Serum Free Cortisol During Glucagon Stimulation Test In Healthy Short-Statured Children And Adolescents

Objective: The total cortisol (TC) response may be measured during the glucagon stimulation test (GST) for growth hormone (GH) reserve in order to assess the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. Measurements of TC are unreliable in conditions of albumin and cortisol-binding globulin (CBG) alterations (e.g., hypoproteinemia or CBG deficiency). We aimed to measure the serum free cortisol (sFC) response to the GST in children and adolescents and determine whether it could predict the GH response to glucagon stimulation.Methods: Infants and children with either short stature or growth attenuation who were referred for evaluation of GH reserve underwent the GST.Results: The study population consisted of 103 subjects (62 females), median age 3.9 years (range, 0.5–14). The mean basal and peak TC levels were 13.3 ± 6.7 μg/dL and 29.6 ± 8.8 μg/dL, respectively. The mean basal and peak sFC levels were 0.7 ± 0.8 μg/dL and 1.7 ± 1.1 μg/dL, respectively. There was a negative correlation between peak TC and age (r = -0.3, P = .007) but not between peak sFC and age (r = -0.09, P = .36). Ninety-five percent of the patients had peak TC levels >15.8 μg/dL and peak sFC levels >0.6 μg/dL.Conclusion: Our results on a cohort of healthy short-statured children can serve as reference values for the sFC response during GST. Based on these results, we propose peak TC levels >15.8 μg/dL and peak sFC levels >0.6 μg/dL for defining normalcy of the HPA axis during the GST in children and adolescents.Abbreviations:ACTH = adrenocorticotrophic hormoneBMI = body mass indexCBG = cortisol-binding globulinGH = growth hormoneGST = glucagon stimulation testHPA = hypothalamic-pituitary-adrenalSDS = standard deviation scoresFC = serum free cortisolTC = total cortisol     

Incidence of Central Diabetes Insipidus in Children Presenting with Polydipsia and Polyuria

Objective: Polydipsia and polyuria are common reasons for referral to the Pediatric Endocrine clinic. In the absence of hyperglycemia, diabetes insipidus (DI) should be considered. The objectives of the study were to determine the prevalence of central DI (CDI) in a group of children presenting for evaluation of polydipsia and polyuria, and to determine if predictive features were present in patients in whom the diagnosis of DI was made.Methods: The study was a retrospective chart review of children presenting to the endocrine clinic with complaints of polydipsia and polyuria over a 5-year period.Results: The charts of 41 patients (mean age 4.9 ± 3.7 years, 28 males) were reviewed. CDI was diagnosed in 8 (20%) children based on abnormal water deprivation test (WDT) results. All but one patient had abnormal magnetic resonance imaging (MRI) findings, the most common being pituitary stalk thickening. Children with DI were older (7.86 ± 4.40 vs. 4.18 ± 3.20 years, P = .01) and had a higher propensity for cold beverages intake and unusual water-seeking behaviors compared to those without DI. Baseline WDT also revealed higher serum sodium (Na) and osmolality.Conclusion: The incidence of CDI in children presenting with polydipsia and polyuria is low. Factors associated with higher likelihood of pathology include older age, propensity for cold beverage intake, and higher baseline serum Na and osmolality on a WDT.Abbreviations:BMI = body mass indexCDI = central diabetes insipidusDI = diabetes insipidusNa = sodiumWDT = water deprivation test     

Comparison of the Expectation of Caregivers and Children with Type 1 Diabetes Mellitus Doe Independence in Diabetes Care-Related Tasks

ObjectiveChildren who are given unsupervised responsibility for their diabetes care prior to developmental and/or emotional readiness may have poorer glycemic control. The purpose of this study was to assess the age-related expectations of children and caregivers for independence in diabetes care-related tasks.MethodsA total of 150 participants with type 1 diabetes mellitus (T1DM) receiving multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) were enrolled in this study. All caregivers and participants older than 10 years of age completed questionnaires evaluating the expected age of independence for different diabetes care-related tasks.ResultsThe participants expected independence with no direct supervision in most diabetes care-related tasks at a younger age than their caregivers (P < .05). The difference was more prominent for those on CSII compared to MDI (P < .01). There was a positive correlation between the age when caregivers expect independence for most of the diabetes-related tasks and the age at diagnosis, regardless of the use of MDI or CSII (P < .01).ConclusionChildren with T1DM expect to assume independence at a younger age than their caregivers do. The younger the children are at diagnosis, the younger they are expected by their caregivers to be independent, especially those on CSII. (Endocr Pract. 2014;20:629-637)     

Timing of GH Peak in Both Glucagon and Clonidine Tests is of Major Clinical Importance

Objective: To detect a possible correlation between timing of the peak value of growth hormone (GH) during stimulatory tests (STs) and the effectiveness of treatment with recombinant human growth hormone (rhGH) in children with idiopathic GH deficiency (iGHD).Methods: We retrospectively studied 92 patients with iGHD (57 boys; mean age at diagnosis: 9.93 years). Diagnosis was confirmed by 2 different STs, glucagon stimulation test (GST), and clonidine stimulation test (CST). Auxologic parameters were recorded, while observed and predicted (according to KIGS Prediction Model) height velocity during the first year of treatment and the index of responsiveness (IoR) were calculated for the prepubertal children (n = 65).Results: Atypical GST was defined as that with peak GH value at time 0 minutes, 30 minutes, 60 minutes, or 180 minutes, whereas atypical CST was defined as that with peak timing at 0 minutes, 30 minutes, or 120 minutes. Atypical GST was detected in 18 patients (19.57%). IoR was lower in the prepubertal children with atypical GST (-1.81 ± 0.67 versus -1.34 ± 0.85; P = .051). In the CST, the 18 children who had atypical timing, had significantly lower IoR (-1.86 ± 0.66 versus -1.35 ± 0.84; P = .047). When the patients were categorized according to the number of atypical tests, significant differences in the IoR were detected (-2.09 ± 0.68 with 2 atypical STs &lsqb;n = 6], -1.64 ± 0.61 with 1 atypical ST &lsqb;n = 16], and -1.29 ± 0.87 with no atypical ST &lsqb;n = 43], P = .045).Conclusion: The presence of atypical peak GH timing during ST may be a factor that predicts lower growth hormone velocity during the first year of rhGH treatment in prepubertal children with iGHD.Abbreviations: CST = clonidine stimulation test; GH = growth hormone; GHD = growth hormone deficiency; GST = glucagon stimulation test; iGHD = idiopathic growth hormone deficiency; IoR = index of responsiveness; rhGH = recombinant human growth hormone; SDS = standard deviation scores; ST = stimulatory test     

Children and Adolescents with Gender Dysphoria in Israel: Increasing Referral and Fertility Preservation Rates

Objective: To describe patient characteristics at presentation, management, and fertility preservation rates among a cohort of Israeli children and adolescents with gender dysphoria (GD).Methods: We performed a retrospective chart review of 106 consecutive children and adolescents with GD (<18 years) referred to and followed at the multidisciplinary Israeli Pediatric Gender Dysphoria Clinic from March 2013 through December 2018.Results: Of the 106 patients, 10 were prepubertal (9 prepubertal transgender females), and 96 were pubertal (38 pubertal transgender females). The GD population increased 11-fold since the establishment of our clinic in 2013. The subject's median age at referral was 15.5 years (range, 4.6 to 18 years). At the time of referral, 91 (95%) of the pubertal group had completed sexual maturation in their assigned gender at birth. Thirteen (13.5%) patients had attempted suicide, and 11 (11.5%) reported having had suicidal thoughts. Fourteen (45%) pubertal transgender females and 3 (6.5%) pubertal transgender males completed fertility preservation. Gonadotropin-releasing hormone analog treatment was prescribed in 77 (80%) patients at a mean age of 15.9 ± 1.6 years. Gender-affirming hormones were prescribed in 61 (64%) patients at a mean age of 16.5 ± 1.3 years. No severe side effects were recorded. Two (2%) of the pubertal group expressed regret about medical treatment.Conclusion: Children and adolescents with GD are presenting for medical attention at increasing rates. Israeli adolescents with GD have high fertility preservation rates, perhaps attributable to cultural perspectives. Taking advantage of the option to preserve fertility can be achieved when proper counseling is both available and promoted by medical personnel.Abbreviations: GAH = gender-affirming hormone; GD = gender dysphoria; GnRHa = gonadotropin-releasing hormone analog; MHP = mental health professional     

Bird's-Eye View of GnRH Analog use in a Pediatric Endocrinology Referral Center

Objective: Gonadotropin-releasing hormone analogs (GnRHa) are standard of care for the treatment of central precocious puberty (CPP). GnRHa have also been prescribed in other clinical settings with the hope of increasing adult stature, although evidence to support this practice is lacking. The degree to which GnRHa are being prescribed for indications other than CPP in routine clinical care has not been described. We sought to systematically examine GnRHa prescribing practices among the pediatric endocrinologists at our academic medical center.Methods: We reviewed medical records of children treated with GnRHa during a 6-year interval. Variables analyzed included gender, age at start of treatment, indication for therapy, and use of growth hormone as adjunctive treatment. Nonparametric analyses were utilized to compare treatment characteristics of those with CPP versus those without.Results: A total of 260 patients (82% female) aged 8.06 ± 2.68 years were identified. Of these, 191 (73.5%) were treated for CPP, whereas 69 (26.5%) were treated for normally timed puberty in the context of idiopathic short stature/poor predicted height (n = 37), growth hormone deficiency (n = 17), congenital adrenal hyperplasia (n = 10), primary hypothyroidism (n = 4), and developmental delay (n = 1). Of the 161 girls with CPP, GnRHa therapy was initiated at =8 years of age in 62 (39%).Conclusion: Whereas most patients were treated for CPP, ~27% were treated for other indications. Of girls with CPP, 39% were treated at an age when benefit in terms of height is unlikely. This highlights the need for rigorous studies of GnRHa use for indications beyond CPP.Abbreviations: CPP = central precocious puberty GnRHa = gonadotropin-releasing hormone analogs     

Synthesis and initial in vitro biological evaluation of two new zinc-chelating compounds: Comparison with TPEN and PAC-1

The lipophilic, cell-penetrating zinc chelator N,N,N′,N′,-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN, 1) and the zinc chelating procaspase-activating compound PAC-1 (2) both have been reported to induce apoptosis in various cell types. The relationship between apoptosis-inducing ability and zinc affinity (K_d), have been investigated with two new model compounds, ZnA-DPA (3) and ZnA-Pyr (4), and compared to that of TPEN and PAC-1. The zinc-chelating o-hydroxybenzylidene moiety in PAC-1 was replaced with a 2,2′-dipicoylamine (DPA) unit (ZnA-DPA, 3) and a 4-pyridoxyl unit (ZnA-Pyr, 4), rendering an order of zinc affinity TPEN > ZnA-Pyr > ZnA-DPA > PAC-1. The compounds were incubated with the rat pheochromocytoma cell line PC12 and cell death was measured in combination with ZnSO₄, a caspase-3 inhibitor, or a ROS scavenger. The model compounds ZnA-DPA (3) and ZnA-Pyr (4) induced cell death at higher concentrations as compared to PAC-1 and TPEN, reflecting differences in lipophilicity and thereby cell-penetrating ability. Addition of ZnSO₄ reduced cell death induced by ZnA-Pyr (4) more than for ZnA-DPA (3). The ability to induce cell death could be reversed for all compounds using a caspase-3-inhibitor, and most so for TPEN (1) and ZnA-Pyr (4). Reactive oxygen species (ROS), as monitored using dihydro-rhodamine (DHR), were involved in cell death induced by all compounds. These results indicate that the Zn-chelators ZnA-DPA (3) and ZnA-Pyr (4) exercise their apoptosis-inducing effect by mechanisms similar to TPEN (1) and PAC-1 (2), by chelation of zinc, caspase-3 activation, and ROS production.     

Decaturenol A and known oxalicine related meroterpenoids isolated from Penicillium decaturense RO050, and their new biological activities

Decaturenol A (1), a new oxalicine related meroterpenoid, has been isolated from Penicillium decaturense RO050 along with seven known compounds (2–8). The structure of 1 was elucidated by spectroscopic data. The effects of isolated compounds (1–8) on endoplasmic reticulum (ER) stress-induced cell death in HT22 hippocampal nerve cells and on the interleukin 10 (IL-10)-induced expression of CD163, a M2 phenotype marker, in human monocyte-derived macrophages were evaluated. While decaturenol A (1) exhibited a protective effect on ER stress-induced cell death in HT22 cells at 10 µM, on the other hand oxalicine A (7) showed cytotoxic activity (IC₅₀ = 5.9 µM). Additionally, decaturenol A (1), decaturins D (2), E (3), and B (4) inhibited the IL-10-induced expression of CD163 each at a concentration of 20 µg/mL.     

Diabetes and Prediabetes are Significantly Higher in Morbidly Obese Children Compared With Obese Children

Objective: The objective of this study was to examine the prevalence and characteristics of comorbidities in obese and morbidly obese children with a comparison between the 2 sets of children.Methods: This was a retrospective electronic chart review of obese and morbidly obese children and adolescents as defined by body mass index. We evaluated medical history of comorbid conditions, medication use, and cardiovascular risk markers, including blood pressure, lipid profile, and glycosylated hemoglobin.Results: There were 1,111 subjects (African American = 635; non-Hispanic white = 364; Hispanic = 36; others = 86), of which 274 were obese and 837 were morbidly obese children with a mean age of 12.7 ± 3.37 years. Morbidly obese children had a higher prevalence of prediabetes (19.5% of obese versus 27.3% of morbidly obese; P<.0001) and type 2 diabetes (39.8% of obese versus 52.4% of morbidly obese; P<.0001). Use of medications for treatment of asthma was significantly higher in the morbidly obese group compared with the obese group (21% versus 14%; P = .01).Conclusion: Morbidly obese children have a higher prevalence of diabetes, prediabetes, and use of asthma medications compared with obese children.Abbreviations: AA = African American ADHD = attention deficit hyperactivity disorder BMI = body mass index BP = blood pressure CVD = cardiovascular disease DBP = diastolic blood pressure EMR = electronic medical record GERD = gastroesophageal reflux disease HbA_1c = glycated hemoglobin HDL = high-density lipoprotein HTN = hypertension LDL = low-density lipoprotein NHW = non-Hispanic white SBP = systolic blood pressure T2DM = type 2 diabetes mellitus     

Challenges of Securing Growth Hormone Coverage for Idiopathic Short Stature: Review of the 7-Year Experience at one Institution

Objective: Despite U.S. Food & Drug Administration (FDA) approval of growth hormone (GH) for idiopathic short stature (ISS), many providers face challenges obtaining insurance coverage. We reviewed the insurance coverage experience for ISS at our hospital to identify factors predictive of approval or denial.Methods: We reviewed charts of patients who underwent GH stimulation testing from July 1, 2009, to April 30, 2017, to identify ISS patients (height <-2.25 SD, subnormal predicted adult height (PAH) and peak GH >10 ng/mL).Results: Eighty-seven patients met ISS criteria, of whom 47 (29 male/18 female) had a GH request submitted to insurance. Mean age, height, and growth velocity were 8.6 ± 2.7 years, 2.83 ± 0.4 SD, and 4.4 ± 1.7 cm/year, respectively. Mean PAH based on bone age was -2.50 ± 0.9 SD, equaling 62 inches for males and 58 inches for females. Most had private managed care insurance (74%). Overall, 17/47 (36%) received treatment approval, 7 immediately and 10 more on appeal. There were no differences in age, height SD, growth rate, insurance type, or PAH between the 17 who were approved and the 30 denied. For 21 patients who were treated, a mean increase in 0.6 SD in height was seen after 1 year.Conclusion: At our institution, GH coverage requests for ISS included very short children mostly ages 6 to 11, with heights well below -2.25 SD and poor PAH. Only 36% were approved even after appeal. This highlights the challenge in our area to secure GH treatment for a FDA-approved indication. Collaboration between pediatric endocrinologists and insurers focusing on height SD and PAH, may improve cost-effective coverage to deserving short children who meet FDA guidelines for ISS treatment.Abbreviations: FDA = Food and Drug Administration; GH = growth hormone; IGF-1 = insulin-like growth factor 1; ISS = idiopathic short stature; PAH = predicted adult height     

Characteristics And Outcomes Of Metastatic Sdhb And Sporadic Pheochromocytoma/Paraganglioma: An National Institutes Of Health Study

Objective: Overall about 10 to 20% of pheochromocytomas/paragangliomas (PHEOs/PGLs) are metastatic, with higher metastatic potential observed in succinate dehydrogenase subunit B/fumarate hydratase (SDHB/FH)-related tumors. Due to the improved availability of biochemical and genetic testing and the frequent use of anatomical/functional imaging, there is currently a higher detection rate of metastatic PHEO/PGL.Methods: A retrospective analysis of 132 patients (27 children, 105 adults) with metastatic PHEO/PGL diagnosed and treated from 2000 to 2014 was conducted.Results: Seventy-seven (58%) males and 55 (42%) females were included; 39 (30%) have died, with no sex preference. Seventy-three (55%) patients had SDHB mutations; 59 (45%) patients had apparently sporadic tumors (AST). SDHB patients had an average age at primary tumor diagnosis of 31 ± 16 years compared to 40 ± 15 years in AST patients (P<.001). The average metastatic interval (MI) decreased with increasing age in both SDHB and AST patients (P = .013 for both). Only 16% of all primary tumors were smaller than 4.5 cm. Eleven percent of patients had biochemically silent disease, more with SDHB. Of SDHB patients, 23% had metastatic tumors at first diagnosis, compared to 15% of AST patients. Five- and 10-year survival rates were significantly better for metastatic AST than SDHB patients (P = .01). Overall survival was significantly different between children and adults (P = .037); this was mostly attributed to the SDHB patients, in whom children had statistically significantly longer survival than adults (P = .006). The deceased patients all died due to the PHEO/PGL and mainly had noradrenergic phenotypes.Conclusion: In children, metastatic PHEOs/PGLs are mainly due to SDHB mutations; in adults they are equally distributed between in SDHB mutations and AST, with better 5- and 10-year survival rates for ASTs. In SDHB patients, children survive longer than adults. Primary metastatic tumors, most presenting as noradrenergic PGLs, are larger than 4.5 cm in >80% of patients. The frequency of metastatic tumors from primary AST increases with age, including a decreased MI compared to SDHB tumors. These results support several recommendations that are summarized in the Discussion.Abbreviations:A = adrenalAMTD = age at the initial metastatic tumor diagnosisAPTD = age of patients at the time of the primary tumor diagnosisAST = apparently sporadic tumorCI = confidence intervalCT = computed tomographyDA = dopamineEA = extra-adrenalEPI = epinephrine[18F]-FDA = [18F]-fluorodopamine[18F]-FDG = [18F]-fluorodeoxyglucoseFH = fumarate hydrataseHIF2A = hypoxia-inducible factor 2αMAX = myc-associated factor XMI = metastatic intervalMIBG = metaiodobenzylguanidineMN = metanephrineMRI = magnetic resonance imagingNE = norepinephrineNF1 = neurofibromatosis type 1NIH = National Institutes of HealthNMN = normetanephrinePET = positron emission tomographyPGL = paragangliomaPHEO = pheochromocytomaRET = rearranged during transfectionSDHA = succinate dehydrogenase subunit ASDHAF2 = encoding SDH complex assembly factor 2SDHB = succinate dehydrogenase subunit BSDHC = succinate dehydrogenase subunit CSDHD = succinate dehydrogenase subunit DTMEM127 = transmembrane protein 127VHL = von Hippel-Lindau     

Performance and carcass quality traits of Iberian × Duroc crossbred pig subject to gender and age at the beginning of the free-range finishing phase

The traditional production of the Iberian breed pig involves a long production cycle. It might be shortened by using Iberian pigs crossed with Duroc and by reducing the growing phase, but the age-related changes on productive performance and carcass quality should be addressed. Thus, productive performance, live measurements and carcass and primal cut traits were evaluated on Iberian × Duroc 50:50 crossed pigs according to animal age at the beginning of the free-range finishing phase (Montanera): 10, 12 and 14 months old (IBxD10 (n = 15), IBxD12 (n = 17) and IBxD14 (n = 18) animal batches, respectively) and gender (immunologically castrated female -consisted of the Improvac® vaccination- and surgically castrated males). During the growing period, animals were fed with restrictions; 1.49, 1.29 and 1.20 ± 0.023 (mean ± SEM) kg/day of commercial feeds to start Montanera with similar BW; 103.9, 102.9 and 102.1 ± 0.22 kg, for IBxD10, IBxD12 and IBxD14, respectively. IBxD14 animals yielded the highest average daily gain (ADG) and BW after Montanera, as well as larger rump height and croup width. In contrast, these animals had the lowest carcass yield. Although animals from IBxD10 yielded hams of inferior size, this could be of interest to the sector, as there is a certain segment of the market that demands hams of smaller size and, generally, this is difficult to obtain with the traditional Montanera production system. The gender had no major effects on performance and carcass and primal cut traits, so both immunologically castrated female and surgically castrated males are suitable for finishing in Montanera.     

Genotype × region and genotype × production level interactions in Holstein cows

The identification of the presence of genotype by environment interaction effects on important traits in Holstein cattle allows for the use of international genetic evaluations and a more efficient design of regional genetic evaluation programmes. The aim of this study was to determine the genotype × environment interaction effects in Chilean Holstein dairy cattle through the analysis of records corresponding to calvings between 1998 and 2015. Herds were classified in the central and southern regions of Chile based on herd location as well as by high and low levels of production environments based on the fat plus protein yield averages per herd within each region. The central region has a Mediterranean climate and a confined production system while the southern region has a humid temperate climate and a production system based on grazing with supplementation. Traits studied were milk yield (MY), fat yield (FY), protein yield (PY), fat content (FC) and protein content (PC) by lactation, age at first calving (AFC) and calving interval (CI). Several four-trait mixed animal models were applied to environmental category data as different traits, which included herd-year-calving season (herd-year-birth season for AFC) and lactation number as fixed effects, and animal additive genetic, sire-herd, permanent environment and residual effects as random effects. Genetic correlations (r_g) for MY, FY, FC, PC and CI were found to decrease as differences between environmental categories increased. The r_g between the most extreme environmental categories considered in this study for AFC (0.26) was the only one found statistically lower than 0.60. Genetic correlation values statistically lower than 0.80 (P < 0.05) were observed for AFC, CI, MY, FY and PY between some environmental categories. If separate genetic evaluations are adopted as practical criteria when the value of r_g is lower than 0.60, the consequence of improving a multi-trait economic breeding objective in this population is likely to be small unless extreme environmental categories are considered. However, a moderate decrease in selection response and re-ranking of selection candidates is expected for AFC, CI and yield traits when selection is performed in different environmental conditions. Genotype × environment interaction effects involving production systems in a Mediterranean climate and confinement vs. Temperate Oceanic climate and grazing with supplementation, and between two fat plus protein yield level categories within each environment, were at most moderate for the studied traits.     

Effects of triterpene derivatives from Maytenus rigida on VEGF-induced Kaposi's sarcoma cell proliferation

Betulinic acid (BA) is a naturally occurring lupane-type triterpene which exhibits a variety of biological activities including potent cytotoxic properties. On the basis of the structural similarity to BA, two lupane derivatives namely lup-20(29)-ene-3β,30-diol (1) and lup-20(29)-ene-3β,28-diol (2), along with two friedelane derivatives, namely friedelan-3-one (3) and friedelan-3β-ol (4), isolated from the Brazilian plant Maytenus rigida, have been evaluated for their anti-proliferative effect. Similarly to BA, compounds 1 and 3 at 1 μM concentration significantly inhibited the VEGF-induced Kaposi's sarcoma (KS) cell proliferation by 50%. In contrast, this effect was not found in control endothelial cells (EC).Moreover, compounds 1 and 3 showed a dose-dependent effect on the apoptotic cell death, as detected by FACS analysis and caspase-3 assay. Specifically, at 10 μM concentration, apoptosis was significantly induced (from 45% to 55% of hypodiploid cells vs control cells) and showed the same potency order observed for the anti-proliferative effect at 1 μM, i.e., compound 3 > BA > compound 1.Taking into account the interest given rise by BA as anticancer agent, the comparable anti-proliferative activity shown by compounds 1 and 3 and BA, can give an impulse to further investigate lupane and friedelane derivatives as cytotoxic agents.     

Osteoporotic Fractures During Bisphosphonate Drug Holiday

Objective: Bisphosphonate (BP) drug holidays are recommended to lower the risk of rare adverse events, such as atypical femoral fractures and osteonecrosis of the jaw. However, there are minimal data on the optimal duration of these holidays. Our aim was to determine the clinical and laboratory parameters associated with increased fracture risk in patients on BP drug holiday.Methods: A retrospective chart review was conducted of 401 patients with osteopenia or osteoporosis who began a BP drug holiday from 2004 to 2013. Collected parameters included demographics, prior therapy, bone mineral density (BMD), bone turnover markers, parathyroid hormone, calcium & vitamin D status, and clinical reports of fractures.Results: Sixty-two (15.4%) patients developed a fracture during follow-up. The yearly incidence of fractures ranged from 3.7 to 9.9%, peaking at 9.9% and 9.8% during years 4 and 5, respectively. The mean age of the fracture group was higher than the nonfracture group, though not significantly different (69.24 ± 12.26 years vs. 66.42 ± 10.18 years; P = .09). Compared to the nonfracture group, the fracture group had lower femoral neck BMD (0.75 ± 0.12 g/cm² vs. 0.79 ± 0.10 g/cm²; P = .03) and T-scores (-2.13 ± 0.99 vs. -1.78 ± 0.79; P = .01) at baseline.Conclusion: Patients who begin BP drug holidays at high risk of fracture based on BMD, age, or other clinical risk factors warrant close follow-up, especially as its duration lengthens. Fracture risk analysis needs to be regularly assessed during the drug holiday and treatment resumed accordingly.Abbreviations:25-OHD = 25-hydroxyvitamin DAACE = American Association of Clinical EndocrinologistsACE = American College of EndocrinologyBMD = bone mineral densityBP = bisphosphonateBSAP = bone-specific alkaline phosphataseBTM = bone turnover markerFN = femoral neckLS = lumbar spinePTH = parathyroid hormone     

The role of basicranial synchondroses in flexure processes and ontogenetic development of the skull base

The contribution of the basicranial synchondroses in the growth of neurocranial length and ontogenetic development of the cranial base were investigated. The study concentrated on the midsphenoidal synchondrosis and its delayed fusion in nonhuman primates when compared to man, and on the spheno-occipital synchondrosis. The mode and time of fusion of both growth centers were observed, and their role in the ontogenetic growth changes (flattening processes) of the cranial base were established. The chondrogenic ossification of midsphenoidal and spheno-occipital synchondroses was studied on 20 skulls of Macaca mulatta females, ranging in age from newborn specimens to those 24 months old. The technique of in vivo tetracycline bone labeling was used for histologic evaluation of the material. Different chondrogenic growth patterns were observed in both synchondroses. The endochondral activity of the spheno-occipital synchondrosis increased with age, from a nonactive narrow cartilaginous column in the neonatal specimen to a broad band with high chondrogenic ossification in the 24-month-old specimens. This growth center contributes to elongation of the posterior portion of the cranial base and is a secondary factor in its flexion. The midsphenoidal synchondrosis seems to be the primary factor in the mode of flexure of the cranial base in Macaques. This growth center is very active in the first ten months of life but later exhibits cessation of chondrogenic activity and long remains unfused. The first signs of fusion were observed as late as 72 months of age. At the same time, the continuous process of cranial base flattening showed the first signs of tapering off.     

Evaluation of Treatment of Central Hypothyroidism Versus Primary Hypothyroidism in Relation to Levothyroxine Replacement Dose

Objective: The aim of this study was to evaluate levothyroxine (LT4) replacement daily doses in patients with central hypothyroidism (CeH) and compare them with those adequate for patients with primary hypothyroidism (P-HYPO).Methods: We included 53 patients with CeH and 57 with P-HYPO, matched by sex, age, weight, and body mass index, in the period of 1 year. At the time of inclusion, all presented a stable and adequate dose of LT4 for at least 3 months, considering as adequate the dose associated with normal thyroid-stimulating hormone (TSH) levels and free thyroxine (T4) in P-HYPO patients, and free T4 levels in CeH patients.Results: The absolute daily dose of LT4 differed significantly between the two groups, 103.0 ± 27.1 μg (CeH) and 89.3 ± 32.0 μg (P-HYPO) (P = .017), even after adjustment for age, gender, and free T4 (P = .04). The LT4 dose adjusted to weight was also higher after adjustment for age, gender and free T4 (P = .04), with an average of 1.3 ± 0.4 μg/kg (CeH) and 1.2 ± 0.4 μg/kg (P-HYPO). Sheehan syndrome patients had a lower absolute daily dose of LT4 (P = .001), and patients who underwent pituitary radiotherapy required higher doses (P = .008). There was no difference in the daily dose of LT4 according to other pituitary hormone deficiencies.Conclusion: The results reinforce the relevance of a careful individualization of LT4 replacement in CeH management and the need for new markers for proper LT4 replacement therapy in such cases.Abbreviations: BMI = body mass index; CeH = central hypothyroidism; GH = growth hormone; LT4 = levothyroxine; P-HYPO = primary hypothyroidism; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone     

Pediatric Visceral Adiposity Index Adaptation Correlates with Homa-Ir,Matsuda, and Transaminases

Objective: Visceral adiposity index (VAI) is a mathematical model associated with cardiometabolic risk in adults, but studies on children failed to support this association. Our group has proposed a pediatric VAI model using pediatric ranges, but it has not yet been evaluated and needs further adjustments. The objective of this study was to further adjust the proposed pediatric VAI by age, creating a new pediatric metabolic index (PMI), and assess the correlation of the PMI with insulin resistance indexes and hepatic enzymes.Methods: A cross-sectional design with data from 396 children (age 5 to 17 years) was analyzed with a generalized linear model to find the coefficients for triglycerides, high-density-lipoprotein cholesterol, and waist circumference–body mass index quotient. The model was constructed according to sex and age and designated PMI. A cross-validation analysis was performed and a receiver operating characteristic curve was used to determine cut-off points.Results: Significant moderate correlation was found between PMI and homeostatic model assessment of insulin resistance (HOMA-IR) (r = 0.452; P = .003), Matsuda (r = -0.366; P = .019), alanine aminotransferase (r = 0.315, P = .045), and γ-glutamyltransferase (r = 0.397; P = .010). A PMI score >1.7 was considered as risk.Conclusion: PMI correlates with HOMA-IR, Matsuda, and hepatic enzymes. It could be helpful for identifying children at risk for cardiometabolic diseases.Abbreviations:ALT = alanine transaminaseBMI = body mass indexGGT = γ-glutamyltransferaseHDL-C = high-density-lipoprotein cholesterolHOMA-IR = homeostatic model assessment of insulin resistancehs-CRP = high sensitivity C-reactive proteinISI = insulin sensitivity indexNAFLD = nonalcoholic fatty liver diseasePMI = pediatric metabolic indexQUICKI = quantitative insulin sensitivity check indexROC = receiver operating characteristicTG = triglycerideTNF-α = tumor necrosis factor–alphaVAI = visceral adiposity indexVAT = visceral adipose tissueWC = waist circumference     

Découverte d’un micro-organisme commensal impliqué dans une crise biologique chez les gilianelles du Crétacé de Tercis (Landes,France) : Convictorella pusula,nov. gen. nov. sp. (microproblematica)

Discovery of a commensal microfossil involved in a biological crisis among the Cretaceous gilianelles of Tercis (Landes, France): Convictorella pusula nov. gen., nov. sp., (microproblematica). The recently discovered gilianelles commonly show attached microspheres. The morphological relationships indicate that this association is of biological origin with benefit for the microspheres but not for the gilianelles. A local bloom of the commensal microspheres (age estimate: about 73 Ma) coincides with a biological crisis in the evolutionary pattern of the gilianelles. The group convictorelles (microproblematica) and the species Convictorella pusula n. gen. n. sp. are created for this original ethological relationship.     

Serum biomarkers differentiating Kawasaki disease from febrile infections: A pilot case-control study

Although some serum biomarkers are elevated in both Kawasaki disease (KD) and infections, these conditions have not been compared by individual or combined biomarkers. The aim of this study, undertaken between January 2016 and May 2018 in a large teaching hospital, was to compare the serum concentration of cytokines, metalloproteinases (MMP) and heat shock protein (HSP) between cases defined as children with Kawasaki disease (KD) and those with febrile infections (controls). Serum concentrations of tumour necrosis factor-alpha (TNF-alpha), interleukins (IL 1beta, 6, and 8), heat shock proteins (HSP 60 and 70) and matrix metalloproteinase (MMP 9) were measured on admission in 17 children under six years of age with a temperature >38.5 °C for ≥five days, and compared between the two groups. The median age was 25 months and the median duration of fever eight days. Seven children were diagnosed with KD and ten had a febrile infection. Only the serum concentrations of IL-6 and TNF-alpha were significantly higher in the former than in the latter group (P = 0.01 and 0.04 respectively). To differentiate between the two groups with the best sensitivity and specificity, the optimal cut-off value for IL-6 was 12.6 pg/mL, and for TNF-alpha 47.9 pg/mL. Their combined increase, however, outperformed their individual concentrations. The characteristic diagnostic “signature” of the combined elevation of IL-6 and TNF-alpha serum levels has the potential, in febrile children, to differentiate early KD from febrile infections, allowing the institution of appropriate therapy.