Is Suppression of Hypothalamic-Pituitary-Adrenal Axis Significant During Clinical Treatment of Phimosis?

Purpose: Corticoids have been an option for phimosis treatment since 1993. However, long-term use or repeated cycles pose a concern regarding drug absorption and consequent systemic effects. The aim of this study was to investigate the effect of topical corticoids used in treating phimosis on the hypothalamus-pituitary-adrenal axis in children. Materials and Methods: A total of 31 children were included in the study. Cortisol secretion was evaluated by the measurement of salivary cortisol in saliva samples collected at 9:00 a.m, before starting treatment and after 8 weeks of topical treatment with 0.05% clobetasol propionate. Salivary cortisol was determined by radioimmunoassay. To confirm that use of clobetasol propionate was not detected by the assay, the presence of cortisol circadian rhythm was checked by an extra saliva sample obtained at 11:00 p.m. from 10 children, and was observed to be maintained in all of them. Results: No significant difference in salivary cortisol levels was observed between samples obtained at 9:00 a.m. before starting treatment and after completing treatment when the entire group was analyzed. However, in 2 children the salivary cortisol levels after treatment were lower than the cutoff value (358 ng/dl) assumed to be suggestive of hypothalamus-pituitary-adrenal axis suppression. Conclusions: Topical clobetasol propionate used twice daily for clinical treatment of phimosis does not affect the hypothalamus-pituitary-adrenal axis in most patients. However, salivary cortisol level should be considered as a laboratory marker in long-term treatment or during repeated cycles to detect possible hypothalamus-pituitary-adrenal axis suppression.

alpha 1-acid glycoprotein and alpha 1-antitrypsin as early markers of treatment response in patients receiving the intensive phase of tuberculosis therapy

The identification of early markers that predict the response to anti-tuberculosis treatment would facilitate evaluation of new drugs and improve patient management. This study aimed to determine whether selected acute phase proteins and micronutrients measured at the time of diagnosis and during the first weeks of treatment could predict treatment responses during the 2-month standard intensive phase of therapy. For this purpose, alpha 1-antitrypsin, alpha 1-acid gtycoprotein, alpha 2-macroglobutin, C-reactive protein, C3, C4, zinc, copper and selenium concentrations were measured in Brazilian patients with smear-positive tuberculosis at the time of diagnosis and 1, 3, 5 and 8 weeks after initiation of therapy. Patients were classified into fast (n = 29), intermediate (n = 18) and slow responders (n = 10) if they were smear-negative at 3, 5 or 8 weeks of treatment. alpha 1-acid gtycoprotein on enrolment and 1 week of treatment, alpha 1-antitrypsin at week 1 and C-reactive protein and C3 after 3 weeks of therapy were higher in slow responders than in fast responders. alpha 1-antitrypsin and alpha 1-acid glycoprotein may be helpful in predicting treatment response at the time of initiation of therapy, and could be used as early markers to identify patients with an increased likelihood of treatment failure. (C) 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.

The-202 A Allele of Insulin-Like Growth Factor Binding Protein-3 (IGFBP3) Promoter Polymorphism Is Associated with Higher IGFBP-3 Serum Levels and Better Growth Response to Growth Hormone Treatment in Patients with Severe Growth Hormone Deficiency

Context: Genetic factors that influence the response to recombinant human GH (rhGH) therapy remain mostly unknown. To date, only the GH receptor gene has been investigated. Objective: The aim of the study was to assess the influence of a polymorphism in the IGF-binding protein-3 (IGFBP-3) promoter region (-202 A/C) on circulating IGFBP-3 levels and growth response to rhGH therapy in children with GH deficiency (GHD). Design and Patients: -202 A/C IGFBP3 genotyping (rs2854744) was correlated with data of 71 children with severe GHD who remained prepubertal during the first year of rhGH treatment. Main Outcome Measures: We measured IGFBP-3 levels and first year growth velocity (GV) during rhGH treatment. Results: Clinical and laboratory data at the start of treatment were indistinguishable among patients with different -202 A/C IGFBP3 genotypes. Despite similar rhGH doses, patients homozygous for the A allele presented higher IGFBP-3 SD score levels and higher mean GV in the first year of rhGH treatment than patients with AC or CC genotypes (first year GV, AA = 13.0 +/- 2.1 cm/yr, AC = 11.4 +/- 2.5 cm/yr, and CC = 10.8 +/- 1.9 cm/yr; P = 0.016). Multiple linear regression analyses demonstrated that the influence of -202 A/C IGFBP3 genotype on IGFBP-3 levels and GV during the first year of rhGH treatment was independent of other variables. Conclusion: The -202 A allele of IGFBP3 promoter region is associated with increased IGFBP-3 levels and GV during rhGH treatment in prepubertal GHD children. (J Clin Endocrinol Metab 94: 588-595, 2009)

Long-term treatment of familial male-limited precocious puberty (testotoxicosis) with cyproterone acetate or ketoconazole

Background Familial male-limited precocious puberty (FMPP) or testotoxicosis is a rare gonadotrophin-independent form of sexual precocity caused by constitutively activating mutations of the LH receptor. Several clinical therapeutic approaches have been reported for this disorder, but with a paucity of long-term outcome data. Objective To evaluate the long-term treatment of testotoxicosis with cyproterone acetate or ketoconazole. Design A multicentric retrospective clinical study. Patients Ten boys from eight unrelated Brazilian families who carried known LH-receptor activating mutations were treated with 70 mg/m(2) cyproterone acetate (n = 5) or 10 mg/kg ketoconazole (n = 5) for a mean period of 5 and 8 years, respectively. Measurements Chronological and bone ages, bone age/chronological age ratio, target height (TH) range, adult height, basal and GnRH-stimulated gonadotrophin levels and basal testosterone levels were assessed. Results Growth velocity decreased significantly during treatment with cyproterone acetate or ketoconazole when compared to pretreatment value in each group (P < 0.05). Bone age/chronological age ratio decreased significantly after cyproterone acetate or ketoconazole therapy. Basal testosterone levels were significantly lower in patients undergoing ketoconazole compared to cyproterone acetate treatment [0.6 +/- 0.3 nmol/l (42 +/- 21 ng/dl) vs. 5.6 +/- 4.0 nmol/l (392 +/- 280 ng/dl); P < 0.05], as expected. Secondary gonadotrophin-dependent precocious puberty occurred at a similar frequency (40%) in both groups. Five patients have attained adult height and two patients have already reached 90% of their adult height. Two of them achieved their TH range and one patient, for whom TH was not available, had an adult height of 0.3 SDS. Four boys (two in each group) did not attain their TH range. Conclusion Long-term treatment with cyproterone acetate or ketoconazole resulted in similar outcomes without important side-effects in boys with testotoxicosis. However, both therapies showed limited efficacy in attaining normal adult height.

Benefits of the Intermittent Use of 6-Mercaptopurine and Methotrexate in Maintenance Treatment for Low-Risk Acute Lymphoblastic Leukemia in Children: Randomized Trial From the Brazilian Childhood Cooperative Group Protocol ALL-99

Purpose To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MIX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. Patients and Methods Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n=544) were randomly allocated to receive either continuous 6-ME/MIX (group 1, n 272) or intermittent 6-MP (100 mg/m(2)/d for 10 days, with 11 days resting) and MIX (200 mg/m(2) every 3 weeks; group 2, n = 272). Results The 5-year overall survival (OS) and EFS were 92.5% +/- 1.5% SE and 83.6% +/- 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% +/- 2.2% SE (group 1) and 93.6% +/- 2.1% SE (group 2; P=.28) and EFS 80.9% +/- 3.2% SE (group 1) and 86.5% +/- 2.8% SE (group 2; P=.089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P=027), while no difference was seen for girls (87.0% v 88.8% SE; P=.78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P=.002), and 772 and 636 for hematologic episodes (P=.005). Deaths on maintenance were: seven (group 1) and one (group 2). Conclusion The intermittent use of 6-MP and MIX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.

Treatment of Hepatocellular Carcinoma With Liver Transplantation: A Single-Center Experience From Brazil

Introduction. Orthotopic liver transplantation (OLT) is the treatment of choice of hepatocellular carcinoma (HCC) for patients with cirrhosis, mainly those with early HCC. Herein we have present the clinical characteristics and outcomes of cirrhotic patients with HCC who underwent OLT from cadaveric donors in our institution. Methods. From May 2001 to May 2009, we performed 121 OLT including 24 patients (19.8%) with cirrhosis and HCC within the Milan criteria. In 4 cases, HCC was an incidental finding in the explants. Results. The patients` average age was 55 +/- 10 years, including 82% men. Fifty percent of patients were Child class B or C. The average Model for End Stage Liver Disease for Child A, B, and C categories were 11, 15, and 18, respectively. The HCC diagnosis was made by 2 dynamic images in 16 cases; 1 dynamic image plus alphafetoprotein >400 ng/mL in 4; and 4 by histologic confirmation. Twenty patients received a locoregional treatment before OLT: 6 percutaneous ethanol injection, 9 transarterial chemoembolization, 1 transarterial embolization, and 4 a combination of these modalities. The median follow-up after OLT was 19.7 months (range, 1-51). A vascular invasion was observed in the explant of 1 patient, who developed an HCC recurrence and succumbed at 8 months after OLT. Two further patients, without vascular invasion or satellite tumor displayed tumor recurrences at 7 and 3 months after OLT, and death at 2 and 1 month after the diagnosis. The remaining 25 patients have not shown a tumor recurrence. Conclusion. In the present evaluation, OLT patients with early HCC and no vascular invasion showed satisfactory results and good disease-free survival. Strictly following the Milan criteria for liver transplantation in patients with HCC greatly reduces but does not completely avoid, the chances of tumor recurrence.

Sexual Dysfunction Treatment in a Patient With Mullerian Agenesy Submitted to Neovaginoplasty: A Case Report

Vagina agenesis is a rare entity. Mayer-Rokitansky-Kuster-Hauser syndrome is the most significant cause of vagina agenesis, whereas the second most common cause is complete androgen syndrome. Surgical treatment can propitiate a vaginal reconstruction, but sexual function depends on several factors that affect sexual performance. Many reports focus on the intraoperative and postoperative results and only describe the global approach to these patients, but reports focusing on the management of these patients to enable them to have a normal sexual life are lacking. This case report highlights a multidisciplinary treatment for this kind of morbidity and emphasizes the necessity of incorporating careful attention to sexual health in the treatment of these patients so that they may achieve a good therapeutic response, resulting in a pleasurable sexual life and a good quality of living.

Development and agronomic performance of common bean lines simultaneously resistant to anthracnose, angular leaf spot and rust

The common bean is affected by several pathogens that can cause severe yield losses. Here we report the introgression of resistance genes to anthracnose, angular leaf spot and rust in the `carioca-type` bean cultivar `Ruda`. Initially, four backcross (BC) lines were obtained using `TO`, `AB 136`, `Ouro Negro` and `AND 277` as donor parents. Molecular fingerprinting was used to select the lines genetically closer to the recurrent parent. The relative genetic distances between `Ruda` and the BC lines varied between 0.0% and 1.99%. The BC lines were intercrossed and molecular markers linked to the resistance genes were used to identify the plants containing the genes of interest. These plants were selfed to obtain the F(2), F(3) and F(4) plants which were selected based on the presence of the molecular markers mentioned and resistance was confirmed in the F(4) generation by inoculation. Four F(4:7) pyramid lines with all the resistance genes showed resistance spectra equivalent to those of their respective donor parents. Yield tests showed that these lines are as productive as the best `carioca-type` cultivars.

The presence of CD56/CD16 in T-cell acute lymphoblastic leukaemia correlates with the expression of cytotoxic molecules and is associated with worse response to treatment

Some cases of T-cell acute lymphoblastic leukaemia (ALL) express markers found in natural-killer (NK) cells, such as CD56 and CD16. Out of 84 T-cell ALL cases diagnosed at our Institution, CD56 and/or CD16 was detected in 24 (28.5%), which we designated T/NK-ALL group. Clinical features, laboratory characteristics, survival and expression of cytotoxic molecules were compared in T/NK-ALL and T-ALL patients. Significant differences were observed regarding age (24.9 vs. 16.4 years in T/NK-ALL and T-ALL, respectively, P = 0.006) and platelet counts (177 x 10(9)/l vs. 75 x 10(9)/l in T/NK-ALL and T-ALL, respectively, P = 0.03). Immunophenotypic analysis demonstrated that CD34, CD45RA and CD33 were more expressed in T/NK-ALL patients, whereas CD8 and terminal deoxynucleotidyl transferase were more expressed in T-ALL patients (P < 0.05). The mean overall survival (863 vs. 1869 d, P = 0.02) and disease-free survival (855 vs. 2095 d, P = 0.002) were shorter in patients expressing CD56/CD16. However, multivariate analysis identified CD56/CD16 as an independent prognostic factor only for DFS. Cytotoxic molecules were highly expressed in T/NK-ALL compared to T-ALL. Perforin, granzyme B and TIA-1 were detected in 12/17, 4/17 and 7/24 T/NK-ALL patients and in 1/20, 0/20 and 1/20 T-ALL respectively (P < 0.001, P = 0.036 and P = 0.054). Therefore, the presence of CD56/CD16 was associated with distinct clinical features and expression of cytotoxic molecules in the blasts.

CHRONIC LITHIUM TREATMENT PREVENT ANXIETY-LIKE BEHAVIOR RELATED TO DIETARY RESTRICTION

Caloric intake reduction has been considered as the major experimental manipulation able to increase longevity in experimental models. Therefore, its effects upon cognition and mood like behavior are poorly explored. On the other hand, Li(+) is a re-emergent therapeutic drug used to treat mood disorders, mainly bipolar disorder, with antipanic and antidepressant actions. On the hypothesis that lithium treatment could attenuate the negatives effects of stress on Central Nervous Systems (CNS), we evaluated the role of chronic lithium treatment on anxiety-like behaviors in animals submitted to stress by chronic moderated feed restriction (FR). Male wistar rats were divided into four groups (n = 7-8/group) according to dietary and drug manipulation: ad libitum (AL) with unlimited access to standard rat diet, lithium treatment ( AL + Li) which received approximately 50 mg/Kg animal/day of LiCl solved in water and ad libitum diet, FR that were fed with equivalent to 70% of total rat diet consumed by AL group, and FR + Li which received diet corresponding to FR and Li administration. After 12 weeks of drug and FR manipulation, anxiety like behavior was evaluated in elevated plus mazes (EPM). Chronic lithium treatment prevent the anxiogenic like effect of FR ( open time, F(3,30) = 3.588; P = 0.0265; percentage of open entries, F(3,30) = 6.004; P= 0.00029; and open time at the first min, 2.35; F(3,30) = 4.937; P = 0.0073, Duncan test P < 0.05) compared to AL diet. Ours results adding to evidences that moderate feed restriction my increase anxiety-like behavior; also suggest that chronic lithium treatment may be attenuated this effects.

Determination of P-glycoprotein, MDR-related protein 1, breast cancer resistance protein, and lung-resistance protein expression in leukemic stem cells of acute myeloid leukemia

Background: The most primitive leukemic precursor in acute myeloid leukemia (AML) is thought to be the leukemic stem cell (LSC), which retains the properties of self-renewal and high proliferative capacity and quiescence of the hematopoietic stem cell. LSC seems to be immunophenotypically distinct and more resistant to chemotherapy than the more committed blasts. Considering that the multidrug resistance (MDR) constitutive expression may be a barrier to therapy in AML, we have investigated whether various MDR transporters were differentially expressed at the protein level by different leukemic subsets. Methods: The relative expression of the drug-efflux pumps P-gp, MRP, LRP, and BCRP was evaluated by mean fluorescence index (MFI) and the Kolmogorov-Smirnov analysis (D values) in five leukemic subpopulations: CD34(+)CD38(-)CD123(+) (LSCs), CD34(+)CD38(+)CD123(-), CD34(+)CD38(+)CD123(+), CD34(+)CD38(+)CD123(-), and CD34(-) mature cells in 26 bone marrow samples of CD34(+) AML cases. Results: The comparison between the two more immature subsets (LSC versus CD34(+)CD38(-)CD123(-) cells) revealed a higher P-gp, MRP, and LRP expression in LSCs. The comparative analysis between LSCs and subsets of intermediate maturation (CD34(+)CD38(+)) demonstrated the higher BCRP expression in the LSCs. In addition, P-gp expression was also significantly higher in the LSC compared to CD34(+)CD38(+)CD123(-) subpopulation. Finally, the comparative analysis between LSC and the most mature subset (CD34(-)) revealed higher MRP and LRP and lower P-gp expression in the LSCs. Conclusions: Considering the cellular heterogeneity of AML, the higher MDR transporters expression at the most immature, self-renewable, and quiescent LSC population reinforces that MDR is one of the mechanisms responsible for treatment failure. (C) 2008 Clinical Cytometry Society.

Doxycycline Dose-dependently Inhibits MMP-2-Mediated Vascular Changes in 2K1C Hypertension

Hypertension induces vascular alterations that are associated with up-regulation of matrix metalloproteinases (MMPs). While these alterations may be blunted by doxycycline, a non-selective MMPs inhibitor, no previous study has examined the effects of different doses of doxycycline on these alterations. This is important because doxycycline has been used at sub-antimicrobial doses, and the use of lower doses may prevent the emergence of antibiotic-resistant microorganisms. We studied the effects of doxycycline at 3, 10 and 30 mg/kg per day on the vascular alterations found in the rat two kidneyone clip (2K1C) hypertension (n = 20 rats/group). Systolic blood pressure (SBP) was monitored during 4 weeks of treatment. We assessed endothelium-dependent and independent relaxations. Quantitative morphometry of structural changes in the aortic wall was studied, and aortic MMP-2 levels/proteolytic activity were determined by gelatin and in situ zymography, respectively. All treatments attenuated the increases in SBP in hypertensive rats (195.4 +/- 3.9 versus 177.2 +/- 6.2, 176.3 +/- 4.5, and 173 +/- 5.1 mmHg in 2K1C hypertensive rats treated with vehicle, or doxycycline at 3, 10, 30 mg/kg per day, respectively (all p < 0.01). However, only the highest dose prevented 2K1C-induced reduction in endothelium-dependent vasorelaxation (p < 0.05), vascular hypertrophy and increases in MMP-2 levels (all p < 0.05). In conclusion, our results suggest that relatively lower doses of doxycycline do not attenuate the vascular alterations found in the 2K1C hypertension model, and only the highest dose of doxycycline affects MMPs and vascular structure. Our results support the idea that the effects of doxycycline on MMP-2 and vascular structure are pressure independent.

Microscopic Evidences That Bone Marrow Mononuclear Cell Treatment Improves Sciatic Nerve Regeneration After Neurorrhaphy

Cell therapy constitutes a possibility for improving nerve regeneration, increasing the success of nerve repair. We evaluate the use of mononuclear cells in the regeneration of the sciatic nerve after axotomy followed by end-to-end neurorrhaphy. Forty adult male Wistar rats (250300 g) were divided into four groups: (1) sham, (2) neurorrhaphy: the sciatic nerve was sectioned and repaired using epineural sutures, (3) culture medium: after the suture, received an injection of 10 mu L of culture medium into the nerve, and (4) mononuclear cell: after the suture, a concentration of 3 X 10(6) of mononuclear cell was injected in epineurium region. Mononuclear cells were obtained from the bone marrow aspirates and separated by Ficoll-Hypaque method. The histological analyses were performed at the 4th postoperative day. The sciatic functional index, histological, and morphometric analyzes were used to evaluate nerve regeneration at the 6th postoperative week. Six rats were used for immunohistochemical analysis on the 4th postoperative day. In the group 4, on the fourth day, the histological analysis demonstrated a more accelerated degenerative process and an increase of the neurotrophic factors was observed. In the 6th week, all the morphometric results of the group 4 were statistically better compared with groups 2 and 3. There was a statistically significant improvement in the sciatic functional index for group 4 compared with groups 2 and 3. Mononuclear cells stimulated nerve regeneration, most probably by speeding up the Wallerian degeneration process as well as stimulating the synthesis of neurotrophic factors. Microsc. Res. Tech. 74:355-363, 2011. (C) 2010 Wiley-Liss, Inc.

Treatment of Brain Arteriovenous Malformations by Double Arterial Catheterization with Simultaneous Injection of Onyx: Retrospective Series of 17 Patients

BACKGROUND AND PURPOSE: The use of Onyx in the treatment of intracranial AVMs has increased the cure rate of endovascular embolization compared with the use of liquid adhesive agents. Inadvertent occlusion of the draining veins before the complete exclusion of the nidus constitutes a major risk of bleeding. We report a case series using the technique of double simultaneous arterial catheterization as an approach to achieve the complete, exclusion of the nidus before reaching the venous drainage, through a more controlled hemodynamic filling. MATERIALS AND METHODS: Between April 2008 and November 2009, 17 patients with brain AVMs were treated by the DACT. The mean age of the patients was 32.7 years (range, 6-54 years), with 9 females and 8 males. The clinical onset was characterized by intracranial hemorrhage in 8 patients and by seizures in 7. The size of the AVMs ranged from 13 to 54 mm (average, 26.2 mm). The DACT was always used with the objective of curing the AVM. RESULTS: All 17 patients completed the EVT. The average number of sessions conducted was 1.4 (range, 1-3 sessions), with the average injection amount of 6.9 mL of Onyx (range, 2-25.2 mL). Sixteen AVMs (94.1%) were angiographically cured by embolization. Clinical complications occurred in 2 patients (11.7%); 1 of these was permanent (5.9%). No deaths were registered. CONCLUSIONS: This preliminary series shows that the DACT presents satisfactory results when used with curative intent.