Prevenção da repetição de episódos de reação tipo 2 da Hanseníase com o uso da talidomida na dose de 100mg/dia

Introdução: A hanseníase é doença crônica que pode ter seu curso interrompido por episódios reacionais tipo 1 e 2 ou ENH, sendo que estes podem ser repetitivos, com conseqüentes danos ao paciente.A talidomida é a medicação de eleição para o controle, desde 1965. Objetivo: Evitar repetição de episódios reacionais. Material e Método: Após o controle da reação com dose tradicional, utilizou-se 100mg/d, pelo período de seis meses, com acompanhamento por seis meses após a suspensão. Resultados: Foram avaliados 42 pacientes MB, 39 (92,85%) da forma V e 3(7,15%) da D, que apresentaram ENH, como primeiro episódio ou repetição, 33(78,6%) do sexo masculino e9(21,4%) do feminino. As idades variaram de 18 a 84 anos, predomínio acima de 49 anos.Não se observou repetição em 100% dos pacientes durante o uso dessa dose.Durante a observação clinica, 33(78,6%)continuaram sem apresentar reação e9(21,4%), todos da forma V,a apresentaram, de forma leve,sem sinais e sintomas, controlada com antinflamatórios não hormonais. Não houve efeitos adversos. Conclusões: sugere-se o uso da talidomida, 100mg/ dia, como manutenção, que foi efetiva, impedindo a repetição das reações tipo 2.

Effect of low-dose combined oral contraceptives on bone mineral density in adolescents: a 1-year follow-up

Purpose: To assess the bone mineral density (BMD) and bone mineral content (BMC) of female adolescents in use of standard low-dose combined oral contraceptives (COC) (EE 20 mcg/ Desogestrel 150 mcg) for a one-year period and to compare results against healthy controls matched for age and gender not in use of COC. Methods: A prospective, longitudinal study was conducted.Fifty adolescents, 12 to 20 years of age, were divided into a COC user group (n 35) and a control group (n 15) and submitted to a Bone Densitometry scan using dual-energy X-ray absorptiometry (DXA) at study inclusion and again at 12-month follow-up. Results: Results showed no statistically significant differences between the COC user and control groups at the initial moment. However, at 12-month follow-up, COC users showed negative mean percentage variation between initial and follow-up values for lumbar spine BMD and BMC of -1.09% and -1.58%, respectively, whereas controls had positive variations of +12.44% and +15.87%, respectively. Thus, the adolescents in use of COC showed a loss, albeit slight, in bone mass whereas the control group showed an increase. Conclusions: The low dose COC assessed (EE 20 mcg/Desogestrel 150 mcg) appeared to negatively affect the process of bone mass acquisition which occurs during adolescence.

PS-042c is low-dose combined oral contraceptives use associated to lower bone mineral content variation in adolescents over a one-year period?

Background Low dose combined oral contraceptives (COC) can interfere in bone mass acquisition during adolescence. To evaluate bone mineral density (BMD) and bone mineral content (BMC) in female adolescents taking a standard low-dose (EE 20 µg/Desogestrel 150 µg) combination oral contraceptive (COC) over a one-year period and compare with healthy adolescents from the same age group not taking COCs.Methods A non-randomised parallel control study with one-year follow-up. Sixty-seven adolescents from 12 to 20 years of age, divided into COC users (n = 41) taking 20 µg EE/150 µg Desogestrel and non-user controls (n = 26), were evaluated through bone densitometry examinations at baseline and 12 months later. Comparisons between groups at study start was done through the Mann-Whitney test with significance level fixed at 5% or corresponding p value; comparisons between groups at study start and 12 months later used variations in median percentages for bone mass variables.Results COC users presented low bone mass acquisition in the lumbar spine and BMD and BMC median variations between baseline and at 12 months of 2.07% and +1.57% respectively whereas the control group presented variations of +12.16% and +16.84% for BMD and BMC, respectively, over the same period. The total body BMD and BMC presented similar evolution during the study in both groups. Statistical significance (pConclusion The use of a low COC dose (EE 20 µg/Desogestrel 150 µg) was associated to lower bone mass acquisition in adolescents during the study period.Trial registration: (Register Number):RBR-5 h9b3c

A matheuristic for the selection of beam directions and dose distribution in radiotherapy planning

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Dinâmica de corpos lúteos em protocolos com redução da dose de FSH na superovulação em ovelhas

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Modulação da doença periodontal por curcumin modificado quimicamente. Estudo de dose-resposta em roedor

Pós-graduação em Odontologia - FOAR

Competition Between Novelty and Cocaine Conditioned Reward Is Sensitive to Drug Dose and Retention Interval

The conditioned rewarding effects of novelty compete with those of cocaine for control over choice behavior using a place conditioning task. The purpose of the present study was to use multiple doses of cocaine to determine the extent of this competition and to determine whether novelty’s impact on cocaine reward was maintained over an abstinence period. In Experiment 1, rats were conditioned with cocaine (7.5, 20, or 30 mg/kg ip) to prefer one side of an unbiased place conditioning apparatus relative to the other. In a subsequent phase, all rats received alternating daily confinements to the previously cocaine paired and unpaired sides of the apparatus. During this phase, half the rats had access to a novel object on their initially unpaired side; the remaining rats did not receive objects. The ability of novelty to compete with cocaine in a drug free and cocaine challenge test was sensitive to cocaine dose. In Experiment 2, a place preference was established with 10 mg/kg cocaine and testing occurred after 1, 14, or 28 day retention intervals. Findings indicate that choice behaviors mediated by cocaine conditioning are reduced with the passing of time. Taken together, competition between cocaine and novelty conditioned rewards are sensitive to drug dose and retention interval.

Dose-dependent effect of Resveratrol on bladder cancer cells: Chemoprevention and oxidative stress

Background: Over 6 million people die annually in the world because of cancer. Several groups are focused on studying cancer chemoprevention approaches. Resveratrol, a polyphenol, at high dosages, has been reported as antitumor and chemopreventive. However, it has a dose-dependent effect on cell death, even on some cancer cells. Objectives: Our aim was to investigate this dose-dependent effect on human bladder carcinoma ECV304 cells during oxidative stress condition. Methods: For this purpose. ECV304 cells incubated with different Resveratrol concentrations were analyzed as for their metabolic rate, membrane permeability, DNA fragmentation, anti/proapoptotic protein levels and phosphatidylserine exposure after oxidative stress. Results: Resveratrol induced cell death at high concentrations (>20 mu M), but not at low ones (0.1-20 mu M). Pretreatment with 2.5 mu M protected the cells from oxidative damage, whereas 50 mu M intensified the cell death and significantly increased Bad/Bcl-2 ratio (proapoptotic/antiapoptotic proteins). Resveratrol was able to modulate NO and PGE(2) secretion and performed an anti-adhesion activity of neutrophils on PMA-activated ECV304 cells. Conclusions: Resveratrol at high doses induces cell death of ECV304 cells whereas low doses induce protection. Modulation of Bcl-2 protein induced by Resveratrol could be mediating this effect. This information about the role of Resveratrol on cancer alerts us about its dose-dependent effects and could lead the design of future chemoprevention strategies. Published by Elsevier Ireland Ltd.

Dose-dependent change in biomarkers during neoadjuvant endocrine therapy with fulvestrant: results from NEWEST, a randomized Phase II study

NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) is the first study to compare biological and clinical activity of fulvestrant 500 versus 250 mg in the neoadjuvant breast cancer setting. We hypothesized that fulvestrant 500 mg may be superior to 250 mg in blocking estrogen receptor (ER) signaling and growth. A multicenter, randomized, open-label, Phase II study was performed to compare fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) versus fulvestrant 250 mg/month for 16 weeks prior to surgery in postmenopausal women with ER+ locally advanced breast cancer. Core biopsies at baseline, week 4, and surgery were assessed for biomarker changes. Primary endpoint: change in Ki67 labeling index (LI) from baseline to week 4 determined by automated computer imaging system (ACIS). Secondary endpoints: ER protein expression and function; progesterone receptor (PgR) expression; tumor response; tolerability. ER and PgR were examined retrospectively using the H score method. A total of 211 patients were randomized (fulvestrant 500 mg: n = 109; 250 mg: n = 102). At week 4, fulvestrant 500 mg resulted in greater reduction of Ki67 LI and ER expression versus 250 mg (-78.8 vs. -47.4% [p < 0.0001] and -25.0 vs. -13.5% [p = 0.0002], respectively [ACIS]); PgR suppression was not significantly different (-22.7 vs. -17.6; p = 0.5677). However, H score detected even greater suppression of ER (-50.3 vs. -13.7%; p < 0.0001) and greater PgR suppression (-80.5 vs. -46.3%; p = 0.0018) for fulvestrant 500 versus 250 mg. At week 16, tumor response rates were 22.9 and 20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by both ACIS and H score. No detrimental effects on endometrial thickness or bone markers and no new safety concerns were identified. This provides the first evidence of greater biological activity for fulvestrant 500 versus 250 mg in depleting ER expression, function, and growth.

Effluent volume and dialysis dose in CRRT: time for reappraisal

The results of several studies assessing dialysis dose have dampened the enthusiasm of clinicians for considering dialysis dose as a modifiable factor influencing outcomes in patients with acute kidney injury. Powerful evidence from two large, multicenter trials indicates that increasing the dialysis dose, measured as hourly effluent volume, has no benefit in continuous renal replacement therapy (CRRT). However, some important operational characteristics that affect delivered dose were not evaluated. Effluent volume does not correspond to the actual delivered dose, as a decline in filter efficacy reduces solute removal during therapy. We believe that providing accurate parameters of delivered dose could improve the delivery of a prescribed dose and refine the assessment of the effect of dose on outcomes in critically ill patients treated with CRRT.

Lethal effects of abamectin on the aquatic organisms Daphnia similis, Chironomus xanthus and Danio rerio

Abamectin is used as an acaricide and insecticide for fruits, vegetables and ornamental plants, as well as a parasiticide for animals. One of the major problems of applying pesticides to crops is the likelihood of contaminating aquatic ecosystems by drift or runoff. Therefore, toxicity tests in the laboratory are important tools to predict the effects of chemical substances in aquatic ecosystems. The aim of this study was to assess the potential hazards of abamectin to the freshwater biota and consequently the possible losses of ecological services in contaminated water bodies. For this purpose, we identified the toxicity of abamectin on daphnids, insects and fish. Abamectin was highly toxic, with an EC50 48 h for Daphnia similis of 5.1 ng L-1, LC50 96 h for Chironomus xanthus of 2.67 mu g L-1 and LC50 48 h for Danio rerio of 33 mu g L-1. (C) 2011 Elsevier Ltd. All rights reserved.

ABCB1 haplotype is associated with major molecular response in chronic myeloid leukemia patients treated with standard-dose of imatinib

Background: Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor used for treating chronic myeloid leukemia (CML). IM has high efficacy, however some individuals develop a resistance due to impaired bio-availability. Polymorphisms in genes encoding membrane transporters such as ABCB1 have been associated with differences in protein expression and function that influence the response to several drugs. Aim: To investigate the relationship of ABCB1 polymorphisms with markers of response to IM in patients with CML Methods: One hundred eighteen CML patients initially treated with a standard dose of IM (400 mg/day) for 18 months were selected at two health centers in Sao Paulo City, Brazil. The response criteria were based on the European LeukemiaNet recommendations. ABCB1 polymorphisms c.1236C>T (rs1128503), c.3435C>T (rs1045642) and c.2677G>T/A (rs2032582) were evaluated by PCR-RFLP. Results: ABCB1 polymorphisms were not related with a risk for CML in this sample population (p<0.05). In the CML group, frequencies of ABCB1 SNPs were similar between responder and non-responder patients (p>0.05). In the responder group, the frequency of ABCB11236CT/2677GT/3435CT haplotype was higher in patients with major molecular response (MMR) (51.7%) than in patients without MMR (8.3%, p = 0.010). Furthermore, carriers of this haplotype had increased the probability of reaching the MMR compared with the non-carriers (OR: 11.8; 95% CI: 1.43-97.3, p = 0.022). Conclusions: The ABCB1 1236CT/2677GT/3435CT haplotype is positively associated with the major molecular response to IM in CML patients. (C) 2011 Elsevier Inc. All rights reserved.

Antihypertensive and antioxidant effects of a single daily dose of sodium nitrite in a model of renovascular hypertension

Dietary nitrite and nitrate have been reported as alternative sources of nitric oxide (NO). In this regard, we reported previously that sodium nitrite added to drinking water was able to exert antihypertensive effects in an experimental model of hypertension in a dose-dependent manner. Taking into consideration that nitrite is continuously converted to nitrate in the bloodstream, here we expanded our previous report and evaluate whether a single daily dose of sodium nitrite could exert antihypertensive effects in 2 kidney-1 clip (2K1C) hypertensive rats. Sham-operated and 2K1C rats were treated with vehicle or sodium nitrite (15 mg/kg/day) for 4 weeks. We evaluated the effects induced by sodium nitrite treatment on systolic blood pressure (SBP) and NO markers such as plasma nitrite, nitrite + nitrate (NOx), cGMP, and blood levels of nitrosyl-hemoglobin. In addition, we also evaluated effects of nitrite on oxidative stress and antioxidant enzymes. Dihydroethidium (DHE) was used to evaluate aortic reactive oxygen species (ROS) production by fluorescence microscopy, and plasma levels of thiobarbituric acid-reactive species (TBARS) were measured in plasma samples from all experimental groups. Red blood cell superoxide dismutase (SOD) and catalase activity were evaluated with commercial kits. Sodium nitrite treatment reduced SBP in 2K1C rats (P < 0.05). We found lower plasma nitrite and NOx levels in 2K1C rats compared with normotensive controls (both P < 0.05). Nitrite treatment restored the lower levels of nitrite and NOx. While no change was found in the blood levels of nitrosyl-hemoglobin (P > 0.05), nitrite treatment increased the plasma levels of cGMP in 2K1C rats (P < 0.05). Higher plasma TBARS levels and aortic ROS levels were found in hypertensive rats compared with controls (P < 0.05), and nitrite blunted these alterations. Lower SOD and catalase activities were found in 2K1C hypertensive rats compared with controls (both P < 0.05). Nitrite treatment restored SOD activity (P < 0.05), whereas catalase was not affected. These data suggest that even a single daily oral dose of sodium nitrite is able to lower SBP and exert antioxidant effects in renovascular hypertension.

Gastrin-Releasing Peptide Receptor Antagonism Induces Protection from Lethal Sepsis: Involvement of Toll-like Receptor 4 Signaling

In sepsis, toll-like receptor (TLR)-4 modulates the migration of neutrophils to infectious foci, favoring bacteremia and mortality. In experimental sepsis, organ dysfunction and cytokines released by activated macrophages can be reduced by gastrin-releasing peptide (GRP) receptor (GRPR) antagonist RC-3095. Here we report a link between GRPR and TLR-4 in experimental models and in sepsis patients. RAW 264.7 culture cells were exposed to lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-alpha and RC-3095 (10 ng/mL), Male Wistar rats were subjected to cecal ligation and puncture (CLP), and RC-3095 was administered (3 mg/kg, subcutaneously); after 6 h, we removed the blood, bronchoalveolar lavage, peritoneal lavage and lung. Human patients with a clinical diagnosis of sepsis received a continuous infusion with RC-3095 (3 mg/kg, intravenous) over a period of 12 h, and plasma was collected before and after RC-3095 administration and, in a different set of patients with systemic inflammatory response syndrome (SIRS) or sepsis. GRP plasma levels were determined. RC-3095 inhibited TLR-4, extracellular-signal-related kinase (ERK)-1/2, Jun NH2-terminal kinase (JNK) and Akt and decreased activation of activator protein 1 (AP-1), nuclear factor (NF)-kappa B and interleukin (IL)-6 in macrophages stimulated by LPS. It also decreased IL-6 release from macrophages stimulated by TNF-alpha. RC-3095 treatment in CLP rats decreased lung TLR-4, reduced the migration of cells to the lung and reduced systemic cytokines and bacterial dissemination. Patients with sepsis and systemic inflammatory response syndrome have elevated plasma levels of GRP which associates with clinical outcome in the sepsis patients. These findings highlight the role of GRPR signaling in sepsis outcome and the beneficial action of GRPR antagonists in controlling the inflammatory response in sepsis through a mechanism involving at least inhibition of TLR-4 signaling. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00083

Action of ANP on the nongenomic dose-dependent biphasic effect of aldosterone on NHE1 in proximal S3 segment

The rapid (2 min) nongenomic effects of aldosterone (ALDO) and/or spironolactone (MR antagonist), RU 486 (GR antagonist), atrial natriuretic peptide (ANP) and dimethyl-BAPTA (BAPTA) on the intracellular pH recovery rate (pHirr) via NHE1 (basolateral Na+/H+ exchanger isoform), after the acid load induced by NH4Cl, and on the cytosolic free calcium concentration ([Ca2+](i)) were investigated in the proximal S3 segment isolated from rats, by the probes BCECF-AM and FLUO-4-AM, respectively. The basal pHi was 7.15+/-0.008 and the basal pHirr was 0.195+/-0.012 pH units/min (number of tubules/number of tubular areas = 16/96). Our results confirmed the rapid biphasic effect of ALDO on NHE1: ALDO (10(-12) M) increases the pHirr to approximately 59% of control value, and ALDO (10(-6)M) decreases it to approximately 49%. Spironolactone did not change these effects, but RU 486 inhibited the stimulatory effect and maintained the inhibitory effect. ANP (10(-6) M) or BAPTA (5 x 10(-5) M) alone had no significant effect on NHE1 but prevented both effects of ALDO on this exchanger. The basal [Ca2+](i) was 104+/-3 nM (15), and ALDO (10(-12) or 10(-6) M) increased the basal [Ca2+](i) to approximately 50% or 124%, respectively. RU 486, ANP and BAPTA decreased the [Ca2+](i) and inhibited the stimulatory effect of both doses of ALDO. The results suggest the involvement of GR on the nongenomic effects of ALDO and indicate a pHirr-regulating role for [Ca2+](i) that is mediated by NHE1, stimulated/impaired by ALDO, and affected by ANP or BAPTA with ALDO. The observed nongenomic hormonal interaction in the S3 segment may represent a rapid and physiologically relevant regulatory mechanism in the intact animal under conditions of volume alterations. (C) 2011 Elsevier Ltd. All rights reserved.