Evaluate of the efficacy and safety of tacrolimus ointment 0,03% to treat atopic dermatitis in pediatric patients

BACKGROUND: Tacrolimus ointment has been shown to be effective in treatment of atopic dermatitis. OBJECTIVES: To evaluate the efficacy and safety of 0.03% tacrolimus ointment (Protopic(R)) in pediatric patients with mild, moderate and severe atopic dermatitis. METHODS.. Open, non-comparative, multicentric study carried out in Brazil. 174 patients (ages from two to 10) with mild to severe atopic dermatitis were included. Patients were instructed to apply Protopic(R) twice a day for six weeks. Primary efficacy criterion was clinical improvement >= 90% assessed by the pbysician (Clinical Response Global Evaluation Scale). Other efficacy criteria included reduction of the Eczema Area Severity Index (EASI), decrease of the affected body surface area (%BSA) and evaluation of the itching by the patients or their guardians (visual analogical scale). Safety was evaluated by adverse events reported by patients and/or guardians or by investigators. RESULTS: Thirty-three percent of patients showed clinical improvement 90%. 45.5% of patients (1st week) decreased EASI and 61.8% (6th week) (p<0,001). %BSA decreased 30.4% and 55.5% in the first and sixth week. improvement was also significant when measured by itching (p<0, 001). Most frequent adverse effects were: burning and itching. CONCLUSION: 0.03% tacrolimus ointment is a safe and effective therapy for mild to severe atopic dermatitis in pediatric patients.

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

Considering that mycobacterial heat-shock protein 65 (hsp65) gene transfer can elicit a profound antitumoral effect, this study aimed to establish the safety, maximum-tolerated dose (MTD) and preliminary efficacy of DNA-hsp65 immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). For this purpose, 21 patients with unresectable and recurrent HNSCC were studied. Each patient received three ultrasound-guided injections at 21-day intervals of: 150, 600 or 400 mu g of DNA-hsp65. Toxicity was graded according to CTCAE directions. Tumor volume was measured before and after treatment using computed tomography scan. The evaluation included tumor mass variation, delayed-type hypersensitivity response and spontaneous peripheral blood mononuclear cell proliferation before and after treatment. The MTD was 400 mg per dose. DNA-hsp65 immunotherapy was well tolerated with moderate pain, edema and infections as the most frequent adverse effects. None of the patients showed clinical or laboratory alterations compatible with autoimmune reactions. Partial response was observed in 4 out of 14 patients who completed treatment, 2 of which are still alive more than 3 years after the completion of the trial. Therefore, DNA-hsp65 immunotherapy is a feasible and safe approach at the dose of 400 mg per injection in patients with HNSCC refractory to standard treatment. Further studies in a larger number of patients are needed to confirm the efficacy of this novel strategy.

Thirty-Day Morbidity and Mortality of the Laparoscopic Ileal Interposition Associated with Sleeve Gastrectomy for the Treatment of Type 2 Diabetic Patients with BMI < 35: An Analysis of 454 Consecutive Patients

Background The objective of this study was to evaluate the early results of the laparoscopic interposition of a segment of ileum associated with a sleeve gastrectomy (LII-SG) in order to treat patients with type 2 diabetes mellitus (T2DM) and BMI <35. Data regarding morbidly obese diabetic patients subjected to surgery has consistently been validated. To date, there is scarce information about morbidity and mortality related to the surgical treatment of a ""true"" typical diabetic population with BMI <35. Methods The procedures were performed in 454 patients (322 male, 132 female). Mean age was 53.6 +/- 8 years (range = 27-75). Mean BMI was 29.7 +/- 3.6 kg/m(2) (range = 19-34.8). All patients had the diagnosis of T2DM for at least 3 years. Insulin therapy was used by 45.6% of patients. Mean duration of T2DM was 10.8 +/- 5.9 years (range = 3-35). Mean hemoglobin A(1c) was 8.8 +/- 1.9%. Dyslipidemia was observed in 78.4%, hypertension in 64.8%, nephropathy in 28.6%, retinopathy in 32.6%, neuropathy in 34.6%, and coronary heart disease in 13%. Results There was no conversion to open surgery. All patients were evaluated postoperatively. Mortality was 0.4%. There were 29 major complications (6.4%) in 22 patients (4.8%) and 51 minor complications (11.2%). Reoperations were performed on 8 patients (1.7%). Twenty patients (4.4%) were readmitted to the hospital. Mean postoperative BMI was 25.8 +/- 3.5 kg/m(2). Mean fasting plasma glucose decreased from 198 +/- 69 to 128 +/- 67 mg/dl and mean postprandial plasma glucose decreased from 262 +/- 101 to 136 +/- 43 mg/dl. Conclusions The laparoscopic ileal interposition associated with a sleeve gastrectomy was considered a safe operation with low rates of morbidity and mortality in a diabetic population with BMI < 35. An early control of postprandial glycemia was observed.

Effect of the bilateral hip bone density measurement on clinical practice in elderly subjects

Objectives: The aim of this study was to determine whether the addition of the measurement of bilateral hip bone mineral density (BMD) has an impact on indications for osteoporosis (OP) treatment in community-dwelling elderly individuals, based on criteria from the National Osteoporosis Foundation (NOF). Methods: In total, 605 consecutive community-dwelling elderly individuals who were 65 years and older were evaluated. Dual energy X-ray absorptiometry was used to determine the lowest T-score in the lumbar spine + unilateral hip, the bilateral hips, and the lumbar spine + bilateral hips. Risk factors associated with the lowest T-score in these three conditions were applied to indicate treatment in accordance with NOF criteria. McNemar`s test was used to assess the difference of adding bilateral hip BMD measurements. Results: There was a significant difference in the frequency of pharmacological indication using NOF criteria together with the lowest T-score for the three tests (72.8% for lumbar spine + bilateral hips and 71.2% for lumbar spine + unilateral hip; p=0.002). A higher frequency of treatment indication was also observed for lumbar spine + unilateral hip (71.2%) compared to bilateral hips (61.1%) (p<0.001). The discrepancies in treatment appeared to be more evident in women when analyzed by gender distribution. Conclusion: Our finding supports the theory that evaluation of the bilateral hips with the lumbar spine seems to be more sensitive measure for identifying patients with an osteoporosis treatment indication. Furthermore, despite the well-known artifact in the lumbar spine, this site should not be excluded when determining the indication for OP treatment in elderly people. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

KISS1R Intracellular Trafficking and Degradation: Effect of the Arg386Pro Disease-Associated Mutation

The goal of this study was to investigate how the Arg386Pro mutation prolongs KiSS-1 receptor (KISS1R) responsiveness to kisspeptin, contributing to human central precocious puberty. Confocal imaging showed colocalization of wild-type (WT) KISS1R with a membrane marker, which persisted for up to 5 h of stimulation. Conversely, no colocalization with a lysosome marker was detected. Also, overnight treatment with a lysosome inhibitor did not affect WT KISS1R protein, whereas overnight treatment with a proteasome inhibitor increased protein levels by 24-fold. WT and Arg386Pro KISS1R showed time-dependent internalization upon stimulation. However, both receptors were recycled back to the membrane. The Arg386Pro mutation did not affect the relative distribution of KISS1R in membrane and internalized fractions when compared to WT KISS1R for up to 120 min of stimulation, demonstrating that this mutation does not affect KISS1R trafficking rate. Nonetheless, total Arg386Pro KISS1R was substantially increased compared with WT after 120 min of kisspeptin stimulation. This net increase was eliminated by blockade of detection of recycled receptors, demonstrating that recycled receptors account for the increased responsiveness of this mutant to kisspeptin. We therefore conclude the following: 1) WT KISS1R is degraded by proteasomes rather than lysosomes; 2) WT and Arg386Pro KISS1R are internalized upon stimulation, but most of the internalized receptors are recycled back to the membrane rather than degraded; 3) the Arg386Pro mutation does not affect the rate of KISS1R trafficking-instead, it prolongs responsiveness to kisspeptin by decreasing KISS1R degradation, resulting in the net increase on mutant receptor recycled back to the plasma membrane.(Endocrinology 152: 1616-1626,2011)

Effect of the Novel Thienopyridine Prasugrel Compared With Clopidogrel on Spontaneous and Procedural Myocardial Infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 An Application of the Classification System From the Universal Definition of Myocardial Infarction

Background-Prasugrel is a novel thienopyridine that reduces new or recurrent myocardial infarctions (MIs) compared with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. This effect must be balanced against an increased bleeding risk. We aimed to characterize the effect of prasugrel with respect to the type, size, and timing of MI using the universal classification of MI. Methods and Results-We studied 13 608 patients with acute coronary syndrome undergoing percutaneous coronary intervention randomized to prasugrel or clopidogrel and treated for 6 to 15 months in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). Each MI underwent supplemental classification as spontaneous, secondary, or sudden cardiac death (types 1, 2, and 3) or procedure related (Types 4 and 5) and examined events occurring early and after 30 days. Prasugrel significantly reduced the overall risk of MI (7.4% versus 9.7%; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.67 to 0.85; P < 0.0001). This benefit was present for procedure-related MIs (4.9% versus 6.4%; HR, 0.76; 95% CI, 0.66 to 0.88; P = 0.0002) and nonprocedural (type 1, 2, or 3) MIs (2.8% versus 3.7%; HR, 0.72; 95% CI, 0.59 to 0.88; P = 0.0013) and consistently across MI size, including MIs with a biomarker peak >= 5 times the reference limit (HR. 0.74; 95% CI, 0.64 to 0.86; P = 0.0001). In landmark analyses starting at 30 days, patients treated with prasugrel had a lower risk of any MI (2.9% versus 3.7%; HR, 0.77; P = 0.014), including nonprocedural MI (2.3% versus 3.1%; HR, 0.74; 95% CI, 0.60 to 0.92; P = 0.0069). Conclusion-Treatment with prasugrel compared with clopidogrel for up to 15 months in patients with acute coronary syndrome undergoing percutaneous coronary intervention significantly reduces the risk of MIs that are procedure related and spontaneous and those that are small and large, including new MIs occurring during maintenance therapy. (Circulation. 2009; 119: 2758-2764.)

Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia

We assessed for the first time the long-term maintenance of repetitive transcranial magnetic stimulation (rTMS)-induced analgesia in patients with chronic widespread pain due to fibromyalgia. Forty consecutive patients were randomly assigned, in a double-blind fashion, to 2 groups: one receiving active rTMS (n = 20) and the other, sham stimulation (n = 20), applied to the left primary motor cortex. The stimulation protocol consisted of 14 sessions: an ""induction phase"" of 5 daily sessions followed by a ""maintenance phase"" of 3 sessions a week apart, 3 sessions a fortnight apart, and 3 sessions a month apart. The primary outcome was average pain intensity over the last 24 hours, measured before each stimulation from day 1 to week 21 and at week 25 (1 month after the last stimulation). Other outcomes measured included quality of life, mood and anxiety, and several parameters of motor cortical excitability. Thirty patients completed the study (14 in the sham stimulation group and 16 in the active stimulation group). Active rTMS significantly reduced pain intensity from day 5 to week 25. These analgesic effects were associated with a long-term improvement in items related to quality of life (including fatigue, morning tiredness, general activity, walking, and sleep) and were directly correlated with changes in intracortical inhibition. In conclusion, these results suggest that TMS may be a valuable and safe new therapeutic option in patients with fibromyalgia. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

An Eight-week, Multicentric, Randomized, Interventional, Open-label, Phase 4, Parallel Comparison of the Efficacy and Tolerability of the Fixed Combination of Timolol Maleate 0.5%/Brimonidine Tartrate 0.2% Versus Fixed Combination of Timolol Maleate 0.5%/Dorzolamide 2% in Patients With Elevated Intraocular Pressure

Purpose: To compare the efficacy and tolerability of the fixed combination of timolol maleate 0.5%/brimonidine tartrate 0.2% versus fixed combination of timolol maleate 0.5%/dorzolamide 2% in patients with elevated intraocular pressure (IOP) over 8 weeks. Patients and Methods: This 8-week, multicentric. interventional, randomized, open-label, parallel group study was conducted Lit 4 centers in Brazil and 1 center in Argentina. Patients with open-angle glaucoma or ocular hypertension were randomized to receive bilaterally fixed combination of brimonidine/timolol maleate 0.5% or fixed combination of dorzolamide 2%/timolol 0.5% twice daily at 8:00 AM and 8:00 PM. A modified diurnal tension curve (8:00 AM 10:30 AM, 02:00 PM, and 4:00 PM) followed by the water drinking test (WDT), which estimates IOP peak of diurnal tension curve, were performed in the baseline and week-8 visits. Adverse events data were recorded at each visit. Results: A total of 210 patients were randomized (brimonidine/timolol, n = 111; dorzolamide/timolol, n = 99). Mean baseline IOP was 23.43 +/- 3.22 mm Hg and 23.43 +/- 4.06 mm Hg in the patients treated with brimonidine/timolol and dorzolamide/timolol, respectively (P = 0.993). Mean diurnal IOP reduction after 8 weeks were 7.02 +/- 3.06 mm Hg and 6.91 +/- 3.67 mm Hg. respectively (P = 0.811). The adjusted difference between groups (analysis of covariance) Lit week 8 was not statistically significant (P = 0.847). Mean baseline WDT peak was 27.79 +/- 4.29 mm Hg in the brimonidine/timolol group and 27.68 +/- 5.46 mm Hg in the dorzolamide/timolol group. After 8 weeks of treatment, mean WDT peaks were 20.94 +/- 3.76 mm Hg (P < 0.001) and 20.98 +/- 4.19 (P < 0.001), respectively. The adjusted difference between groups (analysis of covariance) was not statistically significant (P = 0.469). No statistical difference in terms of adverse events was Found between groups. Conclusions: Both fixed combinations were capable of significantly reducing the mean diurnal IOP, mean diurnal peak, and mean WDT peak after 8 weeks of treatment. Also, both fixed combinations are well tolerated with few side effects.

Balance between early life tolerance and sensitization in allergy: dependence on the timing and intensity of prenatal and postnatal allergen exposure of the mother

P>Allergens can be maternally transferred to the fetus or neonate, though it is uncertain how this initial allergen exposure may impact the development of allergy responses. To evaluate the roles of timing and level of maternal allergen exposure in the early life sensitization of progeny, female BALB/c mice were given ovalbumin (OVA) orally during pregnancy, lactation or weekly at each stage to investigate the immunoglobulin E (IgE) antibody production and cellular responsiveness of their offspring. Exposure to OVA during pregnancy was also evaluated in OVA-specific T-cell receptor (TCR) transgenic (DO11.10) mice. The effect of prenatal antigen exposure on offspring sensitization was dependent on antigen intake, with low-dose OVA inducing tolerance followed by neonatal immunization that was sustained even when pups were immunized when 3 weeks old. These offspring received high levels of transforming growth factor-beta via breastfeeding. High-dose exposure during the first week of pregnancy or perinatal period induced transient inhibition of IgE production following neonatal immunization; although for later immunization IgE production was enhanced in these offspring. Postnatal maternal antigen exposure provided OVA transference via breastfeeding, which consequently induced increased offspring susceptibility to IgE antibody production according to week post-birth. The effect of low-dose maternal exposure during pregnancy was further evaluated using OVA transgenic TCR dams as a model. These progeny presented pronounced entry of CD4(+) T cells into the S phase of the cell cycle with a skewed T helper type 2 response early in life, revealing the occurrence of allergen priming in utero. The balance between tolerance and sensitization depended on the amount and timing of maternal allergen intake during pregnancy.

Comparison of the efficacy of two commercially available media for culturing one-cell embryos in the in vitro fertilization mouse model

Objective: To examine the effects of two commercial media on the development of mouse ova fertilized in vitro to the blastocyst stage. Design: Animal model. Setting: Academic institution. Animal(s): Eight-week old, superovulated mice. Intervention(s): One-cell embryos cultured in vitro up to the blastocyst stage in potassium-enriched simplex optimized medium (KSOM) or G1/G2 medium. Main Outcome Measure(s): Blastocyst and hatching rates, total cell number count, and proportion of allocation of cells to the inner cell mass (ICM) and trophectoderm (TE). Result(s): The percentage of zygotes that developed to the blastocyst stage 96 and 120 hours after insemination was statistically significantly higher in the KSOM group. The percentage of blastocysts that partially or completely hatched by day 5 of culture was 84% and 71% for the KSOM and G1/G2 groups, respectively, showing a statistically significant difference between the groups. The mean number of ICM cells was 11.7 +/- 4.0 and 9.2 +/- 5.2 for the zygotes cultured in KSOM and G1/G2 media, respectively, revealing a statistically significantly higher cell number in the ICM of blastocysts derived from culture in KSOM medium. The ICM/TE ratio in the blastocysts cultured in KSOM or G1/G2 media was similar in both groups. Conclusion(s): Commercially available KSOM medium is superior to sequential G1/G2 media for culturing one-cell embryos up to the blastocyst stage in the mouse IVF model.

The effect of the number of biopsy cores on the concordance between prostate biopsy and prostatectomy Gleason score - A prostate volume-controlled study

Context.-Studies analyzing the concordance of biopsy and radical prostatectomy (RP) Gleason scores have limitations. Some included 2 or more centers, used historical controls from the early prostate specific antigen era or lacked a clear definition of the biopsy schemes. Furthermore, most did not control the results for prostate volume. Objective.-To confirm whether prediction of RP Gleason score can be optimized by taking more biopsy cores in a contemporary series of patients, with pathologic samples analyzed by the same pathologist, and controlling these results for prostate volume. Design.-The study comprised a retrospective case-control analysis of 393 patients with prostate cancer treated with RP. Patients were divided into 3 groups: those in group 1 underwent a 6-core biopsy; group 2, an 8-core biopsy; and group 3, a 10 or more-core biopsy. Concordance rates between biopsy and RP Gleason scores, as well as the rates of undergrading and overgrading, were determined for each biopsy scheme. Results.-Concordance rates were 60.9%, 58.3%, and 64.6% for patients from groups 1, 2, and 3, respectively (P = .18). When we analyzed patients with prostate volumes of less than 50 cm(3), concordance rates were 58.3%, 58.3%, and 65.1% for each group, respectively (P = .03). Among patients with prostate volumes of 50 cm3 or more, concordance rates were 70%, 58.1%, and 63.6%, respectively (P = .66). Conclusions.-Taking 10 or more cores can improve the prediction of RP Gleason score in patients with prostate volumes of less than 50 cm3. For patients with prostate volumes of 50 cm3 or more, increasing the biopsy cores to 10 or more did not improve prediction of RP Gleason score.

Neonatal BCG Immunization Followed by DNAhsp65 Boosters: Highly Immunogenic but not Protective Against Tuberculosis - a Paradoxical Effect of the Vector?

A new tuberculosis vaccine is urgently needed. Prime-boost strategies are considered very promising and the inclusion of BCG is highly desirable. In this investigation, we tested the protective efficacy of BCG delivered in the neonatal period followed by boosters in the adult phase with a DNA vaccine containing the hsp65 gene from Mycobacterium leprae (pVAXhsp65). Immune responses were characterized by serum anti-hsp65 antibody levels and IFN-gamma and IL-5 production by the spleen. Amounts of these cytokines were also determined in lung homogenates. Protective efficacy was established by the number of colony-forming units (CFU) and histopathological analysis of the lungs after challenge with Mycobacterium tuberculosis. Immunization with BCG alone triggered a significant reduction of CFU in the lungs and also clearly preserved the pulmonary parenchyma. BCG priming also increased the immunogenicity of pVAXhsp65. However, boosters with pVAXhsp65 or the empty vector abolished the protective efficacy of BCG. Also, higher IL-5 levels were produced by spleen and lungs after DNA boosters. These results demonstrated that neonatal BCG immunization followed by DNAhsp65 boosters is highly immunogenic but is not protective against tuberculosis.

The Protective Effect of CAPE on Hepatic Ischemia/Reperfusion Injury in Rats

Background/Aims. The transcription factor nuclear factor-kappa B (NF-kappa B) exerts a pivotal role in the pathogenesis of hepatic ischemia/reperfusion (I/R) injury. Caffeic acid phenyl ester (CAPE), a potent and specific NF-kappa B inhibitor, presents protective effects on I/R injury in some tissues. This study aimed to evaluate the effect of CAPE on hepatic I/R injury in rats. Materials and methods. Wistar rats were submitted to a sham operation, 60 min ischemia, or 60 min ischemia plus saline or CAPE treatment followed by 6 h reperfusion. Liver tissue injury was evaluated by alanine aminotransferase, aspartate aminotransferase, and tissue glutathione measurement, and histological damage score. Apoptotic hepatocytes were determined by the transferase-mediated dUTP-biotin nick-end labeling assay. Hepatic neutrophil accumulation was assessed by the naphthol method. Lipid peroxidation and NF-kappa B activation were evaluated by 4-hydroxynonenal and NF-kappa B p65 immunohistochemistry, respectively. Results. Animals submitted to ischemia showed a marked increase of alanine aminotransferase and aspartate aminotransferase after reperfusion, but with lower levels in CAPE group. Tissue glutathione content declined gradually during ischemia to reperfusion and was partially recovered with CAPE treatment. The histological damage score, apoptosis index, and neutrophil infiltration, as well as 4-hydroxynonenal and NF-kappa B p65 nuclear labeling, were higher in the liver of animals submitted to I/R compared to the ischemia group. However, the CAPE treatment significantly reduced all of these alterations. Conclusions. CAPE was able to protect the liver against normothermic I/R injury in rats. This effect may be associated with the inhibition of the NF-kappa B signaling pathway and decrease of the acute inflammatory response following I/R in the liver. (C) 2008 Elsevier Inc. All rights reserved.

EFFECT OF THE TEMPERATURE AND pH ON METHANOL RELEASE IN COFFEE BREW SWEETENED WITH ASPARTAME

Methanol is an alcohol which is metabolized to folmaldehyde in humans. It is a very toxic substance, responsible for blindness in cases of methanol intoxication. This study shows the production of methanol when aspartame is used to sweeten coffee brew. The temperature versus pH binomium was also tested. When assayed at 90 degrees C coffee brew+aspartame and aspartame solution showed an increase in methanol release of 17.8 and 19.3%, respectively, as compared with coffee brew. At 180 degrees C, the increase was 32.5 and 26.3%, respectively. Our data revealed a protective effect of the pH of coffee on the degradation of aspartame and formation of methanol; an important fact, mainly for specific populations that use aspartame, like diabetics.

Effect of the glycemic control on intracellular cytokine production from peripheral blood mononuclear cells of type 1 and type 2 diabetic patients

Aims: To evaluate the intracellular production of tumor necrosis factor (TNF-alpha), interleukine-6 (IL-6), INF-gamma, IL-8 and IL-10 in peripheral blood lympbomononuclear cells from type 1 and type 2 diabetic patients, stratified according to the glycemic control. Methods: Thirty-five diabetic patients (17 type 1 and 18 type 2) and nine healthy individuals paired to patients in terms of sex and age were studied. Nine patients of each group were on inadequate glycemic controls. Intracellular cytokines were evaluated using flow cytometry. Cell cultures were stimulated with LPS to evaluate TNF-alpha and IL-6 or with PMA and lonomycin to evaluate IFN-gamma, IL-8 and IL-10 intracellular staining. Results: The percentages of CD33(+) cells bearing TNF-alpha and CD3(+) cells bearing IL-10 were increased in type 1 diabetic patients with inadequate glycemic control in relation to those with adequate control. In contrast, the percentage of CD3(+) cells bearing IL-8 was decreased in type 2 patients under inadequate glycemic control. Conclusions: The glycemic control is important for the detection of intracellular cytokines, and may contribute towards the susceptibility to infections in diabetic patients. (c) 2008 Elsevier Ireland Ltd. All rights reserved.