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1.
J Visc Surg ; 158(3S): S18-S25, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33712411

RESUMO

Effective and safe surgery results from a complex sociotechnical process prone to human error. Acquiring large amount of data on surgical care and modelling the process of surgery with artificial intelligence's computational methods could shed lights on system strengths and limitations and enable computer-based smart assistance. With this vision in mind, surgeons and computer scientists have joined forces in a novel discipline called Surgical Data Science. In this regard, operating room (OR) black boxes and surgical control towers are being developed to systematically capture comprehensive data on surgical procedures and to oversee and assist during operating rooms activities, respectively. Most of the early Surgical Data Science works have focused on understanding risks and resilience factors affecting surgical safety, the context and workflow of procedures, and team behaviors. These pioneering efforts in sensing and analyzing surgical activities, together with the advent of precise robotic actuators, bring surgery on the verge of a fourth revolution characterized by smart assistance in perceptual, cognitive and physical tasks. Barriers to implement this vision exist, but the surgical-technical partnerships set by ambitious efforts such as the OR black box and the surgical control tower are working to overcome these roadblocks and translate the vision and early works described in the manuscript into value for patients, surgeons and health systems.


Assuntos
Salas Cirúrgicas , Cirurgiões , Inteligência Artificial , Humanos , Fluxo de Trabalho
2.
Br J Surg ; 107(13): 1780-1790, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32869868

RESUMO

BACKGROUND: A surgical approach preserving functional adrenal tissue allows biochemical cure while avoiding the need for lifelong steroid replacement. The aim of this experimental study was to evaluate the impact of intraoperative imaging during bilateral partial adrenalectomy on remnant perfusion and function. METHODS: Five pigs underwent bilateral posterior retroperitoneoscopic central adrenal gland division (9 divided glands, 1 undivided). Intraoperative perfusion assessment included computer-assisted quantitative fluorescence imaging, contrast-enhanced CT, confocal laser endomicroscopy (CLE) and local lactate sampling. Specimen analysis after completion adrenalectomy (10 adrenal glands) comprised mitochondrial activity and electron microscopy. RESULTS: Fluorescence signal intensity evolution over time was significantly lower in the cranial segment of each adrenal gland (mean(s.d.) 0·052(0·057) versus 0·133(0·057) change in intensity per s for cranial versus caudal parts respectively; P = 0·020). Concordantly, intraoperative CT in the portal phase demonstrated significantly lower contrast uptake in cranial segments (P = 0·031). In CLE, fluorescein contrast was observed in all caudal segments, but in only four of nine cranial segments (P = 0·035). Imaging findings favouring caudal perfusion were congruent, with significantly lower local capillary lactate levels caudally (mean(s.d.) 5·66(5·79) versus 11·58(6·53) mmol/l for caudal versus cranial parts respectively; P = 0·008). Electron microscopy showed more necrotic cells cranially (P = 0·031). There was no disparity in mitochondrial activity (respiratory rates, reactive oxygen species and hydrogen peroxide production) between the different segments. CONCLUSION: In a model of bilateral partial adrenalectomy, three intraoperative imaging modalities consistently discriminated between regular and reduced adrenal remnant perfusion. By avoiding circumferential dissection, mitochondrial function was preserved in each segment of the adrenal glands. Surgical relevance Preservation of adrenal tissue to maintain postoperative function is essential in bilateral and hereditary adrenal pathologies. There is interindividual variation in residual adrenocortical stress capacity, and the minimal functional remnant size is unknown. New intraoperative imaging technologies allow improved remnant size and perfusion assessment. Fluorescence imaging and contrast-enhanced intraoperative CT showed congruent results in evaluation of perfusion. Intraoperative imaging can help to visualize the remnant vascular supply in partial adrenalectomy. Intraoperative assessment of perfusion may foster maximal functional tissue preservation in bilateral adrenal pathologies and procedures.


ANTECEDENTES: Un abordaje quirúrgico que preserve la función del tejido suprarrenal permite lograr la curación bioquímica, a la vez que evita la necesidad de tratamiento sustitutivo con corticoides de por vida. El objetivo de este estudio experimental fue evaluar el impacto de las técnicas de imagen intraoperatorias en la suprarrenalectomía parcial (partial adrenalectomy, AE) bilateral sobre la perfusión y función del remanente glandular. MÉTODOS: Cinco cerdos fueron sometidos a una división bilateral central de la glándula suprarrenal por retroperitoneoscopia posterior (n = 9, 1 sin dividir). Durante la intervención, la evaluación de la perfusión incluyó la fluorescencia con cuantificación asistida por ordenador (Realidad Aumentada basada en la Fluorescencia, FLuorescence-based Enhanced Reality, FLER), tomografía computarizada (computed tomography, CT), endomicroscopia con laser confocal (confocal laser endomicroscopy, CLE) y un muestreo local de lactato. El análisis de la pieza quirúrgica tras completar la AE (n = 10) incluyó actividad mitocondrial y microscopia electrónica. RESULTADOS: La evolución de la intensidad de la señal de fluorescencia a lo largo del tiempo (ΔI/s) fue significativamente más baja en el segmento craneal de cada una de las glándulas (0,052 ± 0,057 craneal versus 0,133 ± 0,057 caudal, P = 0,02). De forma concordante, la CT intraoperatoria en la fase portal demostró una captación de contraste significativamente más baja en los segmentos craneales (P = 0,03). En la CLE, el contraste de fluoresceína se observó en todos los segmentos caudales, pero solo en el 44% de los segmentos craneales (P = 0,04). Los hallazgos obtenidos en las pruebas de imagen favorables a la perfusión caudal fueron congruentes con niveles significativamente más bajos de lactato capilar a nivel local (11,58 ± 6,53 mmol/L craneal versus 5,66 ± 5,79 mmol/L caudal, P = 0,008). A nivel craneal, la microscopia electrónica mostró más células necróticas (P = 0,03). La actividad mitocondrial (tasas de respiración, especies reactivas de oxígeno y producción de H2 O2 ) no mostraron disparidad entre los diferentes segmentos. CONCLUSIÓN: En un modelo de AE parcial bilateral, las tres modalidades de pruebas de imagen intraoperatorias podrían discriminar de forma consistente una perfusión regular y reducida del remanente suprarrenal. Al evitar una disección circunferencial, se preservó la función mitocondrial en cada segmento de las glándulas suprarrenales.


Assuntos
Glândulas Suprarrenais/irrigação sanguínea , Glândulas Suprarrenais/diagnóstico por imagem , Adrenalectomia/métodos , Cuidados Intraoperatórios/métodos , Glândulas Suprarrenais/fisiologia , Glândulas Suprarrenais/cirurgia , Animais , Biomarcadores/metabolismo , Feminino , Ácido Láctico/metabolismo , Masculino , Microscopia Confocal , Microscopia Eletrônica , Mitocôndrias/metabolismo , Modelos Animais , Imagem Óptica , Período Pós-Operatório , Sus scrofa , Tomografia Computadorizada por Raios X
3.
G Chir ; 40(1): 39-43, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30771797

RESUMO

BACKGROUND: Inflammatory bowel diseases may be associated with many extraintestinal complications, that in some cases can represent the first onset of these disorders. In particular during the course of the disease, Ulcerative Colitis develops extraintestinal manifestations very frequently. One of the rarest is pyoderma gangrenosum, a noninfectious neuthrophilic dermatosis, that can involve most commonly legs but also other parts of the skin or mucosas. It can be idiopathic or associated with gammopathies, vasculitis, chronic arthritis or, like in our case, with inflammatory bowel disease and malignancies. CASE PRESENTATION: A 38-year-old man was referred to our Department with a colo-cutaneous fistula in the left quadrant of abdominal wall. In the anamnesis he reported a trauma during a soccer match three weeks before. Through a CT scan and endoscopy with biopsy an inflammatory bowel disease with a segmental colitis and stenosis was diagnosed. After medical therapy, an initial radiological drainage and a period of parenteral nutrition, he underwent a left hemicolectomy. Despite the previous endoscopic biopsy the histopathological examination put in evidence not only inflammatory disease (in particular Ulcerative Colitis) but also a colorectal tumor pT4pN0. After the full recovery before chemotherapy he has developed on the chest and on the abdomen some painful nodules, with central necrosis, one of those in contact with one of the ribs. Through TC and RM it was impossible to understand the precise nature of these skin lesions. With biopsy a pyoderma gangrenosum was diagnosed and treated until complete resolution. DISCUSSION AND CONCLUSION: Management of inflammatory bowel diseases can be a true challenge, not only for the intestinal manifestations, but also for all the other features not related to gut. In some cases the same patient can develop many complications, such as malignancies or rare cutaneous diseases. Despite the initial surprise for such a weird evolution in a same patient, from fistula to inflammatory disease to cancer and finally to pyoderma gangrenosum, to face every single complication following consolidated diagnostic and pathological paths has been the correct strategy for controlling the disease.


Assuntos
Colite Ulcerativa/complicações , Doenças do Colo/etiologia , Fístula Cutânea/etiologia , Fístula Intestinal/etiologia , Pioderma Gangrenoso/complicações , Parede Abdominal , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adulto , Colite Ulcerativa/diagnóstico por imagem , Doenças do Colo/diagnóstico por imagem , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/patologia , Fístula Cutânea/diagnóstico por imagem , Humanos , Fístula Intestinal/diagnóstico por imagem , Masculino , Pioderma Gangrenoso/diagnóstico
4.
G Chir ; 38(6): 313-317, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29442064

RESUMO

AIM: Anal fistula is a common disease originated from abscess according the cryptoglandular theory. A rare etiology is the pilonidal disease. In our case we observed a pilonidal disease mimicking an anterior perianal fistula, associated with another posterior anal fistula. CASE PRESENTATION: A 36-year old man was referred to our department with an anal fistula with an anterior opening. Despite the clinical examination and the endoanal ultrasound, only during the surgery we discovered the origin of the anterior fistula from a misdiagnosed pilonidal sinus. There was also a posterior anal fistula in communication with the same abscess of the anterior one. We performed a two-step surgery with a first fistulectomy of the anterior tract, a drainage of abscess and the positioning of a seton for the posterior fistula. After about one month and the fall of the seton we evaluate the good healing of posterior anal fistula and excised the residual pilonidal sinus. CONCLUSION: This misdiagnosed pilonidal disease created in our clinical report a true challenge. Our goal was to eliminate as much disease as possible, but also to avoid major complications or recurrences. We refused an aggressive approach and chose a two-step surgery, with in the first approach not only a demolitive time but also a reconstruction to facilitate healing, and in the second time the complete eradication of the pathology.


Assuntos
Seio Pilonidal/diagnóstico , Fístula Retal/diagnóstico , Adulto , Diagnóstico Diferencial , Humanos , Masculino , Seio Pilonidal/complicações , Seio Pilonidal/cirurgia , Fístula Retal/complicações , Fístula Retal/cirurgia , Procedimentos Cirúrgicos Operatórios
5.
Diabetologia ; 55(9): 2421-31, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22772764

RESUMO

AIMS/HYPOTHESIS: Histone deacetylases (HDACs) are promising pharmacological targets in cancer and autoimmune diseases. All 11 classical HDACs (HDAC1-11) are found in the pancreatic beta cell, and HDAC inhibitors (HDACi) protect beta cells from inflammatory insults. We investigated which HDACs mediate inflammatory beta cell damage and how the islet content of these HDACs is regulated in recent-onset type 1 diabetes. METHODS: The rat beta cell line INS-1 and dispersed primary islets from rats, either wild type or HDAC1-3 deficient, were exposed to cytokines and HDACi. Molecular mechanisms were investigated using real-time PCR, chromatin immunoprecipitation and ELISA assays. Pancreases from healthy children and children with type 1 diabetes were assessed using immunohistochemistry and immunofluorescence. RESULTS: Screening of 19 compounds with different HDAC selectivity revealed that inhibitors of HDAC1, -2 and -3 rescued INS-1 cells from inflammatory damage. Small hairpin RNAs against HDAC1 and -3, but not HDAC2, reduced pro-inflammatory cytokine-induced beta cell apoptosis in INS-1 and primary rat islets. The protective properties of specific HDAC knock-down correlated with attenuated cytokine-induced iNos expression but not with altered expression of the pro-inflammatory mediators Il1α, Il1ß, Tnfα or Cxcl2. HDAC3 knock-down reduced nuclear factor κB binding to the iNos promoter and HDAC1 knock-down restored insulin secretion. In pancreatic sections from children with type 1 diabetes of recent onset, HDAC1 was upregulated in beta cells whereas HDAC2 and -3 were downregulated in comparison with five paediatric controls. CONCLUSIONS/INTERPRETATION: These data demonstrate non-redundant functions of islet class I HDACs and suggest that targeting HDAC1 and HDAC3 would provide optimal protection of beta cell mass and function in clinical islet transplantation and recent-onset type 1 diabetic patients.


Assuntos
Apoptose , Diabetes Mellitus Tipo 1/metabolismo , Histona Desacetilase 1/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/metabolismo , Células Secretoras de Insulina/metabolismo , Pâncreas/metabolismo , Animais , Apoptose/genética , Criança , Pré-Escolar , Citocinas , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Feminino , Humanos , Lactente , Masculino , NF-kappa B/metabolismo , Pâncreas/patologia , RNA Interferente Pequeno , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
6.
Med Lav ; 103(3): 220-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22838300

RESUMO

INTRODUCTION: The development in an extremely short time of an efficacious and safe vaccine against the pandemi A/H1N1 virus was a challenge that involved the entire scientific community. AIMS: To assess the immunological and clinical efficacy of the new H1N1v monovalent influenza vaccine (Focetria Novartis Vaccines, Siena, Italy) in a group of health care workers (HCWs). METHODS: A total of 148 volunteer HCWs were enrolled between Mid-Novembre 2009 and December 2009. After measuring antibody titers, a single intramuscular dose of 7.5 microg of Focetria monovalent vaccine against A/H1N1/2009 influenza virus with MF59C.1 adjuvant was administered. RESULTS: Antibody titers (median value) before and after a single dose of vaccine, measured by means of standard beam-agglutination inhibition test (HAI), increased from 32 to 256 (p < 0.001). After vaccination, 79.7% of the subjects showed antibody seroconversion, and in 97.3% seroprotection was achieved. The ratio between the geometric means of antibody titers (GMTR) was 6.69. For the 3 subjects who reported symptoms of ILI (Influenza-like illness), a regular nasal-pharyngeal swab sample was taken to identify the virus type by RT-PCR, the laboratory results of tests performed on these samples were negative for pandemic A/H1N1/2009 virus. During the entire follow-up period of 6 months no severe adverse events occurred. CONCLUSIONS: The vaccine against pandemic A/H1N1/2009 virus provided protection against the virus and not only contributed to a significant immunization (according to EMEA criteria), but kept all 148 subjects under study free from A/H1N1/2009 influenza illness.


Assuntos
Anticorpos Antivirais/sangue , Pessoal de Saúde , Imunização , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza , Influenza Humana/prevenção & controle , Adulto , Idoso , Feminino , Humanos , Vacinas contra Influenza/efeitos adversos , Masculino , Pessoa de Meia-Idade , Segurança , Adulto Jovem
7.
G Ital Med Lav Ergon ; 34(3 Suppl): 252-6, 2012.
Artigo em Italiano | MEDLINE | ID: mdl-23405634

RESUMO

The aim of this review is pointing out the most relevant allergic and chemical risk factors in health care settings. Some tables summarize the main sensitizing agents, the most frequent allergic diseases and examples of alternative gloves and materials currently available. Some suggestions, to evaluate the allergic risk related to specific tasks in the different hospital departments, are given in order to underline possible failures and to plan focused preventive actions. The chemical hazard has been valued on the basis of the current exposure, which is significantly improved due to structural and technological changes adopted in almost all hospitals. However there are still some critical points due to the use of particularly toxic substances and new molecules, whose health effects should be carefully evaluated, and to a more extensive use of techniques and procedures previously limited to a few work realities.


Assuntos
Substâncias Perigosas/efeitos adversos , Hospitais/normas , Hipersensibilidade/etiologia , Saúde Ocupacional/normas , Gestão de Riscos , Humanos
8.
G Ital Med Lav Ergon ; 34(3 Suppl): 682-6, 2012.
Artigo em Italiano | MEDLINE | ID: mdl-23405751

RESUMO

Nickel compounds have proven lung carcinogenic effects and their processing involve a large amount of population. The aim of this study was to investigate the metabolomic profiles of Exhaled Breath Condensate (EBC) of a group of nickel exposed workers. Nickel in blood, urine and EBC of 39 workers (electroplaters) and 50 controls was measured. The 10 most nickel exposed workers were chosen for the analysis of EBC metabolomic profiles, matched to controls by gender and smoke habits. All the samples were analyzed using the HPLC-MS/MS system (High-Performance Liquid Chromatography/Mass Spectrometry). The profiles of the spectra obtained by the mass spectrometer (Orbitrap) analysis were processed using the MZmine 2.4 software. Nickel concentrations in EBC of the exposed workers were significantly higher compared to controls (1.39 microg/L; 0.039 microg/L, p = 0.017). The observation of the metabolomic profiles pointed out a significantly different response pattern between the exposed and the controls. This result was further studied by a subsequent processing with the XCMS program: an overexpression of 3 hypothetical substances in controls compared to exposed was detected. Although these data must be considered as preliminary, it has been observed that the mass-to-charge ratio of one of these substances may respond to the Phenylacethylglutamine (PAG) one, whose role in the control of cellular cycle is controversial and uncertain. Even if further studies to confirm these results are necessary, the analysis of the metabolomic profiles in the biological matrices is supposed to provide useful information both in the clinical and in the prevention fields.


Assuntos
Testes Respiratórios , Metabolômica , Níquel/efeitos adversos , Exposição Ocupacional/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Diabetologia ; 53(12): 2569-78, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20878317

RESUMO

AIMS/HYPOTHESIS: Cytokine-induced beta cell toxicity is abrogated by non-selective inhibitors of lysine deacetylases (KDACs). The KDAC family consists of 11 members, namely histone deacetylases HDAC1 to HDAC11, but it is not known which KDAC members play a role in cytokine-mediated beta cell death. The aim of the present study was to examine the KDAC gene expression profile of the beta cell and to investigate whether KDAC expression is regulated by cytokines. In addition, the protective effect of the non-selective KDAC inhibitor ITF2357 and interdependent regulation of four selected KDACs were investigated. METHODS: The beta cell line INS-1 and intact rat and human islets were exposed to cytokines with or without ITF2357. Expression of mRNA was assessed by real-time PCR and selected targets validated at the protein level by immunoblotting. Effects on cytokine-induced toxicity were investigated by in vitro assays. RESULTS: Hdac1 to Hdac11 were expressed and differentially regulated by cytokines in INS-1 cells and rat islets. HDAC1, -2, -6 and -11 were found to be expressed and regulated by cytokines in human islets. ITF2357 protected against cytokine-induced beta cell apoptosis and counteracted cytokine-induced attenuation of basal insulin secretion. In addition, cytokine-induced regulation of Hdac2 and Hdac6, but not Hdac1 and Hdac11, was reduced by KDAC inhibition. CONCLUSIONS/INTERPRETATION: All classical KDAC genes are expressed by beta cells and differentially regulated by cytokines. Based on the relative expression levels and degree of regulation by cytokines, we propose that HDAC1, -2, -6 and -11 are of particular importance for beta cell function. These observations may help in the design of specific KDAC inhibitors to prevent beta cell destruction in situ and in islet grafts.


Assuntos
Citocinas/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Mediadores da Inflamação/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Lisina/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Células Cultivadas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ratos , Ratos Wistar , Fatores de Tempo
10.
Gut ; 57(5): 613-22, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18194985

RESUMO

OBJECTIVE: Inhibition of histone deacetylases, well known for its antiproliferative efficacy in vivo, was recently shown to ameliorate inflammation in experimental colitis. Since inflammatory bowel disease is associated with an increased risk of developing colon cancer, here the combined anti-inflammatory and proapoptotic efficacy of histone deacetylase inhibitors was studied in mouse models. METHODS: The novel histone deacetylase inhibitor ITF2357 was compared with suberoylanilide hydroxamic acid in models of experimental colitis. Effects on tumour growth were studied after treatment of mice with azoxymethane and dextran sulphate sodium, and in interleukin 10 (IL10) knockout mice, respectively. Possible underlying mechanisms involving apoptosis and nuclear factor (NF)-kappaB activation were addressed by flow cytometry and western blot. RESULTS: In dextran sulphate sodium- and trinitrobenzene sulphonic acid-induced colitis, treatment with ITF2357 was superior to suberoylanilide hydroxamic acid as shown by macroscopic and histological amelioration of inflammation, by reduced production of interferon gamma (IFN gamma) and by increased production of IL10. In both models of inflammation-mediated tumourigenesis, inhibition of histone deacetylases resulted in a significant suppression of tumour growth in terms of size and number, along with reduced signs of inflammation. As for potential mechanisms of ITF2357 action, increased acetylation of histone 3, reduced production of IFN gamma and enhanced apoptosis in lamina propria mononuclear cells were found to accompany a histone deacetylase-dependent activation of NF-kappaB. CONCLUSIONS: These results indicate that inhibition of histone deactylases can attenuate inflammation-mediated tumour growth, which is paralled by an inhibition of NF-kappaB. Thus histone deacetylase inhibitors provide a promising strategy that combines anti-inflammatory and proapoptotic modes of action.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticarcinógenos/uso terapêutico , Colite/prevenção & controle , Neoplasias do Colo/prevenção & controle , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Colite/enzimologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/etiologia , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Vorinostat
11.
Oncogene ; 27(12): 1767-78, 2008 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-17891169

RESUMO

We analysed the in vitro effects of a new hydroxamate derivative, ITF2357, on AML cells. ITF2357 potently induced histone acetylation. ITF2357 0.1 microM blocked proliferation and induced apoptosis in AML1/ETO-positive Kasumi-1 cells, while AML1/ETO-negative HL60, THP1 and NB4 cell lines were sensitive only to 1 microM ITF2357. Apoptosis was induced by 0.1 microM ITF2357 in AML1/ETO-positive primary blasts and U937-A/E cells induced to express AML1/ETO, but not in U937-A/E cells non-expressing AML1/ETO. In Kasumi-1 cells 0.1 microM ITF2357 induced AML1/ETO degradation through a caspase-dependent mechanism. ITF2357 0.1 microM also determined DNMT1 efflux from, and p300 influx to, the nucleus. Moreover, 0.1 microM ITF2357 determined local H4 acetylation and release of DNMT1, HDAC1 and AML1/ETO, paralleled by recruitment of p300 to the IL-3 gene promoter. ITF2357 treatment, however, did not induce re-expression of IL-3 gene. Accordingly, the methylation level of IL-3 promoter, as well as of several other genes, was unmodified. In conclusion, ITF2357 emerged as an anti-leukaemic agent very potent on AML cells, and on AML1/ETO-positive cells in particular. More relevantly, clearly emerged from our results that ITF2357 could be an ideal agent to treat AML subtypes presenting AML1/ETO fusion protein which determine HDAC involvement in leukaemogenesis.


Assuntos
Antineoplásicos/farmacologia , Subunidade alfa 2 de Fator de Ligação ao Core/biossíntese , Proteínas de Ligação a DNA/biossíntese , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/farmacologia , Leucemia/tratamento farmacológico , Proteínas Proto-Oncogênicas/biossíntese , Fatores de Transcrição/biossíntese , Acetilação , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Células HL-60 , Humanos , Leucemia/enzimologia , Leucemia/patologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/enzimologia , Proteína 1 Parceira de Translocação de RUNX1 , Células U937
12.
Leukemia ; 21(9): 1892-900, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17637810

RESUMO

We have investigated the activity of ITF2357, a novel hydroxamate histone deacetylase inhibitor, on multiple myeloma (MM) and acute myelogenous leukemia (AML) cells in vitro and in vivo. ITF2357 induced apoptosis in 8/9 MM and 6/7 AML cell lines, as well as 4/4 MM and 18/20 AML freshly isolated cases, with a mean IC(50) of 0.2 microM. ITF2357 activated the intrinsic apoptotic pathway, upregulated p21 and downmodulated Bcl-2 and Mcl-1. The drug induced hyperacetylation of histone H3, H4 and tubulin. When studied in more physiological conditions, ITF2357 was still strongly cytotoxic for the interleukin-6 (IL-6)-dependent MM cell line CMA-03, or for AML samples maximally stimulated by co-culture on mesenchymal stromal cells (MSCs), but not for the MSCs themselves. Interestingly, ITF2357 inhibited the production of IL-6, vascular endothelial growth factor (VEGF) and interferon-gamma by MSCs by 80-95%. Finally, the drug significantly prolonged survival of severe combined immunodeficient mice inoculated with the AML-PS in vivo passaged cell line already at the 10 mg/kg oral dose. These data demonstrate that ITF2357 has potent anti-neoplastic activity in vitro and in vivo through direct induction of leukemic cell apoptosis. Furthermore, the drug inhibits production of growth and angiogenic factors by bone marrow stromal cells, in particular IL-6 and VEGF.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/farmacologia , Interleucina-6/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Acetilação/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Histonas/metabolismo , Humanos , Técnicas In Vitro , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos SCID , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/patologia , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Taxa de Sobrevida , Tubulina (Proteína)/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Diabetologia ; 50(4): 779-89, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17265033

RESUMO

AIMS/HYPOTHESIS: The immune-mediated elimination of pancreatic beta cells in type 1 diabetes involves release of cytotoxic cytokines such as IL-1beta and IFNgamma, which induce beta cell death in vitro by mechanisms that are both dependent and independent of nitric oxide (NO). Nuclear factor kappa B (NFkappaB) is a critical signalling molecule in inflammation and is required for expression of the gene encoding inducible NO synthase (iNOS) and of pro-apoptotic genes. NFkappaB has recently been shown to associate with chromatin-modifying enzymes histone acetyltransferases and histone deacetylases (HDAC), and positive effects of HDAC inhibition have been obtained in several inflammatory diseases. Thus, the aim of this study was to investigate whether HDAC inhibition protects beta cells against cytokine-induced toxicity. MATERIALS AND METHODS: The beta cell line, INS-1, or intact rat islets were precultured with HDAC inhibitors suberoylanilide hydroxamic acid or trichostatin A in the absence or presence of IL-1beta and IFNgamma. Effects on insulin secretion and NO formation were measured by ELISA and Griess reagent, respectively. iNOS levels and NFkappaB activity were measured by immunoblotting and by immunoblotting combined with electrophoretic mobility shift assay, respectively. Viability was analysed by 3-(4,5-dimethyldiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and apoptosis by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay and histone-DNA complex ELISA. RESULTS: HDAC inhibition reduced cytokine-mediated decrease in insulin secretion and increase in iNOS levels, NO formation and apoptosis. IL-1beta induced a bi-phasic phosphorylation of inhibitor protein kappa Balpha (IkappaBalpha) with the 2nd peak being sensitive to HDAC inhibition. No effect was seen on IkappaBalpha degradation and NFkappaB DNA binding. CONCLUSIONS/INTERPRETATION: HDAC inhibition prevents cytokine-induced beta cell apoptosis and impaired beta cell function associated with a downregulation of NFkappaB transactivating activity.


Assuntos
Citocinas/metabolismo , Regulação Enzimológica da Expressão Gênica , Inibidores de Histona Desacetilases , Células Secretoras de Insulina/metabolismo , Animais , Apoptose , Sobrevivência Celular , Inibidores Enzimáticos/farmacologia , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Proteínas Recombinantes/química , Transdução de Sinais
14.
Med Lav ; 98(1): 25-9, 2007.
Artigo em Italiano | MEDLINE | ID: mdl-17240642

RESUMO

BACKGROUND: Very few references on the usability of presence of asbestos bodies (AB) in induced sputum as an indicator of asbestos exposure are to be found in the scientific literature. OBJECTIVES: The purpose of this study was to prove whether the presence of AB in induced sputum is a valid assessor of asbestos exposure. METHOD: This was achieved by comparing the above-mentioned method with the search for AB in bronchoalveolar lavage (BAL) fluid and repeating the trials over time in order to study the reproducibility of the results. RESULTS: There was good agreement of results for the presence/absence of AB in induced sputum and in BAL among subjects who were environmentally exposed and those with 'a medium-high risk occupational exposure (100%), and poor agreement (66%) among subjects with a low risk occupational exposure. Agreement of results regarding the amount of particles per test was low. The method showed a sufficient reproducibility level (Cohen K=0.5). CONCLUSION: Although the presence of asbestos bodies in induced sputum cannot replace bronchoalveolar lavage, it can however be used as a screening test for selecting subjects who should undergo BAL.


Assuntos
Amianto/análise , Líquido da Lavagem Broncoalveolar/química , Exposição Ocupacional/análise , Escarro/química , Adulto , Humanos , Pessoa de Meia-Idade , Fibras Minerais/análise
15.
G Ital Med Lav Ergon ; 29(3 Suppl): 248-50, 2007.
Artigo em Italiano | MEDLINE | ID: mdl-18409669

RESUMO

The purpose of this paper is to evaluate alterations in the nasal mucosa in workers that for professional purpose, are exposed, for a long period of time, to wood dust (WD). The increased frequency in alterations could underline a mechanism for chronic damage that could lead to cancer This study took into account 50 cabinet workers (EW) who had been exposed to WD for an average of 33 years and were compared to 48 controls (CC). A questionnaire regarding nasal symptoms was submitted, the nasal mucosa was examined by fibroscopy, secretions were valuated, cytogram from a nasal swap was also done. 44% of the EW and 33.4% of CC showed macroscopic alterations of the mucosa (PR 1,32 IC95% 0,79-2,19). The cytogram was altered in 24% of EW and in 12.5% of CC (PR 1,92 IC95% 0,78-4,71). In EW there was an abnormal significant increase in nasal secretions compared to CS, 28% vs 11,4% (PR 2,69 IC95% 1,05-6,89). The results do not confirm our hypothesis, but they show an unexpected prevalence of alteration in the CC. While waiting for further results, we express doubts in proposing routinary specialistic evaluation to all the EW to WD. At present it is hard to pin point indicators that could help reach an early diagnosis in the development of sinus-nasal cancer.


Assuntos
Poeira , Mucosa Nasal/patologia , Exposição Ocupacional/efeitos adversos , Saúde Ocupacional , Vigilância da População , Madeira , Humanos , Masculino , Pessoa de Meia-Idade
16.
G Ital Med Lav Ergon ; 29(3 Suppl): 277-9, 2007.
Artigo em Italiano | MEDLINE | ID: mdl-18409685

RESUMO

The aim of the study was to investigate the ototoxic effects of occupational styrene exposure, in absence of other risk factors. Pure-tone audiometric thresholds of 32 workers exposed to styrene, but not to noise, in fibreglass reinforced plastic boat manufacturing process were detected and compared to audiometric thresholds of a control unexposed group composed by 60 subjects. Exposure to styrene was measured by urinary mandelic + phenylglyoxylic acid (mean value 149 mg/g crea, SD 80 mg/g crea). For all the frequencies investigated (0,5-1-2-3-4-6-8 KHz) the exposed group showed slight higher mean (median) audiometric thresholds (p < 0.05) compared to controls matched by age and sex, except for 8 KHz in the right ear. The present experience seems to confirm the hypothesis that styrene exposure alone can determine a weak sensorineural high-frequency hearing loss. Such slight impairment, even if statistically significant, does not remarkably limit social hearing and do not involve legal medical aspects. Sample expansion and objective diagnostic tests (auditory brainstem evoked potentials, acoustic otoemissions) are needed.


Assuntos
Audição/efeitos dos fármacos , Exposição Ocupacional , Solventes/farmacologia , Estireno/farmacologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
G Ital Med Lav Ergon ; 29(3 Suppl): 460-3, 2007.
Artigo em Italiano | MEDLINE | ID: mdl-18409777

RESUMO

The aims of this study are to verify the potential lead damage on olfactory function and to identify early effects due to lead exposure. Our diagnostic evaluation included: (i) questionnaire to collect data about work and clinical history, (ii) olfactory evaluation: threshold test (Single-Starcaise) and identification/discrimination test (Wright). Lead exposure was evaluated by air sampling and biological monitoring (PbB, lead in blood). A sample of 18 exposed workers (mean age: 41.3 +/- 7.8; years exposure: 8.38 +/- 6) and of 39 controls (mean age: 41.9 +/- 9.7) were evaluated. The comparison between the threshold test of two groups confirmed a worse olfactory function in exposed (-4.97 log(10)vol/vol) compared to controls (-6.37 log(10)vol/vol), while the Wright test didn't show any significant correlation. The study didn't find a significant association between individual PbB levels and the threshold test. Knowledge of the effect of chronic occupational exposure to industrial chemicals on olfactory function is largely incomplete, but supports the hypothesis that olfactory neuroepithelium is susceptible to environmental exposures to chemicals. Occupational-related olfactory impairment is usually sub-clinical, and can be only detected using adeguate quantitative olfactory function testing procedures for quality research in this field.


Assuntos
Chumbo/efeitos adversos , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Transtornos do Olfato/induzido quimicamente , Adulto , Humanos
18.
Med Lav ; 96(3): 231-7, 2005.
Artigo em Italiano | MEDLINE | ID: mdl-16273841

RESUMO

BACKGROUND: Mutants of the hepatitis B virus (HBV) following vaccination (escape mutants) have been isolated over the course of the last decade. They consist most commonly of an aminoacid change from glycine to arginine at position 145 of the highly antigenic a determinant of the surface antigen (HBsAg). OBJECTIVE: Description of an escape mutant of HBV identified in the course of the post-exposure follow-up of a percutaneous exposure. METHODS: The viral DNA was extracted from serum samples of a dialysed patient vaccinated against hepatitis B, who developed an acute infection. A direct sequencing was performed on the amplified DNA followed by a sequence analysis. RESULTS AND CONCLUSIONS: A threonine to lysine substitution at position 118 of HBsAg (Thrll8Lys) was observed in the analysed viral aminoacid sequence. Such mutation could have significantly changed the antigenic profile of the HBsAg compared to that of the wild type.


Assuntos
Acidentes de Trabalho , Variação Antigênica , DNA Viral/genética , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Hepatite B/virologia , Ferimentos Penetrantes Produzidos por Agulha , Enfermeiras e Enfermeiros , Mutação Puntual , Diálise Renal , Doença Aguda , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Reações Antígeno-Anticorpo , Sequência de Bases , Códon/genética , DNA Viral/isolamento & purificação , Feminino , Traumatismos dos Dedos/etiologia , Seguimentos , Hepatite B/etiologia , Anticorpos Anti-Hepatite B/sangue , Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/isolamento & purificação , Vacinas contra Hepatite B , Vírus da Hepatite B/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , Diálise Renal/efeitos adversos , Alinhamento de Sequência , Análise de Sequência de DNA , Homologia de Sequência , Vacinação , Vacinas Sintéticas
19.
G Ital Med Lav Ergon ; 26(1): 40-4, 2004.
Artigo em Italiano | MEDLINE | ID: mdl-15134398

RESUMO

The Nordic Institute of Advanced Training in Occupational Health (NIVA), has been organising courses for around 10 years, aimed to the constant up-date of Occupational Medicine. The courses "Occupational dermatology" and "Occupational skin and respiratory allergies", held in 2001 and 2002, analysed some occupational medicine aspects such as allergic contact dermatitis in metal workers, latex disease, allergies in odontoiatric workers, correct patch test performing. The courses has underlined the importance of the cooperation between occupational physician and dermatologist or other specialists, and the project of a standard questionnaire monitoring the exposure to allergic substances. This article is a summary of an extended publication available on the following URLs: http://www.unibs.it/medlav http://www.gimle.fsm.it.


Assuntos
Alergia e Imunologia/educação , Dermatologia/educação , Educação Médica Continuada , Medicina do Trabalho/educação , Currículo , Dermatite Atópica/diagnóstico , Finlândia , Humanos , Hipersensibilidade/diagnóstico , Itália , Hipersensibilidade Respiratória/diagnóstico , Inquéritos e Questionários , Organização Mundial da Saúde
20.
Surg Endosc ; 18(2): 232-6, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14691705

RESUMO

BACKGROUND: Bile duct injuries (BDIs) during laparoscopic cholecystectomy (LC) still are reported with greater frequency than during open cholecystectomy (OC). METHODS: In 1999, a retrospective study evaluating the incidence of BDIs during LC in the area of Rome from 1994 to 1998 (group A) was performed. In addition, a prospective audit was started, ending in December 2001 (group B). RESULTS: In group A, 6,419 LCs were performed (222 were converted to OC; 3.4%). In group B, 7,299 LCs were performed (225 were converted to OC; 3.1%). Seventeen BDIs (0.26%) occurred in group A and 16 (0.22%) in group B. Overall, mortality and major morbidity rates were 12.1% and 30.3%, respectively, without significant differences between the two groups. CONCLUSIONS: The incidence and clinical relevance of BDIs during LC in the area of Rome appeared to be stable over the past 8 years and were not influenced by the use of a prospective audit, as compared with a retrospective survey.


Assuntos
Ductos Biliares/lesões , Colecistectomia Laparoscópica/estatística & dados numéricos , Complicações Intraoperatórias/epidemiologia , Idoso , Ductos Biliares/cirurgia , Colecistectomia/estatística & dados numéricos , Colelitíase/cirurgia , Feminino , Seguimentos , Humanos , Incidência , Complicações Intraoperatórias/mortalidade , Complicações Intraoperatórias/cirurgia , Jejuno/cirurgia , Fígado/cirurgia , Masculino , Auditoria Médica , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Cidade de Roma/epidemiologia , Inquéritos e Questionários
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