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BACKGROUND: Severe pulmonary hypertension (PH) has been associated with decreased post-kidney transplant survival and increased rate of long-term cardiovascular complications. Despite a high prevalence of PH in patients with end-stage renal disease, data on post-transplant renal allograft survival in recipients with pre-existing mild-to-moderate PH are limited. METHODS: The single-center retrospective study cohort consisted of 192 consecutive (2008-2015) renal transplant recipients with documented pretransplantation transthoracic echocardiogram (TTE) pulmonary artery systolic pressure (PASP). Mean age was 50.9 ± 12.4 years, 36.5% were females, and 81.25% were Caucasians. RESULTS: Elevated PASP ≥ 37 mm Hg was present in 51 patients. Elevated PASP was more common in patients with decreased <50% left ventricular ejection fraction (13.73% vs 3.55%, P = 0.010); otherwise, there were no significant differences in baseline demographic (age, ethnicity, gender, and donor status) and clinical parameters between patients with normal and elevated PASP. Four-year mortality (5.7%) was not significantly affected by elevated PASP. However, elevated PASP was associated with significantly decreased estimated glomerular filtration rate (eGFR) at 1 year (52.26 vs 60.13 mL/min, P = 0.019) and 2 years (51.04 vs 60.28 mL/min, P = 0.006) post-transplant. CONCLUSION: Mild and moderately elevated pre-kidney transplant PASP does not affect 4-year post-transplant mortality or graft loss. However, elevated pretransplant PASP is significantly associated with decreased 1 year and 2 years post-transplant eGFR. Preoperative echocardiographic evaluation for PH may be useful in predicting the probability of short-term renal graft and long-term graft dysfunction in these patients.
Assuntos
Ecocardiografia/métodos , Sobrevivência de Enxerto/fisiologia , Hipertensão Pulmonar/diagnóstico , Transplante de Rim/mortalidade , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
We examined the wavelength dependence of ultraviolet (UV) ra-diation (UVR)-induced melanoma in a Xiphophorus backcross hybrid model previously reported to be susceptible to melanoma induction by ultraviolet A (UVA) and visible light. Whereas ultraviolet B (UVB) irradiation of neonates yielded high frequencies of melanomas in pigmented fish, UVA irradiation resulted in melanoma frequencies that were not significantly different from unirradiated fish. Spontaneous and UV-induced melanoma frequencies correlated with the degree of pigmentation as expected from previous studies, and the histopathology phenotypes of the melanomas were not found in significantly different proportions in UV-treated and -untreated tumor-bearing fish. Our results support the conclusion that a brief early-life exposure to UVB radiation causes melanoma formation in this animal model. These data are consistent with an essential role for direct DNA damage, including cyclobutane dimers and (6-4) photoproducts, in the etiology of melanoma.
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Hibridização Genética , Melanoma Experimental/etiologia , Neoplasias Induzidas por Radiação/etiologia , Pigmentação/efeitos da radiação , Neoplasias Cutâneas/etiologia , Raios Ultravioleta , Animais , Cruzamentos Genéticos , Ciprinodontiformes , Melanoma Experimental/patologia , Neoplasias Induzidas por Radiação/patologia , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND & AIMS: The µ opioid receptor (µOR) undergoes rapid endocytosis after acute stimulation with opioids and most opiates, but not with morphine. We investigated whether prolonged activation of µOR affects morphine's ability to induce receptor endocytosis in enteric neurons. METHODS: We compared the effects of morphine, a poor µOR-internalizing opiate, and (D-Ala2,MePhe4,Gly-ol5) enkephalin (DAMGO), a potent µOR-internalizing agonist, on µOR trafficking in enteric neurons and on the expression of dynamin and ß-arrestin immunoreactivity in the ileum of guinea pigs rendered tolerant by chronic administration of morphine. RESULTS: Morphine (100 µmol/L) strongly induced endocytosis of µOR in tolerant but not naive neurons (55.7% ± 9.3% vs 24.2% ± 7.3%; P < .001) whereas DAMGO (10 µmol/L) strongly induced internalization of µOR in neurons from tolerant and naive animals (63.6% ± 8.4% and 66.5% ± 3.6%). Morphine- or DAMGO-induced µOR endocytosis resulted from direct interactions between the ligand and the µOR because endocytosis was not affected by tetrodotoxin, a blocker of endogenous neurotransmitter release. Ligand-induced µOR internalization was inhibited by pretreatment with the dynamin inhibitor, dynasore. Chronic morphine administration resulted in a significant increase and translocation of dynamin immunoreactivity from the intracellular pool to the plasma membrane, but did not affect ß-arrestin immunoreactivity. CONCLUSIONS: Chronic activation of µORs increases the ability of morphine to induce µOR endocytosis in enteric neurons, which depends on the level and cellular localization of dynamin, a regulatory protein that has an important role in receptor-mediated signal transduction in cells.
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Analgésicos Opioides/farmacologia , Endocitose/efeitos dos fármacos , Sistema Nervoso Entérico/efeitos dos fármacos , Morfina/farmacologia , Receptores Opioides mu/agonistas , Animais , Arrestinas/análise , Dinaminas/análise , Dinaminas/antagonistas & inibidores , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Cobaias , Hidrazonas/farmacologia , Íleo/química , Íleo/efeitos dos fármacos , Masculino , Transdução de Sinais/efeitos dos fármacos , Tetrodotoxina/farmacologia , beta-ArrestinasRESUMO
OBJECTIVE: This study examined factors that influence mammography use and breast cancer detection, including education, health insurance, and acculturation, among Mexican-American (MA) and African-American (AA) women. METHODS: The study included 670 breast cancer cases (388 MAs and 282 AAs), aged 40-86 years at diagnosis. Data on mammography use, detection, and delay in seeking care were collected via questionnaires and medical records. Using a language-based bidimensional acculturation measure, MAs were classified as English-dominant (n = 67), bilingual (n = 173), and Spanish-dominant (n = 148). Mammography prior to diagnosis was assessed by racial/ethnic acculturation subgroup using logistic regression. RESULTS: In age-adjusted models, mammography use was non-significantly lower among English-dominant (OR = 0.84; 95% CI: 0.45-1.59) and bilingual (OR = 0.86; 95% CI: 0.55-1.35) MAs and significantly lower among Spanish-dominant MAs (OR = 0.53; 95% CI: 0.34-0.83) than among AA women. After adjustment for education or insurance, there was no difference in mammography use by race/ethnicity and acculturation subgroup. Despite high self-reported mammography use (75%), a large proportion of cases reported self-detection (59%) and delay in seeking care >90 days (17%). CONCLUSIONS: These findings favor promoting culturally appropriate messaging about the benefits and limitations of mammography, education about breast awareness, and prompt reporting of findings to a health professional.
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Negro ou Afro-Americano/estatística & dados numéricos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/etnologia , Mamografia/métodos , Americanos Mexicanos/estatística & dados numéricos , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Choice of assignment has been shown to increase student engagement, improve academic outcomes, and promote student satisfaction in higher education courses (Hanewicz, Platt, & Arendt, Distance Education, 38(3), 273-287, 2017). However, in previous research, choice resulted in complex procedures and increased response effort for instructors (e.g., Arendt, Trego, & Allred, Journal of Applied Research in Higher Education, 8(1), 2-17, 2016). Using simplified procedures, the current study employed a repeated-measures with an alternating-treatments design to evaluate the effects of assignment choice (flash cards, study guide) on the academic outcomes of 42 graduate students in an online, asynchronous course. Slight differences between conditions were observed, but differences were not statistically significant. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40617-021-00566-8.
RESUMO
The site of electron-transfer reduction of AuPQ(+) (PQ = 5,10,15,20-tetrakis(3,5-di-tert-butylphenyl)quino-xalino[2, 3-b']porphyrin) and AuQPQ(+) (QPQ = 5,10,15,20-tetrakis(3,5-di-tert-butylphenyl)bisquinoxalino[2,3-b':12,13-b'']porphyrin) is changed from the Au(III) center to the quinoxaline part of the PQ macrocycle in the presence of Sc(3+) in benzonitrile because of strong binding of Sc(3+) to the two nitrogen atoms of the quinoxaline moiety. Strong binding of Sc(3+) to the corresponding nitrogen atoms on the quinoxaline unit of ZnPQ also occurs for the neutral form. The effects of Sc(3+) on the photodynamics of an electron donor-acceptor compound containing a linked Zn(II) and Au(III) porphyrin ([ZnPQ-AuPQ]PF(6)) have been examined by femto- and nanosecond laser flash photolysis measurements. The observed transient absorption bands at 630 and 670 nm after laser pulse irradiation in the absence of Sc(3+) in benzonitrile are assigned to the charge-shifted (CS) state (ZnPQ(*)(+)-AuPQ). The CS state decays through back electron transfer (BET) to the ground state rather than to the triplet excited state. The BET rate was determined from the disappearance of the absorption band due to the CS state. The decay of the CS state obeys first-order kinetics. The CS lifetime was determined to be 250 ps in benzonitrile. Addition of Sc(3+) to a solution of ZnPQ-AuPQ(+) in benzonitrile caused a drastic lengthening of the CS lifetime that was determined to be 430 ns, a value 1700 times longer than the 250 ps lifetime measured in the absence of Sc(3+). Such remarkable prolongation of the CS lifetime in the presence of Sc(3+) results from a change in the site of electron transfer from the Au(III) center to the quinoxaline part of the PQ macrocycle when Sc(3+) binds to the quinoxaline moiety, which decelerate BET due to a large reorganization energy of electron transfer. The change in the site of electron transfer was confirmed by ESR measurements, redox potentials, and UV/Vis spectra of the singly reduced products.
RESUMO
BACKGROUND: Only a limited number of studies have performed comprehensive investigations of coding variation in relation to breast cancer risk. Given the established role of estrogens in breast cancer, we hypothesized that coding variation in steroid receptor coactivator and corepressor genes may alter inter-individual response to estrogen and serve as markers of breast cancer risk. METHODS: We sequenced the coding exons of 17 genes (EP300, CCND1, NME1, NCOA1, NCOA2, NCOA3, SMARCA4, SMARCA2, CARM1, FOXA1, MPG, NCOR1, NCOR2, CALCOCO1, PRMT1, PPARBP and CREBBP) suggested to influence transcriptional activation by steroid hormone receptors in a multiethnic panel of women with advanced breast cancer (n = 95): African Americans, Latinos, Japanese, Native Hawaiians and European Americans. Association testing of validated coding variants was conducted in a breast cancer case-control study (1,612 invasive cases and 1,961 controls) nested in the Multiethnic Cohort. We used logistic regression to estimate odds ratios for allelic effects in ethnic-pooled analyses as well as in subgroups defined by disease stage and steroid hormone receptor status. We also investigated effect modification by established breast cancer risk factors that are associated with steroid hormone exposure. RESULTS: We identified 45 coding variants with frequencies > or = 1% in any one ethnic group (43 non-synonymous variants). We observed nominally significant positive associations with two coding variants in ethnic-pooled analyses (NCOR2: His52Arg, OR = 1.79; 95% CI, 1.05-3.05; CALCOCO1: Arg12His, OR = 2.29; 95% CI, 1.00-5.26). A small number of variants were associated with risk in disease subgroup analyses and we observed no strong evidence of effect modification by breast cancer risk factors. Based on the large number of statistical tests conducted in this study, the nominally significant associations that we observed may be due to chance, and will need to be confirmed in other studies. CONCLUSION: Our findings suggest that common coding variation in these candidate genes do not make a substantial contribution to breast cancer risk in the general population. Cataloging and testing of coding variants in coactivator and corepressor genes should continue and may serve as a valuable resource for investigations of other hormone-related phenotypes, such as inter-individual response to hormonal therapies used for cancer treatment and prevention.
Assuntos
Neoplasias da Mama/genética , Variação Genética/genética , Receptores de Estrogênio/genética , Fatores de Transcrição/genética , Negro ou Afro-Americano/genética , Idoso , Alelos , Asiático/genética , Neoplasias da Mama/etnologia , Estudos de Coortes , Feminino , Havaí , Hispânico ou Latino/genética , Humanos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo Genético , Análise de Sequência de DNA , População Branca/genéticaRESUMO
Background The American Speech-Language-Hearing Association (ASHA) advocates using the National Outcomes Measurement System (NOMS) scales to assist speech-language pathologists (SLPs) in the mandated assigning of "functional limitation levels" and G-Code for Medicare Part B claims. Unfortunately, not all SLPs have access to this tool, and it is unclear how other common outcome measurement scales relate to ASHA NOMS or G-Codes. To explore the utility of other scales in reporting Centers for Medicare & Medicaid Services G-Codes, we conducted a comparative validity study comparing ASHA NOMS Dysphagia Scale, Functional Oral Intake Scale (FOIS), and Mann Assessment of Swallowing Ability to G-Codes on a sample of 105 patients who had stroke. Method Nine SLP student researchers trained to criterion on the NOMS and FOIS blindly and independently scored 105 stroke cases with dysphagia de-identified from a past study. Three graduate SLP clinicians independently assigned G-Codes. Data from the student researchers and Mann Assessment of Swallowing Ability scores were compared for admission and discharge from subacute rehabilitation. Analysis included intraclass correlation for reliability, Spearman correlation for comparative validity, and area under the receiver operating characteristic curve to compare the validity and discriminatory utility of measures in classifying dysphagia. Results Strong correlations (> .6) were noted between all measures at baseline, particularly FOIS and NOMS coding ( r = .919). At discharge, superior performance by the FOIS (area under the receiver operating characteristic curve = 0.819) was demonstrated. Code missingness was higher for the NOMS than the other scales. Discussion All 3 clinical dysphagia tools demonstrate acceptable validity in supporting G-Code designation to stroke cases. The FOIS demonstrated superior validity and utility across time points. The NOMS Dysphagia Scale was significantly affected by data missingness due to the multiconstruct nature of the tool.
Assuntos
Transtornos de Deglutição/diagnóstico , Deglutição , Patologia da Fala e Linguagem/métodos , Acidente Vascular Cerebral/complicações , Idoso , Idoso de 80 Anos ou mais , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/fisiopatologia , Transtornos de Deglutição/terapia , Feminino , Humanos , Masculino , Medicare , Pessoa de Meia-Idade , Variações Dependentes do Observador , Alta do Paciente , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia , Resultado do Tratamento , Estados UnidosRESUMO
The electrochemistry and spectroelectrochemistry of a novel series of mixed-ligand diruthenium compounds were examined. The investigated compounds having the formula Ru(2)(CH(3)CO(2))(x)(Fap)(4-x)Cl where x = 1-3 and Fap is 2-(2-fluoroanilino)pyridinate anion were made from the reaction of Ru(2)(CH(3)CO(2))(4)Cl with 2-(2-fluoroanilino)pyridine (HFap) in refluxing methanol. The previously characterized Ru(2)(Fap)(4)Cl as well as the three newly isolated compounds represented as Ru(2)(CH(3)CO(2))(Fap)(3)Cl (1), Ru(2)(CH(3)CO(2))(2)(Fap)(2)Cl (2), and Ru(2)(CH(3)CO(2))(3)(Fap)Cl (3) possess three unpaired electrons with a Ru(2)(5+) dimetal core. Complexes 1 and 2 have well-defined Ru(2)(5+/4+) and Ru(2)(5+/6+) redox couples in CH(2)Cl(2), but 3 exhibits a more complicated electrochemical behavior due to equilibria involving association or dissociation of the anionic chloride axial ligand on the initial and oxidized or reduced forms of the compound. The E(1/2) values for the Ru(2)(5+/4+) and Ru(2)(5+/6+) processes vary linearly with the number of CH(3)CO(2)(-) bridging ligands on Ru(2)(CH(3)CO(2))(x)(Fap)(4-x)Cl and plots of reversible half-wave potentials vs the number of acetate groups follow linear free energy relationships with the largest substituent effect being observed for the oxidation. The major UV-visible band of the examined compounds in their neutral Ru(2)(5+) form is located between 550 and 800 nm in CH(2)Cl(2) and also varies linearly with the number of CH(3)CO(2)(-) ligands on Ru(2)(CH(3)CO(2))(x)(Fap)(4-x)Cl. The electronic spectra of the singly oxidized and singly reduced forms of each diruthenium species were characterized by UV-visible spectroelectrochemistry in CH(2)Cl(2).
RESUMO
We report the oral vaccination of SWISS mice with an Aro attenuated Salmonella enterica var. Typhimurium vaccine strain expressing the 14-kDa Schistosoma mansoni antigen, Sm14. Bacterial adjuvants, including (i) Lactococcus lactis expressing interleukin-12 (IL-12) and (ii) Lactobacillus delbrueckii UFV-H2b20, were also employed in oral immunization assays. Detection assays to specific IgG and IgA anti-Sm14 antibodies were performed to evaluate humoral immune responses in vaccinated mice. An increase in specific IgG titers was observed; however, no IgA production was detected. The protection levels against schistosomiasis (34.9-49.5%) obtained with all experimental formulations in this work were very similar to values reported by previous studies, which used purified recombinant Sm14 for parenteral vaccination of mice. There was a slight reduction in hepatic granulomas of mice vaccinated with Salmonella. Oogram studies showed diminished numbers of S. mansoni eggs in the intestinal wall of vaccinated mice, but individual female worm fecundity did not seem to be affected by our immunization protocol.
Assuntos
Antígenos de Helmintos/imunologia , Proteínas de Helminto/imunologia , Proteínas de Membrana Transportadoras/imunologia , Vacinas contra Salmonella/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose/imunologia , Animais , Antígenos de Helmintos/isolamento & purificação , Ensaio de Imunoadsorção Enzimática , Proteínas de Transporte de Ácido Graxo , Feminino , Proteínas de Helminto/biossíntese , Proteínas de Helminto/efeitos dos fármacos , Proteínas de Membrana Transportadoras/biossíntese , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Camundongos , Plasmídeos/efeitos dos fármacos , Plasmídeos/genética , Esquistossomose/prevenção & controleRESUMO
A colony of rainbow trout (Oncorhynchus mykiss) in a decentralized aquatic animal facility was noted to have an increase in morbidity and mortality (from 4 or 5 fish each month to 3 or 4 fish daily) approximately 2 wk after experimental procedures began. The primary clinical signs were erratic swimming behavior and 'flashing' of fish against surfaces within housing enclosures. Moribund and normal rainbow trout were presented alive for diagnostic evaluation; samples of water from housing enclosures were provided for water quality assessment. The trout were determined to be infected with gyrodactylids, a common monogenean ectoparasite of the skin and gills in both marine and freshwater fish. This case report describes the diagnosis, pathology, and treatment of gyrodactylids and husbandry modifications associated with the resolution of this clinical aquatic-animal case.
Assuntos
Ectoparasitoses/parasitologia , Oncorhynchus mykiss/parasitologia , Animais , Ectoparasitoses/patologia , Brânquias/parasitologiaRESUMO
Using the Xiphophorus fish melanoma model, we show a strong male bias for sunlight-induced malignant melanoma, consistent with that seen in the human population. To examine underlying factors, we exposed adult X. couchianus fish to a single, sublethal dose of UVB and measured circulating sex steroid hormones and expression of associated hormone receptor genes over a 24-h period. We found that a single exposure had profound effects on circulating levels of steroid hormones with significant decreases for all free sex steroids at 6 and 24 h and increases in conjugated 2-estradiol and 11-ketotestosterone at 6 and 24 h, respectively. Whereas ARα expression increased in male and female skin, neither ARß nor either of the ERs showed significant responses to UVB in either sex. The rapid response of male androgens and their receptors in the skin after UVB irradiation implicates hormones in the male bias of skin cancer and suggests that the photoendocrine response immediately after UV exposure may be relevant to melanomagenesis.
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Ciprinodontiformes/genética , Hormônios Esteroides Gonadais/biossíntese , Melanoma Experimental/genética , Modelos Animais , Neoplasias Induzidas por Radiação/genética , Receptores Androgênicos/biossíntese , Receptores de Estrogênio/biossíntese , Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/efeitos da radiação , Dano ao DNA , Feminino , Doenças dos Peixes/epidemiologia , Hormônios Esteroides Gonadais/genética , Humanos , Hidrocortisona/biossíntese , Incidência , Masculino , Melanoma/epidemiologia , Melanoma/veterinária , Melanoma Experimental/etiologia , Neoplasias Induzidas por Radiação/etiologia , Estresse Oxidativo , Receptores Androgênicos/genética , Receptores de Estrogênio/genética , Distribuição por Sexo , Pele/metabolismoRESUMO
Unlike breast and prostate cancers, the nature and sequence of critical genetic and epigenetic events involved in the initiation and progression of melanoma are not well understood. A contributing factor to this dilemma, especially given our current understanding of the importance of UV light in melanoma etiology, is the lack of quality UV-inducible melanoma animal models. In this study we elaborate on the capability of UV light to induce cutaneous malignant melanomas (CMM) in Xiphophorus fishes, which were previously found to develop melanomas after acute neonatal UVB irradiation. In two separate tumorigenesis experiments, we exposed adult Xiphophorus hybrids to either acute UVB irradiations (5 consecutive daily treatments) or chronic solar irradiations (continuous UVA/UVB treatment for 9 months). Acute adult UVB irradiation resulted in the significant induction of melanomas, and moreover, this induction rate is equivalent to that of animals exposed to acute neonatal UVB irradiation. This study represents the first evidence that acute adult UVB irradiation, in the absence of any early life exposures, induces CMM. Similar to the findings conducted on other divergent melanoma models, including HGF/SF transgenic mice and Monodelphis domestica, prolonged chronic solar UV was not a factor in melanomagenesis.
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Ciprinodontiformes/genética , Melanoma Experimental/etiologia , Neoplasias Induzidas por Radiação/etiologia , Luz Solar/efeitos adversos , Raios Ultravioleta/efeitos adversos , Animais , Cruzamento/métodos , Ciprinodontiformes/fisiologia , Dano ao DNA , Feminino , Masculino , Melanoma Experimental/genética , Neoplasias Induzidas por Radiação/genética , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Fatores de TempoRESUMO
Appropriate cleaning and disinfection procedures in zebrafish (Danio rerio) laboratories are crucial in preventing the spread of aquatic animal pathogens and minimizing the build-up of waste products and biologic matter. The procedures selected should accomplish these goals and incorporate the individual needs of various laboratories. In this study of a single zebrafish facility, we assessed the efficacy of 2 different cleaning and disinfection procedures for nets, tanks, and lids. ATP levels were used as a surrogate biomarker for microbial burden. We measured the number of relative light units (RLU), as an expression of the amount of ATP present, on items before and after disinfection and calculated the percentage reduction. We compared daily replacement of a commercial net disinfection product in J lab with weekly replacement in H lab and found a 96.6% reduction in RLU in H lab and a 91.2% reduction in J lab. These results indicate that either replacement schedule is effective. Evaluation of tanks and lids soaked in a bleach disinfection bath for 30 or 60 min revealed a 99.7% reduction in RLU at 30 min compared with 97.1% at 60 min. Therefore a 30-min soak in a bleach bath achieved a similar level of disinfection as did a 60-min soak. The current results demonstrate that these cleaning and disinfection methods are efficacious.
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Animais de Laboratório , Desinfecção/métodos , Abrigo para Animais/normas , Peixe-Zebra , Trifosfato de Adenosina/análise , Animais , Medições Luminescentes , Fatores de TempoRESUMO
Nucleotide excision repair (NER) is the primary defense against the DNA damage implicit in skin cancer formation and is negatively affected by chronic exposure to UVB radiation. However, in situ and in vitro studies consistently yield equivocal results when addressing individual DNA repair capacity and melanoma susceptibility. The primary objective of this study was to determine if individual global NER capacity is a risk factor for melanoma formation in a prominent UVB-inducible melanoma model, hybrid Xiphophorus fishes. After neonatal UVB irradiation, adult tumor-bearing and tumor-free fish were given a challenge UVB dose and (6-4) photoproduct repair was quantified in individual fish at 24 h using radioimmunoassay. Despite considerable inter-individual variation in repair capacity, ranging from 13% to 91%, we found no difference in mean NER capacity between fish with and without melanomas, thus detaching global NER from melanomagenesis. Furthermore, despite epidemiological data indicating that sex and age are important risk factors underlying melanoma susceptibility, we found no difference in mean NER rates among the sexes or as a function of age. We conclude with a discussion of the apparent paradox of how inter-individual variation in NER is not a risk factor given the clear evidence that DNA damage underlies melanoma susceptibility.
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Ciprinodontiformes , Reparo do DNA , Melanoma Experimental , Neoplasias Cutâneas , Raios Ultravioleta , Fatores Etários , Animais , Reparo do DNA/genética , Modelos Animais de Doenças , Variação Genética , Fatores de Risco , Fatores SexuaisRESUMO
IGF2R has been proposed to be a tumor suppressor gene given its antagonist role on cellular growth and evidence of loss of heterozygosity in several cancers, including breast cancer. To investigate whether inherited differences in potentially functional IGF2R variants influence the risk of breast cancer, we sequenced 46 exons of IGF2R to identify novel missense single-nucleotide polymorphisms (SNP) and tested 12 missense SNPs for their associations with breast cancer risk among 1,614 breast cancer cases and 1,960 controls from the Multiethnic Cohort. None of these missense SNPs were significantly associated with breast cancer risk. Our findings provide no evidence that missense SNPs in IGF2R influence breast cancer susceptibility
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Neoplasias da Mama/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Receptor IGF Tipo 2/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Etnicidade , Feminino , Genótipo , Humanos , Pessoa de Meia-IdadeRESUMO
O uso de ácido poli-L-lático (PLLA) vem aprimorando os procedimentos de preenchimento e restauração de volume. Por ser abordagem extensa com produto injetável, observa-se alguma resistência por parte dos pacientes, temendo a dor e equimoses posteriores. Além disso, a técnica com agulha curta tradicionalmente utilizada dificulta a abordagem de regiões profundas. Descreve-se, então, nova forma de aplicação, utilizando microcânula (instrumento longo de ponta romba) 40 x 0,8mm, com retroinjeção em algumas áreas da face. Essa nova abordagem apresentou resultados satisfatórios, com boa aceitação pelos pacientes e redução de efeitos adversos.
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The gastric H,K-ATPase catalyzes electroneutral exchange of H(+) for K(+) as a function of enzyme phosphorylation and dephosphorylation during transition between E(1)/E(1)-P (ion site in) and E(2)-P/E(2) (ion site out) conformations. Here we present homology modeling of the H,K-ATPase in the E(2)-P conformation as a means of predicting the interaction of the enzyme with two known classes of specific inhibitors. All known proton pump inhibitors, PPIs, form a disulfide bond with cysteine 813 that is accessible from the luminal surface. This allows allocation of the binding site to a luminal vestibule adjacent to Cys813 enclosed by part of TM4 and the loop between TM5 and TM6. K(+) competitive imidazo-1,2alpha-pyridines also bind to the luminal surface of the E(2)-P conformation, and their binding excludes PPI reaction. This overlap of the binding sites of the two classes of inhibitors combined with the results of site-directed mutagenesis and cysteine cross-linking allowed preliminary assignment of a docking mode for these reversible compounds in a position close to Glu795 that accounts for the detailed structure/activity relationships known for these compounds. The new E(2)-P model is able to assign a possible mechanism for acid secretion by this P(2)-type ATPase. Several ion binding side chains identified in the sr Ca-ATPase by crystallography are conserved in the Na,K- and H,K-ATPases. Poised in the middle of these, the H,K-ATPase substitutes lysine in place of a serine implicated in K(+) binding in the Na,K-ATPase. Molecular models for hydronium binding to E(1) versus E(2)-P predict outward displacement of the hydronium bound between Asp824, Glu820, and Glu795 by the R-NH(3)(+) of Lys791 during the conformational transition from E(1)P and E(2)P. The site for luminal K(+) binding at low pH is proposed to be between carbonyl oxygens in the nonhelical part of the fourth membrane span and carboxyl oxygens of Glu795 and Glu820. This site of K(+) binding is predicted to destabilize hydrogen bonds between these carboxylates and the -NH(3)(+) group of Lys791, allowing the Lys791 side chain to return to its E(1) position.
Assuntos
Inibidores Enzimáticos/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Estômago/enzimologia , Sequência de Aminoácidos , Sítios de Ligação , Western Blotting , Catálise , ATPase Trocadora de Hidrogênio-Potássio/química , ATPase Trocadora de Hidrogênio-Potássio/genética , Íons , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Conformação Proteica , Inibidores da Bomba de Prótons , Homologia de Sequência de AminoácidosRESUMO
The electrochemistry of 16 different water-soluble porphyrins of the type [(TMpyP)M(II)]4+ (X-)4 or [(TMpyP)M(III)Cl]4+ (Cl-)4 is reported in nonaqueous media where TMpyP is the dianion of meso-tetrakis(N-methylpyridiniumyl)porphyrin and X- = Cl- or BPh4-. These studies were carried out to examine the effect of the metal ion and porphyrin counterion (X-) on the electrochemical properties of the TMpyP complexes with a special emphasis being given to the overall number of electrons added and the number of electrode processes upon reduction. All of the investigated compounds with electroinactive central metal ions undergo an overall addition of six electrons. This occurs for most compounds via three two-electron-transfer steps, but more than three processes are observed for porphyrins having metal ions with a low electronegativity (e.g., Cd(II)). The first reduction of each porphyrin having an M(II) ion or an electroinactive M(III) ion yields a porphyrin dianion which is characterized by an intense band located close to 800 nm, and this reversible reduction is followed by further reductions of the 1-methyl-4-pyridyl groups at more negative potentials. Four of the compounds with electroactive central metal ions, [(TMpyP)M(III)Cl]4+(Cl-)4 (M = Co, Fe, Mn, or Au), undergo an additional reversible M(III)/M(II) process prior to reactions involving the porphyrin pi-ring system and the 1-methyl-4-pyridyl substituents.
RESUMO
Three Ru2(5+) diruthenium complexes, (4,0) Ru2(2-CH3ap)4Cl, (3,1) Ru2(2-Fap)4Cl, and (3,1) Ru2(2,4,6-F3ap)4Cl where ap is the 2-anilinopyridinate anion, were examined as to their electrochemical and spectroelectrochemical properties in five different nonaqueous solvents (CH2Cl2, THF, PhCN, DMF, and DMSO). Each compound undergoes a single one-electron metal-centered oxidation in THF, DMF, and DMSO and two one-electron metal-centered oxidations in CH2Cl2 and PhCN. The three diruthenium complexes also undergo two reductions in each solvent except for CH2Cl2, and these electrode processes are assigned as Ru2(5+/4+) and Ru2(4+/3+). Each neutral, singly reduced, and singly oxidized species was characterized by UV-vis thin-layer spectroelectrochemistry, and the data are discussed in terms of the most probable electronic configuration of the compound in solution. The three neutral complexes contain three unpaired electrons as indicated by magnetic susceptibility measurements using the Evans method (3.91-3.95 muB), and the electronic configuration is assigned as sigma2pi4delta2pi(*2)delta, independent of the solvent. The three singly oxidized compounds have two unpaired electrons in CD2Cl2, DMSO-d6, or CD3CN (2.65-3.03 muB), and the electronic configuration is here assigned as sigma2pi4delta2pi(*2). The singly reduced compound also has two unpaired electrons (2.70-2.80 muB) in all three solvents, consistent with the electronic configuration sigma2pi4delta2pi(*2)delta(*2) or sigma2pi4delta2pi(*3)delta*. Finally, the overall effect of solvent on the number of observed redox processes is discussed in terms of solvent binding, and several formation constants were calculated.