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BACKGROUND AND PURPOSE: Hereditary ataxias are heterogeneous groups of neurodegenerative disorders, characterized by cerebellar syndromes associated with dysarthria, oculomotor and corticospinal signs, neuropathy and cognitive impairment. Recent reports have suggested mutations in the SPG7 gene, causing the most common form of autosomal recessive spastic paraplegia (MIM#607259), as a main cause of ataxias. The majority of described patients were homozygotes or compound heterozygotes for the c.1529C>T (p.Ala510Val) change. We screened a cohort of 895 Italian patients with ataxia for p.Ala510Val in order to define the prevalence and genotype-phenotype correlation of this variant. METHODS: We set up a rapid assay for c.1529C>T using restriction enzyme analysis after polymerase chain reaction amplification. We confirmed the diagnosis with Sanger sequencing. RESULTS: We identified eight homozygotes and 13 compound heterozygotes, including two novel variants affecting splicing. Mutated patients showed a pure cerebellar ataxia at onset, evolving in mild spastic ataxia (alternatively) associated with dysarthria (~80% of patients), urinary urgency (~30%) and pyramidal signs (~70%). Comparing homozygotes and compound heterozygotes, we noted a difference in age at onset and Scale for the Assessment and Rating of Ataxia score between the two groups, supporting an earlier and more severe phenotype in compound heterozygotes versus homozygotes. CONCLUSIONS: The SPG7 c.1529C>T (p.Ala510Val) mutants accounted for 2.3% of cerebellar ataxia cases in Italy, suggesting that this variant should be considered as a priority test in the presence of late-onset pure ataxia. Moreover, the heterozygous/homozygous genotype appeared to predict the onset of clinical manifestation and disease progression.
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ATPases Associadas a Diversas Atividades Celulares/genética , Ataxia Cerebelar/epidemiologia , Ataxia Cerebelar/genética , Metaloendopeptidases/genética , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Estudos de Associação Genética , Heterozigoto , Homozigoto , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , PrevalênciaRESUMO
BACKGROUND: Array-comparative genomic hybridization (array-CGH) is a widely used technique to detect copy number variants (CNVs) associated with developmental delay/intellectual disability (DD/ID). AIMS: Identification of genomic disorders in DD/ID. MATERIALS AND METHODS: We performed a comprehensive array-CGH investigation of 1,015 consecutive cases with DD/ID and combined literature mining, genetic evidence, evolutionary constraint scores, and functional information in order to assess the pathogenicity of the CNVs. RESULTS: We identified non-benign CNVs in 29% of patients. Amongst the pathogenic variants (11%), detected with a yield consistent with the literature, we found rare genomic disorders and CNVs spanning known disease genes. We further identified and discussed 51 cases with likely pathogenic CNVs spanning novel candidate genes, including genes encoding synaptic components and/or proteins involved in corticogenesis. Additionally, we identified two deletions spanning potential Topological Associated Domain (TAD) boundaries probably affecting the regulatory landscape. DISCUSSION AND CONCLUSION: We show how phenotypic and genetic analyses of array-CGH data allow unraveling complex cases, identifying rare disease genes, and revealing unexpected position effects.
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Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Adolescente , Adulto , Criança , Pré-Escolar , Efeitos da Posição Cromossômica/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/patologia , Feminino , Estudos de Associação Genética , Genômica , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Linhagem , Fenótipo , Deleção de Sequência/genética , Adulto JovemRESUMO
We present the results of direct interferometric measurements on the pulse-to-pulse phase jitter of a metrological, fiber-based, infrared (IR) frequency comb. We show that the short-time evolution of such phase fluctuations, which cannot be actively controlled by any feedback system, imposes a stringent limit on the tooth linewidth of extreme ultraviolet (XUV) combs produced by high-order harmonic conversion, thus explaining the difference of 9 orders of magnitude between the coherence times of state-of-the-art IR and XUV frequency combs.
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PURPOSE: Liquid-chromatography tandem mass-spectrometry (LC-MS/MS) was developed in parallel to Immunoassays (IAs) and today is proposed as the "gold standard" for steroid assays. Leydig cells of men with Klinefelter syndrome (KS) are able to respond to human chorionic gonadotropin (hCG) stimulation, even if testosterone (T) production was impaired. The aim was to evaluate how results obtained by IAs and LC-MS/MS can differently impact on the outcome of a clinical research on gonadal steroidogenesis after hCG stimulation. METHODS: A longitudinal, prospective, case-control clinical trial. (clinicaltrial.gov NCT02788136) was carried out, enrolling KS men and healthy age-matched controls, stimulated by hCG administration. Serum steroids were evaluated at baseline and for 5 days after intramuscular injection of 5000 IU hCG using both IAs and LC-MS/MS. RESULTS: 13 KS patients (36 ± 9 years) not receiving T replacement therapy and 14 controls (32 ± 8 years) were enrolled. T, progesterone, cortisol, 17-hydroxy-progesterone (17OHP) and androstenedione, were significantly higher using IAs than LC-MS/MS. IAs and LC-MS/MS showed direct correlation for all five steroids, although the constant overestimation detected by IAs. Either methodology found the same 17OHP and T increasing profile after hCG stimulation, with equal areas under the curves (AUCs). CONCLUSIONS: Although a linearity between IA and LC-MS/MS is demonstrated, LC-MS/MS is more sensitive and accurate, whereas IA shows a constant overestimation of sex steroid levels. This result suggests the need of reference intervals built on the specific assay. This fundamental difference between these two methodologies opens a deep reconsideration of what is needed to improve the accuracy of steroid hormone assays.
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Gonadotropina Coriônica/uso terapêutico , Hormônios Esteroides Gonadais/sangue , Imunoensaio/métodos , Síndrome de Klinefelter/sangue , Espectrometria de Massas em Tandem/métodos , 17-alfa-Hidroxiprogesterona/sangue , Adolescente , Adulto , Estudos de Casos e Controles , Humanos , Hidrocortisona/sangue , Síndrome de Klinefelter/tratamento farmacológico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Progesterona/sangue , Estudos Prospectivos , Testosterona/sangue , Adulto JovemRESUMO
We developed an ultra-stable and accurately-controllable Michelson interferometer to be used in a deeply unbalanced arm configuration for split-pulse XUV Ramsey-type spectroscopy with high-order laser harmonics. The implemented active and passive stabilization systems allow one to reach instabilities in the nanometer range over meters of relative optical path differences. Producing precisely delayed pairs of pump pulses will generate XUV harmonic pulses that may significantly improve the achievable spectral resolution and the precision of absolute frequency measurements in the XUV.
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A split-pulse spectrometer based on pairs of time-delayed femtosecond pulses can give access to accurate frequency measurements in the extreme ultraviolet (XUV) spectral domain. We demonstrate this approach by measuring the absolute frequency of a single-XUV-photon transition to a bound state of atomic argon excited with the ninth harmonic of an amplified Ti:sapphire laser.
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Ramsey-like schemes have been recently introduced in combination with high-order laser harmonic sources for high-resolution spectroscopic studies in the extreme ultraviolet (XUV). Here we demonstrate a novel method, combining measurements only in a limited subset of randomly chosen time-sampling intervals, which lead us to perform the first high-resolution XUV spectroscopy of atomic argon with a simple split-pulse setup. Providing an experimentally simple and convenient solution to the problem of performing high-resolution absolute frequency measurements in the XUV, our approach will help paving new roads into this challenging spectral territory.
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PURPOSE: Radioactive-iodine (RAI)-resistant differentiated thyroid cancer (DTC) patients benefit from multi-kinase inhibitors (MKIs), such as lenvatinib. Incidence of treatment-related (TR) late toxicities has been not yet described. METHODS: From January 2015 to June 2019 we retrospectively reviewed clinical records of patients with RAI-resistant DTC treated with lenvatinib at Istituto Nazionale dei Tumori (Milan, Italy). New side effect of any grade, appeared after 12 months of lenvatinib, was defined as late adverse event (AE). Descriptive analyses were performed. Survival curves were estimated with Kaplan-Meier method and compared with log-rank test. RESULTS: Thirty-seven patients were included, 65% had ≥65 years and 68% were female. Thirty patients received lenvatinib for >12 months. Lenvatinib was started at ≤20 mg/daily in 59% of patients, 64% were ≥65 years. The frequency of late AEs was 80% and cardiovascular toxicity was the most common (57%). There was no difference in the incidence of late AEs between younger/older population (77% and 82%, respectively). Median lenvatinib treatment duration (TD) was 39.96 months (95% CI 21.64-NR): 39.96 months for patients <65 years (95% CI: 13.25-NR) and 37.53 months for those ≥65 years, respectively (95% CI: 15.85-NR). Median overall survival (OS) was 39.96 months (95% CI: 21.84-NR), no statistically differences in OS was observed between younger (<65 years) and older patients (≥65 years) (HR 1.013; 95% CI 0.963-1.065; p = 0.62). CONCLUSION: Late toxicity burden of lenvatinib is not negligible. Cardiovascular toxicity remains the principal side effect even after a prolonged lenvatinib exposition.
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Antineoplásicos , Quinolinas , Neoplasias da Glândula Tireoide , Antineoplásicos/efeitos adversos , Feminino , Humanos , Radioisótopos do Iodo/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/radioterapiaRESUMO
We report the experimental measurement of Ramsey interference fringes in the single-photon excitation to a high-lying bound state of atomic argon by pairs of phase-locked, time-delayed, extreme UV high-order-harmonic pulses at 87 nm. High-visibility Ramsey fringes are observed for delays larger than 100 ps, thus demonstrating a potential resolving power >10(5) at this wavelength.
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BACKGROUND AND PURPOSE: Duplications of lamin B1 (LMNB1) at 5q23 are implicated in adult-onset autosomal dominant leukodystrophy (ADLD) having been described in six families with diverse ethnic background but with a homogeneous phenotype. In a large Italian family, we recently identified a variant form of ADLD characterized clinically by absence of the autonomic dysfunction at onset described in ADLD and, on MRI, by milder cerebellar involvement with sparing of hemispheric white matter. Aim of this study was to investigate the genetic basis of this variant form of ADLD. METHODS: We carried out a genome-wide linkage analysis using microsatellite markers, and the genes in the candidate region were screened for point mutations. LMNB1 was also screened for deletions/duplications by real-time PCR, multiplex ligation-dependent probe amplification and Southern blot. RESULTS: We mapped the variant ADLD locus to 5q23.2-q23.3, a genomic region containing 11 genes including LMNB1. Neither gene copy-number defects nor point mutations in the LMNB1 gene were found. We also excluded point mutations in the coding exons of the other ten genes in the candidate region. However, expression of lamin B1 evaluated in lymphoblastoid cells was higher in patients than in healthy controls, and was similar to the lamin B1 expression levels found in a patient with LMNB1 duplication. CONCLUSIONS: This observation suggests that a mutation in an LMNB1 regulatory sequence underlies the variant ADLD phenotype. Thus, adult forms of ADLD linked to 5q23 appear to be more heterogeneous clinically and genetically than previously thought.
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Cromossomos Humanos Par 5 , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Lamina Tipo B/genética , Leucodistrofia de Células Globoides/genética , Leucoencefalopatias/genética , Adulto , Idade de Início , Idoso , Variações do Número de Cópias de DNA , Família , Feminino , Duplicação Gênica , Ligação Genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Itália , Lamina Tipo B/metabolismo , Leucodistrofia de Células Globoides/metabolismo , Leucodistrofia de Células Globoides/patologia , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação , Fenótipo , Mutação Puntual , Deleção de SequênciaRESUMO
AIM: Salivary duct carcinoma (SDC), an aggressive subtype of salivary gland cancer, is androgen receptor (AR)-positive in 67-96% of cases. In patients with locally recurrent and metastatic (R/M) AR-positive SDC, androgen deprivation therapy (ADT) has an overall response rate of 18-64.7%. In this study, we describe the efficacy of adjuvant ADT in patients with poor-risk (stage 4a) AR-positive SDC. METHODS: This is a retrospective cohort study in which patients with stage 4a AR-positive SDC were offered adjuvant ADT, i.e. bicalutamide, luteinizing hormone-releasing hormone (LHRH) analogue or a combination of these after tumour resection. In the control group, data were collected on patients with stage 4a SDC who underwent a tumour resection but did not receive adjuvant ADT. RESULTS: Twenty-two AR-positive SDC patients were treated with adjuvant ADT for a median duration of 12 months. The control group consisted of 111 SDC patients. After a median follow-up of 20 months in the ADT-treated patients and 26 months in the control group, the 3-year disease-free survival (DFS) was estimated as 48.2% (95% confidence interval [CI] 14.0-82.4%) and 27.7% (95% CI 18.5-36.9%) (P = 0.037). Multivariable Cox regression analysis showed a hazard ratio of 0.138 (95% CI 0.025-0.751, P = 0.022) for DFS and 0.064 (95% CI 0.005-0.764, P = 0.030) for overall survival (OS) in favour of the ADT-treated patients. CONCLUSION: Poor-risk, AR-positive SDC patients who received adjuvant ADT have a significantly longer DFS compared with patients in the control group, who did not receive adjuvant ADT. For OS, this was just below and above the significance level, in case there was or was no correction for confounders.
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Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias das Glândulas Salivares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Androgênicos/metabolismo , Fatores de Risco , Ductos Salivares , Resultado do TratamentoRESUMO
BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.
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Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Quinazolinonas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundário , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Taxa de SobrevidaRESUMO
The term lymphoepithelioma-like carcinoma identifies a group of nasopharingeal epithelial tumors characterized by aggregates of malignant undifferentiated cells surrounded by a dense reactive lymphoplasmacellular infiltrate. Primary cutaneous localization is rare, with approximately 30 cases reported in literature. We describe a case of primary lymphoepithelioma-like carcinoma of the skin in a 92-year-old woman. Immunohistochemical examination was positive for cytokeratine (KL1 and EMA) as regards epithelial cells, while the lymphocitic infiltrate was positive for LCA and CD3. In situ hybridization for Epstein Barr virus in tumor cells was negative. Electron microscopy showed rounded and occasionally spindle-shaped poorly-differentiated squamous epithelial cells, and a lymphoid stroma consisting mostly of normal-appearing small lymphocytes. Examination of the nasopharynx did not show any tumoral mass and after a 7 years follow-up the patient is free of local and distant recurrences. This tumor affects people aged over 50 years and is localized to the face, but scalp, shoulder and forearm may be involved. Research of Epstein-Barr virus is always negative in this tumor, unlike nasopharingeal epithelial carcinoma. The differential diagnosis of lymphoepithelioma-like carcinoma of the skin may present some difficulties and includes squamous cell carcinoma. Lymphoepithelioma-like carcinoma of the skin is a malignant neoplasm which tends to relapse locally and has a moderate tendency to metastatize.
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Carcinoma de Células Escamosas/patologia , Neoplasias Cutâneas/patologia , Idoso de 80 Anos ou mais , Complexo CD3/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/cirurgia , Diagnóstico Diferencial , Células Epiteliais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Queratinas/metabolismo , Microscopia Eletrônica , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgiaRESUMO
Four tyrosine kinase inhibitors (TKIs) have been recently licensed in thyroid cancer (TC), sorafenib and lenvatinib for differentiated TC, vandetanib and cabozantinib for medullary TC. Others TKIs such as axitinib, pazopanib, sunitinib, have been tested within phase II trials. The toxicity burden associated to TKIs is not negligible. Drug reductions and interruptions are common, definitive drug withdrawals have also been reported as well as toxic deaths in more rare cases. In this context, the prevention of toxicities is mandatory to allow patients to stay on treatment as long as possible without dose and schedule modifications. Both physicians and patients should be educated to recognize drug-related toxicities in order to manage them in an early phase. Tools (e.g. toxicities summary booklet) for physicians and patients could be considered to improve the knowledge on side effects management. Guidelines, whenever available, should be followed.
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Carcinoma Neuroendócrino/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Carcinoma Neuroendócrino/patologia , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Diagnóstico Precoce , Humanos , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Neoplasias da Glândula Tireoide/patologia , Suspensão de TratamentoRESUMO
The interaction of cells with extracellular matrix components plays a significant role in the regulation of cell biology. Laminin is a large glycoprotein involved in fundamental interactions between cells and the basement membrane. Several cell surface receptors are responsible for cell-matrix interactions. The 67 kDa high affinity laminin receptor, 67LR, is involved in the adhesion of normal cells to the laminin network and is also associated with the metastatic phenotype of some tumoral cells. We have investigated the expression of laminin and of the 67LR in normal human skin using immunoperoxidase staining. Twenty samples of skin were analyzed. Antibody against laminin reacted in a continuous linear band at the dermal-epidermal junction, as well as basement membranes of hair follicles, sebaceous and eccrine sweat glands, and dermal blood vessels. The epidermis and the follicular epithelium were negative for laminin. The 67LR seemed not to be expressed on the basal surface of basal keratinocytes. The major expression of this receptor may be detected in the upper half of the spinous layer and in the granular layer. The cells of the outer root sheath in hair follicle showed the same immunohistochemical pattern described for epidermis. In sebaceous glands and in eccrine sweat glands the secreting epithelium was positive. Endothelial cells of dermal blood vessels were routinely positive for 67LR. We observed that the expression of the 67LR in normal human skin is mostly located in epidermal areas in which the keratinizing process was particularly advanced.
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Laminina/metabolismo , Receptores de Laminina/biossíntese , Pele/metabolismo , Adulto , Membrana Basal/metabolismo , Folículo Piloso/metabolismo , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Glândulas Sebáceas/metabolismo , Pele/irrigação sanguínea , Glândulas Sudoríparas/metabolismoRESUMO
Eight hospital workers with chronic ethylene oxide exposure were age-sex matched with eight nonexposed controls with no significant differences in educational backgrounds and vocabulary scores. The exposed group performed more poorly on all eight measures of cognition, memory, attention, and coordination, with 71.3% less accuracy on the Hand-Eye Coordination Test. There was a dose-response relationship between exposure and the following: Continuous Performance Test and sural velocity. These findings suggest that neurologic dysfunction may result from long-term low-dose exposure to ethylene oxide, and that these effects may occur at exposure levels common in hospital sterilizer operations.
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Óxido de Etileno/efeitos adversos , Doenças do Sistema Nervoso/induzido quimicamente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/psicologia , Condução Nervosa , Recursos Humanos em Hospital , PsicometriaRESUMO
The E Test (PDM Epsilometer; AB Biodisk, Solna, Sweden) was compared with microbroth dilution and disk diffusion for antimicrobial susceptibility testing of Nocardia as a collaborative study by two geographically separate laboratories. A total of 52 clinical isolates and five species of Nocardia were used in this comparative evaluation. Susceptibility testing was performed with Mueller-Hinton media and eight antimicrobial agents. Growth of the test strains with Mueller-Hinton medium was generally satisfactory, with the majority of isolates producing adequate growth within 24-36 h. Growth inhibition ellipses were generally well delineated and uniform for most drugs, and the points of intersection with the E Test strip were generally easy to determine. An inoculum size of approximately 2.0 x 10(7) CFU/ml was optimal for performance of the E Test method with the Nocardiae. Comparison of E Test and microbroth dilution MICs revealed 89.4% agreement for all drugs within +/- 1 log2 dilution. Using NCCLS interpretive criteria for susceptible and resistant results, complete agreement between E Test and disk diffusion results was 93.3%, and between E Test and microbroth dilution results was 96.2%. Interpretive category errors occurred at rates of 18.2% (risk corrected), 0, and 4.1% for very major, major, and minor errors, respectively, when E Test results were compared with disk diffusion results, and 0, 0, and 3.8%, respectively, when E Test was compared with microbroth dilution. Inter- and intra-laboratory reproducibility, within +/- 1 log2 dilution for all drugs, was 95% and 98%, respectively. Results from this study suggest that E Test may be suited for use as an alternative method for antimicrobial susceptibility testing of Nocardia species.
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Testes de Sensibilidade Microbiana/métodos , Nocardia/efeitos dos fármacos , Meios de CulturaRESUMO
Alpha haemolysin, produced by Escherichia coli, grown in a chemically defined medium, was purified 19-fold and the endotoxin content reduced 2176-fold by ultrafiltration and glycerol-gradient ultracentrifugation. Immunodiffusion of purified alpha haemolysin (PH) against antiserum to crude haemolysin (CH) revealed only one precipitation line. PH was cytotoxic in nanogram amounts for mouse-fibroblast 3T3 cells, and the cytotoxicity exhibited proportional dose-response and time-course kinetics. The cytotoxic and haemolytic activities of PH were neutralised by immunoglobulins to CH. A mutant, produced by treating the haemolytic wild type with mitomycin C, possessed all of the biochemical characteristics of the wild type with the exception that the extracellular products of the mutant were non-haemolytic and non-cytotoxic.
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Proteínas de Bactérias/farmacologia , Toxinas Bacterianas/isolamento & purificação , Proteínas de Escherichia coli , Escherichia coli/metabolismo , Proteínas Hemolisinas/isolamento & purificação , Animais , Proteínas de Bactérias/isolamento & purificação , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Proteínas Hemolisinas/farmacologia , Imunodifusão , Camundongos , Peso Molecular , Testes de Neutralização , UltracentrifugaçãoRESUMO
The place of whole-lung tomography in urologic malignancy has not been established. We reviewed 88 cases of known or suspected urologic malignancy in which tomography was used. Most patients had renal, bladder, or testicular tumors. Of the 68 patients with negative screening chest roentgenograms, all but 2 had negative tomograms. One of these 2 patients had a normal chest film (the other had extrapulmonary metastasis), and he did not have the renal carcinoma initially suspected. Tomography discovered no metastases from urologic malignancy that was not already known about from the screening x-ray film. In 20 cases with a positive screening x-ray film, tomography was of limited value. It cleared two suspicious chest films and added information on extent of metastatic involvement in three. We conclude that whole-lung tomography adds little information not available by chest roentgenogram in our selected population, and with a negative screening chest film no additional chest study is needed.
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Neoplasias Pulmonares/secundário , Pulmão/diagnóstico por imagem , Neoplasias Urogenitais , Custos e Análise de Custo , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Tomografia por Raios X , Tomografia Computadorizada por Raios XRESUMO
This paper presents the use of Hopfield-type neural networks for process scheduling in the area of factory automation, where bus-based communication systems, called FieldBuses, are widely used to connect sensors and actuators to the control systems. We show how it overcomes the problem of the computational complexity of the algorithmic solution. The neural model proposed allows several processes to be scheduled simultaneously; the time required is polynomial with respect to the number of processes being scheduled. This feature allows real-time process scheduling and makes it possible for the scheduling table to adapt to changes in process control features. The paper presents the neural model for process scheduling and assesses its computational complexity, pointing out the drastic reduction in the time needed to generate a schedule as compared with the algorithmic scheduling solution. Finally, the authors propose an on-line scheduling strategy based on the neural model which can achieve real-time adaptation of the scheduling table to changes in the manufacturing environment.