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OBJECTIVE: To determine the safety and efficacy of a transdermal nanostructured formulation of progesterone (10%) combined with estriol (0.1%) + estradiol (0.25%) for relieving postmenopausal symptoms. METHODS: A total of 66 postmenopausal Brazilian women with climacteric symptoms of natural menopause received transdermal nanostructured formulations of progesterone and estrogens in the forearm daily for 60 months to mimic the normal ovarian secretory pattern. Confocal Raman spectroscopy of hormones in skin layers was performed. Clinical parameters, serum concentrations of estradiol and follicle-stimulating hormone, blood pressure, BI-RADS classification from bilateral mammography, and symptomatic relief were compared between baseline and 60 months post-treatment. Clinicaltrials.gov: NCT02033512. RESULTS: An improvement in climacteric symptoms was reported in 92.5% of women evaluated before and after 60 months of treatment. The serum concentrations of estradiol and follicle-stimulating hormone changed significantly (p<0.05) after treatment; the values of serum follicle-stimulating hormone decreased after 60 months from 82.04±4.9 to 57.12±4.1 IU/mL. A bilateral mammography assessment of the breasts revealed normal results in all women. No adverse health-related events were attributed to this hormone replacement therapy protocol. CONCLUSION: The nanostructured formulation is safe and effective in re-establishing optimal serum levels of estradiol and follicle-stimulating hormone and relieving the symptoms of menopause. This transdermal hormone replacement therapy may alleviate climacteric symptoms in postmenopausal women.

Resumo em Inglês:

OBJECTIVE: The aim of this study was to determine the effects of occupational noise on sound localization in different spatial planes and frequencies among normal hearing firefighters. METHOD: A total of 29 adults with pure-tone hearing thresholds below 25 dB took part in the study. The participants were divided into a group of 19 firefighters exposed to occupational noise and a control group of 10 adults who were not exposed to such noise. All subjects were assigned a sound localization task involving 117 stimuli from 13 sound sources that were spatially distributed in horizontal, vertical, midsagittal and transverse planes. The three stimuli, which were square waves with fundamental frequencies of 500, 2,000 and 4,000 Hz, were presented at a sound level of 70 dB and were randomly repeated three times from each sound source. The angle between the speaker's axis in the same plane was 45°, and the distance to the subject was 1 m. RESULT: The results demonstrate that the sound localization ability of the firefighters was significantly lower (p<0.01) than that of the control group. CONCLUSION: Exposure to occupational noise, even when not resulting in hearing loss, may lead to a diminished ability to locate a sound source.

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OBJECTIVES: Despite evidence suggesting that Doppler ultrasonography can help to differentiate between benign and malignant breast lesions, it is rarely applied in clinical practice. The aim of this study was to determine whether certain vascular features of breast masses observed by duplex Doppler and color Doppler ultrasonography (before and/or after microbubble contrast injection) add information to the gray-scale analysis and support the Breast Imaging-Reporting and Data System (BI-RADS) classification. METHODS: Seventy solid lesions were prospectively evaluated with gray-scale ultrasonography, color Doppler ultrasonography, and contrast-enhanced ultrasonography. The morphological analysis and lesion vascularity were correlated with the histological results. RESULTS: Percutaneous core biopsies revealed that 25/70 (17.5%) lesions were malignant, while 45 were benign. Hypervascular lesions with tortuous and central vessels, a resistive index (RI)≥0.73 before contrast injection, and an RI≥0.75 after contrast injection were significantly predictive of malignancy (p<0.001). CONCLUSION: The combination of gray-scale ultrasonography data with unenhanced or enhanced duplex Doppler and color Doppler US data can provide diagnostically useful information. These techniques can be easily implemented because Doppler devices are already present in most health centers.

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OBJECTIVE: This study compares the clinical, ultrasonography, radiography, and laboratory outcomes of painless and painful chronic synovitis in patients with established rheumatoid arthritis. METHODS: This cross-sectional study involved 60 patients with rheumatoid arthritis and synovitis in the metacarpophalangeal joints; 30 of the patients did not experience pain, and 30 had experienced pain for at least 6 months prior to the study. The radiocarpal, distal radioulnar, and metacarpophalangeal joints were evaluated using the ultrasound gray scale, power Doppler, and radiography. Past and present clinical and laboratory findings were also evaluated. RESULTS: There were no statistically significant differences between the groups for most of the outcomes. The group with pain scored worse on the disease activity indices (e.g., DAS 28 and SDAI), function questionnaires (HAQ and Cochin), and pinch strength test. A logistic regression analysis revealed that the use of an immunobiological agent was associated with a 3-fold greater chance of belonging to the group that experienced pain. The painless group had worse erosion scores in the second and fifth metacarpophalangeal with odd ratios (ORs) of 6.5 and 3.5, respectively. The painless group had more cartilage with grade 4 damage in the third metacarpophalangeal. CONCLUSIONS: The rheumatoid arthritis patients with both painless and painful synovitis exhibited similar disease histories and radiographic and ultrasound findings. However, the ultrasonography evaluation revealed worse scores in the second and fifth metacarpophalangeal of the synovitis patients who did not experience pain.

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OBJECTIVE: Hyperhidrosis is a common disease, and thoracoscopic sympathectomy improves its symptoms in up to 95% of cases. Unfortunately, after surgery, plantar hyperhidrosis may remain in 50% of patients, and compensatory sweating may be observed in 70%. This clinical scenario remains a challenge. Our objective was to evaluate the effectiveness of oxybutynin in the treatment of persistent plantar hyperhidrosis and compensatory sweating and its effects on quality of life in women after thoracoscopic sympathectomy. METHOD: We conducted a prospective, randomized study to compare the effects of oxybutynin at 10 mg daily and placebo in women with persistent plantar hyperhidrosis. The assessment was performed using a quality-of-life questionnaire for hyperhidrosis and sweating measurement with a device for quantifying transepidermal water loss. Clinicaltrials.gov: NCT01328015. RESULTS: Sixteen patients were included in each group (placebo and oxybutynin). There were no significant differences between the groups prior to treatment. After oxybutynin treatment, there was a decrease in symptoms and clinical improvement based on the quality-of-life questionnaire (before treatment, 40.4 vs. after treatment, 17.5; p = 0.001). The placebo group showed modest improvement (p = 0.09). The outcomes of the transepidermal water loss measurements in the placebo group showed no differences (p = 0.95), whereas the oxybutynin group revealed a significant decrease (p = 0.001). The most common side effect was dry mouth (100% in the oxybutynin group vs. 43.8% in the placebo group; p = 0.001). CONCLUSION: Oxybutynin was effective in the treatment of persistent plantar hyperhidrosis, resulting in a better quality of life in women who had undergone thoracoscopic sympathectomy.

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OBJECTIVE: This study was conducted to investigate factors associated with thrombocytopenia in a large cohort of patients with leptospirosis in an endemic area. METHODS: This retrospective study included 374 consecutive patients with leptospirosis who were admitted to tertiary hospitals in Fortaleza, Brazil. All patients had a diagnosis of severe leptospirosis (Weil's disease). Acute kidney injury was defined according to the RIFLE criteria. Thrombocytopenia was defined as a platelet count <100,000/mm3. RESULTS: A total of 374 patients were included, with a mean age of 36.1±15.5 years, and 83.4% were male. Thrombocytopenia was present at the time of hospital admission in 200 cases (53.5%), and it developed during the hospital stay in 150 cases (40.3%). The patients with thrombocytopenia had higher frequencies of dehydration (53% vs. 35.3%, p = 0.001), epistaxis (5.7% vs. 0.8%, p = 0.033), hematemesis (13% vs. 4.6%, p = 0.006), myalgia (91.5% vs. 84.5%, p = 0.038), hematuria (54.8% vs. 37.6%, p = 0.011), metabolic acidosis (18% vs. 9.2%, p = 0.016) and hypoalbuminemia (17.8% vs. 7.5%, p = 0.005). The independent risk factors associated with thrombocytopenia during the hospital stay were lengthy disease (OR: 1.2, p = 0.001) and acute kidney injury (OR: 6.6, p = 0.004). Mortality was not associated with thrombocytopenia at admission (12.5% vs. 12.6%, p = 1.000) or during the hospital stay (12.6% vs. 11.3%, p = 0.748). CONCLUSIONS: Thrombocytopenia is a frequent complication in leptospirosis, and this condition was present in more than half of patients at the time of hospital admission. Lengthy disease and acute kidney injury are risk factors for thrombocytopenia. There was no significant association between thrombocytopenia and mortality.

Resumo em Inglês:

OBJECTIVE: High genistein doses have been reported to induce fluid accumulation in the uteri of ovariectomised rats, although the mechanism underlying this effect remains unknown. Because genistein binds to the oestrogen receptor and the cystic fibrosis transmembrane regulator mediates uterine fluid secretion, we hypothesised that this genistein effect involves both the oestrogen receptor and cystic fibrosis transmembrane regulator. METHODS: Ovariectomised adult female Sprague-Dawley rats were treated with 25, 50, or 100 mg/kg/day genistein for three consecutive days with and without the ER antagonist ICI 182780. One day after the final drug injection, the animals were humanely sacrificed, and the uteri were removed for histology and cystic fibrosis transmembrane regulator mRNA and protein expression analysis using real-time polymerase chain reaction and Western blotting, respectively. The cystic fibrosis transmembrane regulator protein distribution was analysed visually by immunohistochemistry. RESULTS: The histological analysis revealed an increase in the circumference of the uterine lumen with increasing doses of genistein, which was suggestive of fluid accumulation. Moreover, genistein stimulated a dose-dependent increase in the expression of cystic fibrosis transmembrane regulator protein and mRNA, and high-intensity cystic fibrosis transmembrane regulator immunostaining was observed at the apical membrane of the luminal epithelium following 50 and 100 mg/kg/day genistein treatment. The genistein-induced increase in uterine luminal circumference and cystic fibrosis transmembrane regulator expression was antagonised by treatment with ICI 182780. CONCLUSION: Genistein-induced luminal fluid accumulation in ovariectomised rats' uteri involves the oestrogen receptor and up-regulation of cystic fibrosis transmembrane regulator expression, and these findings reveal the mechanism underlying the effect of this compound on changes in fluid volume in the uterus after menopause.

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OBJECTIVE: To evaluate whether the pathophysiology of shock syndromes can be better understood by comparing central hemodynamics with kinetic data on fluid and electrolyte shifts. METHODS: We studied the dilutional hyponatremic shock that developed in response to overhydration with electrolyte-free irrigating fluid - the so-called ‘transurethral resection syndrome' - by comparing cardiac output, arterial pressures, and volume kinetic parameters in 17 pigs that were administered 150 ml/kg of either 1.5% glycine or 5% mannitol by intravenous infusion over 90 minutes. RESULTS: Natriuresis appeared to be the key factor promoting hypovolemic hypotension 15-20 minutes after fluid administration ended. Excessive sodium excretion, due to osmotic diuresis caused by the irrigant solutes, was associated with high estimates of the elimination rate constant (k10) and low or negative estimates of the rate constant describing re-distribution of fluid to the plasma after translocation to the interstitium (k21). These characteristics indicated a high urinary flow rate and the development of peripheral edema at the expense of plasma volume and were correlated with reductions in cardiac output. The same general effects of natriuresis were observed for both irrigating solutions, although the volume of infused 1.5% glycine had a higher tendency to enter the intracellular fluid space. CONCLUSION: Comparisons between hemodynamics and fluid turnover showed a likely sequence of events that led to hypovolemia despite intravenous administration of large amounts of fluid.

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OBJECTIVE: Most lung transplants are obtained from brain-dead donors. The physiopathology of brain death involves hemodynamics, the sympathetic nervous system, and inflammatory mechanisms. Administering methylprednisolone 60 min after inducing brain death in rats has been shown to modulate pulmonary inflammatory activity. Our objective was to evaluate the effects of methylprednisolone on transplanted rat lungs from donors treated 60 min after brain death. METHODS: Twelve Wistar rats were anesthetized, and brain death was induced. They were randomly divided into two groups (n = 6), namely a control group, which was administered saline solution, and a methylprednisolone group, which received the drug 60 min after the induction of brain death. All of the animals were observed and ventilated for 2 h prior to being submitted to lung transplantation. We evaluated the hemodynamic and blood gas parameters, histological score, lung tissue levels of thiobarbituric acid-reactive substances, level of superoxide dismutase, level of tumor necrosis factor-alpha, and level of interleukin-1 beta. RESULTS: After transplantation, a significant reduction in the levels of tumor necrosis factor-alpha and IL-1β was observed in the group that received methylprednisolone (p = 0.0084 and p = 0.0155, respectively). There were no significant differences in tumor necrosis factor-alpha and superoxide dismutase levels between the control and methylprednisolone groups (p = 0.2644 and p = 0.7461, respectively). There were no significant differences in the blood gas parameters, hemodynamics, and histological alterations between the groups. CONCLUSION: The administration of methylprednisolone after brain death in donor rats reduces inflammatory activity in transplanted lungs but has no influence on parameters related to oxidative stress.

Resumo em Inglês:

OBJECTIVE: The present study aimed to investigate the mechanisms underlying the anti-inflammatory and anti-angiogenic effects of ethyl-p-methoxycinnamate isolated from Kaempferia galanga. METHODS: The anti-inflammatory effects of ethyl-p-methoxycinnamate were assessed using the cotton pellet granuloma assay in rats, whereby the levels of interleukin-1 and tumor necrosis factor-α were measured in the animals' blood. In addition, the levels of interleukin, tumor necrosis factor, and nitric oxide were measured in vitro using the human macrophage cell line (U937). The analgesic effects of ethyl-p-methoxycinnamate were assessed by the tail flick assay in rats. The anti-angiogenic effects were evaluated first by the rat aortic ring assay and, subsequently, by assessing the inhibitory effects of ethyl-p-methoxycinnamate on vascular endothelial growth factor, proliferation, migration, and tube formation in human umbilical vein endothelial cells. RESULTS: Ethyl-p-methoxycinnamate strongly inhibited granuloma tissue formation in rats. It prolonged the tail flick time in rats by more than two-fold compared with the control animals. The inhibition of interleukin and tumor necrosis factor by ethyl-p-methoxycinnamate was significant in both in vivo and in vitro models; however, only a moderate inhibition of nitric oxide was observed in macrophages. Furthermore, ethyl-p-methoxycinnamate considerably inhibited microvessel sprouting from the rat aorta. These mechanistic studies showed that ethyl-p-methoxycinnamate strongly inhibited the differentiation and migration of endothelial cells, which was further confirmed by the reduced level of vascular endothelial growth factor. CONCLUSION: Ethyl-p-methoxycinnamate exhibits significant anti-inflammatory potential by inhibiting pro-inflammatory cytokines and angiogenesis, thus inhibiting the main functions of endothelial cells. Thus, ethyl-p-methoxycinnamate could be a promising therapeutic agent for the treatment of inflammatory and angiogenesis-related diseases.

Resumo em Inglês:

OBJECTIVE: To evaluate the effect of blocking the angiotensin II AT-1 receptor by the systemic administration of candesartan on the expression of intercellular adhesion molecule-1 in the sclera and choroid of hypercholesterolemic rabbits. METHODS: New Zealand rabbits were divided into 3 groups, as follows: GI, which was fed a rabbit standard diet; GII, which was fed a hypercholesterolemic diet; and GIII, which received hypercholesterolemic diet plus candesartan. Samples of the rabbits' sclera and choroid were then studied by hematoxylin-eosin staining and histomorphometric and immunohistochemical analyses for intercellular adhesion molecule-1 expression. RESULTS: Histological analysis of hematoxylin- and eosin-stained sclera and choroid revealed that macrophages were rarely present in GI, and GII had significantly increased macrophage numbers compared to GIII. Moreover, in GII, the sclera and choroid morphometry showed a significant increase in thickness in comparison to GI and GIII. GIII presented a significant increase in thickness in relation to GI. Sclera and choroid immunohistochemical analysis for intercellular adhesion molecule-1 expression revealed a significant increase in immunoreactivity in GII in relation to GI and GIII. GIII showed a significant increase in immunoreactivity in relation to GI. CONCLUSION: Candesartan reduced the expression of intercellular adhesion molecule-1 and consequently macrophage accumulation in the sclera and choroid of hypercholesterolemic rabbits.