RESUMO
Central disorders of hypersomnolence include narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia and hypersomnia associated with medical or mental disorders. Treatment is both non-pharmacological and pharmacological, including wake enhancing drugs and stimulants. One of the first-line treatment (modafinil, MODIODAL®) was the subject of a health authority alert in 2019 concerning a risk of major congenital malformations when taken during organogenesis. Since this date, three epidemiological studies have presented contradictory results. Given their methodological weaknesses, it is not possible at this stage to confirm or deny such a risk for the embryo and its nature if there is one. In clinical practice, because of these uncertainties, it is preferable if possible to suspend the treatment of a pregnant woman during the first 10 weeks from last menstrual period (organogenesis). There is an unmet clinical need for research to clarify the potential teratogenic impact of modafinil.
Assuntos
Estimulantes do Sistema Nervoso Central , Distúrbios do Sono por Sonolência Excessiva , Hipersonia Idiopática , Narcolepsia , Feminino , Humanos , Modafinila/efeitos adversos , Narcolepsia/tratamento farmacológico , Narcolepsia/etiologia , Distúrbios do Sono por Sonolência Excessiva/induzido quimicamente , Distúrbios do Sono por Sonolência Excessiva/complicações , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Hipersonia Idiopática/complicações , Hipersonia Idiopática/tratamento farmacológicoRESUMO
INTRODUCTION: The implementation of Quality Management Systems (QMS) is one of the fundamental and future-oriented elements for the improvement of modern health systems. The objective of implementing a QMS in accordance with the requirements of the ISO 9001: 2015 Standard is to effectively carry out its activities, covering both technical and management aspects, guaranteeing the satisfaction of the needs and expectations of all its stakeholders, as well as compliance with legal and regulatory requirements. It must contemplate all those aspects that have an impact on the final quality of the product or service provided by the organization. OBJECTIVE: The main objective is to describe the process of implementing a QMS under the ISO 9001: 2015 Standard in the Surgical Intensive Care Unit of the General University Hospital of Elche and evaluate its results. METHODOLOGY: Carrying out and implementing a QMS in the Surgical Intensive Care Unit of the General University Hospital of Elche applying the points of the ISO 9001: 2015 Standard. The SGC has followed the benchmark of management by processes, identifying from its strategic core of mission, vision and values, the different processes involved and their interrelation reflected in the process map. Based on it, the necessary documents have been developed to describe the operation of the Unit both at an operational level through the key processes (admission and initial assessment of the patient, stabilization, follow-up, complementary tests, interconsultations, transfers and discharge) as well as which refers to procedures of a strategic or support type. RESULTS: The strategic lines that marked the beginning of the deployment of our QMS were defined with the drafting of 7 objectives, achieving 100% compliance. The key processes (7) that described the functioning of our organization were elaborated, as well as those of a strategic type (14) and support or support (5), complemented with 55 medical and nursing protocols. 20 monitoring indicators were analyzed: 6 organizational and planning type, and 14 clinical. 46 incidents were detected in the first year of implementation of the QMS that were analyzed by the Quality Commission, emerging 7 corrective actions. 14 improvement actions were developed after the application of the AMFE methodology for key processes, achieving an average of greater than 70% effectiveness after reassessment. From the analysis of patient and family satisfaction through SAIP case management, 41 of a total of 52 cases were acknowledgments in writing. CONCLUSIONS: Implementing a QMS in our Surgical Intensive Care Unit has made it possible to define the strategic lines of our organization, develop objectives, establish monitoring indicators, standardize the work of the Unit through procedures and protocols, increase safety at work through the use of lists of verification, initiate improvement actions to strengthen the weak points of the QMS itself, as well as know the degree of satisfaction and needs of our patients and the personnel who work in it.
Assuntos
Cuidados Críticos , Unidades de Terapia Intensiva , Gestão da Qualidade Total , Humanos , Cuidados Críticos/normas , Unidades de Terapia Intensiva/normasRESUMO
Despite the widespread use of triptans in the treatment of migraine during pregnancy, questions relating to their vasoconstrictive properties have been raised following recent reports of rare fetal deaths and intrauterine growth restrictions. However, to date, analysis of these data does not allow to conclude to a direct effect of triptans, which remain a second line treatment of migraine attacks during pregnancy at any term and under normal conditions of use.
Assuntos
Transtornos de Enxaqueca , Triptaminas , Feminino , Retardo do Crescimento Fetal , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , GravidezRESUMO
AIMS/HYPOTHESIS: Prolonged exposure of pancreatic beta cells to excessive levels of glucose and fatty acids, referred to as glucolipotoxicity, is postulated to contribute to impaired glucose homeostasis in patients with type 2 diabetes. However, the relative contribution of defective beta cell function vs diminished beta cell mass under glucolipotoxic conditions in vivo remains a subject of debate. We therefore sought to determine whether glucolipotoxicity in rats is due to impaired beta cell function and/or reduced beta cell mass, and whether older animals are more susceptible to glucolipotoxic condition. METHODS: Wistar rats (2 and 6 months old) received a 72 h infusion of glucose + intravenous fat emulsion or saline control. In vivo insulin secretion and sensitivity were assessed by hyperglycaemic clamps. Ex vivo insulin secretion, insulin biosynthesis and gene expression were measured in isolated islets. Beta cell mass and proliferation were examined by immunohistochemistry. RESULTS: A 72 h infusion of glucose + intravenous fat emulsion in 2-month-old Wistar rats did not affect insulin sensitivity, insulin secretion or beta cell mass. In 6-month-old rats by contrast it led to insulin resistance and reduced insulin secretion in vivo, despite an increase in beta cell mass and proliferation. This was associated with: (1) diminished glucose-stimulated second-phase insulin secretion and proinsulin biosynthesis; (2) lower insulin content; and (3) reduced expression of beta cell genes in isolated islets. CONCLUSIONS/INTERPRETATION: In this in vivo model, glucolipotoxicity is characterised by an age-dependent impairment of glucose-regulated beta cell function despite a marked increase in beta cell mass.
Assuntos
Ácidos Graxos/toxicidade , Glucose/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Imuno-Histoquímica , Técnicas In Vitro , Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Proinsulina/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
AIMS/HYPOTHESIS: The Zucker fatty (ZF) rat subjected to 60% pancreatectomy (Px) develops moderate diabetes by 3 weeks. We determined whether a progressive fall in beta cell mass and/or beta cell dysfunction contribute to beta cell failure in this type 2 diabetes model. METHODS: Partial (60%) or sham Px was performed in ZF and Zucker lean (ZL) rats. At 3 weeks post-surgery, beta cell mass and proliferation, proinsulin biosynthesis, pancreatic insulin content, insulin secretion, and islet glucose and lipid metabolism were measured. RESULTS: ZL-Px rats maintained normal glycaemia and glucose-stimulated insulin secretion (GSIS) despite incomplete recovery of beta cell mass possibly due to compensatory enhanced islet glucose metabolism and lipolysis. ZF-Px rats developed moderate hyperglycaemia (14 mmol/l), hypertriacylglycerolaemia and relative hypoinsulinaemia. Despite beta cell mass recovery and normal arginine-induced insulin secretion, GSIS and pancreatic insulin content were profoundly lowered in ZF-Px rats. Proinsulin biosynthesis was not reduced. Compensatory increases in islet glucose metabolism above those observed in ZF-Sham rats were not seen in ZF-Px rats. Triacylglycerol content was not increased in ZF-Px islets, possibly due to lipodetoxification by enhanced lipolysis and fatty acid oxidation. Fatty acid accumulation into monoacylglycerol and diacylglycerol was increased in ZF-Px islets together with a 4.5-fold elevation in stearoyl-CoA desaturase mRNA expression. CONCLUSIONS/INTERPRETATION: Falling beta cell mass, reduced proinsulin biosynthesis and islet steatosis are not implicated in early beta cell failure and glucolipotoxicity in ZF-Px rats. Rather, severe beta cell dysfunction with a specific reduction in GSIS and marked depletion of beta cell insulin stores with altered lipid partitioning underlie beta cell failure in this animal model of type 2 diabetes.
Assuntos
Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/patologia , Obesidade/metabolismo , Obesidade/patologia , Animais , Peso Corporal , Proliferação de Células , Células Cultivadas , Ácidos Graxos não Esterificados/metabolismo , Hiperlipidemias/fisiopatologia , Imuno-Histoquímica , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Metabolismo dos Lipídeos/fisiologia , Masculino , Obesidade/fisiopatologia , Pancreatectomia , Proinsulina/metabolismo , Ratos , Ratos ZuckerRESUMO
G-protein coupled receptors (GPCRs) are targets of approximately 30% of currently marketed drugs. Over the last few years, a number of GPCRs expressed in pancreatic beta-cells and activated by lipids have been discovered. GPR40 was shown to be activated by medium- to long-chain fatty acids (FAs). It has since been shown that GPR40 contributes to FA amplification of glucose-induced insulin secretion. Although some controversy still exists as to whether GPR40 agonists or antagonists should be designed as novel type 2 diabetes drugs, data obtained in our laboratory and others strongly suggest that GPR40 agonism might represent a valuable therapeutic approach. GPR119 is expressed in pancreatic beta-cells and enteroendocrine L-cells, and augments circulating insulin levels both through its direct insulinotropic action on beta-cells and through FA stimulation of glucagon-like peptide 1 (GLP-1) secretion. GPR120 is expressed in L-cells and was also shown to mediate FA-stimulated GLP-1 release. Finally, GPR41 and GPR43 are receptors for short-chain FAs and may indirectly regulate beta-cell function via adipokine secretion. Although the discovery of these various lipid receptors opens new and exciting avenues of research for drug development, a number of questions regarding their mechanisms of action and physiological roles remain to be answered.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Ácidos Graxos não Esterificados/metabolismo , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Insulina/metabolismo , Ilhotas Pancreáticas/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Expressão Gênica , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Secreção de Insulina , Camundongos , Camundongos Mutantes , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismoRESUMO
Previous work in our laboratory showed that including 125 ppm of l-carnitine in the diets of roosters increased sperm concentration. The objective of this experiment was to determine whether reproductive efficiency could be improved by feeding l-carnitine to both parents over that of feeding l-carnitine to only the male or female. Diets formulated to contain 0 or 125 ppm of l-carnitine were fed to male and female birds from hatch until 37 wk of age. Eighty-four roosters were used, with the semen of 2 roosters constituting an experimental unit. Pools of semen from either l-carnitine-supplemented or control roosters were artificially inseminated into each of 288 hens with 23.5 muL of semen at weekly intervals, in a 2 x 2 factorial arrangement, resulting in a mean insemination dose of 1.2 and 1.1 x 10(8) sperm/hen for l-carnitine and control hens, respectively. Dietary l-carnitine, as compared with the control diet, increased egg yolk l-carnitine concentration (P = 0.001), decreased hatchling yolk sac weights (P = 0.0001), decreased yolk sac lipid content at hatch (P = 0.01), and culminated in compositional changes of yolk fatty acids, but it did not affect hatch rate, egg production, and egg traits. Although supplementing diets with l-carnitine improved sperm concentration, it did not result in a subsequent improvement in hatch rate, most likely because of the high numbers of sperm that were inseminated artificially in both the control and l-carnitine-supplemented hens. The higher concentrations of l-carnitine in the yolk of hatching eggs obtained from hens consuming l-carnitine as compared with controls may have encouraged the utilization of fat by developing embryos, as indicated by the decreased hatchling yolk sac weights and yolk sac lipid content, perhaps leading to the selective utilization of linoleic (C18:2n-6) and alpha-linolenic (C18:3n-3) acids for growth and development over myristic (C14:0) and oleic (C18:1n-9) acids.
Assuntos
Ração Animal , Carnitina/farmacologia , Galinhas/fisiologia , Suplementos Nutricionais , Reprodução/efeitos dos fármacos , Animais , Ingestão de Energia , Feminino , Masculino , Caracteres SexuaisRESUMO
Two experiments were conducted to determine if L-carnitine injected in ovo affected hatchability. Eggs of experiment 1 were injected with sterilized saline (0.85%) or L-carnitine (0.25, 0.50, 1.00, or 2.00 micromol dissolved in saline). An additional group of eggs served as noninjected controls. Hatchabilities were unaffected by treatment (94% for noninjected controls; 94% for saline injected eggs; and 87, 87, 88, and 88% for eggs injected with 0.25, 0.50, 1.00, or 2.00 micromol of L-carnitine, respectively; SEM = 1). Yolk sac weights retrieved from hatchings that were subjected to 0, 0.25, or 0.50 micromol of L-carnitine as embryos through in ovo injection were 3.9, 3.8, and 3.6 g, respectively (SEM = 0.1, P = 0.71). Eggs used in experiment 2 were injected with a wider dosimetry of l-carnitine. Fertile eggs were injected with sterilized saline (0.85%) or L-carnitine (0.05, 0.5, 5, or 10 micromol dissolved in saline). An additional group of eggs served as noninjected controls. Chick BW and % hatch were unaffected by treatment (76% for noninjected controls; 74% for saline injected eggs; and 77, 77, 68, and 76% for eggs injected with 0.05, 0.5, 5, or 10 micromol of L-carnitine, respectively; SEM = 3). In ovo injection of L-carnitine into fertile chicken eggs at 17 or 18 d of incubation did not affect hatchability, yolk sac weight, or BW.
Assuntos
Carnitina/farmacologia , Embrião de Galinha/efeitos dos fármacos , Galinhas/crescimento & desenvolvimento , Saco Vitelino/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Embrião de Galinha/crescimento & desenvolvimento , Relação Dose-Resposta a Droga , Gema de Ovo , Ovos , Injeções/veterinária , Tamanho do Órgão , Distribuição AleatóriaRESUMO
Apo B-100 of LDL can bind to both the LDL receptor and megalin, but the molecular interactions of apo B-100 with these 2 receptors are not completely understood. Naturally occurring mutant forms of apo B may be a source of valuable information on these interactions. Apo B-70.5 is uniquely useful because it contains the NH2-terminal portion of apo B-100, that includes only one of the two putative LDL receptor-binding sites (site A). The lipoprotein containing apo B-70. 5 (Lp B-70.5) was purified from apo B-100/apo B-70.5 heterozygotes by sequential ultracentrifugation combined with immunoaffinity chromatography. Cell culture experiments, ligand blot analysis, and in vivo studies all consistently showed that Lp B-70.5 is not recognized by the LDL receptor. The kidney was identified as a major organ in catabolism of Lp B-70.5 in New Zealand white rabbits. Autoradiographic analysis revealed that renal proximal tubular cells selectively removed Lp B-70.5. On ligand blotting of renal cortical membranes, Lp B-70.5 bound only to megalin. The ability of megalin to mediate cellular endocytosis of Lp B-70.5 was confirmed using retinoic acid/dibutyryl cAMP-treated F9 cells. This study suggests that the putative LDL receptor-binding site A on apo B-100 might not by itself be a functional binding domain and that the apo B-binding sites recognized by the LDL receptor and by megalin may be different. Moreover, megalin may play an important role in renal catabolism of apo B truncations, including apo B-70.5.
Assuntos
Apolipoproteínas B/metabolismo , Glicoproteínas de Membrana/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores de LDL/metabolismo , Animais , Apolipoproteína B-100 , Apolipoproteínas B/química , Apolipoproteínas B/genética , Autorradiografia , Sítios de Ligação/genética , Ligação Competitiva , Linhagem Celular , Complexo Antigênico da Nefrite de Heymann , Humanos , Rim/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Coelhos , Receptores de LDL/genética , TransfecçãoRESUMO
A previous study conducted in our laboratory showed that feeding 500 ppm of dietary L-carnitine to young and aging White Leghorns for 5 wk improved sperm concentration and reduced sperm lipid peroxidation during the last half of supplementation. The current study examined the effect of feeding dosimetric as well as lower levels of L-carnitine for longer durations on semen traits of White Leghorns. In experiments 1 and 2, White Leghorns consumed diets supplemented with 0, 125, 250, or 500 mg of L-carnitine/kg of feed. For experiment 1, an 8-wk trial was conducted with 48 White Leghorns from 46 to 54 wk of age. For experiment 2, a 17-wk trial was conducted with 96 White Leghorn roosters from 46 to 63 wk of age. For experiment 3, 84 roosters were provided for ad libitum consumption a diet formulated to contain 0 or 125 ppm of L-carnitine beginning at hatch until 37 wk of age. Long-term consumption of 125 ppm of L-carnitine beginning at hatch was the only dietary treatment that sustained a persistent increase in sperm concentration. These results suggest that L-carnitine's antioxidant influence on sperm production begins before the onset of sexual maturity.
Assuntos
Carnitina/farmacologia , Galinhas/fisiologia , Dieta/veterinária , Sêmen/efeitos dos fármacos , Envelhecimento , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Carnitina/sangue , Suplementos Nutricionais , Relação Dose-Resposta a Droga , MasculinoRESUMO
VVA-B4 lectin was used to investigate the differences in Tn antigen expression in tissues of different types of human breast cancer (benign lesions, carcinoma in situ, invasive carcinoma) and in normal tissues neighboring lobular carcinoma. Locations in which Tn antigen was expressed were identified using the avidin-biotin-peroxidase labeling system. Tissues collected during cosmetic procedures and classified as normal were completely negative, except for one case. Benign proliferative changes including fibroadenoma, apocrine and cylindrical metaplasia showed a very weak positive reaction, although strongly positive cells were also observed. The reaction in non-invasive cases of atypical hyperplasia was diversified depending on site. Intralobular hyperplasia was characterized by a particularly high percentage of labeled cells. A majority (up to 80%) of ductal and lobular carcinoma in situ showed very strong or moderate staining. In invasive cancers, there were conspicuous differences between stage of cancer development and tendency towards a decrease in intensely labeled cell count in the most advanced stages. In normal tissues in the direct neighborhood of carcinoma in situ, the cytoplasm of 40% of cells was strongly labeled. However, the findings for normal tissues in the close vicinity of invasive cancer were the most surprising, since there was either no or only very weak positive reaction. It can be concluded that glycosylation modifications during carcinogenesis, as demonstrated by the presence of Tn epitope, develop very early, before any destructive changes in proliferation/apoptosis or cell differentiation become discernible.
Assuntos
Antígenos Glicosídicos Associados a Tumores/biossíntese , Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Transformação Celular Neoplásica/metabolismo , Lectinas , Neoplasias da Mama/patologia , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Fibroadenoma/metabolismo , Fibroadenoma/patologia , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Imuno-Histoquímica , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologiaRESUMO
N'-(2-Chloroethyl)-N-(2-(methylsulfonyl)-ethyl)-N'-nitrosourea (cystemustine) is a chloroethylnitrosourea that has been used in the treatment of human melanoma. Its main antitumor effect is DNA damage to malignant melanocytes. Although unreported at present, other effects may also account for its cytotoxicity, some of them could be more or less delayed with respect to its administration. In this report, we have developed a model of secondary tumor with B16 melanoma in syngeneic C57B16 recipients to investigate the impact of cystemustine treatment of primary B16 melanoma tumors on the fate of secondary implanted untreated tumors. The data presented in this report indicate that cystemustine-treated cells or the administration of cystemustine provoke an important growth delay of primary melanoma tumors, together with an increase in cell pigmentation and cell morphology changes. Data also show that prime treatment induces a dramatic decrease in tumor weight of secondary untreated tumors accompanied by an increase in melanin content and an alteration of cell morphology. Finally, 1H-NMR spectroscopy was performed on treated B16 cells, showing an alteration in the phospholipid derivatives of melanocytes, suggesting subsequent modifications of membrane phospholipid composition. In conclusion, the data highlight two important findings: (a) cystemustine produces modifications other than DNA damage, i.e., cell morphology changes, pigmentation, and phospholipid metabolism alterations, indicating an interference with cell cycle, cell redifferentiation, and proliferation programs; and (b) cystemustine-treated tumors appear to confer a protective effect against the development of secondary untreated tumors that may be mediated by cytokines or an immune response.
Assuntos
Antineoplásicos/farmacologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Segunda Neoplasia Primária/prevenção & controle , Compostos de Nitrosoureia/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/patologia , Ressonância Magnética Nuclear Biomolecular , Células Tumorais CultivadasRESUMO
A predisposing gene (BRCA-1) for breast and ovarian cancer has been located on chromosomal region 17q12-21. According to Knudson's hypothesis if this gene is a tumor suppressor gene, allelic losses would be found in tumors occurring in families with cancer aggregations. We studied 25 samples of both benign lesions and malignant tumors, from breast cancer site-specific families and other familial cancer aggregations. Allelic losses seem to be more frequent in tumors from breast site-specific families but also include the predisposing locus in other syndromes, suggesting a role of BRCA-1 in such families. Finding of allele losses near this locus in benign lesions suggests that such alterations may represent a first step in breast carcinogenesis. It is noteworthy that allele losses involve larger chromosome fragments in malignant tumors than in benign lesions where BRCA-1 is not lost, suggesting a similar mechanism for genomic deletion in the tumorigenesis of the colon and of the breast.
Assuntos
Alelos , Neoplasias da Mama/genética , Cromossomos Humanos Par 17 , DNA de Neoplasias/genética , Fibroadenoma/genética , Neoplasias Ovarianas/genética , Neoplasias da Próstata/genética , Sequência de Bases , Neoplasias da Mama/patologia , DNA de Neoplasias/análise , Saúde da Família , Feminino , Fibroadenoma/patologia , Genes Supressores de Tumor/genética , Heterozigoto , Humanos , Hiperplasia/patologia , Masculino , Dados de Sequência Molecular , Neoplasias Ovarianas/patologia , Reação em Cadeia da Polimerase , Neoplasias da Próstata/patologiaRESUMO
Between 1978 and 1987, 109 patients without metastatic disease were treated by induction chemotherapy for inflammatory breast cancer (IBC) or "neglected" locally advanced breast cancer (LABC): 62 patients had a clinical history of rapidly growing tumours (doubling time < or = 4 months) and inflammatory signs; conversely, the 47 neglected patients had local inflammation with a longer history of LABC. 103 patients were fully evaluable. All patients received the same induction chemotherapy with doxorubicin, vincristine, cyclophosphamide and 5-fluorouracil. After six cycles, locoregional treatment was by radiotherapy if a complete or nearly complete response had been obtained, and total mastectomy, with pre or postoperative radiotherapy, in other cases. The chemotherapy after local treatment comprised of six cycles for LABC and 12 cycles for IBC (six without doxorubicin). With a median follow-up of 120 months, the median overall survival (OS) time was 70 months as against 45 months for disease-free survival (DFS). No difference was observed for OS and DFS between LABC and IBC. The regional recurrence rate was 24% (15% for radiotherapy alone). 20 factors of potential prognostic significance were evaluated by univariate and multivariate analysis. For DFS and OS, univariate analysis suggested a worse prognostic significance for "peau d'orange" appearance of the skin, clinical evidence of node involvement and poor response to chemotherapy after three cycles, on mammographic criteria. The cumulative dose of doxorubicin after three cycles seemed to have a significant effect on OS (P < 0.03) but was too closely correlated with age to draw definite conclusions. In the multivariate analysis, "peau d'orange", menopausal status and clinical node involvement predicted DFS. "Peau d'orange" and clinical node involvement also predicted OS. Our results indicate that IBC and LABC do not behave differently when treated with our procedure.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Fatores de TempoRESUMO
Neoadjuvant chemotherapy is used to improve patients' survival in locally-advanced and inflammatory breast cancer and to increase conservative surgical procedures in bulky tumours. Pathological complete responses are unusual. The aim of this pilot study was to assess the clinical and pathological response rates and to evaluate toxicity with a new protocol of primary chemotherapy in 50 high-risk breast cancer patients. All tumours were > 3 cm and had at least one other adverse prognostic factor: lymph node involvement (32 N1, 6 N2), SBR grade III (20), aneuploidy (29), negative hormonal receptors (19). Patients were treated by 3-week cycles of THP-doxorubicin 20 mg/m2 D1 to 3, vinorelbine 25 mg/m2 D1 and 4, cyclophosphamide 300 mg/m2 and 5-fluorouracil 400 mg/m2 D1 to 4 (TNCF). 38 patients received G-CSF or GM-CSF support. After 4-6 cycles, all underwent surgery (39 conservative, 11 modified radical). Tumour response was assessed clinically, by mammography and echography and on pathological specimens. An objective clinical response was observed for 43 patients: 26 complete (51%) and 18 partial (37%). After pathological review, 11 patients (22%) were devoid of any tumour cells, 4 others (8%) had only in situ carcinoma. From 253 evaluated cycles, grade III-IV toxicity occurred, 81% with neutropenia, 25% with anaemia, and 20% with thrombocytopenia. All patients recovered. This regimen induced a severe but not life-threatening haematological toxicity and resulted in a high pathological response rate (30%).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Mastectomia , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Projetos Piloto , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/análogos & derivados , VinorelbinaRESUMO
Familial hypobetalipoproteinemia is an autosomal co-dominant disorder, which in a minority of cases is due to a truncation producing mutation in the apoB gene. We have identified an apoB mutation in a 40-year old hypobetalipoproteinemic man with Type II diabetes mellitus. Immunoblotting of plasma revealed a major band for apoB-100 and a minor band with estimated size between apoB-52 and apoB-55. The proband's 75-year old father with Type II diabetes and a non-diabetic daughter also possessed the truncated protein. Direct sequencing of the amplified fragment of genomic DNA revealed a C-->T transition at nt 7692 in exon 26 of the apoB gene. This substitution yielded a premature stop codon at residue 2495 and abolished a BsaI restriction endonuclease site. The identical mutation has been described previously; however, the genotypes and ancestors of the kindred were different, suggesting that the mutation may have occurred independently. The majority of apoB-55 was eluted as particles smaller than LDL-sized apoB-100, and floated mostly between the LDL and HDL density range. It is worth noting that despite the presence of Type II diabetes, both the proband and his father have very low plasma lipid levels and neither have any clinically manifest macrovascular complications.
Assuntos
Apolipoproteínas B/genética , Diabetes Mellitus Tipo 2/genética , Hipobetalipoproteinemias/genética , Mutação , Adulto , Idoso , Sequência de Bases , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Hipobetalipoproteinemias/sangue , Hipobetalipoproteinemias/complicações , Masculino , Reação em Cadeia da Polimerase , Polimorfismo GenéticoRESUMO
Antiblast globulins (GAB) were prepared by immunization of rabbits with activated T lymphocytes (AT) derived from a rejected kidney allograft. AT consisted of a CD4+ (CD3+, CD2+ TCR alpha+ beta+) clone cytotoxic for HLA DR8-positive targets. The immunizing cells were adapted to industrial growth conditions by repetitive stimulations with an EBV-transformed line from the kidney donor and recombinant IL-2. In the pilot study, GAB (1.0-1.5 mg/kg/day) was given in 12-hr infusions, in association with prednisone (Pred) 1 mg/kg/day and azathioprine (Aza) 2 mg/kg/day, as prophylactic treatment of rejection in 12 kidney-transplanted patients during the first 2 weeks postgrafting. GAB dosage was further adapted according to the level of circulating E-rosette-forming T cells (ERFT). Cyclosporine A (8 mg/kg/day) was given at day 14 as a monotherapy after Pred and Aza were progressively tapered. No patient died, but one kidney was lost from surgical complication. No rejection occurred under GAB treatment; 41% of patients had at least one episode in the first 3 months and 16% from 3 to 9 months. GAB side effects were minor (skin rash: 2, low grade fever: 4) except for one acute serum sickness. Platelet and white blood cell counts were unchanged, but there was a significant decrease in hemoglobin during the 2 weeks of GAB infusions. Few infectious episodes occurred (3 bacterial, 2 viral). GAB monitoring showed a dramatic drop in T11+, T3+, T4+, and T8+ circulating T cells (less than 10% of normal values between days 3 and 14), whereas EFRT cells had a delayed and somewhat lower decrease (less than 10% after day 6 only). Consequently, mean GAB doses had to be raised to 1.3 mg/kg/day at day 4 and 1.6 at days 8 and 14. This pilot study suggests that this new bioreagent should be of major interest in the prophylaxis and treatment of rejection in allograft recipients. A controlled study is in progress.
Assuntos
Soro Antilinfocitário/imunologia , Linfócitos T CD4-Positivos/imunologia , Terapia de Imunossupressão/métodos , Transplante de Rim , Linfócitos T Citotóxicos/imunologia , gama-Globulinas/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/análise , Soro Antilinfocitário/efeitos adversos , Células Clonais/imunologia , Citometria de Fluxo , Sobrevivência de Enxerto , Humanos , Coelhos , Linfócitos T/classificação , gama-Globulinas/efeitos adversosRESUMO
Antihuman lymphocyte rabbit (or horse) gamma globulins used in recipients of organ transplantation are prepared against thymocytes or immortalized cell lines, the only two sources so far allowing enough antigen preparation. These cells lack, however, the surface determinants characteristic of alloreactive blasts involved in the rejection process. We have derived long-term cultures of a panel of alloreactive (untransformed) clones from a rejected kidney. Among them, clone 1E7 has been chosen as a cytotoxic CD4+ (CD2+ CD3+ TCR alpha beta+) clone proliferating against HLA-DR8 targets. This clone (clonality assessed on T cell receptor genomic rearrangements) has been grown using weekly stimulations with the kidney donor-derived EBV cell line and recombinant IL-2. Clone cultures have been adapted to mass production after optimization of culture conditions satisfying pharmaceutical requirements. This procedure warranted a reproducible source of antigen since the functional and phenotypic characteristics of the immunizing 1E7 cells remained identical through the life span of the culture. In addition, the study of the total growth capacity of 1E7 cells showed consistent expansion until the 40th cell cycle, ensuring a progeny that will satisfy the large-scale requirement for a clinical trial. Rabbits were injected with 100 x 10(6) 1E7 cells (21, 14, and 7 days before bleeding). Sera were depleted of agglutinin by red blood cell absorption and globulin antiblast (GAB) prepared by SO4Na precipitation and ion exchange chromatography; 50% complement-mediated target cell lysis and 50% inhibition of E rosette formation and alloproliferation were obtained at GAB dilutions of about 1:250-1:500. Prescreened on cynomolgus monkeys, GAB could significantly prolong skin grafts when given prophylactically. Finally GAB have been used in human recipients of kidney grafts for prophylaxis of early rejection. Results of this pilot study are given in a separate report in this issue. In conclusion we have, for the first time, set up a large-scale preparation of polyclonal globulin against a normal human alloreactive clone, and this new reagent should present several advantages over classic antilymphocyte or antithymocyte sera because it contains specificities against activation antigens and has less crossreactivity variation among batches.
Assuntos
Soro Antilinfocitário/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T Citotóxicos/imunologia , gama-Globulinas/imunologia , Animais , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação de Linfócitos T/análise , Antígenos de Diferenciação de Linfócitos T/imunologia , Biotecnologia/métodos , Antígenos CD11 , Complexo CD3 , Linfócitos T CD4-Positivos/classificação , Células Cultivadas , Células Clonais , Humanos , Técnicas In Vitro , Ativação Linfocitária , Coelhos , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
UNLABELLED: The aim of this study was to investigate joint scintigraphy in rabbits with 99mTc-N-[3-(triethylammonio)propyl]-15ane-N5 (NTP 15-5), a new radiopharmaceutical that specifically localizes in cartilaginous tissues. METHODS: Scans obtained after intravenous injection of the 99mTc-labeled compound in normal and arthropathy-induced rabbits were compared with those of the bone-imaging agent 99mTc-methylene diphosphonate (99mTc-MDP). RESULTS: The radioactive uptake of 99mTc-NTP 15-5 was detected in cartilaginous tissues 5 min after injection and was stable for 2 h. The uptake intensity was related to age and joint disease severity, and cartilage alterations not revealed by radiography induced a significant decrease of radiotracer uptake. On the other hand, imaging performed with 99mTc-MDP did not reveal the early changes in arthrosis but was more specific for bone remodeling in advanced stages of diseases or in inflammatory processes. CONCLUSION: Our results indicate that 99mTc-NTP 15-5 could be a good tracer for human arthrosic and arthritic cartilage detection, especially for the early diagnosis of joint diseases.