DIANA-TarBase v8: a decade-long collection of experimentally supported miRNA-gene interactions.

DIANA-TarBase v8 (http://www.microrna.gr/tarbase) is a reference database devoted to the indexing of experimentally supported microRNA (miRNA) targets. Its eighth version is the first database indexing >1 million entries, corresponding to ∼670 000 unique miRNA-target pairs. The interactions are supported by >33 experimental methodologies, applied to ∼600 cell types/tissues under ∼451 experimental conditions. It integrates information on cell-type specific miRNA-gene regulation, while hundreds of thousands of miRNA-binding locations are reported. TarBase is coming of age, with more than a decade of continuous support in the non-coding RNA field. A new module has been implemented that enables the browsing of interactions through different filtering combinations. It permits easy retrieval of positive and negative miRNA targets per species, methodology, cell type and tissue. An incorporated ranking system is utilized for the display of interactions based on the robustness of their supporting methodologies. Statistics, pie-charts and interactive bar-plots depicting the database content are available through a dedicated result page. An intuitive interface is introduced, providing a user-friendly application with flexible options to different queries.

Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.

BACKGROUND: DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated. METHODS: We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies. RESULTS: Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC). CONCLUSIONS: We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function.

Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections.

CONTEXT: Among 22 independent patients from the GENHYPOPIT network who had ACTH deficiency and no identified mutation of TPIT, three of them (13.6%) displayed common variable immunodeficiency (CVID), characterized by defective Ig production. OBJECTIVE: Our objective was to describe an as yet unrecognized disease association. DESIGN: We considered the hypothesis of ACTH deficiency being associated with antipituitary autoimmunity or lymphocytic hypophysitis. In the context of a functional network between the immune and endocrine systems, we also tested the hypothesis of a common genetic cause using a candidate gene approach. SETTING: This was a multicentric study in three academic hospitals. PATIENTS: We report four patients from three unrelated families presenting with ACTH deficiency and CVID. MAIN OUTCOME MEASURES: Detection of antipituitary autoantibodies, and sequencing of candidate genes (LIF, IKAROS, EOS) were the main outcome measures. RESULTS: All patients including a pedigree with two affected siblings had ACTH deficit diagnosed from 5-15 yr, with symptomatic hypoglycemia, and CVID diagnosed from 2-8 yr revealed by recurrent infections. Three of the four patients had a hypoplastic pituitary. One patient had low IGF-I and subnormal GH response to stimulation, suggesting that secretion of other pituitary hormones may also be affected. All patients proved negative for pituitary autoantibodies and had no alteration in any of the genes tested. CONCLUSIONS: The remarkable association of two rare disorders affecting two functionally related systems in four patients from three independent pedigrees including a familial case provides strong evidence of the existence of a disease association: deficit in anterior pituitary function and variable immune deficiency, or DAVID.

Pubertal maturation of contemporary Greek boys: no evidence of a secular trend.

PURPOSE: To examine pubertal status of contemporary Greek boys and compare the data with those of a previous study we performed in the year 1996. METHODS: We performed a cross-sectional study of 932 healthy boys, aged from 8.05 to 16.05 years. Development of the genitalia (G) and pubic hair was assessed by the method of Tanner and testicular volume (TV) was determined with a Prader orchidometer. Genitalia stage 2 (G2) was assessed by probit analysis. RESULTS: Median (95% confidence interval [CI]) age at G2, defined as TV 4 mL, was 11.3 (10.9-11.6) years, almost the same age as in our study performed in 1996, which was 11.4 (10.7-11.7) years (p = .21). When G2 was defined as change in scrotum texture and TV2 mL, median (95% CI) age at onset of puberty was 10.9 (10.5-11.3) years, again similar to the study performed in 1996 which was 11.0 (10.7-11.4) (p = .32). Median (95% CI) age of pubic hair development was 11.2 (10.8-11.6) years versus 11.5 (11.1-12.0) years in 1996, p = .015. CONCLUSIONS: Our data provide no evidence of a secular trend for gonadarche in Greek boys, although such a trend was evident for pubarche.

Change in preoperative strategy based on intraoperative ultrasound findings.

Forty patients with primary liver carcinoma and 52 with liver secondaries underwent careful preoperative evaluation using computed tomography and magnetic resonance imaging, as well as intraoperative studies using intraoperative ultrasound (IOUS). The results were compared to histological findings. In the 40 patients with primary tumors who underwent hepatic resection, 4 (9.1%) additional lesions were found using IOUS, and in 10 (25%) instances, our preoperative strategy was changed (either a more extensive or more conservative excision was performed). In the 52 cases with metastatic disease who underwent hepatic resection, 14 (21.2%) more lesions were detected, and in 15 (29%) patients, the preoperative strategy was changed. Based on IOUS findings, of 92 patients, a total of 18 (16.4%) additional lesions were detected; in addition, our preoperative strategy changed in 25 (27.2%) of the cases with primary and secondary liver tumors.

Mid-term comparison of bifurcated modular endograft versus aorto-uni-iliac endograft in patients with abdominal aortic aneurysm.

The aim of this prospective study was to compare the outcome of the Talent bifurcated endograft versus the Endofit aorto-uni-iliac endograft in the short-term and mid-term. Between March 2000 and December 2003, 86 patients were treated with the Talent bifurcated endograft (group A) and 21 with the Endofit aorto-uni-iliac endograft (group B) in the same institute by the same surgical team. All patients followed a prospective protocol of preoperative evaluation and postoperative follow-up. We compared groups A and B in terms of perioperative mortality and morbidity, mid-term endoleak rate, mid-term success rate, and mid-term survival. The perioperative mortality for group A was 1.63%, while that for group B was 0% (P = 0.62). The endoleak rate for group A was 4.65%, and that for group B was 14.29% (P = 0.135). The mid-term success rate was 96.5% for group A and 100% for group B (P = 0.386). There was no significant difference in outcome between the patients treated with the Talent and those treated with the Endofit endoprosthesis. Treating abdominal aortic aneurysms with aorto-uni-iliac endoprosthesis is as safe and effective as treating them with bifurcated endografts.

Mineralocorticoid receptor mutations are the principal cause of renal type 1 pseudohypoaldosteronism.

Aldosterone plays a key role in electrolyte balance and blood pressure regulation. Type 1 pseudohypoaldosteronism (PHA1) is a primary form of mineralocorticoid resistance characterized in the newborn by salt wasting, hyperkalemia, and failure to thrive. Inactivating mutations of the mineralocorticoid receptor (MR; NR3C2) are responsible for autosomal dominant and some sporadic cases of PHA1. The question as to whether other genes may be involved in the disease is of major importance because of the potential life-threatening character of the disease, the potential cardiovascular effects of compensatory aldosterone excess, and the role of the mineralocorticoid system in human hypertension. We present the first comprehensive study seeking nucleotide substitutions in coding regions, intron-exon junctions, and untranslated exons, as well as for large deletions. A total of 22 MR gene abnormalities were found in 33 patients. We demonstrate that MR mutations are extremely frequent in PHA1 patients classified according to aldosterone and potassium levels and give indications for accurate clinical and biological investigation. In our study the possibility of a genocopy exists in three PHA1 kindreds. The other patients without MR mutations might have different diseases resembling to PHA1 in the neonatal period, which could be identified by extensive clinical and functional exploration.

Differentiated thyroid cancer: comparison of therapeutic iodine 131 biological elimination after discontinuation of levothyroxine versus administration of recombinant human thyrotropin.

The biological elimination of therapeutic 131I in patients with differentiated thyroid cancer (DTC), post total or near-total thyroidectomy, was compared after withholding levothyroxine suppression against administration of recombinant human thyrotropin without stopping levothyroxine. In 163 patients (group G1) levothyroxine was withheld before 131I therapy: in 138 patients the tumor was limited to the thyroid bed (group G1.1) and in 25 patients metastases were present (group G1.2). A second group of patients (G2; n = 28) received 131I therapy after administration of recombinant human thyrotropin without stopping levothyroxine. Mean retained 131I activity (as a percentage of the administered dose) was 5%-29% (group G1.1), 20%-43% (group G1.2) and 1%-17% (group G2). The effective half-life of 131I was 0.59-0.69 days (group G1.1), 0.87-1.22 days (group G1.2) and 0.38-0.44 days (group G2). In conclusion, the use of recombinant human thyrotropin to prepare patients with thyroid cancer for therapy with 131I shortens its effective half-life and reduces its retained activity compared to preparation with discontinuation of levothyroxine suppression.