RESUMO
The objectives of this study were to assess the effects of feeding 2 different diets, a diet with low dietary cation-anion difference (DCAD) or a diet with synthetic zeolite A, to multiparous Holstein cows during the close-up period on dry matter intake (DMI) and energy metabolism, as well as to evaluate colostrum and milk production. A total of 121 multiparous Holstein cows, blocked by lactation number and expected parturition date were enrolled at 254 d of gestation and randomly assigned to 1 of 3 dietary treatments: control (CON; +190 mEq/kg; n = 40), negative DCAD (-DCAD, -65 mEq/kg; n = 41; Ultra Chlor; Vita Plus, Lake Mills, WI), or a diet containing sodium aluminum silicate zeolite (XZ; +278 mEq/kg, fed at 3.3% dry matter, targeting 500 g/d; n = 40; X-Zelit, Protekta Inc., Lucknow, ON, Canada/Vilofoss, Graasten, Denmark). Prepartum DMI was measured daily using Insentec roughage intake control (RIC) gates (RIC System, Holofarm Group, the Netherlands). All cows received the same postpartum diet. Blood and urine samples were collected daily beginning 14 d before parturition (d -14) until parturition (d 0), and on 1, 2, 3, 6, 9, 12, 15, 18, 21, 35, and 49 d postpartum. Colostrum collected within 6 h of parturition, weighed, and based on samples' Brix value, IgG concentrations, and nutrient composition were analyzed. Prepartum, cows fed the XZ diet had decreased DMI (11.70 ± 0.26, 13.88 ± 0.26, and 13.45 ± 0.25 kg/d for XZ, CON, and -DCAD, respectively) and lower rumination (487 ± 8.1, 531 ± 8.3, and 527 ± 8.5 min for XZ, CON, and -DCAD, respectively) compared with CON and -DCAD. However, rumination was not different postpartum due to treatment. No prepartum or postpartum differences were observed for glucose or BHB concentrations in blood between dietary treatments. Colostrum collected from cows fed XZ had the highest IgG concentrations (91.10 ± 2.63, 78.00 ± 2.63, and 78.90 ± 2.63 mg/mL for XZ, CON, and -DCAD, respectively), but yield did not differ between dietary treatments. Additionally, cows in their third lactation or greater fed XZ had the highest milk production (51.0 ± 1.1 kg) during the first 49 d in milk. This study demonstrates that despite a decrease in DMI and rumination in cows fed XZ prepartum, blood BHB concentrations were not altered. Additionally, cows fed XZ had higher colostral IgG concentrations and cows in their third lactation or greater fed XZ produced the most milk. These data suggest that feeding XZ prepartum may improve colostrum quality and milk yield in mature cows, and does not affect energy metabolism.
Assuntos
Ração Animal , Dieta , Ingestão de Alimentos , Metabolismo Energético , Lactação , Leite , Zeolitas , Animais , Bovinos , Feminino , Dieta/veterinária , Leite/química , Leite/metabolismo , Zeolitas/farmacologia , Cátions , Colostro/química , Colostro/metabolismo , Ânions , GravidezRESUMO
The onset of lactation is characterized by substantially altered calcium (Ca) metabolism; recently, emphasis has been placed on understanding the dynamics of blood Ca in the peripartal cow in response to this change. Thus, the aim of our study was to delineate how prepartum dietary cation-anion difference (DCAD) diets and the magnitude of Ca decline at the onset of lactation altered blood Ca dynamics in the periparturient cow. Thirty-two multiparous Holstein cows were blocked by parity, previous 305-d milk yield and expected parturition date, and randomly allocated to either a positive (+120 mEq/kg) or negative (-120 mEq/kg) DCAD diet from 251 d of gestation until parturition (n = 16/diet). Immediately after parturition cows were continuously infused for 24 h with (1) an intravenous solution of 10% dextrose or (2) Ca gluconate (CaGlc) to maintain blood ionized (iCa) concentrations at â¼1.2 mM (normocalcemia) to form 4 treatment groups (n = 8/treatment). Blood was sampled every 6 h from 102 h before parturition until 96 h after parturition and every 30 min during 24 h continuous infusion. Cows fed a negative DCAD diet prepartum exhibited a less pronounced decline in blood iCa approaching parturition with lesser magnitude of decline relative to positive DCAD-fed cows. Cows fed a negative DCAD diet prepartum required lower rates of CaGlc infusion to maintain normocalcemia in the 24 h postpartum relative to positive DCAD-fed cows. Infusion of CaGlc disrupted blood Ca and P dynamics in the immediate 24 h after parturition and in the days following infusion. Collectively, these data demonstrate that prepartum negative DCAD diets facilitate a more transient hypocalcemia and improve blood Ca profiles at the onset of lactation whereas CaGlc infusion disrupts mineral metabolism.
Assuntos
Cálcio , Suplementos Nutricionais , Gravidez , Feminino , Bovinos , Animais , Lactação/fisiologia , Dieta/veterinária , Cálcio da Dieta , Período Pós-Parto/metabolismo , Ânions , Minerais/metabolismo , Cátions , Ração Animal/análiseRESUMO
BACKGROUND: Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF. METHODS AND RESULTS: This was a post hoc analysis of 79 patients with acute HF included in the EMPA-RESPONSE-AHF trial, which compared sodium-dependent glucose-cotransporter protein 2 inhibitor treatment with empagliflozin for 30 days with placebo in patients with acute HF [NCT03200860]. Plasma concentrations of ketone bodies acetone, ß-hydroxybutyrate, and acetoacetate were measured at baseline and 5 different timepoints. Changes in ketone bodies over time were monitored using repeated measures analysis of variance. In the total cohort, median total ketone body concentration was 251 µmol/L (interquartile range, 178-377 µmol/L) at baseline, which gradually decreased to 202 µmol/L (interquartile range, 156-240 µmol/L) at day 30 (Pâ¯=â¯.041). Acetone decreased from 60 µmol/L (interquartile range, 34-94 µmol/L) at baseline to 30 µmol/L (interquartile range, 21-42 µmol/L) ( P < .001), whereas ß-hydroxybutyrate and acetoacetate remained stable over time. Higher acetone concentrations were correlated with higher N-terminal pro brain natriuretic peptide levels (râ¯=â¯0.234; Pâ¯=â¯.039). Circulating ketone bodies did not differ between patients treated with empagliflozin or placebo throughout the study period. A higher acetone concentration at baseline was univariately associated with a greater risk of the composite end point, including in-hospital worsening HF, HF rehospitalizations, and all-cause mortality after 30 days. However, after adjustment for age and sex, acetone did not remain an independent predictor for the combined end point. CONCLUSIONS: Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization. Treatment with empagliflozin did not affect ketone body concentrations in patients with acute HF.
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Acetoacetatos , Insuficiência Cardíaca , Humanos , Ácido 3-Hidroxibutírico , Acetona , Corpos Cetônicos/metabolismoRESUMO
The peripartal cow experiences a rapid change in calcium metabolism at the onset of lactation. Research has focused on understanding how mammary-derived factors, such as serotonin (5HT) and parathyroid hormone like hormone (PTHLH), aid in coordinating these calcemic adaptations to lactation. Therefore, the aim of our study was to determine how induced subclinical hypocalcemia influences physiological responses, specifically the 5HT-PTHLH-Ca axis, in lactating and nonlactating dairy cows to elucidate the potential contribution of the mammary gland. Twelve nonlactating, nonpregnant (NL) multiparous Holstein cows and 12 early-lactation (EL) multiparous Holstein cows received either (1) a continuous 24-h intravenous solution of 0.9% NaCl or (2) 5% ethylene glycol tetraacetic acid (EGTA) solution in 0.9% NaCl (n = 6 EL, n = 6 NL per treatment) with the aim of maintaining blood ionized calcium (iCa) less than 1.0 mM. Mammary gland biopsies were taken immediately after and 48 h after termination of infusion. Blood was sampled hourly during infusion and 4, 8, 12, 24, 48, and 72 h after termination of infusion. Infusion of EGTA successfully decreased blood iCa concentrations. However, EL EGTA-infused cows required increased rates of EGTA infusion to maintain iCa below 1.0 mM. Circulating and mammary serotonin concentrations were increased in EL relative to NL cows, with no difference as a result of EGTA infusion. Mammary PTHLH expression was increased in EL cows, with highest expression observed in EL EGTA-infused cows. Collectively, these data demonstrate the robust adaptations EL cows have to maintain Ca homeostasis and the supporting roles 5HT and PTHLH may play.
Assuntos
Doenças dos Bovinos , Hipocalcemia , Adaptação Fisiológica , Animais , Cálcio , Cálcio da Dieta , Bovinos , Feminino , Hipocalcemia/veterinária , LactaçãoRESUMO
The peripartum period is characterized by dynamic shifts in metabolic, mineral, and immune metabolism as the dairy cow adapts to the demands of lactation. Emphasis over the past decade has been placed on understanding the biology of the large shift in calcium metabolism in particular. Moreover, research has also focused on exploring the role of serotonin during the transition period and lactation and further unraveling its relationship with calcium. This review aimed to demonstrate the integration of calcium physiology during the peripartal period and throughout lactation. More specifically, we sought to discuss the knowledge gained in recent years on calcium metabolism, mammary calcium transport, serotonin metabolism, and the serotonin-calcium axis. Herein we also discuss the challenges and limitations of current research and where that leaves the present understanding of the serotonin-calcium axis as we seek to move forward and continue exploring this interesting relationship.
Assuntos
Cálcio , Bovinos , Serotonina , Animais , Feminino , Lactação , Proteína Relacionada ao Hormônio Paratireóideo , Período PeripartoRESUMO
Serotonin's role as a hormone has been demonstrated through modulating calcium metabolism, energy homeostasis, and immune function in the preweaned and lactating bovine. Recently, manipulation of the serotonergic axis in calves via administration of 5-hydroxy-l-tryptophan (5-HTP), the serotonin precursor, elicited immunomodulatory effects and regulated serotonin transport and metabolism genes in leukocytes. However, serotonin's ability to modulate whole-blood gene expression in lactating dairy cows is unknown. Our objective was to explore the effect of infusing 5-HTP on whole-blood expression of genes regulating serotonin transport (reuptake transporter), signaling (receptors), metabolism (synthesis and degradation), and cytokines in dairy cows. Twelve lactating multiparous Holstein dairy cows were blocked by parity, milk production, and days in milk in a randomized complete block design and randomly assigned to intravenous infusion of either 1 L of 1.5 mg/kg 5-HTP dissolved in saline (n = 6) or 1 L of saline solution (n = 6) for 3 consecutive days. Whole blood was collected at 48, 56, and 72 h relative to termination of first infusion to analyze whole-blood gene expression. Infusion of 5-HTP increased whole-blood mRNA expression of monoamine oxidase-A and serotonin receptor 7 across the experimental period. Forty-eight hours from termination of first infusion, the mRNA of monoamine oxidase-A, serotonin reuptake transporter, and serotonin receptor 7 were increased in blood relative to the control. Interleukin-8 concentrations and mRNA were unchanged in response to 5-HTP infusion. Collectively, these data suggest that infusion of 5-HTP may alter mRNA of serotonin metabolism, transport, and signaling genes in whole blood of lactating dairy cows.
RESUMO
The monoamine serotonin has been shown to regulate peripartal calcium homeostasis in multiparous cows and be a possible mitigation tool for hypocalcemia. Increasing circulating serotonin concentrations via prepartum intravenous (IV) administration of the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) increases postpartum calcium concentrations. However, the ability of 5-HTP to be used orally or ruminally to alter circulating serotonin concentrations has not been established. Hence, our objective was to determine if ruminal administration of 5-HTP altered circulating serotonin concentrations. Four ruminally cannulated, nonlactating, nonpregnant multiparous Holstein dairy cows were randomly assigned to 1 of 4 treatments in a 4 × 4 replicated Latin square with 4-d periods separated by a 7-d washout. On d 1 and 2 of each period, cows were dosed with 1 of 4 experimental treatments as follows: (1) 0 mg/kg of body weight (BW) of 5-HTP, (2) 1 mg/kg of BW of intraruminal 5-HTP, (3) 2 mg/kg of BW of intraruminal 5-HTP, or (4) 1 mg/kg of BW of IV 5-HTP. Infusions were administered over a 1-h period, and all groups not receiving 5-HTP IV were infused with an equal volume of IV saline to that of IV 1 mg/kg of BW of 5-HTP treatment. Continuous serial blood samples were collected beginning after d 2 of treatment administration. Whole blood serotonin concentrations were higher in cows dosed with 2 mg/kg of BW of intraruminal 5-HTP immediately after dosing when compared with cows dosed with 0 mg/kg of BW of 5-HTP on d 2, but were similar on d 3 and 4 of the experimental period. Cows receiving IV 5-HTP had the highest circulating serotonin concentrations relative to all other treatments. These findings demonstrated that 2 intraruminal dosings of 5-HTP at 2 mg/kg of BW resulted in elevated circulating serotonin concentrations relative to the control immediately after dosing. This supports the potential for 5-HTP to be used orally to manipulate circulating serotonin concentrations.
Assuntos
5-Hidroxitriptofano/farmacologia , Bovinos/sangue , Serotonina/sangue , 5-Hidroxitriptofano/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Feminino , Lactação/sangue , Período Pós-Parto/sangue , Rúmen , TriptofanoRESUMO
The phase-mismatch effect due to polarization-dependent mode confinement factor has been shown to be not a crucial problem in semiconductor optical amplifiers (SOAs) and is usually not accounted for. The phase-mismatch four-wave mixing (FWM) process in SOA devices is experimentally reported. The results reveal a sinc-like behavior in the intensity of FWM conjugate as a function of wavelength separation between transverse electric (TE)/transverse magnetic (TM) pumps due to induced confinement factors difference. Efficient FWM occurred for a detuning shift of about 500 GHz, limited by phase-mismatch conditions and determined by coherence length required for low and high frequencies to complete a full phase-match cycle. Phase-match FWM with an infinity coherence length can be fulfilled by proper alignments of co-polarized TE/TM modes of input waves with respect to the birefringent axes of the device structure.
RESUMO
BACKGROUND: Chronic diseases are associated with an inflammatory response. We determined the association of two inflammatory markers, GlycA and high-sensitivity C-reactive protein (hsCRP), with overall and cause-specific mortality in a cohort of men and women. METHODS: Cox regression analyses were used to examine associations of GlycA and hsCRP with all-cause, cancer and cardiovascular mortality in 5526 subjects (PREVEND cohort; average follow-up 12.6 years). RESULTS: GlycA was associated with all-cause mortality (n = 838), independent of clinical risk factors and hsCRP (hazard ratio 1.43 [95% confidence interval (CI): 1.09-1.87] for top versus bottom quartiles). For hsCRP, the association with all-cause mortality was nonsignificant after adjustment for GlycA. GlycA and hsCRP were associated with cancer mortality in men (n = 248), but not in women (n = 132). Neither GlycA nor hsCRP was independently associated with cardiovascular mortality (n = 201). In a meta-analysis of seven population-based studies, including 8153 deaths, the pooled multivariable-adjusted relative risk of GlycA for all-cause mortality was 1.74 (95% CI: 1.40-2.17) for top versus bottom quartiles. The association of GlycA with all-cause mortality was somewhat stronger than that of hsCRP. GlycA and hsCRP were not independently associated with cardiovascular mortality. The associations of GlycA and hsCRP with cancer mortality were present in men, but not in women. CONCLUSIONS: GlycA is significantly associated with all-cause mortality. GlycA and hsCRP were each not independently associated with cardiovascular mortality. The association of GlycA and hsCRP with cancer mortality appears to be driven by men.
Assuntos
Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/mortalidade , Glicoproteínas/sangue , Nefropatias/mortalidade , Adulto , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Estudos de Coortes , Feminino , Humanos , Nefropatias/sangue , Nefropatias/prevenção & controle , Masculino , Pessoa de Meia-IdadeRESUMO
Despite the frequency of liver transplantation in alcoholic recipients, the burden of co-occurring psychosocial comorbidities remains poorly defined. METHODS: A survey study was conducted to examine demographic, substance use, mental health, and social support variables among liver transplant (LT) recipients with alcoholic liver disease (ALD) (LT-ALD: n = 67). Survey completers (n = 67) were compared to a sample of liver transplant recipients without ALD (LT: n = 134). RESULTS: Survey participants (n = 67) were predominately male, in their mid-fifties, and were retired or on disability. Alcohol consumption during the 6 months prior to transplant was reported by more than a third of participants. Alcohol consumption post-transplant was reported by 21.2% of respondents, with 4.5% of participants reporting "at-risk" levels of post-transplant alcohol use. Illicit drug use prior to transplant was reported by nearly half of participants (47.8%), and 16.4% reported illicit drug use post-transplant. Approximately half of the sample reported a history of cigarette smoking, and one-third of respondents (29.2%) reported current cigarette smoking. Participants frequently endorsed mental health symptoms consistent with moderate to severe depression (22.4%) and anxiety (17.9%). CONCLUSIONS: Despite relatively low rates of problematic alcohol use post-transplant, there is a significant burden of disability, substance use, and psychiatric symptomatology in this population.
Assuntos
Transplante de Fígado/psicologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Apoio Social , Transtornos Relacionados ao Uso de Substâncias/psicologiaRESUMO
BACKGROUND: GlycA is a novel marker of systemic inflammation detected by nuclear magnetic resonance (NMR) spectroscopy. In the general population, GlycA is correlated with inflammatory markers such as C-reactive protein (CRP) and associated with coronary heart disease and diabetes. The utility of GlycA in patients with systemic lupus erythematosus (SLE) has not been defined. Therefore, we tested the hypothesis that GlycA concentrations are elevated in patients with SLE and associated with other markers of inflammation and coronary atherosclerosis. METHODS: We compared concentrations of GlycA, detected by NMR, in 116 patients with SLE and 84 control subjects frequency-matched for age, sex, and race. SLE disease activity index (SLEDAI) and the SLE Collaborating Clinics damage index (SLICC) were calculated. Acute phase reactants, a panel of cytokines, and a lipid panel were measured. Electron beam computer tomography (EBCT) was used to quantify coronary artery calcification, a measure of coronary artery atherosclerosis. RESULTS: Patients with SLE had higher concentrations of GlycA (398 (350-445)) than control subjects (339 (299-391)) µmol/L, p < 0.001. In patients with SLE, concentrations of GlycA were significantly associated with sedimentation rate (rho = 0.43), C-reactive protein (rho = 0.59), e-selectin (rho = 0.28), intracellular adhesion molecule-1 (rho = 0.30), triglycerides (rho = 0.45), all p < 0.0023 to account for multiple comparisons, but not with creatinine, SLEDAI, SLICC, or coronary calcium scores. CONCLUSIONS: Concentrations of GlycA are higher in patients with SLE than control subjects and associated with markers of inflammation but not with SLE disease activity or chronicity scores or coronary artery calcification.
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Biomarcadores/química , Mediadores da Inflamação/sangue , Lúpus Eritematoso Sistêmico/sangue , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Lipídeos/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Regulação para CimaRESUMO
UNLABELLED: Guidelines recommend screening for osteoporosis with bone mineral density (BMD) testing in menopausal women, particularly those with additional risk factors for fracture. Many eligible women remain unscreened. This randomized study demonstrates that a single outreach interactive voice response phone call improves rates of BMD screening among high-risk women age 50-64. INTRODUCTION: Osteoporotic fractures are a major cause of disability and mortality. Guidelines recommend screening with BMD for menopausal women, particularly those with additional risk factors for fracture. However, many women remain unscreened. We examined whether telephonic interactive voice response (IVR) or patient mailing could increase rates of BMD testing in high risk, menopausal women. METHODS: We studied 4,685 women age 50-64 years within a not-for-profit health plan in the United States. All women had risk factors for developing osteoporosis and no prior BMD testing or treatment for osteoporosis. Patients were randomly allocated to usual care, usual care plus IVR, or usual care plus mailed educational materials. To avoid contamination, patients within a single primary care physician practice were randomized to receive the same intervention. The primary endpoint was BMD testing at 12 months. Secondary outcomes included BMD testing at 6 months and medication use at 12 months. RESULTS: Mean age was 57 years. Baseline demographic and clinical characteristics were similar across the three study groups. In adjusted analyses, the incidence of BMD screening was 24.6% in the IVR group compared with 18.6% in the usual care group (P < 0.001). There was no difference between the patient mailing group and the usual care group (P = 0.3). CONCLUSIONS: In this large community-based randomized trial of high risk, menopausal women age 50-64, IVR, but not patient mailing, improved rates of BMD screening. IVR remains a viable strategy to incorporate in population screening interventions.
Assuntos
Programas de Rastreamento/organização & administração , Osteoporose Pós-Menopausa/diagnóstico , Serviços Postais , Telefone , Densidade Óssea , Diagnóstico por Computador/métodos , Feminino , Educação em Saúde/organização & administração , Promoção da Saúde/organização & administração , Humanos , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Osteoporose Pós-Menopausa/fisiopatologia , Fraturas por Osteoporose/prevenção & controle , Avaliação de Resultados em Cuidados de Saúde/métodos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Interface para o Reconhecimento da Fala , Estados Unidos , Interface Usuário-ComputadorRESUMO
There are a number of reports of interstitial deletions of the long arm of chromosome 6 that have developmental delay and obesity suggesting that this is a distinct phenotype almost like Prader-Willi syndrome. Here we report a patient with a similar deletion but a strikingly different phenotype, one more in keeping with Marfan syndrome, although he does not fulfil the criteria for that syndrome. Array comparative genomic hybridization was performed to investigate a patient with a striking phenotype. This revealed an interstitial deletion of 6q14.1q15. Parental FISH studies were normal, indicating that this is a de novo deletion. Our patient has a completely different phenotype compared to other patients reported to have similar deletions. The common feature is developmental delay, but the body features are quite different in that our patient is tall, strikingly thin with pectus excavatum, scoliosis, skin striae, arachnodactyly, pes planus, cataracts, and a high-arched palate. This contrasts with other patients who have a similar deletion but have short stature and obesity. 6q14.1q15 interstitial deletions can have a very variable phenotype and do not necessarily conform to a clinical recognizable microdeletion syndrome caused by haploinsufficiency of dosage-sensitive genes in that region as proposed by others.
RESUMO
By screening directed libraries of serine hydrolase inhibitors using the cell surface form of endothelial lipase (EL), we identified a series of carbamate-derived (EL) inhibitors. Compound 3 raised plasma HDL-C levels in the mouse, and a correlation was found between HDL-C and plasma compound levels. Spectroscopic and kinetic studies support a covalent mechanism of inhibition. Our findings represent the first report of EL inhibition as an effective means for increasing HDL-C in an in vivo model.
Assuntos
HDL-Colesterol/sangue , Endotélio Vascular/enzimologia , Inibidores Enzimáticos/química , Lipase/antagonistas & inibidores , Tiocarbamatos/química , Animais , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Concentração de Íons de Hidrogênio , Lipase/metabolismo , Lipoproteínas HDL/deficiência , Lipoproteínas HDL/genética , Lipoproteínas HDL/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Tiocarbamatos/síntese química , Tiocarbamatos/farmacologiaRESUMO
Each year roughly 800 000 people die of malaria, with 95% being African children. The shortcomings of the current drugs and the emergence of P. falciparum resistance to the artemisinin class of compounds warrant the search for new classes or derivatives. In search for such compounds, a series of 10ß-amino-quinolinylethylethers of artemisinin, previously synthesized from this laboratory were screened for antimalarial activity against both the chloroquine-susceptible 3D7 and -resistant K1 strains of P. falciparum. Their cytotoxicity was also assessed against HEK 293 and HepG2 cell lines.The parasitic and mammalian cells were incubated with compounds at various concentrations for 72 h. The antimalarial activity was determined using SYBR Green I-based fluorescence. For cytotoxicity determination, cells were grown to confluence and CellTiter-Glo luminescent cell viability assay was used.All derivatives proved to be active against both strains with good selectivity towards the parasitic cells. The derivative 11 featuring 2 artemisinin moieties and an aminoethylpiperazine linker was the most active of all. It possessed 17- and 166-fold more potency than artemether against 3D7 (EC50: 9.5 vs. 166 nM) and K1 (10.9 vs. 1723.3 nM), respectively, while was found to be as potent as artesunate against both strains.Derivative 11 stands as a good candidate to be further investigated primarily in vitro in comparison with an equimolar combination of chloroquine (CQ) and artemisinin to ascertain its advantages, if any, over the combination.
Assuntos
Antimaláricos/farmacologia , Artemisininas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Células HEK293 , Células Hep G2 , HumanosRESUMO
A validated assay for the enumeration of circulating melanoma cells (CMCs) may facilitate the development of more effective therapies for metastatic melanoma patients. In this study CD146+ cells were immunomagnetically enriched from 7.5 ml of blood. Isolated cells were fluorescently stained with DAPI, anti-molecular weight melanoma-associated antigen (HMW-MAA), anti-CD45 and CD34 and Ki67. CMCs were identified as CD146+, HMW-MAA+, CD45-, CD34-, Ki67-/+ cells. Eighty-eight percent of spiked SK-MEL28 cells in 7.5 ml blood were recovered. In all 55 healthy donors ≤1 CMCs were detected in 7.5 ml of blood. A retrospective analysis was conducted comparing CMC counts and overall survival in 79 blood samples from 44 melanoma patients. CMCs ranged from 0 to 8,042 per 7.5 ml. Two or more CMCs were detected in 18 (23%) of the patients and 30-100% (mean 84%) of the CMCs expressed the proliferation marker Ki67. Patients with ≥2 CMCs per 7.5 ml of whole blood, as compared with the group with <2 CMCs, had a shorter overall survival (2.0 months vs. 12.1 months, P=0.001).
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Melanoma/mortalidade , Melanoma/patologia , Células Neoplásicas Circulantes/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Contagem de Células/métodos , Proliferação de Células , Feminino , Humanos , Masculino , Melanoma/sangue , Melanoma/diagnóstico , Antígenos Específicos de Melanoma/análise , Antígenos Específicos de Melanoma/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/diagnóstico , Análise de SobrevidaRESUMO
Hydrocarbon resins are used to modify polymer products to achieve desired functional properties for a diverse range of products. These complex hydrocarbon-based mixtures are typically poorly soluble in water. However, resins may leach lower-molecular-weight monomers or impurities upon contact with water, thus posing a potential hazard to the aquatic environment. The bioavailability and toxicity of leachable constituents of four solid and three liquid resins were evaluated by analyzing water-accommodated fractions prepared with each resin, using biomimetic solid phase microextraction (SPME) techniques. Liquid resins exhibited concentrations of bioavailable constituents that were sufficiently elevated to cause acute toxicity to the aquatic organism Daphnia magna. All solid resins exhibited lower bioavailable concentrations of leachable constituents that were unlikely to pose an aquatic toxicity concern. Since observed toxicity of both resin types was generally consistent with bioavailable concentrations determined using SPME fiber measurements, it is concluded that this approach provides a convenient in vitro screening tool that can help reduce the use of animal testing in environmental hazard assessment of complex hydrocarbon-based substances.
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Alternativas aos Testes com Animais , Resinas Sintéticas/toxicidade , Testes de Toxicidade/métodos , Poluentes Químicos da Água/toxicidade , Animais , Disponibilidade Biológica , Materiais Biomiméticos , Daphnia , Dimetilpolisiloxanos , Feminino , Hidrocarbonetos/toxicidade , Reprodução/efeitos dos fármacos , Dióxido de Silício , SiliconesRESUMO
An all-optical AND gate based on optically induced nonlinear polarization rotation of a probe light in a bulk semiconductor optical amplifier is realized at a bit rate of 2.5Gbit/s. By operating the AND gate in an up and inverted wavelength conversion scheme, the extinction ratio is improved by 8dB compared with previously published work.