DNA repair complex licenses acetylation of H2A.Z.1 by KAT2A during transcription.

Post-translational modifications of histone variant H2A.Z accompany gene transactivation, but its modifying enzymes still remain elusive. Here, we reveal a hitherto unknown function of human KAT2A (GCN5) as a histone acetyltransferase (HAT) of H2A.Z at the promoters of a set of transactivated genes. Expression of these genes also depends on the DNA repair complex XPC-RAD23-CEN2. We established that XPC-RAD23-CEN2 interacts both with H2A.Z and KAT2A to drive the recruitment of the HAT at promoters and license H2A.Z acetylation. KAT2A selectively acetylates H2A.Z.1 versus H2A.Z.2 in vitro on several well-defined lysines and we unveiled that alanine-14 in H2A.Z.2 is responsible for inhibiting the activity of KAT2A. Notably, the use of a nonacetylable H2A.Z.1 mutant shows that H2A.Z.1ac recruits the epigenetic reader BRD2 to promote RNA polymerase II recruitment. Our studies identify KAT2A as an H2A.Z.1 HAT in mammals and implicate XPC-RAD23-CEN2 as a transcriptional co-activator licensing the reshaping of the promoter epigenetic landscape.

XPC is an RNA polymerase II cofactor recruiting ATAC to promoters by interacting with E2F1.

The DNA damage sensor XPC is involved in nucleotide excision repair. Here we show that in the absence of damage, XPC co-localizes with RNA polymerase II (Pol II) and active post-translational histone modifications marks on a subset of class II promoters in human fibroblasts. XPC depletion triggers specific gene down-expression due to a drop in the deposition of histone H3K9 acetylation mark and pre-initiation complex formation. XPC interacts with the histone acetyltransferase KAT2A and specifically triggers the recruitment of the KAT2A-containing ATAC complex to the promoters of down-expressed genes. We show that a strong E2F1 signature characterizes the XPC/KAT2A-bound promoters and that XPC interacts with E2F1 and promotes its binding to its DNA element. Our data reveal that the DNA repair factor XPC is also an RNA polymerase II cofactor recruiting the ATAC coactivator complex to promoters by interacting with the DNA binding transcription factor E2F1.

Glucagon test in insulinoma: Is it useful?

Diagnosis of endogenous hyperinsulinism caused by insulinoma is based on confirmation of hypoglycemia during the symptoms associated to elevated insulin levels. Patients with insulinoma may demonstrate an excessive insulin response and subsequent hypoglycemia after 1 mg of glucagon iv injection. Glucagon test was performed in 11 patients with insulinoma before therapy and in 4 after therapy. Our study suggests that the presence of plasma glucose levels less than 55 mg/dl and below baseline at time 120 min of glucagon test strongly reinforce the diagnosis of insulinoma.

Resistance to vasopressin action on the kidney in patients with Cushing's disease.

OBJECTIVE: To assess the plasma levels and action of arginine vasopressin (AVP) in patients with Cushing's disease. There are many reports that patients with Addison's disease have increased AVP levels associated with hyponatraemia and hypoosmolality, but none on the dynamics of secretion of this neurohormone during osmolality-based stimulation in patients with chronic hypercortisolism. DESIGN AND SUBJECTS: The plasma AVP concentration and the urinary and plasma osmolality after a 7.5-h water deprivation test (WDT) were evaluated in 13 patients with Cushing's disease and 15 normal (control) individuals. In patients with Cushing's disease we also assessed the urinary osmolality in response to 10 micrograms i.v. desmopressin (DDAVP) administered at the end of the WDT. RESULTS: At the end of the WDT, urinary osmolality was significantly lower in patients with Cushing's disease (511.5 +/- 148.5 mOsm/l) than in the normal subjects (981.1 +/- 107.1 mOsm/l, P < 0.001), whereas plasma osmolality did not differ between the two groups. Consequently, the urine/plasma osmolality ratio (Uosm/Posm) was lower in patients with Cushing's disease than in normal individuals (1.8 +/- 0.5 compared with 3.4 +/- 0.4, P < 0.001). The AVP concentration also was greater (7.3 +/- 3.1 pmol/l) in those with Cushing's disease than in the controls (3.9 +/- 2.3 pmol/l, P < 0.005). After administration of DDAVP to the hypercortisolaemic patients, the urinary osmolality attained (718.0 +/- 200.0 mOsm/l) was still lower than that in the normal group at the end of WDT (P < 0.005). CONCLUSIONS: Patients with Cushing's disease presented higher AVP levels and smaller Uosm/Posm ratios than normal subjects. After DDAVP, the patients with Cushing's disease were unable to concentrate the urine adequately. These data suggest that the kidney shows resistance to the action of both endogenous and exogenous AVP in patients with Cushing's disease.

Effect of glycemic control on growth hormone and IGFBP-1 secretion in patients with type I diabetes mellitus.

Growth hormone (GH) secretion disorders have been reported in poorly controlled type I diabetes mellitus patients. Our work was aimed to evaluate GH secretion in 9 type I young diabetes mellitus patients as well as the low molecular weight IGF-binding protein secretion (IGFBP-1) in 5 of them. The patients did not show any signs of malnutrition or neurovascular complications, neither were they on any medication except for insulin. The study protocol included blood samples collection during a 24-h period for measurement of glucose, glycated hemoglobin, GH IGF-I and IGFBP-1 levels under two situations: on poor glycemic control and after 2-3 months on better control through systematic diet, low in carbohydrates and increase in insulin dosage. GH secretion data were analyzed by Cluster algorithm for pulsatility parameters; for rhythm assessment Cosinor method was used. The first study (poor control) reported significant increase of GH maximal and incremental amplitude and duration pulse values, when compared to the second study (better control). Mean 24-h secretion values as well mean GH for interpulse intervals (valleys) decreased, although not statistically significant. The fraction of pulsatile GH/24 h GH did not change significantly with better glycemic control. No changes in pulse frequency were observed. Mean IGF-I concentrations were significantly higher when patients were on better glycemic control. An ultradian variation for GH secretion was noticed in the first study (poor control) and a circadian variation in the second one (better control). IGFBP-1 analysis showed significant decrease of the mean 24-h values under better glycemic control. Linear regression analysis demonstrated a correlation between IGFBP-1 levels and fasting glucose levels. A circadian variation was present in IGFBP-1 secretion, irrespective of glycemic control. Therefore, we concluded that for type I diabetic patients: 1. GH secretion is increased on poor control, through maximal, incremental amplitude and pulse duration values; 2. IGFBP-1 values were significantly reduced and IGF-1 levels significantly higher after better glycemic control; 4. GH ultradian secretion is reported on poor control, and circadian on the better one, 5. IGFBP-1 circadian secretion occurred irrespective of glycemic control.

Growth hormone axis in cushing's syndrome.

All levels of the growth hormone (GH), GH binding protein (GHBP), insulin-like growth factor (IGF) and IGF binding protein (IGFBP) axis are influenced by chronic hypercortisolism. Thus, there is a blunted response to GHRH alone or together with other stimuli associated with a marked suppression of endogenous GH secretion but accompanied by normal GHBP, normal to low IGF-1 and GHBPs 1 and 3 with the correspondent 41.5 and 38.5-kD molecular forms of the latter presenting values similar to normal. These findings may suggest enhanced GH sensitivity with normal or increased IGF-1 bioavailability to the correspondent tissue receptors. In conclusion, the glucocorticoid (GC)-induced target tissue resistance can neither be attributed to the suppression of the GH axis nor to changes in circulating GHBPs 1 and 3. However, it may be related either to the described 12-to-20-kD inhibitor(s) which antagonizes postbinding IGF-1 bioactivity (gene expression) and/or by the downmodulation of activator protein-1 (Fos/Jun) activity by the GC-GC receptor complex.

Growth hormone pulsatility in active and cured acromegalic subjects.

GH secretion in normal subjects is periodic, with pulses prevailing during sleep. During the day (basal secretion), GH levels are, in general, undetectable. We studied GH secretion by cluster analysis, collecting samples every 20 min for 24 h in 44 subjects: 11 patients with active acromegaly; 16 "cured" acromegalics, and 17 normal subjects. The purpose of this study was to compare GH secretion between patients with active acromegaly and "cured" patients and between "cured" acromegalic patients and normal controls. The number of pulses detected through the 24-h GH profile was not different between acromegalic patients regardless of disease activity (17.5 +/- 4.4 vs. 15.0 +/- 6.0, respectively), but was different when active acromegalic patients and normal controls were compared (8.1 +/- 1.0; P < 0.05) and when cured acromegalic patients and normal controls were compared (P < 0.05). The GH pulsatile secretion/total GH secretion ratio was higher in normal controls than in acromegalic patients regardless of disease activity. We concluded that 1) the increases in GH pulsatility in active and cured acromegalic patients are similar, but most of the 24-h GH secretion is nonpulsatile; 2) half of the GH secretion in normal subjects occurs during pulses; 3) cured acromegalic patients, even those with normal GH and insulin-like growth factor I levels, do not recover a normal GH secretory pattern.

XY gonadal dysgenesis and gonadoblastoma: a study in two sisters with a cryptic deletion of the Y chromosome involving the SRY gene.

This paper reports a case of XY gonadal dysgenesis in two sisters. Both patients presented an eunochoid female phenotype with normal external genitalia. At laparotomy, the elder sister was found to have bilateral gonadoblastoma. Cytogenetic studies, which included G and C banding and in situ hybridization, showed that the patients had an apparently normal 46, XY karyotype. PCR analyses revealed absence of the conserved portion (HMG box) of the SRY gene and of the Y chromosome pseudoautosomal boundary region sequence in both patients. The presence of the ZFY sequence was detected by Southern hybridization in the two affected sisters. The patients' father (46, XY, no mosaicism detected in peripheral blood lymphocytes) was positive for SRY and ZFY sequences. The occurrence of gonadoblastoma is discussed in terms of the genetic factors that may lead to tumor development.

Cistinose nefropática: relato de 2 casos e revisäo da literatura / Nephropathic cystinosis: report of two cases and review of the literature

Os autores descrevem dois casos de cistinose nefropática, da forma infantil, que se apresentaram com síndrome de Fanconi e diabetes insipidus nefrogênico. Após a confirmaçäo diagnóstica através da identificaçäo de cristais de cistina pelo exame de lâmpada de fenda e aspirado de medula óssea, os pacientes receberam tratamento convencional de reposiçäo das perdas renais de eletrólitos e minerais. O paciente 1 evoluiu para óbito após quadro de broncopneumonia. No paciente 2 foi iniciado tratamento com cisteamina, que é eficaz na depleçäo de cistina dos tecidos, na dose média de 50 mg/kg/dia, sendo este o primeiro caso de terapêutica com cisteamina em nosso meio.

[Nephropathic cystinosis: report of 2 cases and review of the literature]. / Cistinose nefropática: relato de 2 casos e revisão da literatura.

We describe two patients with infantile nephropathic cystinosis who presented nephrogenic diabetes insipidus in addition to Fanconi syndrome. After the diagnosis was confirmed by slit-lamp examination that showed crystallization of the cornea and by the presence of cystine crystals in the bone marrow, the patients underwent conservative and supportive treatment including correction of acidosis, replacement of fluid losses and protection from bone demineralization with replacement of phosphorus, calcium and vitamin D. Patient 1 deceased after an episode of bronchopneumonia complicated by profound acidosis. Patient 2 was started on cysteamine which effectively reduce cystine in body tissues and prevents or slows progression of end-organ damage.

Estimulaçäo alfa-adranérgica na secreçäo de hormônio de crescimento: comparaçäo da clonidina com guanabenz / Cepha adrenergic stimulation in growth hormone secretion: comparison between clonidine and guanabenz

Avaliamos o efeito da administraçäo aguda de clonidina e de guanabenz na secreçäo de hormônio de crescimento (GH0 em nove pacientes com deficiência isolada idiopática de GH (DGH), seis do sexo masculino e três do feminino, e em 15 indivíduos de baixa estatura sem deficiência de GH (CN), 11 do sexo masculino e quatro do feminino. Nesses últimos sob hipoglicemia induzida o pico de GH foi de 11,34 ñ 4,48ng/ml e no teste seqüencial exercício L-DOP o pico foi de 12,97 ñ 3,94ng/ml (Mñep). Sob a a çäo da clonidina e do guanabenz os CN apresentaram picos de GH de 22,07 ñ 3,2 e 19,24 ñ 2,26ng/ml respectivamente. Esses resultados näo foram estatisticamente diferentes daqueles obtidos com os testes clássicos de liberaçäo de GH. Os pacientes com DGH näo respoderam a nenhum dos testes de liberaçäo utilizados. Nossos dados sugerem que ambos agonistas alfa-adrenérgicos säo potentes liberadores de GH, podendo ser utilizados na avaliaçäo da reserva hipofisária