & purificação , Feminino , Genótipo , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Controle de Infecções/métodos , Itália , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Ribotipagem , Análise de Sequência de DNARESUMO
This article reports a catheter-related outbreak of bacteraemia involving 38 patients in two haemodialysis units in Verona. Burkholderia cepacia complex strains were isolated from human blood and from an individually wrapped disinfection napkin that was contained in a commercially available, sterile dressing kit used to handle central venous catheters. Micro-organisms isolated from blood cultures and from the napkin were identified by standard procedures and confirmed as B. cenocepacia (genomovar III) by molecular analysis. Using pulsed-field gel electrophoresis analysis, the clinical isolates were indistinguishable or closely related to the B. cenocepacia isolated from the napkin. In conclusion, this study found that a contaminated commercial napkin soaked in quaternary ammonium, even when quality certified, was the source of infection.
Assuntos
Bacteriemia/microbiologia , Infecções por Burkholderia/microbiologia , Complexo Burkholderia cepacia/isolamento & purificação , Infecção Hospitalar/microbiologia , Surtos de Doenças , Contaminação de Equipamentos , Compostos de Amônio Quaternário/farmacologia , Bacteriemia/sangue , Bacteriemia/epidemiologia , Bandagens/microbiologia , Infecções por Burkholderia/epidemiologia , Complexo Burkholderia cepacia/genética , Infecção Hospitalar/epidemiologia , Desinfetantes/farmacologia , Desinfecção/métodos , Eletroforese em Gel de Campo Pulsado/métodos , Humanos , Itália/epidemiologia , Compostos de Amônio Quaternário/antagonistas & inibidores , Diálise RenalRESUMO
Zollinger-Ellison syndrome (ZES) is characterised by refractory peptic ulcer disease, severe diarrhoea and gastric acid hypersecretion associated with an islet-cell tumor of the pancreas (gastrinoma). ZES is sporadic in 62-80% of cases and in 20-38% of cases is associated with multiple endocrine neoplasia type 1 (MEN 1). The diagnosis of ZES is certain when the plasma gastrin is >1000 pg/mL and the basal acid output is >15 mEq/h in patients with an intact stomach, >5 mEq/h in gastrectomised patients, or when the hypergastrinemia is associated with a pH <2. Treatment is based on the control of gastric acid hypersecretion and of the malignant tumor and its possible metastases. Proton pump inhibitors are the most effective antisecretory drugs and can be administered at high dosages without drug-related adverse effects. All sporadic, localised gastrinomas should be excised if possible. When liver metastases are also present, their debulking may improve symptoms and survival, and facilitate medical treatment. There is some controversy as to the surgical approach for gastrinomas associated with MEN 1. Somatostatin analogues can be useful in reducing gastric acid hypersecretion, serum gastrin and gastric enterochromaffin-like cells, and can thus contribute to treating the disease more effectively. Their antiproliferative effect can be used in treating liver metastases. Chemotherapy and/or interferon are indicated only in patients with malignant progressive disease. Embolisation and chemoembolisation are effective in controlling clinical symptoms; however, they do not seem to improve survival.
Assuntos
Síndrome de Zollinger-Ellison/diagnóstico , Síndrome de Zollinger-Ellison/terapia , Biomarcadores/sangue , Gastrinoma/patologia , Gastrinas/sangue , Humanos , Síndrome de Zollinger-Ellison/patologiaRESUMO
The term mitochondrial permeability transition (MPT) is commonly used to indicate an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes. Widespread MPT has catastrophic consequences for the cell, de facto marking the boundary between cellular life and death. MPT results indeed in the structural and functional collapse of mitochondria, an event that commits cells to suicide via regulated necrosis or apoptosis. MPT has a central role in the etiology of both acute and chronic diseases characterized by the loss of post-mitotic cells. Moreover, cancer cells are often relatively insensitive to the induction of MPT, underlying their increased resistance to potentially lethal cues. Thus, intense efforts have been dedicated not only at the understanding of MPT in mechanistic terms, but also at the development of pharmacological MPT modulators. In this setting, multiple mitochondrial and extramitochondrial proteins have been suspected to critically regulate the MPT. So far, however, only peptidylprolyl isomerase F (best known as cyclophilin D) appears to constitute a key component of the so-called permeability transition pore complex (PTPC), the supramolecular entity that is believed to mediate MPT. Here, after reviewing the structural and functional features of the PTPC, we summarize recent findings suggesting that another of its core components is represented by the c subunit of mitochondrial ATP synthase.
Assuntos
Morte Celular , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Animais , Permeabilidade da Membrana Celular , Peptidil-Prolil Isomerase F , Ciclofilinas/metabolismo , Humanos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , ATPases Mitocondriais Próton-Translocadoras/químicaRESUMO
Correction to: Oncogene (2015) 34, 14751486; doi:10.1038/ onc.2014.96; published online 14 April 2014 .The authors wish to amend the wording of the following sentence on page 2, replacing 'intracellular acidification' with 'intracellular alkalinization'
RESUMO
Nociceptin/orphanin FQ (N/OFQ) controls several biological functions by selectively activating an opioid like receptor named N/OFQ peptide receptor (NOP). Biased agonism is emerging as an important and therapeutically relevant pharmacological concept in the field of G protein coupled receptors including opioids. To evaluate the relevance of this phenomenon in the NOP receptor, we used a bioluminescence resonance energy transfer technology to measure the interactions of the NOP receptor with either G proteins or ß-arrestin 2 in the absence and in presence of increasing concentration of ligands. A large panel of receptor ligands was investigated by comparing their ability to promote or block NOP/G protein and NOP/arrestin interactions. In this study we report a systematic analysis of the functional selectivity of NOP receptor ligands. NOP/G protein interactions (investigated in cell membranes) allowed a precise estimation of both ligand potency and efficacy yielding data highly consistent with the known pharmacological profile of this receptor. The same panel of ligands displayed marked differences in the ability to promote NOP/ß-arrestin 2 interactions (evaluated in whole cells). In particular, full agonists displayed a general lower potency and for some ligands an inverted rank order of potency was noted. Most partial agonists behaved as pure competitive antagonists of receptor/arrestin interaction. Antagonists displayed similar values of potency for NOP/Gß1 or NOP/ß-arrestin 2 interaction. Using N/OFQ as reference ligand we computed the bias factors of NOP ligands and a number of agonists with greater efficacy at G protein coupling were identified.
Assuntos
Analgésicos Opioides/farmacologia , Arrestinas/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Humanos , Ligantes , Ligação Proteica , beta-Arrestina 2 , beta-Arrestinas , Receptor de NociceptinaRESUMO
In addition to suppressing breast cancer cell growth, retinoids potentiate growth inhibition in human breast cancer when tested in vitro and in vivo with tamoxifen and/or interferon. The purpose of this study was to ascertain the biologic effects of all-trans-retinoic acid (ATRA) administered alone and with tamoxifen +/- interferon and to identify the relationship between ATRA plasma concentrations and optimal biological dose (the lowest dose that produces a biological response). Three consecutive groups of 15 patients with locally advanced operable breast cancer were treated, in accordance with good clinical practice (GCP) requirements, with ATRA at 3 dose levels alone or with tamoxifen +/- alpha-interferon 2a at flat doses. After 3 weeks, the tumors were surgically removed. Biological parameters measured at the beginning (in biopsy tissue) and end (in surgical tissue) of the study were compared. The optimal biological dose for ATRA was 15 mg/m2/day. Treatments influenced tumor grade but not cell cycle kinetics (G0-G1 phase) or proliferation (Ki67 levels). ATRA induced progesterone receptors independent of dose level and co-administered drugs, but did not induce estrogen receptors when administered alone. Retinoic acid receptor (RAR)-alpha was not affected by treatment and RAR-alpha was moderately influenced whereas RAR-beta (concomitantly with transforming growth factor-beta) was induced in 33% of patients by ATRA alone. ATRA pharmacokinetics were dose- and time-dependent. Neither the ATRA + tamoxifen nor the ATRA + tamoxifen + interferon combinations potentiated the ATRA-induced biological changes. Future studies evaluating the role of RAR-beta as a biological marker of retinoid activity are warranted.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Tretinoína/uso terapêutico , Idoso , Aneuploidia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Área Sob a Curva , Doenças da Medula Óssea/induzido quimicamente , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma/química , Carcinoma/patologia , Carcinoma/cirurgia , Esquema de Medicação , Interações Medicamentosas , Feminino , Seguimentos , Cefaleia/induzido quimicamente , Humanos , Hipercolesterolemia/induzido quimicamente , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Interferon-alfa/farmacocinética , Antígeno Ki-67/análise , Mastectomia , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Receptores do Ácido Retinoico/análise , Receptores de Esteroides/análise , Proteínas Recombinantes , Segurança , Tamoxifeno/administração & dosagem , Tamoxifeno/efeitos adversos , Tamoxifeno/farmacocinética , Fator de Crescimento Transformador beta/análise , Fator de Crescimento Transformador beta1 , Resultado do Tratamento , Tretinoína/administração & dosagem , Tretinoína/efeitos adversos , Tretinoína/farmacocinéticaRESUMO
OBJECTIVE: To evaluate the effect of passive smoking on thyroid function in infants. DESIGN AND METHODS: Cord serum tri-iodiothyronine (T3), free T3 (fT3), thyroxine (T4), free T4 (fT4), TSH, thyroxine binding globulin (TBG), thyroglobulin (TG) and cord plasma thiocyanate were measured at birth, and serum TG and thiocyanate after 1 year of life, in 18 infants born from parents who did not smoke (group A), in 18 infants with a father who smoked (group B) and in 18 infants with parents both being smokers (group C). RESULTS: No significant differences were observed in cord serum concentrations of T3, fT3, T4, fT4, TSH and TBG among the three groups. Median (range) TG concentrations (ng/ml) were 30.2 (5.0-102.0), 56.3 (20.5-208.0) and 76.0 (26.0-199.0) at birth (P=0.009 for groups A and B compared; P=0.0002 for groups A and C compared), and 14.9 (5.4-32.0), 19.5 (10.0-57.5) and 20.0 (14.0-40.7) at 1 year (P=0.017 for groups A and C compared), in the three groups respectively, and thiocyanate concentrations (mmol/l) were 3.3 (0.0-51.4), 12.9 (0.0-122.2) and 27.8 (3.3-184.5) at birth (P=0.015 for groups A and C compared), and 3.1 (0.0-32.7), 6.0 (0.0-47.3) and 20.3 (0.0-230.8) at 1 year (P=0.01 for groups A and C compared) in the three groups respectively. CONCLUSIONS: TG and thiocyanate concentrations at birth and at 1 year of age in infants of smoking parents are greater than in infants with non-smoking parents. These results indicate that the change in thyroid function as evaluated by serum TG concentrations observed at birth can persist at least for 1 year if the exposure to passive smoking from both parents is continued. Increased TG concentrations may be due to a direct effect of thiocyanate on the thyroid gland.
Assuntos
Sangue Fetal/metabolismo , Glândula Tireoide/fisiopatologia , Hormônios Tireóideos/sangue , Poluição por Fumaça de Tabaco/efeitos adversos , Análise de Variância , Humanos , Lactente , Recém-Nascido , Fatores de RiscoRESUMO
Knowing the good penetration of systemic HDara-C into the CNS, we treated with this approach overt meningeal leukemia, either isolated or with bone marrow (BM) disease, in 31 adults: 18 ALL, 4 ANLL, 1 lymphoid blast crisis of CGL (LBC-CGL), and 8 non-Hodgkin's lymphoma (NHL). Treatment consisted of Ara-C, 3 g/m2 i.v. q 12 h, by 3 h infusion for 8 doses, followed by 4 doses at day 21. Complete remitters received consolidation with four monthly 4-dose courses of HDara-C. Additional multidrug consolidation and direct CNS therapy with intrathecal (i.t.) methotrexate (MTX) or Ara-C +/- cranial RT was administered to the 11 remitters last treated. Twenty of 31 patients (64%) achieved CR: 10/10 with isolated meningeal leukemia and 10/21 with concurrent CNS and BM disease. Of the remaining 11 patients, 8 had cerebrospinal fluid (CSF) clearing with persistent BM disease. In all cases but one CNS symptoms resolved promptly. CR median duration was 6 months (range 2 to 20). The main toxicity was myelosuppression requiring intensive support. There was no neurologic toxicity. These results show that systemic HDara-C is highly effective in acute leukemias and NHL with CNS involvement, and suggest the utility of this regimen for sanctuary chemoprophylaxis in patients at high risk for CNS disease.
Assuntos
Citarabina/uso terapêutico , Leucemia/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Terapia Combinada , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Humanos , Leucemia/patologia , Leucemia/radioterapia , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/radioterapia , Masculino , Neoplasias Meníngeas/radioterapia , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Indução de RemissãoRESUMO
A total of 53 vancomycin-resistant vanA-positive enterococci isolates from poultry farms (17 Enterococcus faecium; 8 Enterococcus durans) and from different hospitals (23 E. faecium; 5 Enterococcus faecalis) in northeastern Italy were compared on the basis of their antibiotic susceptibilities, their SmaI pulsed-field gel electrophoresis (PFGE) patterns, and the organization of their Tn1546-related elements. Ampicillin resistance was similar in both groups of isolates (52 and 60.7%, respectively), whereas human strains were more resistant to high-level gentamicin and streptomycin. A total of 52% of animal strains and 60% of human strains were resistant to tetracycline, and 56% and 46.4% to quinupristin/dalfopristin, respectively. In E. faecium and E. durans animal isolates, nine and six distinct PFGE patterns, respectively, were found: in two instances indistinguishable isolates were found from different farms. In E. faecium and E. faecalis human isolates, nine and six distinct PFGE patterns, respectively, were found; among E. faecium strains, 12 were identical or closely related and were isolates from the same hospital. Elements mediating vanA-glycopeptide resistance were characterized by PCR with primers that amplified 10 overlapping fragments of Tn1546. A total of 84.6% of animal strains and 64.2% of human strains contained elements indistinguishable from the prototype Tn1546. In addition, nine different types were identified, but none was common to animal and human strains.
Assuntos
Proteínas de Bactérias/genética , Carbono-Oxigênio Ligases/genética , Enterococcus faecalis/genética , Enterococcus faecium/genética , Animais , Antibacterianos/farmacologia , Portador Sadio/microbiologia , Cromossomos Bacterianos/genética , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Humanos , Hibridização Genética , Itália , Testes de Sensibilidade Microbiana , Epidemiologia Molecular , Aves Domésticas/microbiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vancomicina/farmacologia , Resistência a Vancomicina/genéticaRESUMO
The effects of the level of oxygenation on the respiratory response to heat exposure have been studied in conscious cats during normoxia, severe or mild hypocapnic hypoxia [inspired O2 fraction (FIO2) = 0.11 or 0.13], or hyperoxia. Several cats were also studied during severe normocapnic hypoxia. Experiments were repeated while the same animals were chronically carotid body denervated (CBD). The increase in respiratory frequency (f) leading to thermal tachypnea occurred at a lower body temperature (Tb) in severe hypocapnic hypoxia than in ambient air, but this effect was less pronounced when hypocapnia was corrected. No significant changes were observed during mild hypoxia or hyperoxia compared with normoxia in intact animals. After CBD, thermal tachypnea occurred at lower Tb in air than it did with intact animals in three of five cats, and it also occurred at lower Tb in mild hypocapnic hypoxia compared with air. It appears, therefore, that in conscious cats exposed to heat load 1) severe hypoxia enhances thermal tachypnea, 2) this effect persists after CBD, which suggests that it originates from a central action of hypoxia, and 3) the chemoreceptor afferents, to some degree, inhibit the onset of thermal tachypnea, as was previously observed for hypoxic tachypnea, which appears only in CBD cats (J. Appl. Physiol. 49: 769-777, 1980). Therefore, triggering of thermal and hypoxic tachypnea may involve common central mechanisms, probably located in the diencephalic structures under the control of afferents from arterial chemoreceptors.
Assuntos
Regulação da Temperatura Corporal , Corpo Carotídeo/fisiologia , Consumo de Oxigênio , Animais , Gatos , Células Quimiorreceptoras/fisiologia , Denervação , Pletismografia , RespiraçãoRESUMO
In mammals submitted to a warm environment, intracerebral injection of dopamine (DA) produces no change or an increase in body temperature accompanied by an increase in metabolic heat production, but its effect on heat loss mechanisms such as vasodilation and tachypnea is not clear. Because the principal mechanism of heat loss in the conscious cat is thermal tachypnea, we studied the influence of DA on thermal tachypnea in response to heat stress (ambient temperature = 33-36 degrees C) in five conscious cats. We first studied the steady-state response to a DA agonist, apomorphine, which crosses the blood-brain barrier. Intravenous injection of apomorphine greatly reduced thermal tachypnea by decreasing respiratory frequency (from 94.9 to 52.5 breaths/min) and increasing tidal volume (from 13.2 to 20.4 ml). The subsequent injection of the DA antagonist haloperidol, which also crosses the blood-brain barrier, restored the initial tachypnea. To further investigate the mechanism involved in thermal tachypnea, we studied the influence of peripheral chemoreceptors by transiently stimulating or inhibiting carotid body (CB) activity during tachypneic breathing. CB stimulation by intravenous injection of NaCN or domperidone reduced thermal tachypnea mainly by decreasing the respiratory frequency, whereas CB inhibition by DA tended to increase frequency and thus tachypnea. It is concluded that 1) in a warm environment, central DA receptors are also greatly involved in heat loss mechanisms, 2) arterial chemoreceptor input appears to counteract this tachypneic breathing, and 3) thermal and hypoxic tachypnea may be controlled by the same mechanism in which a DA-like system has a key role.
Assuntos
Células Quimiorreceptoras/fisiologia , Dopamina/fisiologia , Doenças Respiratórias/fisiopatologia , Animais , Apomorfina/farmacologia , Artérias/fisiologia , Gatos , Domperidona/farmacologia , Feminino , Haloperidol/farmacologia , Temperatura Alta , Masculino , Pletismografia , Cianeto de Sódio/farmacologia , Estresse Fisiológico/fisiopatologiaRESUMO
The effects of hypoxia on thermoregulation and ventilatory control were studied in conscious rats before and after carotid denervation (CD). Measurements of metabolic rate (VO2), ventilation (V), shivering intensity (SI), and colonic temperature (Tc) were made in groups of eight rats subjected to three protocols. In protocols 1 and 2, at ambient temperature (Ta) of 25 and 5 degrees C, respectively, rats were exposed to normoxia and hypoxia [inspired O2 fraction (FIO2) 0.13-0.11]. In protocol 3, Ta was decreased from 25 to 5 degrees C in 30-min steps of 5 degrees C. Recordings were made in normoxia and hypoxia (FIO2 0.12). The results show that in both intact and CD rats 1) in normoxia, cold exposure increased VO2, V, and SI, and these increases were proportional to the decrease in Ta; 2) hypoxia induced only a transient decrease in SI, and, for a given Ta, VO2 was reduced whereas V and SI were increased; and 3) in CD rats, V increased less during cold exposure in both normoxia and hypoxia; VO2 and Tc were more depressed during hypoxia. It is concluded that 1) the interaction between Ta and FIO2 in the control of V is partly dependent on the carotid body afferents, 2) shivering thermogenesis may be transiently affected by hypoxia independently of the carotid body afferents, and 3) nonshivering thermogenesis may be directly inhibited by hypoxia, especially during cold exposure.
Assuntos
Corpo Carotídeo/fisiologia , Temperatura Baixa/efeitos adversos , Hipóxia/fisiopatologia , Mecânica Respiratória/fisiologia , Vias Aferentes/fisiologia , Animais , Regulação da Temperatura Corporal/fisiologia , Denervação , Feminino , Consumo de Oxigênio/fisiologia , Ratos , Ratos Wistar , Reflexo/fisiologia , Estremecimento/fisiologiaRESUMO
To assess the role of diaphragmatic activity at the end of expiration (DE) in the control of end-expiratory lung volume (EELV), 1) these two parameters were correlated in anesthetized cats breathing different gas mixtures; and 2) expiratory flow volume curves in normoxia and hypoxia together with changes in esophageal pressure were measured. The influence of volume feedback on DE control was tested by applying positive end-expiratory pressure (PEEP). The effect of anesthesia was determined by measuring DE in unanesthetized cats. In hyperoxia, DE (but not EELV) decreased. In hypocapnic hypoxia (12, 10, and 8% O2), both DE and EELV gradually increased, and these changes were significantly correlated. When normocapnia was restored in 8% O2, DE and EELV decreased but remained higher than in air. Hypercapnia affected neither DE nor EELV. PEEP blocked the hypoxia-induced increase in DE. Hypoxia decreased expiratory flow and esophageal pressure. Finally, the increases in DE at 12 and 10% O2 were more pronounced when the cats were unanesthetized. These results suggest that the increase in diaphragmatic activity induced by hypocapnic hypoxia during expiration affects expiratory flow and thoracic volume and, therefore, plays a major role in increasing EELV. This phenomenon may also be controlled by volume feedback.