Abstract
Context
Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children.
Objective
To describe causes, presentation, ...auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI.
Patients and Methods
Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected.
Results
The following etiologies were reported: 85% (n = 682) congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n = 25) X-linked adrenoleukodystrophy; 3.1% (n = 25) autoimmune polyglandular syndrome type 1; 2.5% (n = 20) autoimmune adrenal insufficiency; 2% (n = 16) adrenal hypoplasia congenital; 1.2% (n = 10) non-21-OHD CAH; 1% (n = 8) rare syndromes; 0.6% (n = 5) familial glucocorticoid deficiency; 0.4% (n = 3) acquired adrenal insufficiency; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis other than 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%), and hypotension (31%). Elevated adrenocorticotropic hormone (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%), and hypoglycemia (33.7%). The median age at presentation was 6.5 ± 5.1 years (0.1-17.8 years) and the mean duration of symptoms before diagnosis was 5.6 ± 11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patient-years. Three patients died from the underlying disease. Adult height, evaluated in 70 patients, was −0.70 ± 1.20 standard deviation score.
Conclusions
We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.
There are two types of vitamin D dependent rickets (VDDR) that cause rickets in children. Vitamin D dependent rickets type 1 (VDDR-I) is caused by an inborn error of vitamin D metabolism, which ...interferes with renal conversion of calcidiol (25OHD) to calcitriol (1,25(OH)2D) by the enzyme 1α-hydroxylase. Vitamin D dependent rickets type 2 (VDDR-II) is caused by a defect in the vitamin D receptor (VDR). We report cases of two African children affected by VDDR-I and VDDR-II, respectively. Establishing an early diagnosis of these genetic forms of rickets is challenging, especially in developing countries where nutritional rickets (NR) is the most common variety of the disease. A prompt diagnosis is necessary to initiate adequate treatment, resolve biochemical features and prevent complications, such as severe deformities that may require surgical intervention.
Abstract Background The growing use of prenatal investigations allows an early detection of several inborn disorders, including disorders of sexual development. The management of these conditions is ...an arising problem. Case 46,XY karyotype and female phenotype were detected in a fetus; 5α-reductase and androgen receptor gene analysis on chorionic villi revealed no relevant mutation. The newborn was assigned to female sex. The diagnosis of 17β-hydroxysteroid dehydrogenase-3 β-OL deficiency was reached at four months of age, by means of a low testosterone/Δ 4-androstenedione ratio after HCG test and HSD17B3 gene analysis. Summary and Conclusion A 46,XY fetus with female external genitalia suggests different conditions, some very rare. Specific genetic investigations should be performed prenatally when possible. A complete evaluation is mandatory after delivery to reach a correct diagnosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The purpose of this study is to validate the accuracy of pelvic ultrasound (US) with the evaluation of uterine artery pulsatility index (PI) to exclude female precocious puberty.
Tanner breast ...development score, luteinizing hormone (LH) peak after gonadotropin-releasing hormone (GnRH) stimulation, and uterine and ovarian volumes and diameters were assessed with pelvic US in 495 girls at a single institution. The study population was divided as follows: prepubertal (
= 207), pubertal with physiologic activation of the hypothalamic-pituitary-ovarian axis (
= 176), and central precocious puberty (CPP;
= 112). PI was measured with spectral Doppler US at the ascending branches of the right uterine artery (50-Hz filter; time gain compensation, 73; pulse repetition frequency, 6.6). ROC analyses and
tests were performed.
The mean (± SD) PI values in the prepubertal, pubertal, and CPP groups were 6.3 ± 1.4, 3.4 ± 1.1, and 4.1 ± 1.5, respectively (
< 0.001). The best PI cutoff value to distinguish pubertal from prepubertal girls was 4.6 (sensitivity, 83%; specificity, 94%; positive predictive value, 95%; negative predictive value, 80%; accuracy, 87%). ROC AUC values for LH peak (cutoff value, 5 mU/mL) and for spectral Doppler US PI plus longitudinal uterine diameter (i.e., the combination of a PI of 4.6 with a longitudinal uterine diameter of 35 mm) were 0.9272 and 0.9439, respectively (
= 0.7925). The negative predictive values for LH peak and for PI plus longitudinal uterine diameter were 89% and 88%, respectively.
A PI greater than 4.6 at spectral Doppler US combined with a longitudinal uterine diameter less than 35 mm allows noninvasive exclusion of female precocious puberty with comparable accuracy and lower costs compared to examination of LH peak after GnRH stimulation. Therefore, PI plus longitudinal uterine diameter might be used as a noninvasive first-line test to exclude precocious puberty and thereby avoid further investigations.
Attenuated Listeria monocytogenes (Lm
-LLO) represents a valuable anticancer vaccine and drug delivery platform. Here we show that in vitro Lm
-LLO causes ROS production and, in turn, apoptotic ...killing of a wide variety of melanoma cells, irrespectively of their stage, mutational status, sensitivity to BRAF inhibitors or degree of stemness. We also show that, when administered in the therapeutic setting to Braf/Pten genetically engineered mice, Lm
-LLO causes a strong decrease in the size and volume of primary melanoma tumors, as well as a reduction of the metastatic burden. At the molecular level, we confirm that the anti-melanoma activity exerted in vivo by Lm
-LLO depends also on its ability to potentiate the immune response of the organism against the infected tumor. Our data pave the way to the preclinical testing of listeria-based immunotherapeutic strategies against metastatic melanoma, using a genetically engineered mouse rather than xenograft models.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In this work we introduce a copula-based method for imputing missing data by using conditional density functions of the missing variables given the observed ones. In theory, such functions can be ...derived from the multivariate distribution of the variables of interest. In practice, it is very difficult to model joint distributions and derive conditional distributions, especially when the margins are different. We propose a natural solution to the problem by exploiting copulas so that we derive conditional density functions through the corresponding conditional copulas. The approach is appealing since copula functions enable us (1) to fit any combination of marginal distribution functions, (2) to take into account complex multivariate dependence relationships and (3) to model the marginal distributions and the dependence structure separately. We describe the method and perform a Monte Carlo study in order to compare it with two well-known imputation techniques: the nearest neighbour donor imputation and the regression imputation by EM algorithm. Our results indicate that the proposal compares favourably with classical methods in terms of preservation of microdata, margins and dependence structure.
Objectives
The aim of this study was to evaluate the acute effects of participation in an Ironman distance triathlon competition on arterial function by ultrasound, in relation to cardiac function ...and body water content.
Methods
Twenty‐eight male triathletes participating in an Ironman distance competition underwent carotid, femoral, and cardiac ultrasound examinations. Moreover, the presence of extravascular lung water was identified by lung echo B‐lines (echogenic coherent wedge‐shaped signal with a narrow origin from the hyperechoic pleural line) at rest and within 20 minutes of arrival.
Results
At the end of the competition, athletes showed an increased heart rate (mean ± SD, from 60.2 ± 13.1 to 82.8 ± 15.6 beats/min; P < .0001) and unchanged mean blood pressure (from 93 ± 14 to 91 ± 10 mm Hg; P > .05) in the presence of negligible dehydration (total body water from 48.0 ± 4.0 to 46.5 ± 3.9 kg; P > .05). Cardiac output increased (from 5.5 ± 1.2 to 6.7 ± 2.4 L/min; P < .05) in the presence of an unchanged stroke volume (from 64 ± 14 to 59 ± 16 mL; P > .05) and unchanged left ventricular elastance (from 1.52 ± 0.48 to 1.39 ± 0.48 mm Hg/mL/m2; P > .05). The mean carotid diameter increased (from 7.19 ± 0.65 to 7.61 ± 0.76 mm; P < .05), whereas the mean femoral diameter was unchanged at the end of the competition (from 10.41 ± 0.83 to 10.49 ± 0.82 mm; P > .05). Carotid intima‐media thickness was significantly reduced (from 537 ± 70 to 495 ± 70 μm; P < .05), whereas B‐lines increased significantly after the competition (from 1 0–4 to 12 5–23; P < .0001).
Conclusions
These data suggest different acute functional adaptation in central arteries with respect to peripheral leg vessels.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract only
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Background: Oxaliplatin is widely used in metastatic colorectal cancer, but currently there are not valid predictors of response to this drug. In our recent retrospective clinical ...study we have shown a greater efficacy of Oxaliplatin in patients with metastatic colorectal cancer with mutated (mt) K-RAS. We hypothesized that the mutational status of K-RAS could influence the expression of ERCC1, one of the main mechanisms of Oxaliplatin resistance.
Methods: We used four cell lines of colorectal cancer: two K-RAS wild type (wt) (HCT-8 and HT-29) and two K-RAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxaliplatin by MTT-test and the ERCC1 levels before and after 24 h exposure to Oxaliplatin by Real-Time PCR. We silenced K-RAS in a K-RAS mt cell line to evaluate the impact on Oxaliplatin sensitivity and ERCC1 levels. We also silenced ERCC1 in order to confirm the importance of this protein as a Oxaliplatin resistance factor.
Results: The K-RAS mt cell lines were more sensitive to Oxaliplatin (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between K-RAS mt and wt cell line, however, after 24 h exposure to Oxaliplatin, only the K-RAS wt lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). The silencing of K-RAS in K-RAS mt cell lines demonstrated to reduce sensitivity to Oxaliplatin associated with the acquisition of the ability to induce ERCC1. The silencing of ERCC1 in K-RAS wt cell lines enhance the sensibility to Oxaliplatin.
Conclusions: The K-RAS mutated cell lines were more sensitive to Oxaliplatin. This feature seems to be secondary to the inability of these cells to induce ERCC1 after exposure to Oxaliplatin. K-RAS can thus be a predictor of response to Oxaliplatin in colorectal cancer representing a surrogate for ability to induce ERCC1.
The cross-sectional study has been based on the implementation of the Obstetric Appropriateness Evaluation Protocol (OAEP) in seven hospitals to determine inappropriate hospital admissions and days ...of stay. The outcomes were: inappropriateness of admission and "percentage of inappropriateness" for one hospitalization. A total number of 2196 clinical records were reviewed. The mean percentage of inappropriateness for hospitalization was 22%. The percentage of inappropriateness for the first 10 d of hospitalization peaked in correspondence of the fourth (42%). The logistic regression model on inappropriated admission reported that emergency admission was a protective factor (OR = 0.4) and to be hospitalized in wards with ≥30 beds risk factor (OR = 5.12). The second linear model on "percentage of inappropriateness" showed that inappropriated admission and wards with ≥30 beds increased the percentage (p < 0.001); whereas the admission in Teaching Hospitals was inversely associated (p < 0.001). The present study suggests that the percentage of inappropriate admission depends especially on the inappropriate admission and the large number of beds in obstetric wards. This probably indicates that management of big hospitals, which is very complex, needs improving the processes of support and coordination of health professionals. The OAEP tool seems to be an useful instrument for the decision-makers to monitor and manage the obstetric wards.
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