Human Endometrial-Derived Mesenchymal Stem Cells Suppress Inflammation in the Central Nervous System of EAE Mice

FAPESP [2009/13109-5]

Congenital Adrenal Hyperplasia Due to 21 Hydroxylase Deficiency: From Birth to Adulthood

The most frequent form of congenital adrenal hyperplasia (CAH) is steroid 21-hydroxylase deficiency, accounting for more than 90% of cases. Affected patients cannot synthesize cortisol efficiently. Thus the adrenal cortex is stimulated by corticotropin (ACTH) and overproduces cortisol precursors. Some precursors are diverted to sex hormone biosynthesis, causing signs of androgen excess including ambiguous genitalia in newborn females and rapid postnatal growth in both sexes. In the most severe "salt wasting" form of CAH (similar to 75% of severe or "classic" cases), concomitant aldosterone deficiency may lead to salt wasting with consequent failure to thrive, hypovolemia, and shock. Newborn screening minimizes delays in diagnosis, especially in males, and reduces morbidity and mortality from adrenal crises. CAH is a recessive disorder caused by mutations in the CYP21 (CYP21A2) gene, most of which arise from recombination between CYP21 and a nearby pseudogene, CYP21P (CYP21A1P). Phenotype is generally correlated with genotype. Classic CAH patients require chronic glucocorticoid treatment at the lowest dose that adequately suppresses adrenal androgens and maintains normal growth and weight gain, and most require mineralocorticoid (fludrocortisone). Transition of care of older patients to adult physicians should be planned in advance as a structured, ongoing process.

Standard surgical treatment for benign prostatic hyperplasia is safe for patients over 75 years: Analysis of 100 cases from a high-volume urologic center

OBJECTIVES: In this study, we aimed to determine the complications of standard surgical treatments among patients over 75 years in a high-volume urologic center. METHODS: We analyzed 100 consecutive patients older than 75 years who had undergone transurethral prostatic resection of the prostate or open prostatectomy for treatment of benign prostatic hyperplasia from January 2008 to March 2010. We analyzed patient age, prostate volume, prostate-specific antigen level, international prostatic symptom score, quality of life score, urinary retention, co-morbidities, surgical technique and satisfaction with treatment. RESULTS: Median age was 79 years. Forty-eight patients had undergone transurethral prostatic resection of the prostate, and 52 had undergone open prostatectomy. The median International Prostatic Symptom Score was 20, the median prostate volume was 83 g, 51% were using an indwelling bladder catheter, and the median prostate-specific antigen level was 5.0 ng/ml. The most common comorbidities were hypertension, diabetes and coronary disease. After a median follow-up period of 17 months, most patients were satisfied. Complications were present in 20% of cases. The most common urological complication was urethral stenosis, followed by bladder neck sclerosis, urinary fistula, late macroscopic hematuria and persistent urinary incontinence. The most common clinical complication was myocardial infarction, followed by acute renal failure requiring dialysis. Incidental carcinoma of the prostate was present in 6% of cases. One case had urothelial bladder cancer. CONCLUSIONS: Standard surgical treatments for benign prostatic hyperplasia are safe and satisfactory among the elderly. Complications are infrequent, and urethral stenosis is the most common. No clinical variable is associated with the occurrence of complications.

Botulinum Neurotoxin Type A for the Treatment of Benign Prostatic Hyperplasia: Randomized Study Comparing Two Doses

Purpose. To assess the efficacy and safety of intraprostatic injection of two botulinum neurotoxin type A (BoNT-A) doses for the treatment of benign prostatic hyperplasia (BPH). Materials and Methods. Men with symptomatic BPH who failed medical treatment were randomized to receive 100 U or 200 U of BoNT-A into the prostate. The International Prostatic Symptom Score (IPSS), maximum flow rate (Q(max)), post-void residual volume (PVR), PSA levels and prostate volume before injection and after 3 and 6 months were evaluated. Adverse events were compared between the groups. Results. Thirty four patients were evaluated, including 17 in the BoNT-A 100 U group and 17 in the BoNT-A 200 U group. Baseline characteristics were similar in both groups. Both doses produced significant improvements in IPSS, Q(max) and PVR after 3 and 6 months and both doses promoted comparable effects. Prostate volume was affected by 200 U BoNT-A injection only after 6 months of treatment. PSA levels were significantly affected in the 100 U group only after 6 months of treatment. In the 200 U group, PSA levels were significantly decreased after 3 and 6 months. The complication rate was similar in both groups. Conclusions. Efficacy and safety of both BoNT-A doses are similar for BPH treatment in the short term followup.

Vaginal morcellation: A new strategy for large gynecological malignant tumor extraction A pilot study

Objective. Evaluate feasibility and safety of a novel technique for uterine morcellation in patients scheduled for laparoscopic treatment of gynecologic malignances. Background. The laparoscopic management of uterine malignancies is progressively gaining importance and popularity over laparotomy. Nevertheless, minimal invasive surgery is of limited use when patients have enlarged uterus or narrow vagina. In these cases, conventional uterus morcellation could be a solution but should not be recommended due to risks of tumor dissemination. Methods. Prospective pilot study of women with endometrial cancer in which uterus removal was a realistic concern due to both organ size and proportionality. Brief technique description: after completion of total laparoscopic hysterectomy and bilateral anexectomy, a nylon with polyurethane Lapsac (R) is vaginally inserted into the abdomen; the specimen is placed inside the pouch that will be closed and rotated 180 degrees toward the vaginal vault and, posteriorly, pushed into the vaginal canal; in the transvaginal phase, the surgeon pulls the edges of the bag up to vaginal introitus and all vaginal walls will be covered; inside the pouch, the operator performs a uterus bisection-morcellation. Results. In our series of 8 cases, we achieved successful completion in all patients, without conversion to laparotomy. Average operative time, blood loss and length of hospitalization were favorable. One patient presented with a vesicovaginal fistula. Conclusion. The vaginal morcellation following oncologic principles is a feasible method that permits a rapid uterine extraction and may avoid a number of unnecessary laparotomies. Further studies are needed to confirm the oncological safety of the technique. (C) 2012 Elsevier Inc. All rights reserved.

Guidelines for the Development of Comprehensive Care Centers for Congenital Adrenal Hyperplasia: Guidance from the CARES Foundation Initiative

Patients with rare and complex diseases such as congenital adrenal hyperplasia (CAH) often receive fragmented and inadequate care unless efforts are coordinated among providers. Translating the concepts of the medical home and comprehensive health care for individuals with CAH offers many benefits for the affected individuals and their families. This manuscript represents the recommendations of a 1.5 day meeting held in September 2009 to discuss the ideal goals for comprehensive care centers for newborns, infants, children, adolescents, and adults with CAH. Participants included pediatric endocrinologists, internal medicine and reproductive endocrinologists, pediatric urologists, pediatric surgeons, psychologists, and pediatric endocrine nurse educators. One unique aspect of this meeting was the active participation of individuals personally affected by CAH as patients or parents of patients. Representatives of Health Research and Services Administration (HRSA), New York-Mid-Atlantic Consortium for Genetics and Newborn Screening Services (NYMAC), and National Newborn Screening and Genetics Resource Center (NNSGRC) also participated. Thus, this document should serve as a "roadmap" for the development phases of comprehensive care centers (CCC) for individuals and families affected by CAH.

Coronoid process hyperplasia: an unusual cause of mandibular hypomobility

A large number of disorders affecting the masticatory system can cause restriction of mouth opening. The most common conditions related to this problem are those involving the temporomandibular joint (TMJ) and the masticatory muscles, when facial pain also is an usual finding. Congenital or developmental mandibular disorders are also possible causes for mouth opening limitation, although in a very small prevalence. Coronoid process hyperplasia (CPH) is an example of these cases, characterized by an excessive coronoid process growing, where mandibular movements become limited by the impaction of this structure on the posterior portion of the zygomatic bone. This condition is rare, painless, usually bilateral and progressive, affecting mainly men. Diagnosis of CPH is made based on clinical signs of mouth opening limitation together with imaging exams, especially panoramic radiography and computerized tomography (CT). Treatment is exclusively surgical. This paper presents a case of a male patient with bilateral coronoid process hyperplasia, initially diagnosed with bilateral disk displacement without reduction, and successfully treated with intraoral coronoidectomy. It is emphasized the importance of differential diagnosis for a correct diagnosis and, consequently, effective management strategy.

Tumor misto de células musculares lisas e do estroma endometrial uterino: relato de caso

Os tumores mistos de células musculares lisas e do estroma endometrial uterino, caracterizados pela presença de componentes de ambas as linhagens, coexistindo em proporções quase equivalentes, são neoplasmas raros. Possuem potencial biológico incerto e se comportam de acordo com o componente estromal. A imuno-histoquímica é uma grande aliada no diagnóstico microscópico, pois a clínica e os exames de imagem não ajudam a diferenciá-los de outras doenças uterinas. Descrevemos o caso de uma paciente cuja hipótese diagnóstica era de leiomioma uterino e que, após cirurgia, foi diagnosticada pelo estudo anatomopatológico como tumor misto de células musculares lisas e do estroma endometrial uterino.

Standard surgical treatment for benign prostatic hyperplasia is safe for patients over 75 years: analysis of 100 cases from a high-volume urologic center

OBJECTIVES: In this study, we aimed to determine the complications of standard surgical treatments among patients over 75 years in a high-volume urologic center. METHODS: We analyzed 100 consecutive patients older than 75 years who had undergone transurethral prostatic resection of the prostate or open prostatectomy for treatment of benign prostatic hyperplasia from January 2008 to March 2010. We analyzed patient age, prostate volume, prostate-specific antigen level, international prostatic symptom score, quality of life score, urinary retention, co-morbidities, surgical technique and satisfaction with treatment. RESULTS: Median age was 79 years. Forty-eight patients had undergone transurethral prostatic resection of the prostate, and 52 had undergone open prostatectomy. The median International Prostatic Symptom Score was 20, the median prostate volume was 83 g, 51% were using an indwelling bladder catheter, and the median prostatespecific antigen level was 5.0 ng/ml. The most common comorbidities were hypertension, diabetes and coronary disease. After a median follow-up period of 17 months, most patients were satisfied. Complications were present in 20% of cases. The most common urological complication was urethral stenosis, followed by bladder neck sclerosis, urinary fistula, late macroscopic hematuria and persistent urinary incontinence. The most common clinical complication was myocardial infarction, followed by acute renal failure requiring dialysis. Incidental carcinoma of the prostate was present in 6% of cases. One case had urothelial bladder cancer. CONCLUSIONS: Standard surgical treatments for benign prostatic hyperplasia are safe and satisfactory among the elderly. Complications are infrequent, and urethral stenosis is the most common. No clinical variable is associated with the occurrence of complications.

Pyloric Brunner’s gland hamartoma with atypical hyperplasia

Brunner’s gland hamartoma (BGH) is an extremely rare benign digestive tumor, generally located in the duodenal bulb. We report the case of a 51-year-old asymptomatic man with a large pedunculated BGH arising from the pylorus. It was successfully removed en bloc by endoscopic resection.

Manipulation of the periovulatory sex steroidal milieu affects endometrial but not luteal gene expression in early diestrus Nelore cows

In beef cattle, the ability to conceive has been associated positively with size of the preovulatory follicle (POF). Proestrus estradiol and subsequent progesterone concentrations can regulate the endometrium to affect receptivity and fertility. The aim of the present study was to verify the effect of the size of the POF on luteal and endometrial gene expression during subsequent early diestrus in beef cattle. Eighty-three multiparous, nonlactating, presynchronized Nelore cows received a progesterone-releasing device and estradiol benzoate on Day–10 (D 10). Animals received cloprostenol (large follicle-large CL group; LF-LCL; N ¼ 42) or not (small follicle-small CL group; SF-SCL; N ¼ 41) on D 10. Progesterone devices were withdrawn and cloprostenol administered 42 to 60 hours (LF-LCL) or 30 to 36 hours (SF-SCL) before GnRH treatment (D0). Tissues were collected at slaughter on D7. The LF-LCL group had larger (P < 0.0001) POF (13.24 0.33 mm vs. 10.76 0.29 mm), greater (P < 0.0007) estradiol concentrations on D0 (2.94 0.28 pg/mL vs. 1.27 0.20 pg/mL), and greater (P < 0.01) progesterone concentrations on D7 (3.71 0.25 ng/mL vs. 2.62 0.26 ng/mL) compared with the SF-SCL group. Luteal gene expression of vascular endothelial growth factor A, kinase insert domain receptor, fms-related tyrosine kinase 1, steroidogenic acute regulatory protein, cytochrome P450, family 11, subfamily A, polypeptide 1, and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid deltaisomerase 7 was similar between groups. Endometrial gene expression of oxytocin receptor and peptidase inhibitor 3, skin-derived was reduced, and estrogen receptor alpha 2, aldo-keto reductase family 1, member C4, and lipoprotein lipase expression was increased in LF-LCL versus SF-SCL. Results support the hypothesis that the size of the POF alters the periovulatory endocrine milieu (i.e., proestrus estradiol and diestrus progesterone concentrations) and acts on the uterus to alter endometrial gene expression. It is proposed that the uterine environment and receptivity might also be modulated. Additionally, it is suggested that increased progesterone secretion of cows ovulating larger follicles is likely due to increased CL size rather than increased luteal expression of steroidogenic genes.

Chronic VEGF Blockade Worsens Glomerular Injury in the Remnant Kidney Model

VEGF inhibition can promote renal vascular and parenchymal injury, causing proteinuria, hypertension and thrombotic microangiopathy. The mechanisms underlying these side effects are unclear. We investigated the renal effects of the administration, during 45 days, of sunitinib (Su), a VEGF receptor inhibitor, to rats with 5/6 renal ablation (Nx). Adult male Munich-Wistar rats were distributed among groups S+V, sham-operated rats receiving vehicle only; S+Su, S rats given Su, 4 mg/kg/day; Nx+V, Nx rats receiving V; and Nx+Su, Nx rats receiving Su. Su caused no change in Group S. Seven and 45 days after renal ablation, renal cortical interstitium was expanded, in association with rarefaction of peritubular capillaries. Su did not worsen hypertension, proteinuria or interstitial expansion, nor did it affect capillary rarefaction, suggesting little angiogenic activity in this model. Nx animals exhibited glomerulosclerosis (GS), which was aggravated by Su. This effect could not be explained by podocyte damage, nor could it be ascribed to tuft hypertrophy or hyperplasia. GS may have derived from organization of capillary microthrombi, frequently observed in Group Nx+Su. Treatment with Su did not reduce the fractional glomerular endothelial area, suggesting functional rather than structural cell injury. Chronic VEGF inhibition has little effect on normal rats, but can affect glomerular endothelium when renal damage is already present.

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.

Experimental infection of suckling mice by subcutaneous inoculation with Oropouche virus

Oropouche virus, of the family Bunyaviridae, genus Orthobunyavirus, serogroup Simbu, is an important causative agent of arboviral febrile illness in Brazil. An estimated 500,000 cases of Oropouche fever have occurred in Brazil in the last 30 years, with recorded cases also in Panama, Peru, Suriname and Trinidad. We have developed an experimental model of Oropouche virus infection in neonatal BALB/c mouse by subcutaneous inoculation. The vast majority of infected animals developed disease on the 5th day post infection, characterized mainly by lethargy and paralysis, progressing to death within 10 days. Viral replication was documented in brain cells by in situ hybridization, immunohistochemistry and virus titration. Multi-step immunohistochemistry indicated neurons as the main target cells of OROV infection. Histopathology revealed glial reaction and astrocyte activation in the brain and spinal cord, with neuronal apoptosis. Spleen hyperplasia and mild meningitis were also found, without viable virus detected in liver and spleen. This is the first report of an experimental mouse model of OROV infection, with severe involvement of the central nervous system, and should become useful in pathogenesis studies, as well as in preclinical testing of therapeutic interventions for this emerging pathogen. (c) 2012 Elsevier B.V. All rights reserved.

Prostate biopsy in patients with long-term use of indwelling bladder catheter: What is the rationale?

Objective: Acute urinary retention (AUR) is expected to occur in 2% to 39% men with benign prostatic hyperplasia. To date, no study has elucidated the effect of long-term use of indwelling bladder catheter on serum prostate specific antigen (PSA) levels and on the incidence of prostate cancer (CaP). The aim of the present study is to analyze the incidence of CaP in patients with long-term use of indwelling bladder catheter and determine some practice patterns on this issue. Materials and methods: The study comprised a retrospective analysis of data from 1,651 patients who had undergone transrectal ultrasound (TRUS)-guided prostate biopsy from July 2004 to June 2009. Among these patients, 198 (12%) were using an indwelling bladder catheter during the biopsy for at least 1 month. The incidence of CaP was recorded according to total PSA levels. Other variables such patient age, free/total PSA rate, PSA density, prostate volume, and duration of catheter use was also analyzed. Men with a digital rectal examination suspicious for cancer were not considered for analysis. Results: Median patient age was 71 years (37 to 89 years). Overall, 25% of patients presented a CaP diagnosis. CaP incidence according to the PSA levels was 0%, 18.9%, 24.5%, and 40.6% for patients with PSA <= 4.0, 4.1-10.0, 10.1-20.0, and >20.0 ng/ml, respectively. When prostate volume was analyzed together, we demonstrated that only 1 (2.4%) patient with PSA below 10.0 ng/ml and prostate volume >60 g had CaP. Median total PSA, PSA density, and prostate volume were statistically different between patients with and without CaP. Conclusions: Prostate biopsy should not be indicated for all patients with diagnosis of BPH and AUR who present an elevated PSA level. Patients with PSA below 10.0 ng/ml, and prostate volume >60 g should only undergo biopsy in selected cases. Patients with PSA >20.0 ng/ml and a prostate volume <= 60 g are at higher risk of CaP diagnosis. (C) 2012 Elsevier Inc. All rights reserved.