The laparoscopic management of intersex patients: the preferred approach

In the world's largest series of patients with intersex treated by laparoscopy, authors from Sao Paulo found that this technique allowed easy identification and removal of gonads. They also found that other organs could be removed and genitoplasty performed. OBJECTIVE: To present possibly the largest series of the use of laparoscopy for treating intersex patients. PATIENTS AND METHODS: Fifty intersex patients (34 with male and two with female pseudohermaphroditism, nine with gonadal dysgenesis, four with true hermaphroditism, and one with complex hypospadias), aged 0.5-46 years (mean 18.3), underwent laparoscopy to remove gonads and/or ductal structures incompatible with the social gender, or for gonadal tumour or a potential risk for malignancy. When necessary, genitoplasty was performed concomitantly. RESULTS: At the laparoscopic evaluation, 10 gonads of six patients were absent, while four were identified as 'vanishing'; 72 gonads (46 dysgenetic, 17 normal testes, one normal ovary, one ovotestis, seven gonadoblastomas or dysgerminomas) were removed; two ovotestes were replaced in the scrotum after removing the ovarian segment, as was one normal testis. Twelve patients with a urogenital sinus had its vaginal component removed, 11 including a hysterectomy. Three of these patients had a combined perineal approach to complete its removal, together with masculinizing genitoplasty. There were no intraoperative complications or conversions; two patients had complications after surgery. CONCLUSIONS: Laparoscopy allows the straightforward identification and removal of gonads. All abnormal ductal structures must be removed, as this increases the chance of resecting unidentified gonads. Removing the uterus and vaginal component of the urogenital sinus in patients with male social sex is feasible, with low morbidity. Genitoplasty, according to the social sex, can be performed in the same procedure.     

Aneural culture of rat myoblasts for myocardial transplant

Due to the peculiar characteristics of skeletal muscle, myoblast transplants have emerged as a therapy for cardiomyopathy, particularly after myocardial infarction. The objectives of this study were to define the mean time of cultivation necessary to obtain a cellular concentration of 10(6) to expand the mass for transplant, and to identify the proliferation phase of myoblasts. Ten myoblast cultures were performed using newborn Wistar rats. The isolation method used enzymatic dissociation in culture medium (HAM-F12 and 199) supplement with basic-fibroblast growth factor (b-FGF) and insulin growth factor (IGF-I). The mean cultivation time to obtain the desired concentration of 10(6) was 7 days, with expansion of up to 10(8)/g. When b-FGF was used, the cellular yield was approximately 10(7), with IGF-I the cellular yield was approximately 10(8), independent of the medium. We concluded that IGF-I is the better option for mass cellular expansion of myoblasts for application in myocardial transplants.     

Rhombencephalosynapsis: CT and MRI findings

An unusual disorder of cerebellar development, rhombencephalosynapsis is a unique entity which presents with cerebellar fusion and absence of cerebellar vermis on imaging studies, often associated with supratentorial findings. No specific clinical syndrome has been described in these patients so far, and most cases are found in infancy and childhood. MRI and its multiplanar capabilities and high spatial and contrast resolution increased its recognition. Two cases are reported, with emphasis on imaging findings.     

A novel class of nonpeptidic biaryl inhibitors of human cathepsin K

A novel series of nonpeptidic biaryl compounds was identified as potent and reversible inhibitors of cathepsin K. The P2-P3 amide bond of a known amino acetonitrile dipeptide 1 was replaced with a phenyl ring, thereby giving rise to this biaryl series that retained potency vs cathepsin K and showed an improved selectivity profile against other cathepsins. Structural modification within this series resulted in the identification of compound (R)-2, a potent human cathepsin K inhibitor (IC(50) = 3 nM) that is selective versus cathepsins B (IC(50) = 3950 nM), L (IC(50) = 3725 nM), and S (IC(50) = 2010 nM). In an in vitro assay involving rabbit osteoclasts and bovine bone, compound (R)-2 inhibited bone resorption with an IC(50) of 95 nM. It was shown that, unlike some peptidic nitrile inhibitors of cysteine proteases, the nitrile moiety of (R)-2 is not converted to the corresponding amide 3 by cathepsin K. This indicates that this class of nonpeptidic nitrile inhibitors is unlikely to be hydrolyzed by cysteine proteases. Furthermore, the inhibition of cathepsin K by compound (R)-2 was shown to be fully reversible and not observably time-dependent. To demonstrate the efficacy of compound (R)-2 in vivo, it was administered to ovariectomized (OVX) rhesus monkeys at 20 mg/kg, po once daily for 8 days, and a urinary marker of bone turnover, N-telopeptide of type I collagen (uNTx), was measured. During the eight-day dosing period, the mean reduction by compound (R)-2 in uNTx was 80% (p < 0.001). This demonstrates that inhibition of cathepsin K leads to an inhibition of this bone resorption marker in OVX rhesus monkeys and strongly suggests that inhibition of cathepsin K is a viable therapeutic approach for the treatment of osteoporosis.     

Adrenal nodules in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: regression after adequate hormonal control

Adrenal nodules have been described in patients with 21-hydroxylase deficiency (21OHD). These nodules are usually considered to be ACTH-dependent, as is the commonly seen diffuse cortical hyperplasia. We evaluated the presence and behavior of adrenal nodules in patients with 21OHD. Based upon hormonal status and treatment compliance, the patients were classified into three categories: poor, regular and good control. Out of the 26 patients, eight had the non-classic, four salt-wasting and 14 simple virilizing forms. All patients underwent initial adrenal morphological studies, either by CT or MRI. Those with nodules were reevaluated after 12 months of adequate replacement therapy. Nodules were found in four of eight untreated patients and two of three patients with poor hormonal control, but not in the 15 patients with regular or good control. Adrenal nodules in these six patients demonstrated a considerable size reduction and even disappearance after adequate replacement therapy, showing that these nodules were ACTH-dependent. Thus, six out of 26 patients with 21OHD presented adrenal nodules, which were more frequent in the untreated or poorly-controlled patients, and all regressed in size after adequate therapy.     

No evidence of somatic activating mutations on gonadotropin receptor genes in sex cord stromal tumors

OBJECTIVE: To search for somatic activating mutations of gonadotropin receptor (FSH-R and LH/chorionic gonadotropin receptor [CG-R]) genes as a cause of sex cord stromal tumors. DESIGN: Molecular studies in human tissue. SETTING: University hospital. SPECIMEN(S): Eight granulosa cell tumors collected from paraffin-embedded tissue, eight Leydig cell tumors, and three thecomas collected from fresh-frozen or paraffin-embedded tissue. INTERVENTION(S): Tumor samples were used for DNA extraction. The entire exon 11 of the LH/CG-R gene and a hot spot for gonadotropin receptor activating mutations on exon 10 of the FSH-R gene were amplified by polymerase chain reaction. The former was analyzed by denaturing gradient gel electrophoresis and automatic direct sequencing, and the latter by automatic direct sequencing. MAIN OUTCOME MEASURE(S): Results of denaturing gradient gel electrophoresis and automatic direct sequencing. RESULT(S): No somatic activating mutation was detected in exon 11 of the LH/CG-R gene in eight Leydig cell tumors and three thecomas. In addition, no mutations were detected in eight granulosa cell tumors in the hot spot for activating mutations in exon 10 of the FSH-R gene. CONCLUSION(S): Somatic activating mutations of gonadotropin receptors seem to play no relevant role in the development of sex cord stromal tumors.     

21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study

OBJECTIVE: Our aim was to determine whether the clinical features of 21-hydroxylase-deficient nonclassic adrenal hyperplasia are correlated with either age at symptom onset or age at presentation, or both, and with the degree of adrenocortical abnormality. STUDY DESIGN: In a multicenter cohort design 220 women with nonclassic adrenal hyperplasia, with a basal or adrenocorticotropic hormone-stimulated 17-hydroxyprogesterone level >30.3 nmol/L, were studied, either prospectively (n = 39) or retrospectively (n = 181). Patients were stratified by age of presentation into 5 groups: (1) <10 years (n = 25), (2) 10 to 19 years (n = 64), (3) 20 to 29 years (n = 83), (4) 30 to 39 years (n = 30), and (5) 40 to 49 years (n = 16). Two patients >50 years old were excluded from the analysis because of age. RESULTS: Ninety-two percent of patients <10 years old had premature pubarche at presentation, whereas clitoromegaly and acne were each present in only 20% of these younger subjects. With only patients > or =10 years old considered, presenting clinical features included hirsutism (59%), oligomenorrhea (54%), acne (33%), infertility (13%), clitoromegaly (10%), alopecia (8%), primary amenorrhea (4%), and premature pubarche (4%). Among the patients >/=10 years old, the prevalence but not the degree of hirsutism increased significantly with age. Basal levels of 17-hydroxyprogesterone in adolescents were significantly higher than the levels found either in children (<10 years old) or women 40 to 49 years old (P <.01 and P <.03, respectively), although no difference was noted in the stimulated 17-hydroxyprogesterone levels between age groups. The adrenocorticotropic hormone-stimulated levels but not the basal levels of 17-hydroxyprogesterone were significantly higher in patients with clitoromegaly than in women without clitoromegaly. Alternatively, there were no differences in either basal or stimulated 17-hydroxyprogesterone levels between patients with and those without hirsutism, acne, or alopecia. CONCLUSION: In children <10 years old the most common presenting complaint was premature pubarche, whereas hirsutism and oligomenorrhea were more common in older patients. The prevalence of hirsutism increased with age, suggesting the progressive nature of nonclassic adrenal hyperplasia. Furthermore, the adrenocorticotropic hormone-stimulated levels of 17-hydroxyprogesterone were higher in patients with clitoromegaly, which suggests that the degree of adrenocortical dysfunction in nonclassic adrenal hyperplasia determines, at least in part, the clinical presentation.     

Catch-up growth up to ten years of age in children born very preterm or with very low birth weight

Background  

Improved survival due to advances in neonatal care has brought issues such as postnatal growth and development more to the focus of our attention. Most studies report stunting in children born very preterm and/or small for gestational age. In this article we study the growth pattern of these children and aim to identify factors associated with postnatal catch-up growth.