Sanidade Uterina Pós Parto: Aspectos Imunológicos e Terapêuticos

Function of the uterus is often compromised in cattle by bacterial contamination of the uterine lumen after parturition. Pathogenic bacteria often persist, causing uterine disease, a major cause of infertility in cattle. Knowledge of the immunological aspects of the uterus involved in maintaining reproductive healthiness is fundamental to the study of uterine infections that affect the uterus postpartum. Polymorphonuclear leukocytes have an important role because they are the first line of defense against colonization of bacteria in utero (Hammon and Goff, 2006). The establishment of uterine infection depends in parts of endocrine environment, particularly progesterone, which suppresses the immune system (Lewis, 2003). In the puerperium may occur uterine disorders, such as retained placenta, puerperal metritis, clinical and subclinical endometritis and pyometra, this review was proposed a study of the immunology involved in uterine health and a better understanding of uterine disorders, using the model of Sheldon et al. al, (2006) for classification of diseases, and a study of best treatment options and discussion about its functionality, because a lot of controversy among authors about choosing a treatment and another and between treated and untreated

Estimulação elétrica com eletrodos não implantáveis no tratamento da bexiga hiperativa em adultos: revisão sistemática de ensaios clínicos randonizados

Pós-graduação em Bases Gerais da Cirurgia - FMB

Response to Chemotherapy in Overweight/Obese Patients With Low-Risk Gestational Trophoblastic Neoplasia

Objective Despite rising global obesity rates, the impact of obesity on gestational trophoblastic neoplasia (GTN) remains uninvestigated. This study aimed at investigating whether overweight/obesity relates to response to chemotherapy in low-risk GTN patients.Methods This nonconcurrent cohort study included 300 patients with International Federation of Gynecology and Obstetrics-defined postmolar low-risk GTN treated with a single-agent chemotherapymethotrexate or actinomycin-D (actD)between 1973 and 2012 at the New England Trophoblastic Disease Center. Chemotherapy dosing was based on actual body weight regardless of obesity status, except for 5-day courses or pulse regimens of actD. Patients were classified as overweight/obese (body mass index [BMI] 25 kg/m(2)) or non-overweight/obese (BMI <25 kg/m(2)). Information on patient characteristics and response to chemotherapy (need for second-line chemotherapy, reason for changing to an alternative chemotherapy, number of cycles, need for combination chemotherapy, and time to human chorionic gonadotropin remission) was obtained.Results Of 300 low-risk GTN patients, 81 (27%) were overweight/obese. Overweight/obese patients were older than the non-overweight/obese patients (median age: 30 vs 28 years, P = 0.004). First-line therapy using actD was more frequent in overweight/obese patients (6.2% vs 1.4%, P = 0.036). Resistance and toxicity were similar between groups. No significant difference in the number of chemotherapy cycles needed for remission or time required to achieve remission was found between groups.Conclusions No association between overweight/obesity and low-risk GTN outcomes was found. Current chemotherapy dosing using BMI seems to be appropriate for overweight/obese patients with low-risk GTN.

Bioactivity of pyridine-2-thiolato-1-oxide metal complexes: Bi(III), Fe(III) and Ga(III) complexes as potent anti-Mycobacterium tuberculosis prospective agents

In the search for new therapeutic tools against tuberculosis and to further address the therapeutic potential of pyridine-2-thiol 1-oxide (Hmpo) metal complexes, two new octahedral [M(III)(mpo)3] complexes, with M = Ga or Bi, were synthesized and characterized in the solid state and in solution. Attempts to crystallize [Ga(III)(mpo)3] in CH2Cl2 led to single crystals of the reaction product [GaCl(mpo)2], where the gallium(III) ion is in a square basis pyramidal environment, trans-coordinated at the basis to two pyridine-2-thiolato 1-oxide anions acting as bidentate ligands through their oxygen and sulfur atoms. The biological activity of the new [M(III)(mpo)3] complexes together with that of the previously reported Fe(III) analogous compound and the pyridine-2-thiol 1-oxide sodium salt (Na mpo) was evaluated on Mycobacterium tuberculosis. The compounds showed excellent activity, both in the standard strain H37Rv ATCC 27294 (pan-susceptible) and in five clinical isolates that are resistant to the standard first-line anti-tuberculosis drugs isoniazid and rifampicin. These pyridine-2-thiol 1-oxide derivatives are promising compounds for the treatment of resistant tuberculosis.

Efeitos das formulações nanoestruturadas de doxorrubicina e cisplatina em dispersão de óxido de grafeno reduzido no tratamento da progressão do câncer de bexiga Não-músculo invasivo

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Farmacocinética do Benznidazol administrado em coelhos na forma de comprimidos de liberação imediata e comprimidos de liberação prolongada

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Perfil global de expressão de micro-RNAS circulantes como marcadores de resposta terapêutica na leucemia mielóide crônica

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Low-Cost Ultra-Wide Genotyping Using Roche/454 Pyrosequencing for Surveillance of HIV Drug Resistance

Background: Great efforts have been made to increase accessibility of HIV antiretroviral therapy (ART) in low and middle-income countries. The threat of wide-scale emergence of drug resistance could severely hamper ART scale-up efforts. Population-based surveillance of transmitted HIV drug resistance ensures the use of appropriate first-line regimens to maximize efficacy of ART programs where drug options are limited. However, traditional HIV genotyping is extremely expensive, providing a cost barrier to wide-scale and frequent HIV drug resistance surveillance. Methods/Results: We have developed a low-cost laboratory-scale next-generation sequencing-based genotyping method to monitor drug resistance. We designed primers specifically to amplify protease and reverse transcriptase from Brazilian HIV subtypes and developed a multiplexing scheme using multiplex identifier tags to minimize cost while providing more robust data than traditional genotyping techniques. Using this approach, we characterized drug resistance from plasma in 81 HIV infected individuals collected in Sao Paulo, Brazil. We describe the complexities of analyzing next-generation sequencing data and present a simplified open-source workflow to analyze drug resistance data. From this data, we identified drug resistance mutations in 20% of treatment naive individuals in our cohort, which is similar to frequencies identified using traditional genotyping in Brazilian patient samples. Conclusion: The developed ultra-wide sequencing approach described here allows multiplexing of at least 48 patient samples per sequencing run, 4 times more than the current genotyping method. This method is also 4-fold more sensitive (5% minimal detection frequency vs. 20%) at a cost 3-5 x less than the traditional Sanger-based genotyping method. Lastly, by using a benchtop next-generation sequencer (Roche/454 GS Junior), this approach can be more easily implemented in low-resource settings. This data provides proof-of-concept that next-generation HIV drug resistance genotyping is a feasible and low-cost alternative to current genotyping methods and may be particularly beneficial for in-country surveillance of transmitted drug resistance.

Oral Contraceptive Containing Chlormadinone Acetate and Ethinylestradiol Reduces Plasma Concentrations of Matrix Metalloproteinase-2 in Women with Polycystic Ovary Syndrome

Biochemical markers of cardiovascular disease, including matrix metalloproteinases (MMPs), are altered in women with polycystic ovary syndrome (PCOS), with many of these alterations thought to be due to excess androgen concentrations. Despite oral contraceptives (OCs) being the first-line pharmacological treatment in women with PCOS and the importance of MMPs in many physiological conditions and pathological states, including cardiovascular diseases, no study has yet evaluated whether OCs alter plasma concentrations of MMPs. We therefore assessed whether treatment with an OC containing the anti-androgenic progestogen alters MMP profiles in women with PCOS. We analysed 20 women with PCOS who wanted hormonal contraception (OC-PCOS group), 20 ovulatory women who required hormonal contraception (OC-control group) and 20 ovulatory women who wanted non-hormonal contraception (non-OC-control group). OC consisted of cyclic use of 2 mg chlormadinone acetate/30 mu g ethinylestradiol for 6 months. Plasma concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 were measured by gelatin zymography or enzyme-linked immunoassays. OC treatment for 6 months significantly reduced plasma MMP-2 concentrations in the OC-control and OC-PCOS groups and TIMP-2 and TIMP-1 concentrations levels in the OC-control group (all p < 0.05), but had no effects on MMP-9 concentrations or on MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in any group (all p > 0.05). These findings indicated that long-term treatment with an OC containing chlormadinone acetate plus ethinylestradiol reduced plasma MMP-2 concentrations in both healthy and PCOS women. As the latter have imbalances in circulating matrix MMPs, treatment of these women with an OC may be beneficial.

Sorafenib in Combination With Capecitabine: An Oral Regimen for Patients With HER2-Negative Locally Advanced or Metastatic Breast Cancer

Purpose Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) -negative breast cancer. Patients and Methods Patients were randomly assigned to first-or second-line capecitabine 1,000 mg/m(2) orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS). Results In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand-foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively). Conclusion Addition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.

Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer

BACKGROUND The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. METHODS We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. RESULTS The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. CONCLUSIONS The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.)

Safety and efficacy of gemcitabine plus cisplatin combination in pretreated metastatic breast cancer patients

Metastatic breast cancers (MBC) previously treated with anthracyclines (A) and taxanes (T) have a complicated management. Gemcitabine (G)-cisplatin (C) combinations have been used as synergistic salvage therapy in MBC and are considered as another option for patients with important symptoms and aggressive visceral disease. We analyzed the safety and efficacy of GC in AT-pretreated MBC, as well as overall survival (OS) and time to progression (TTP). Forty-nine subjects received IV G 750 mg/m(2) and C 30 mg/m(2), both d1 and d8 every 3 weeks. Response evaluation was performed every second cycle and in the end of treatment. GC protocol was the first-line palliative chemotherapy in half of the cases, and median number of cycles/patient were 4(2-12). Lung (75.5%) was the most frequent site of metastasis. Most of the patients related clinical improvement with chemotherapy with minimal/mild tolerable collateral effects in 85.7% of cases. Following 34 months, mean OS/TTP was 13.12/6.6 months. Objective-responded patients (40.3%) were statistically associated with the improvement in symptoms after CT (P < 0.01), and OS was directly correlated with chemotherapy response (P < 0.01). HER-2 overexpression was a prognostic factor with reduced OS (P = 0.01). GC protocol was effective and tolerable in objective-responded patients.

T-cell large granular lymphocytic leukemia: treatment experience with fludarabine

OBJECTIVES: The aim of this retrospective study was to investigate the results of T-cell large granular lymphocytic leukemia treatment with fludarabine by assessing the complete hematologic response, the complete molecular response, progression-free survival, and overall survival. METHODS: We evaluated the records of six patients with T-cell large granular lymphocytic leukemia who were treated with fludarabine as a first-, second-, or third-line therapy, at a dose of 40 mg/m(2), for three to five days per month and 6 to 8 cycles. RESULTS: Of the six patients investigated with T-cell large granular lymphocytic leukemia who were treated with fludarabine, five (83.3%) were female, and their median age was 36.5 years (range 18 to 73). The median lymphocyte level was 3.4x10(9)/L (0.5 to 8.9). All patients exhibited a monoclonal T-cell receptor gamma gene rearrangement at diagnosis. Two (33.3%) patients received fludarabine as first-line treatment, two (33.3%) for refractory disease, one (16.6%) for relapsed disease after the suspension of methotrexate treatment due to liver toxicity, and one (16.6%) due to dyspesia. A complete hematologic response was achieved in all cases, and a complete molecular response was achieved in five out six cases (83.3%). During a mean follow-up period of 12 months, both the progression-free survival and overall survival rates were 100%. CONCLUSION: T-cell large granular lymphocytic leukemia demonstrated a high rate of complete hematologic and molecular response to fludarabine, with excellent compliance and tolerability rates. To confirm our results in this rare disease, we believe that fludarabine should be tested in clinical trials as a first-line treatment for T-cell large granular lymphocytic leukemia.

Does videothoracoscopy improve clinical outcomes when implemented as part of a pleural empyema treatment algorithm?

OBJECTIVE: We aimed to evaluate whether the inclusion of videothoracoscopy in a pleural empyema treatment algorithm would change the clinical outcome of such patients. METHODS: This study performed quality-improvement research. We conducted a retrospective review of patients who underwent pleural decortication for pleural empyema at our institution from 2002 to 2008. With the old algorithm (January 2002 to September 2005), open decortication was the procedure of choice, and videothoracoscopy was only performed in certain sporadic mid-stage cases. With the new algorithm (October 2005 to December 2008), videothoracoscopy became the first-line treatment option, whereas open decortication was only performed in patients with a thick pleural peel (>2 cm) observed by chest scan. The patients were divided into an old algorithm (n = 93) and new algorithm (n = 113) group and compared. The main outcome variables assessed included treatment failure (pleural space reintervention or death up to 60 days after medical discharge) and the occurrence of complications. RESULTS: Videothoracoscopy and open decortication were performed in 13 and 80 patients from the old algorithm group and in 81 and 32 patients from the new algorithm group, respectively (p < 0.01). The patients in the new algorithm group were older (41 +/- 1 vs. 46.3 +/- 16.7 years, p=0.014) and had higher Charlson Comorbidity Index scores [0(0-3) vs. 2(0-4), p = 0.032]. The occurrence of treatment failure was similar in both groups (19.35% vs. 24.77%, p= 0.35), although the complication rate was lower in the new algorithm group (48.3% vs. 33.6%, p = 0.04). CONCLUSIONS: The wider use of videothoracoscopy in pleural empyema treatment was associated with fewer complications and unaltered rates of mortality and reoperation even though more severely ill patients were subjected to videothoracoscopic surgery.

Gray Matter Volumes in Obsessive-Compulsive Disorder Before and After Fluoxetine or Cognitive-Behavior Therapy: A Randomized Clinical Trial

Serotonin reuptake inhibitors and cognitive-behavior therapy (CBT) are considered first-line treatments for obsessive-compulsive disorder (OCD). However, little is known about their modulatory effects on regional brain morphology in OCD patients. We sought to document structural brain abnormalities in treatment-naive OCD patients and to determine the effects of pharmacological and cognitive-behavioral treatments on regional brain volumes. Treatment-naive patients with OCD (n = 38) underwent structural magnetic resonance imaging scan before and after a 12-week randomized clinical trial with either fluoxetine or group CBT. Matched-healthy controls (n = 36) were also scanned at baseline. Voxel-based morphometry was used to compare regional gray matter (GM) volumes of regions of interest (ROIs) placed in the orbitofrontal, anterior cingulate and temporolimbic cortices, striatum, and thalamus. Treatment-naive OCD patients presented smaller GM volume in the left putamen, bilateral medial orbitofrontal, and left anterior cingulate cortices than did controls (p<0.05, corrected for multiple comparisons). After treatment with either fluoxetine or CBT (n = 26), GM volume abnormalities in the left putamen were no longer detectable relative to controls. ROI-based within-group comparisons revealed that GM volume in the left putamen significantly increased (p<0.012) in fluoxetine-treated patients (n = 13), whereas no significant GM volume changes were observed in CBT-treated patients (n = 13). This study supports the involvement of orbitofronto/cingulo-striatal loops in the pathophysiology of OCD and suggests that fluoxetine and CBT may have distinct neurobiological mechanisms of action. Neuropsychopharmacology (2012) 37, 734-745; doi: 10.1038/npp.2011.250; published online 26 October 2011