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INTRODUCTION: Leptospirosis is a zoonotic infection that typically presents with fever, myalgias, nausea, and vomiting after contact with contaminated waters or infected animals (typically rodents); and their excrements. Conditions favorable to the transmission of leptospirosis are common in LA and, without treatment, leptospirosis can lead to both liver and renal failure, meningitis, pulmonary hemorrhage and ultimately death. CASE: A 56 year old woman with no past medical history presented to the Emergency Department with weakness, myalgias, jaundice and decreased urine output for one week. On arrival, she appeared septic with a heart rate of 130 and fever. Her exam was significant for significant jaundice and diffuse abdominal pain. Laboratory studies were notable for WBC 14, hemoglobin of 12 and platelet count of 63. Creatinine was 8.5mg/dL with a blood-urea nitrogen of 96mg/dl. Total bilirubin was 19.4mg/dL and direct bilirubin was 13.7mg/dL. AST/ALT were 69/38 U/L, respectively and the alkaline phosphate was 160U/L. The patient was admitted to the hospital medicine wards for sepsis and multi-organ failure. She was started on broad spectrum antibiotics but her clinical condition continued to worsen with progressive decline in her hemoglobin and thrombocytopenia and worsening liver failure. She quickly became anuric necessitating dialysis and developed respiratory distress with bilateral pulmonary infiltrates and hemoptysis. Additional history was obtained from her employer that she works at a local New Orleans bar and had been cleaning out rats from the kitchen. Leptospirosis antibody was sent, which returned as positive. Her antibiotics were de-escalated to IV Ceftriaxone. She made a slow recovery over the next two-week period. DISCUSSION: Since 1987, there has been an average of 3 cases of Leptospirosis diagnosed per year, most of which have been from southeast LA. This case illustrates the importance of considering the diagnosis of Leptospirosis and Weil's Disease in patients in the southeast region of LA who present with multi-organ failure. In addition, our patient's occupational exposure was key to her diagnosis which emphasizes the importance of a detailed history in clinical decision making and patient outcomes.
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Sagittal abdominal diameter (SAD; 'abdominal height' measured in supine position) may improve upon conventional anthropometry for predicting incident cardiometabolic diseases. However, the SAD is used infrequently by practitioners and epidemiologists. A representative survey of Finnish adults in 2000-2001 collected body measurements including SAD (by sliding-beam calliper) using standardized protocols. Sampled non-pregnant adults (ages 30+ years; 79% participation) provided 6123 SAD measurements from 80 health centre districts. Through stratified, complex survey design, these data represented 2.86 million adults at ages 30+ years. SAD ranged from 13.5 to 38.0 cm, with a population mean (standard error) of 21.7 (0.05) cm and median (interquartile range) of 21.0 (19.1-23.4). Median SAD was higher at ages 50+ years compared with ages 30-49 both for men (22.4 [20.5-24.6] vs. 20.8 [19.3-22.7]) and women (21.7 [19.6-23.9] vs. 19.4 [17.8-21.4]). The SAD/height ratio was similar (0.118) for both sexes at 30-39 years, rising more steeply with age for women than men. Attaining only a basic education, compared with a high level, was associated with increased mean (95% confidence interval) SADs for men (22.6 [22.3-22.8] vs. 22.0 [21.7-22.2]) and women (21.8 [21.5-22.0] vs. 20.6 [20.4-20.8]). Finland's early experience with nationally representative SAD measurements provides normative reference values and physiological insights useful for investigations of cardiometabolic risk.
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Estatura , Diâmetro Abdominal Sagital , Adulto , Distribuição por Idade , Idoso , Antropometria , Doenças Cardiovasculares/epidemiologia , Feminino , Finlândia/epidemiologia , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Reports comparing waist circumference (WC) measurements from young populations are scarce. OBJECTIVES: We compared two protocols for measuring waist circumference in a sample of youth with diabetes. METHODS: Participants were enrolled in the SEARCH for Diabetes in Youth Study (SEARCH). WC was measured at least twice by the National Health and Nutrition Examination Survey (NHANES) protocol and twice by the World Health Organization (WHO) protocol. Method-specific averages were used in these analyses. RESULTS: Among 6248 participants, the mean NHANES WC (76.3 cm) was greater than the mean WHO WC (71.9 cm). Discrepancies between protocols were greater for females than males, among older participants, and in those with higher body mass index (BMI). In both sexes and four age strata, the WCs using either method were highly correlated with BMI z-score. The within-method differences between the first and second measurements were similar for the two methods. CONCLUSIONS: These analyses do not provide evidence that one of these two methods is more reproducible or is a better indicator of obesity as defined by BMI z-scores.
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Pesos e Medidas Corporais/métodos , Diabetes Mellitus , Circunferência da Cintura , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Inquéritos Nutricionais , Reprodutibilidade dos Testes , Fatores Sexuais , Organização Mundial da Saúde , Adulto JovemRESUMO
Previously, we have shown that insulin-like growth factor binding protein-7 (IGFBP-7) expression is inversely correlated with disease progression in breast cancer and is associated with poor outcome. To further investigate the role of IGFBP-7 in the growth and metastatic behavior of breast cancer, primary breast tumors and metastatic tumors derived from the same patients were analyzed for IGFBP-7 expression. Immunohistochemical analysis revealed that IGFBP-7 is downregulated in half of the human metastatic breast tumors tested. IGFBP-7 has been linked to suppression of oncogenic pathways and can directly restore cellular senescence in melanomas, leading to their regression. It is possible that breast tumors with metastatic potential have escaped from IGFBP-7-induced suppression by its down-regulation. Twenty-two human primary breast tumor specimens were transplanted into human-bone NOD/SCID mice. One of the two triple negative primary breast tumors was serially xenotransplanted more than five times. Each serial transplant resulted in increased tumor take and rate of growth. Expression of IGFBP-7 was downregulated upon each serial implantation. To investigate the role of IGFBP-7 in breast tumor suppression, IGFBP-7 was overexpressed in the triple negative MDA-MB-468 human breast cancer line by stable transfection of a pSec-tag2-IGFBP-7 vector. The parental MDA-MB-468 breast cancer cells expressed extremely low levels of endogenous IGFBP-7. The production of IGFBP-7 protein by the MDA-MB-468 cells stably transfected with IGFBP-7 was confirmed by immunoblotting with anti-IGFBP-7 antibody. Ectopic overexpression of IGFBP-7 significantly reduced the growth of the IGFBP-7 transfected MDA-MB-468 cells compared to the parental MDA-MB-468 cells. We also assessed the role of IGFBP-7 on cell migration, a key determinant of malignant progression and metastasis. When parental MDA-MB-468 cells were treated with various amounts of conditioned medium derived from the IGFBP-7 overexpressing cell line, a significant difference in cell migration rate was observed between untreated and treated cells. IGFBP-7 strongly suppressed the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK-1/2, suggesting that IGFBP-7 mediates its anti-proliferative effects through negative feedback signaling. Levels of phospho-ERK-1/2 were higher in the parental MDA-MB-468 than in IGFBP-7-expressing cells derived from it. When injected subcutaneously into NOD/SCID mice, the increased expression of IGFBP-7 in the MDA-MB-468 transfected cells reduced the rate of tumor growth in comparison to the parental MDA-MB-468 controls. These results suggest that the growth of breast cancer could be prevented by the forced expression of IGFBP-7 protein.
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Neoplasias da Mama/patologia , Proliferação de Células , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Proteínas Recombinantes/metabolismo , Animais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Movimento Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/secundário , Meios de Cultivo Condicionados , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/farmacologia , Metástase Linfática , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Recombinantes/farmacologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/secundário , Transplante Heterólogo , Carga Tumoral , Células Tumorais Cultivadas , Regulação para CimaRESUMO
AIMS/HYPOTHESIS: Although diagnosed type 2 diabetes has increased in the past decade, little is known about accompanying changes in fasting plasma glucose (FPG), HbA(1c) and fasting serum insulin (FI) levels in the non-diabetic population. METHODS: Using population estimates from National Health and Nutrition Examination Surveys, we compared distribution of FPG, HbA(1c) and FI in non-diabetic US persons who were >or=20 years old in 1999 to 2006 with that in persons of the same age in 1988 to 1994. RESULTS: Age-, sex- and race-adjusted mean FPG levels between the two study periods did not change, but mean HbA(1c) and FI levels increased (0.10% and 4.8 pmol/l, respectively; p < 0.001 for both). The increased HbA(1c) level was driven largely by an upward shift in the lower end of the HbA(1c) distribution. In contrast, the increased FI level was driven primarily by an upward shift in the middle and higher end of FI distribution, especially among persons aged 20 to 44 years. After adjustments for BMI or waist circumference, the increase in the mean HbA(1c) level was attenuated (0.06%; p < 0.001), whereas the mean FPG level decreased by 0.1 mmol/l (p < 0.001) and the mean FI level no longer demonstrated significant change. CONCLUSIONS/INTERPRETATION: Despite little change in the distribution of FPG levels, HbA(1c) and FI levels increased in the non-diabetic population in the past decade. The increase in FI levels suggests that levels of insulin resistance were greater among US adults, especially young adults, than in the previous decade.
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Glicemia/metabolismo , Jejum/sangue , Hemoglobinas Glicadas/metabolismo , Insulina/sangue , Adulto , Estatura , Índice de Massa Corporal , Peso Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Estados Unidos , Circunferência da Cintura , Adulto JovemRESUMO
The associations between fetal environment and diabetes risk are likely mediated by the offspring's diminished pancreatic ß-cell function or reduced insulin sensitivity. Our ability to distinguish between these mechanisms is impeded by the lack of markers describing an individual's gestational environment. Fingerprints, however, are permanently fixed in the first half of gestation, and increased values of a dermatoglyphic marker that contrasts fingerprint ridge counts between the thumbs and fifth fingers (Md15) have been linked to type 2 diabetes. Among 763 adults without known diabetes from the Dutch Hunger Winter Families Study, we tested the associations of Md15 with homeostatic assessment indices of ß-cell function (HOMA-b) and insulin sensitivity (QUICKI). For either outcome index, linear regression models included terms for Md15 tertiles and for maternal history of diabetes as reported by each participant. All models were corrected for sibling pairs and adjusted for age, sex and famine exposures. Increased Md15 was associated with decreased HOMA-b (P = 0.03 for Md15 tertile 3 v. 1) but not with QUICKI. In contrast, maternal history of diabetes was associated with decreased QUICKI (P < 0.001) but not with HOMA-b. Birth weight (available for 520 participants) was positively associated with increased QUICKI (P = 0.04 for birth weight tertile 3 v. 1) but not with HOMA-b. Fingerprint Md15, maternal history of diabetes and birth weight may help to identify specific defects in the control of adult glucose metabolism. Research into the environment associated with Md15 variation may suggest prenatal strategies for optimizing ß-cell function in adult life.
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Several adjuvant endocrine strategies exist for postmenopausal women with breast cancer. This study compared the effect of two sequences of aromatase inhibitor use [steroidal (exemestane) and non-steroidal (anastrozole)] on serological and pathological biomarkers when given in the neoadjuvant setting to postmenopausal women with breast cancer. Thirty women were assigned to receive exemestane 25 mg or anastrozole 1 mg each given for 8 weeks in a randomized sequence. The effect of this treatment on serum estrone sulfate and estradiol levels, as well as tumor changes in the proliferation biomarker Ki67 were evaluated at baseline, 8 weeks and 16 weeks. WHO clinical response criteria, patient preference, and quality of life were also assessed. Assessable data was available from 28 patients. There were no differences in concentration changes of serum estradiol or Ki67 between patients in the two arms. Overall clinical response rate was 68% (19/28 assessable patients) and clinical benefit was 93% (26/28 assessable patients). There was no significant difference in toxicity or quality of life scores. The majority of patients expressed a personal preference for anastrozole over exemestane. Results suggest that the order of steroidal and non-steroidal aromatase inhibitors has little effect on outcome. The majority of patients express clear preferences for drug treatments.
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Androstadienos/uso terapêutico , Biomarcadores/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Nitrilas/uso terapêutico , Triazóis/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Inibidores da Aromatase/uso terapêutico , Proliferação de Células , Esquema de Medicação , Estradiol/sangue , Feminino , Humanos , Antígeno Ki-67/biossíntese , Pessoa de Meia-Idade , Pós-Menopausa , Resultado do TratamentoRESUMO
This study presents a methodology for the characterization of construction and demolition (C&D) waste recycled aggregates based on a combination of analytical techniques (X-ray fluorescence (XRF), soluble ions, semi-quantitative X-ray diffraction (XRD), thermogravimetric analysis (TGA-DTG) and hydrochloric acid (HCl) selective dissolution). These combined analytical techniques allow for the estimation of the amount of cement paste, its most important hydrated and carbonated phases, as well as the amount of clay and micas. Details of the methodology are presented here and the results of three representative C&D samples taken from the São Paulo region in Brazil are discussed. Chemical compositions of mixed C&D aggregate samples have mostly been influenced by particle size rather than the visual classification of C&D into red or grey and geographical origin. The amount of measured soluble salts in C&D aggregates (0.15-25.4mm) is lower than the usual limits for mortar and concrete production. The content of porous cement paste in the C&D aggregates is around 19.3% (w/w). However, this content is significantly lower than the 43% detected for the C&D powders (<0.15 mm). The clay content of the powders was also high, potentially resulting from soil intermixed with the C&D waste, as well as poorly burnt red ceramic. Since only about 50% of the measured CaO is combined with CO(2), the powders have potential use as raw materials for the cement industry.
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Conservação dos Recursos Naturais/métodos , Materiais de Construção , Teste de Materiais , BrasilRESUMO
AIMS: The treatment of bone metastases in breast cancer is traditionally based upon the receptor status of the primary tumour. However, retrospective studies have shown significant discordance in receptor expression between primary and metastatic tumours. Therefore, the aim of this study was to prospectively assess the incidence of discordant receptor status in primary and metastatic disease and evaluate the role of bone marrow biopsies for the reassessment of receptor status. MATERIALS AND METHODS: Nine patients with known bone metastases were assessed with both a radiologically guided bone biopsy and a bone marrow aspirate and trephine. The oestrogen receptor and progesterone receptor status of these samples was assessed and compared with the primary breast cancer. Bone and bone marrow samples were also evaluated for HER2/neu status and compared with the status of the primary tumour if available. RESULTS: Tumour cells were found in six of the nine bone metastasis specimens and five of the nine bone marrow samples. A discordance rate for the oestrogen receptor was seen in five of nine patients (56%) and for the progesterone receptor in four patients (44%). There seemed to be a correlation between bone and bone marrow biopsies. CONCLUSION: The receptor discordance rate in this study was similar to previous retrospective studies. It seems that bone marrow biopsy may be a simple, safe and well-tolerated way to obtain tissue to reassess the receptor status of metastatic breast cancer.
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Medula Óssea/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Receptor ErbB-2/biossíntese , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Idoso , Biópsia por Agulha , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Neoplasias da Mama/tratamento farmacológico , Difosfonatos/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Breast cancer is the most common female cancer in North America. Axillary lymph node dissection (ALND) is important for staging, prognosis, and adjuvant treatment decisions. The purpose of this study was to identify factors that affect the number of lymph nodes (LN) retrieved in ALND for breast cancer. METHODS: All patients who underwent ALND for breast cancer at Sunnybrook Health Sciences Centre and Women's College Hospital between July 1999 and June 2006 were included. The number of LN retrieved was identified from pathology reports. Univariate and multivariate analysis was undertaken to identify variables influencing this outcome. RESULTS: 1084 patients were identified with a mean number of LN of 14.5. In multivariate analyses, significant covariates included sentinel LN biopsy (P = 0.011), degree of extranodal extension (P = 0.005), tumor grade (P = 0.058), and age (P = 0.043). Thirteen percent of the variation in LN yield was accounted for by institutional, provider, patient, and tumor related factors, leaving 87% attributable to inherent biological or other differences between patients. CONCLUSION: The yield of ALND may be influenced by multiple factors, often not related to the surgery. In settings where >10 LNs are routinely retrieved at ALND, biological variation between patients should be recognized as major a contributor to the LN yield. Adjuvant treatment decisions based on this outcome should take this into consideration.
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Neoplasias da Mama/cirurgia , Excisão de Linfonodo/estatística & dados numéricos , Linfonodos/cirurgia , Biópsia de Linfonodo Sentinela , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Axila , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
There is currently no consensus regarding the optimal protocol for measurement of waist circumference (WC), and no scientific rationale is provided for any of the WC protocols recommended by leading health authorities. A panel of experts conducted a systematic review of 120 studies (236 samples) to determine whether measurement protocol influenced the relationship of WC with morbidity of cardiovascular disease (CVD) and diabetes and with mortality from all causes and from CVD. Statistically significant associations with WC were reported for 65% (152) of the samples across all outcomes combined. Common WC protocols performed measurement at the minimal waist (33%), midpoint (26%) and umbilicus (27%). Non-significant associations were reported for 27% (64) of the samples. Most of these protocols measured WC at the midpoint (36%), umbilicus (28%) or minimal waist (25%). Significant associations were observed for 17 of the remaining 20 samples, but these were not significant when adjustment was made for covariates. For these samples, the most common WC protocols were the midpoint (35%) and umbilicus (30%). Similar patterns of association between the outcomes and all WC protocols were observed across sample size, sex, age, race and ethnicity. Our findings suggest that WC measurement protocol has no substantial influence on the association between WC, all-cause and CVD mortality, CVD and diabetes.
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Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/mortalidade , Obesidade/complicações , Relação Cintura-Quadril , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade , Obesidade/epidemiologia , Fatores de Risco , Revisões Sistemáticas como AssuntoRESUMO
BACKGROUND: Adult obesity prevalence is influenced by rates of weight gain or loss among individual persons, but few studies have measured individual weight change in large populations. Changes in weight may not coincide with changes in the lipid accumulation product (LAP), a continuous index derived from waist circumference and triglycerides concentration for estimating excess lipids. DESIGN AND MEASUREMENTS: Descriptive report of longitudinal changes from US studies that included body mass index (BMI, kg/m(2)) and LAP. SUBJECTS: A total of 16 763 white and black adults studied between 1989 and 1996 in three observational cohorts (Coronary Artery Risk Development in Young Adults, Atherosclerosis Risk in Communities Study and Cardiovascular Health Study). RESULTS: The means of individual annual changes in BMI were positive for young adults, but the mean changes were reduced at older ages (P for linear trend <0.001), becoming negative after 73-83 years old. These mean, individual changes in BMI, specific to sex and age, were approximately 0.1 U/year greater than those reported from previous, representative, longitudinal measurements collected in the United States between 1971 and 1984. Mean, individual annual changes in LAP were strongly positive before middle age. For men, the annual LAP changes were reduced at older ages (P linear trend <0.05). For women, they were greater at older ages (white women, P<0.001) or remained unchanged (black women, P>0.3). With increasing age, there was a greater proportion of persons whose positive LAP change was accompanied by simultaneous BMI change that was negative or zero. CONCLUSIONS: These longitudinal observations made during 1989-1996 suggest greater annual changes in BMI compared to an adult cohort studied during 1971-1984. As estimated by LAP, adults of all ages tended to accumulate excess lipids, including circumstances in which they lost weight.
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Abdome/anatomia & histologia , Negro ou Afro-Americano , Índice de Massa Corporal , Triglicerídeos/sangue , Aumento de Peso/etnologia , População Branca , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
The mechanical response of a biological material to applied forces reflects deformation mechanisms occurring within a hierarchical architecture extending over several distinct length scales. Characterizing and in turn predicting the behaviour of such a material requires an understanding of the mechanical properties of the substructures within the hierarchy, the interaction between the substructures, and the relative influence of each substructure on the overall behaviour. While significant progress has been made in mechanical testing of micrometre to millimetre sized biological specimens, quantitative reproducible experimental techniques for making mechanical measurements on specimens with characteristic dimensions in the smaller range of 10-1000 nm are lacking. Filling this void in experimentation is a necessary step towards the development of realistic multiscale computational models useful to predict and mitigate the risk of bone fracture, design improved synthetic replacements for bones, tendons and ligaments, and engineer bioinspired efficient and environmentally friendly structures. Here, we describe a microelectromechanical systems device for directly measuring the tensile strength, stiffness and fatigue behaviour of nanoscale fibres. We used the device to obtain the first stress-strain curve of an isolated collagen fibril producing the modulus and some fatigue properties of this soft nanofibril.
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Colágeno/química , Colágeno/ultraestrutura , Micromanipulação/instrumentação , Nanotecnologia/instrumentação , Água/química , Elasticidade , Desenho de Equipamento , Análise de Falha de Equipamento , Mecânica , Micromanipulação/métodos , Miniaturização , Nanotecnologia/métodos , Estresse MecânicoRESUMO
OBJECTIVE: The purpose of this study was to evaluate the possible association between menometrorrhagia and the level of endogenous estrogen in perimenopausal women. METHODS: A prospective controlled study in which 28 perimenopausal women > 40 years presenting with menometrorrhagia were compared with 28 age-matched (+/- 2 years) women with normal cyclical menstrual periods concerning levels of estradiol and follicle-stimulating hormone (FSH). Neither of the two groups had received sexual hormone treatment at least in 2 weeks preceding the hormonal assessment. RESULTS: The serum level estradiol in the patients was significantly higher than in the controls (0.55 nmol/l versus 0.24 nmol/l), whereas FSH was not significantly different between the two groups (21.2 IU/l versus 11.8 IU/l). Twenty of the 28 patients had performed at histologic examination of the endometrium, and 10 of these (50%) had signs of endometrial hyperplasia. No relationship was found between the endometrial histology and the estradiol level. CONCLUSIONS: An association between a high endogenous estradiol level and menometrorrhagia in the perimenopause was demonstrated. This may have implications for the choice of treatment in this group of women. It is proposed that this type of bleeding disturbances should be controlled by progestins only, and not with combined estrogen-progestin treatment. Suppression of the associated hyperestrogenism could be achieved by use of oral contraceptives or GnRH agonists.
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Climatério/sangue , Estradiol/sangue , Menorragia/sangue , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
In the absence of a corrosive environment, brittle materials such as silicon should be immune to cyclic fatigue. However, fatigue effects are well known in micrometer-sized polycrystalline silicon (polysilicon) samples tested in air. To investigate the origins of this phenomenon in polysilicon, we developed a fixed-grip fracture mechanics microspecimen but could find no evidence of static stress corrosion cracking. The environmental sensitivity of the fatigue resistance was also investigated under cyclic loading. For low-cycle fatigue, the behavior is independent of the ambient conditions, whether air or vacuum, but is strongly influenced by the ratio of compressive to tensile stresses experienced during each cycle. The fatigue damage most likely originates from contact stresses at processing-related surface asperities; subcritical crack growth then ensues during further cyclic loading. The lower far-field stresses involved in high-cycle fatigue induce reduced levels of fatigue damage. Under these conditions, a corrosive ambient such as laboratory air exacerbates the fatigue process. Without cyclic loading, polysilicon does not undergo stress corrosion cracking.
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Co-transfection studies indicate that HER2 (erbB-2) overexpression results in the phosphorylation and enhanced transcriptional activity of the androgen receptor (AR). This amplification of AR action is further enhanced by the expression of ARA70, a putative co-activator with a predilection for the AR. Because androgens inhibit the growth of breast cancer cells whereas HER2 overexpression stimulates the growth of these cells, it seems possible that loss of expression of AR or ARA70 in some HER2 overexpressing tumors might confer a growth advantage to these cells. We examined ARA70 and AR expression in 20 HER2-positive (overexpressing) and 21 HER2-negative cases of breast invasive ductal carcinoma (IDC) to determine the relationship between loss of ARA70 and/or AR with HER2 overexpression. Strong ARA70 immunostaining was observed in all normal and breast epithelial cells in fibrocystic change and in in situ carcinoma present in the patient samples. Of the 41 cases of IDC, focal or complete loss of ARA70 protein expression was observed in 46% of the cases, with 60% of HER2-positive versus 33% of HER2-negative cases showing loss. Loss of AR expression was observed in 60% of HER2-positive versus 43% of HER2-negative cases. Remarkably, only 20% of HER2-positive tumors expressed both AR and ARA70, while 43% of HER2-negative tumors expressed both of these elements of the AR signaling pathway. This trend is consistent with a possible clinical relevance of the potential crosstalk between the HER2 and AR signaling pathways. Western blot analysis for ARA70 expression performed on frozen breast biopsies of normal or malignant breast tissue from four patients revealed a 70 kDa immunoreactive band in all four normal tissue samples, with an additional 35 kDa band in two of the breast cancer samples and in human breast cancer MCF-7 cells. This may reflect aberrant splicing in some breast cancers, leading to the emergence of the 35 kDa isoform.
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Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/patologia , Divisão Celular , Regulação Neoplásica da Expressão Gênica , Proteínas Oncogênicas , Receptores Androgênicos/biossíntese , Transativadores/biossíntese , Fatores de Transcrição , Biópsia , Western Blotting , Feminino , Humanos , Imuno-Histoquímica , Coativadores de Receptor Nuclear , Fosforilação , Receptores Androgênicos/metabolismo , Transdução de Sinais , Transativadores/metabolismo , Transfecção , Células Tumorais CultivadasRESUMO
In breast cancer amplification of the HER-2/neu oncogene and over-expression of the protein product is associated with poor prognosis, predicts response to some chemotherapeutic regimens and is the target for Herceptin treatment. To date there are several methods to assess the amplification/over-expression of HER-2/neu with each having advantages and disadvantages. We have studied amplification and over-expression of HER-2/neu in 250 consecutive cases of breast cancer (220 invasive and 30 in situ carcinomas) presenting to the Department of Pathology at Women's College Campus of Sunnybrook and Women's College Health Sciences Center. Thirty percent of the invasive carcinomas were node positive. HER-2/neu protein over-expression was assessed by immunohistochemistry (IH) using antibody CB11 and amplification of the gene by differential PCR. The percentage of tumor cells showing CB11 staining was determined and the most significant cut off point for positivity was > or =10% moderate or strong complete membranous staining. The gene was considered amplified if the density score of the product was > or =2. There was 94% concordance between the two methods (P value.0001). Both methods were positive in 16% of cases and negative in 78% of cases. Discrepant cases were examined by FISH which confirmed the IH results in 9/11 invasive carcinomas. These results show that there is excellent concordance between IH and PCR. However, immunohistochemistry is easier to perform and cheaper than PCR and could be used in routine assessment of HER-2/neu in breast cancer patients.