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Journal Cover Journal of Clinical Endocrinology & Metabolism
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   ISSN (Print) 0021-972X - ISSN (Online) 1945-7197
   Published by Endocrine Society, The Homepage  [4 journals]
  • Continuous Glucose Monitoring for Hypoglycemia Avoidance and Glucose
           Counterregulation in Long-Standing Type 1 Diabetes
    • Authors: Rickels M; Peleckis A, Dalton-Bakes C, et al.
      Abstract: AbstractContextPatients with long-standing type 1 diabetes (T1D) are at increased risk for severe hypoglycemia because of defects in glucose counterregulation and recognition of hypoglycemia symptoms, in part mediated through exposure to hypoglycemia.ObjectiveTo determine whether implementation of real-time continuous glucose monitoring (CGM) as a strategy for hypoglycemia avoidance could improve glucose counterregulation in patients with long-standing T1D and hypoglycemia unawareness.Design, Setting, Participants, and InterventionEleven patients with T1D disease duration of ∼31 years were studied longitudinally in the Clinical & Translational Research Center of the University of Pennsylvania before and 6 and 18 months after initiation of CGM and were compared with 12 nondiabetic control participants.Main Outcome MeasureEndogenous glucose production response derived from paired hyperinsulinemic stepped-hypoglycemic and euglycemic clamps with infusion of 6,6-2H2-glucose.ResultsIn patients with T1D, hypoglycemia awareness (Clarke score) and severity (HYPO score and severe events) improved (P < 0.01 for all) without change in hemoglobin A1c (baseline, 7.2% ± 0.2%). In response to insulin-induced hypoglycemia, endogenous glucose production did not change from before to 6 months (0.42 ± 0.08 vs 0.54 ± 0.07 mg·kg−1·min−1) but improved after 18 months (0.84 ± 0.15 mg·kg−1·min−1; P < 0.05 vs before CGM), albeit remaining less than in controls (1.39 ± 0.11 mg·kg−1·min−1; P ≤ 0.01 vs all).ConclusionsReal-time CGM can improve awareness and reduce the burden of problematic hypoglycemia in patients with long-standing T1D, but with only modest improvement in the endogenous glucose production response that is required to prevent or correct low blood glucose.
      PubDate: Tue, 28 Nov 2017 00:00:00 GMT
  • Myonectin Predicts the Development of Type 2 Diabetes
    • Authors: Li K; Liao X, Wang K, et al.
      Abstract: AbstractContextMyonectin has been identified as a myokine, expressed predominantly in skeletal muscle. However, its clinical implications are largely unknown.ObjectiveThe aim of this study is to investigate the relationship between myonectin (C1q tumor necrosis factor-α-related protein isoform 15) and type 2 diabetes mellitus (T2DM) in cross-sectional and interventional studies.DesignIn a separate study, oral glucose tolerance tests, a 45-minute bout of exercise, lipid infusions, and euglycemic-hyperinsulinemic clamps (EHCs) were performed to investigate the association of myonectin with homeostasis model assessment of insulin resistance (HOMA-IR) and T2DM. Circulating myonectin was measured by enzyme-linked immunosorbent assay.PatientsOne hundred four newly diagnosed T2DM (nT2DM), 109 impaired glucose tolerance (IGT), and 128 healthy individuals were recruited for this study.ResultsnT2DM and IGT subjects had higher circulating myonectin concentrations than normal subjects (82.3 ± 47.6 and 68.9 ± 46.6 vs. 45.2 ± 23.5 µg/L, P < 0.05 or P < 0.01). It was also found that in nT2DM individuals, circulating myonectin was higher than in IGT subjects. Plasma myonectin correlated positively with waist/hip ratio, percentage of body fat, triglyceride, fasting blood glucose, 2-hour blood glucose after glucose overload, fasting insulin, hemoglobin A1c, and HOMA-IR and negatively with the insulin sensitivity index in all of the study population. Multivariate logistic regression analysis revealed that circulating myonectin levels were significantly correlated with IGT and T2DM. A 45-minute bout of exercise did not change circulating myonectin levels in healthy, young individuals. Circulating myonectin levels were not significantly altered in response to an oral glucose challenge or EHC. In addition, acute elevated free fatty acid levels induced by lipid infusion had no effects on circulating myonectin.ConclusionsThese data suggest that myonectin may be a useful marker in predicting the development of prediabetes and diabetes.
      PubDate: Thu, 16 Nov 2017 00:00:00 GMT
  • Identification of Novel Potentially Pleiotropic Variants Associated With
           Osteoporosis and Obesity Using the cFDR Method
    • Authors: Hu Y; Tan L, Chen X, et al.
      Abstract: AbstractContextGenome-wide association studies (GWASs) have been successful in identifying loci associated with osteoporosis and obesity. However, the findings explain only a small fraction of the total genetic variance.ObjectiveThe aim of this study was to identify novel pleiotropic genes important in osteoporosis and obesity.Design and SettingA pleiotropic conditional false discovery rate method was applied to three independent GWAS summary statistics of femoral neck bone mineral density, body mass index, and waist-to-hip ratio. Next, differential expression analysis was performed for the potentially pleiotropic genes, and weighted genes coexpression network analysis (WGCNA) was conducted to identify functional connections between the suggested pleiotropic genes and known osteoporosis/obesity genes using transcriptomic expression data sets in osteoporosis/obesity-related cells.ResultsWe identified seven potentially pleiotropic loci—rs3759579 (MARK3), rs2178950 (TRPS1), rs1473 (PUM1), rs9825174 (XXYLT1), rs2047937 (ZNF423), rs17277372 (DNM3), and rs335170 (PRDM6)—associated with osteoporosis and obesity. Of these loci, the PUM1 gene was differentially expressed in osteoporosis-related cells (B lymphocytes) and obesity-related cells (adipocytes). WGCNA showed that PUM1 positively interacted with several known osteoporosis genes (AKAP11, JAG1, and SPTBN1). ZNF423 was the highly connected intramodular hub gene and interconnected with 21 known osteoporosis-related genes, including JAG1, EN1, and FAM3C.ConclusionsOur study identified seven potentially pleiotropic genes associated with osteoporosis and obesity. The findings may provide new insights into a potential genetic determination and codetermination mechanism of osteoporosis and obesity.
      PubDate: Tue, 14 Nov 2017 00:00:00 GMT
  • Cord Metabolic Profiles in Obese Pregnant Women: Insights Into Offspring
           Growth and Body Composition
    • Authors: Patel N; Hellmuth C, Uhl O, et al.
      Abstract: AbstractContextOffspring exposed in utero to maternal obesity have an increased risk of later obesity; however, the underlying mechanisms remain unknown.ObjectiveTo assess the effect of an antenatal lifestyle intervention in obese women on the offspring’s cord blood metabolic profile and to examine associations of the cord blood metabolic profile with maternal clinical characteristics and offspring anthropometry at birth and age 6 months.DesignRandomized controlled trial and cohort study.SettingThe UK Pregnancies Better Eating and Activity Trial.ParticipantsThree hundred forty-four mother-offspring pairs.InterventionAntenatal behavioral lifestyle (diet and physical activity) intervention.Main Outcome MeasuresTargeted cord blood metabolic profile, including candidate hormone and metabolomic analyses.ResultsThe lifestyle intervention was not associated with change in the cord blood metabolic profile. Higher maternal glycemia, specifically fasting glucose at 28 weeks gestation, had a linear association with higher cord blood concentrations of lysophosphatidylcholines (LPCs) 16.1 (β = 0.65; 95% confidence interval: 0.03 to 0.10) and 18.1 (0.52; 0.02 to 0.80), independent of the lifestyle intervention. A principal component of cord blood phosphatidylcholines and LPCs was associated with infant z scores of birth weight (0.04; 0.02 to 0.07) and weight at age 6 months (0.05; 0.00 to 0.10). Cord blood insulin growth factor (IGF)-1 and adiponectin concentrations were positively associated with infant weight z score at birth and at 6 months.ConclusionsConcentrations of LPCs and IGF-1 in cord blood are related to infant weight. These findings support the hypothesis that susceptibility to childhood obesity may be programmed in utero, but further investigation is required to establish whether these associations are causally related.
      PubDate: Mon, 13 Nov 2017 00:00:00 GMT
  • CORRIGENDUM FOR “A Biallelic Mutation in the Homologous Recombination
           Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis”
    • Abstract: In the above-named article by Smirin-Yosef P, Zuckerman-Levin N, Tzur S, Granot Y, Cohen L, Sachsenweger J, Borck G, Lagovsky I, Salmon-Divon M, Wiesmüller L, and Basel-Vanagaite L (J Clin Endocrinol Metab. 2017; 102(2):681–688; doi: 10.1210/jc.2016-2714) the following omission occurred in the published paper: The Funding Support statement should read: “The authors are grateful for the support of The Milken Family Foundation & The Lowell Milken Family Foundation and the Ministry of Science, Technology & Space, Israel [grant number 3-13545] for providing P.-S.Y. scholarship.”
      PubDate: Wed, 08 Nov 2017 00:00:00 GMT
  • Trabecular Bone Morphology Correlates With Skeletal Maturity and Body
           Composition in Healthy Adolescent Girls
    • Authors: Mitchell D; Caksa S, Yuan A, et al.
      Abstract: AbstractContextGrowth in healthy children is associated with changes in bone density and microarchitecture. Trabecular morphology is an additional important determinant of bone strength, but little is currently known about trabecular morphology in healthy young people.ObjectiveTo investigate associations of trabecular morphology with increasing maturity and with body composition in healthy girls.DesignCross-sectional study.SettingAcademic research center.ParticipantsEighty-six healthy girls aged 9 to 18 years.Main Outcome MeasuresHigh-resolution peripheral quantitative computed tomography and individual trabecula segmentation were used to assess volumetric bone density, microarchitecture, and trabecular morphology (plate-like vs rod-like) at the distal radius and tibia.ResultsPlate-like bone volume divided by total volume (pBV/TV) increased statistically significantly at the tibia (R = 0.41, P < 0.001), whereas rod-like BV/TV (rBV/TV) decreased statistically significantly at both the radius and tibia (R = −0.34, P = 0.003 and R = −0.28, P = 0.008, respectively) with increasing bone age. In multivariable models, lean mass positively correlated with pBV/TV and plate number at the radius and with plate thickness at both sites. In contrast, fat mass negatively correlated with plate thickness at the tibia and plate surface at both sites. In addition, fat mass positively correlated with rBV/TV and number at the tibia. pBV/TV at both the distal radius and tibia was positively correlated with spine bone mineral density.ConclusionsIncreasing maturity across late childhood and adolescence is associated with changes in trabecular morphology anticipated to contribute to bone strength. Body composition correlates with trabecular morphology, suggesting that muscle mass and adiposity in youth may contribute to long-term skeletal health.
      PubDate: Tue, 07 Nov 2017 00:00:00 GMT
  • Impaired Insulin Action Is Associated With Increased Glucagon
           Concentrations in Nondiabetic Humans
    • Authors: Sharma A; Varghese R, Shah M, et al.
      Abstract: AbstractContextAbnormal glucagon concentrations contribute to hyperglycemia, but the mechanisms of α-cell dysfunction in prediabetes are unclear.ObjectiveWe sought to determine the relative contributions of insulin secretion and action to α-cell dysfunction in nondiabetic participants across the spectrum of glucose tolerance.DesignThis was a cross-sectional study. A subset of participants (n = 120) was studied in the presence and absence of free fatty acid (FFA) elevation, achieved by infusion of Intralipid (Baxter Healthcare, Deerfield, IL) plus heparin, to cause insulin resistance.SettingAn inpatient clinical research unit at an academic medical center.ParticipantsA total of 310 nondiabetic persons participated in this study.InterventionsParticipants underwent a seven-sample oral glucose tolerance test. Subsequently, 120 participants were studied on two occasions. On one day, infusion of Intralipid plus heparin raised FFA. On the other day, participants received glycerol as a control.Main Outcome Measure(s)We examined the relationship of glucagon concentration with indices of insulin action after adjusting for the effects of age, sex, and weight. Subsequently, we sought to determine whether an acute decrease in insulin action, produced by FFA elevation, altered glucagon concentrations in nondiabetic participants.ResultsFasting glucagon concentrations correlated positively with fasting insulin and C-peptide concentrations and inversely with insulin action. Fasting glucagon was not associated with any index of β-cell function in response to an oral challenge. As expected, FFA elevation decreased insulin action and also raised glucagon concentrations.ConclusionsIn nondiabetic participants, glucagon secretion was altered by changes in insulin action.
      PubDate: Mon, 06 Nov 2017 00:00:00 GMT
  • Adrenocorticotropin Acutely Regulates Pregnenolone Sulfate Production by
           the Human Adrenal In Vivo and In Vitro
    • Authors: Rege J; Nanba A, Auchus R, et al.
      Abstract: AbstractBackgroundDehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in human circulation, and adrenocorticotropic hormone (ACTH) is considered the major regulator of its synthesis. Pregnenolone sulfate (PregS) and 5-androstenediol-3-sulfate (AdiolS) have recently emerged as biomarkers of adrenal disorders.ObjectiveTo define the relative human adrenal production of Δ5-steroid sulfates under basal and cosyntropin-stimulated conditions.MethodsLiquid chromatography-tandem mass spectrometry was used to quantify three unconjugated and four sulfated Δ5-steroids in (1) paired adrenal vein (AV) and mixed venous serum samples (21 patients) and (2) cultured human adrenal cells both before and after cosyntropin stimulation, (3) microdissected zona fasciculata (ZF) and zona reticularis (ZR) from five human adrenal glands, and (4) a reconstituted in vitro human 17α-hydroxylase/17,20-lyase/(P450 17A1) system.ResultsOf the steroid sulfates, PregS had the greatest increase after cosyntropin stimulation in the AV (32-fold), whereas DHEAS responded modestly (1.8-fold). PregS attained concentrations comparable to those of DHEAS in the AV after cosyntropin stimulation (AV DHEAS/PregS, 24 and 1.3 before and after cosyntropin, respectively). In cultured adrenal cells, PregS demonstrated the sharpest response to cosyntropin, whereas DHEAS responded only modestly (21-fold vs 1.8-fold higher compared with unstimulated cells at 3 hours, respectively). Steroid analyses in isolated ZF and ZR showed similar amounts of PregS and 17α-hydroxypregnenolone in both zones, whereas DHEAS and AdiolS were higher in ZR (P < 0.05).ConclusionOur studies demonstrated that unlike DHEAS, PregS displayed a prominent acute response to cosyntropin. PregS could be used to interrogate the acute adrenal response to ACTH stimulation and as a biomarker in various adrenal disorders.
      PubDate: Mon, 06 Nov 2017 00:00:00 GMT
  • High Circulating Free Thyroxine Levels May Increase the Risk of Frailty:
           The Rotterdam Study
    • Authors: Bano A; Chaker L, Schoufour J, et al.
      Abstract: AbstractContextThyroid hormones affect metabolism in various tissues, organs, and systems. However, the overall impact of thyroid function on an individual’s vulnerability to adverse outcomes remains unclear.ObjectiveTo investigate the cross-sectional and prospective association of thyroid function with the frailty index, a well-established measure of overall health.Design and SettingThe Rotterdam Study, a population-based, prospective cohort study.Participants and Main Outcome MeasurementsParticipants with baseline measurements of thyroid function and the frailty index were eligible. The frailty index was measured at baseline and after a median follow-up time of 10.1 years (interquartile range, 5.7 to 10.8 years). A higher frailty index indicated a worse health state. We assessed the association of thyroid function with frailty at baseline, frailty at follow-up, and frailty changes over time, adjusting for age, sex, cohort, smoking, alcohol, and education.ResultsWe included 9640 participants (mean age, 64.9 years). There was a U-shaped association of thyrotropin (TSH; P < 0.0003) and free thyroxine (FT4; P < 0.0001) with frailty at baseline. There was no association of TSH, but a positive association of FT4 with frailty at follow-up and frailty changes over time (β, 1.22; confidence interval, 0.73 to 1.72 per 1 unit FT4).ConclusionIn this population-based study, participants with low and high thyroid function were more likely to be frail than participants with normal thyroid function. However, only those with higher FT4 levels had an increased risk of becoming more frail over time. The identification of FT4 as a potential marker of health deterioration could have future implications regarding the prediction and prevention of frailty.
      PubDate: Mon, 06 Nov 2017 00:00:00 GMT
  • Letter to the Editor: “Development and Risk Factors of Type 2 Diabetes
           in a Nationwide Population of Women With Polycystic Ovary Syndrome”
    • Authors: Livadas S.
      Abstract: The article by Rubin et al. (1) is of great interest, because it clearly demonstrates the high risk of diabetes mellitus (DM) development in women with polycystic ovary syndrome (PCOS) compared with their healthy peers. Specifically, it was shown that DM occurrence is higher in women with PCOS, and, among other factors, increased body mass index (BMI) and insulin resistance (IR), but not age, are positively associated with this phenomenon. Additionally, the subjects who developed DM were significantly more obese than those who remained euglycemic. However, the percentage of lean women with PCOS who developed DM during the follow-up period is not provided, which is crucial information.
      PubDate: Fri, 03 Nov 2017 00:00:00 GMT
  • Response to Letter to the Editor: “Development and Risk Factors of Type
           2 Diabetes in a Nationwide Population of Women With Polycystic Ovary
    • Authors: Glintborg; D, Rubin K, Abrahamsen B, et al.
      Abstract: Thank you very much for the opportunity to add results for normal-weight women in our study population. We agree that these data are important for the current discussion of the risk of type 2 diabetes (T2D) in normal-weight women with polycystic ovary syndrome (PCOS) (1, 2). In addition, we present data for waist circumference ≥88 cm as an indicator for central obesity, confirming it as an important predictor of insulin resistance in our PCOS cohort (3).
      PubDate: Fri, 03 Nov 2017 00:00:00 GMT
  • SDHC Promoter Methylation, a Novel Pathogenic Mechanism in Parasympathetic
    • Authors: Bernardo-Castiñeira C; Valdés N, Sierra M, et al.
      Abstract: AbstractContextGermline mutations in the succinate dehydrogenase A, B, C, and D genes (collectively, SDHx) predispose to the development of paragangliomas (PGLs) arising at the parasympathetic or sympathetic neuroendocrine systems. SDHx mutations cause absence of tumoral immunostaining for SDHB. However, negative SDHB immunostaining has also been found in a subset of PGLs that lack SDHx mutations.SettingsHere, we report the comprehensive molecular characterization of one such a tumor of parasympathetic origin compared with healthy paraganglia and other PGLs with or without SDHx mutations.ResultsIntegration of multiplatform data revealed somatic SDHC methylation and loss of the 1q23.3 region containing the SDHC gene. This correlated with decreased SDHC messenger RNA (mRNA) and protein levels. Furthermore, another genetic event found affected the VHL gene, which showed a decreased DNA copy number, associated with low VHL mRNA levels, and an absence of VHL protein detected by immunohistochemistry. In addition, the tumor displayed a pseudohypoxic phenotype consisting in overexpression of the hypoxia-inducible factor (HIF)-1α and miR-210, as well as downregulation of the iron-sulfur cluster assembly enzyme (ISCU) involved in SDHB maturation. This profile resembles that of SDHx- or VHL-mutated PGLs but not of PGLs with decreased VHL copy number, pointing to SDHC rather than VHL as the pathogenic driver.ConclusionsCollectively, these findings demonstrate the potential importance of both the SDHC epigenomic event and the activation of the HIF-1α/miR-210/ISCU axis in the pathogenesis of SDHx wild-type/SDHB-negative PGLs. To our knowledge, this is the first case of a sporadic parasympathetic PGL that carries silencing of SDHC, fulfilling the two-hit Knudson’s model for tumorigenesis.
      PubDate: Fri, 03 Nov 2017 00:00:00 GMT
  • Alendronate Use and the Risk of Nonvertebral Fracture During
           Glucocorticoid Therapy: A Retrospective Cohort Study
    • Authors: Bergman J; Nordström A, Nordström P.
      Abstract: AbstractContextGlucocorticoids increase the risk of nonvertebral fracture, but no clinical trial has shown that nonvertebral fractures can be prevented by coadministration of an antiosteoporotic drug.ObjectiveTo estimate the effect of alendronate on the risk of nonvertebral fracture in older adults taking oral glucocorticoids.DesignRetrospective cohort study using national Swedish registers.SettingHospitalized care and ambulatory specialist care.PatientsAmong adults aged ≥50 years (N = 3,347,959), we identified those who initiated oral glucocorticoid therapy from 2006 through 2011 (≥2.5 mg/d of prednisone or equivalent for ≥91 days). The final analysis included 16,890 alendronate users and 16,890 nonusers, who were matched using time-dependent propensity scores.Main Outcome MeasureNonvertebral fracture. This was not prespecified.ResultsOver a median follow-up of 14.5 months, the incidence rate of nonvertebral fracture was 2.0 cases/100 person-years in alendronate users and 2.4 cases in nonusers. This difference corresponded to a 16% lower rate in users (hazard ratio 0.84; 95% confidence interval, 0.75 to 0.94). For hip fractures specifically, the rate was 34% lower in alendronate users relative to nonusers (hazard ratio 0.66; 95% confidence interval, 0.55 to 0.78). The association of alendronate use with a lower risk of nonvertebral fracture was strongest in patients who received high doses of glucocorticoid.ConclusionAlendronate use was associated with a lower risk of nonvertebral fracture, including hip fracture. Similar, but not statistically significant, associations have been reported in meta-analyses of clinical trials.
      PubDate: Fri, 03 Nov 2017 00:00:00 GMT
  • Anxiety, Depression, and Impaired Quality of Life in Primary
           Aldosteronism: Why We Shouldn’t Ignore It!
    • Authors: Reincke M.
      Abstract: Many endocrinopathies are associated with impaired quality of life and psychiatric comorbidities. Personality changes are characteristic features of endocrine diseases and can even be the dominating symptom. In such circumstances, a patient will be treated for an apparent primary psychiatric condition, whereas the underlying endocrine diagnosis is delayed for month or even years. It is textbook knowledge that mania and psychosis may be found in patients with severe hyperthyroidism, whereas patients with Cushing syndrome frequently have depressive symptoms and cognitive disturbances. In pituitary diseases, the spectrum depends on the underlying hyperfunction or hypofunction: acromegalic patients often have maladaptive personality traits and higher rates of affective disorders, and patients with prolactinoma have changes in sleep pattern and cognition.
      PubDate: Wed, 01 Nov 2017 00:00:00 GMT
  • Dietary Fatty Acid Spillover in Plasma: A Marker of Good Health, Bad
           Health, or Irrelevant'
    • Authors: Katsanos C.
      Abstract: Among nutrients, lipids, and specifically plasma nonesterified fatty acids (NEFAs), have received particular attention with respect to their role in metabolic health. Evidence that circulating NEFAs may adversely affect metabolic health appeared more than 50 years ago, implicating a role of elevated plasma NEFAs in impairing glucose metabolism (1). Since then, the role of plasma NEFAs in metabolic health has attracted great research interest, and subsequent investigations have implicated increased NEFA availability in plasma in dyslipidemia (2, 3), ectopic tissue (i.e., muscle, liver) lipid deposition (4, 5), and insulin resistance (6).
      PubDate: Wed, 01 Nov 2017 00:00:00 GMT
  • Quality of Life in Primary Aldosteronism: A Comparative Effectiveness
           Study of Adrenalectomy and Medical Treatment
    • Authors: Velema M; Dekkers T, Hermus A, et al.
      Abstract: AbstractContextIn primary aldosteronism (PA), two subtypes are distinguished: aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). In general, these are treated by adrenalectomy (ADX) and mineralocorticoid receptor antagonists (MRA), respectively.ObjectiveTo compare the effects of surgical treatment and medical treatment on quality of life (QoL).DesignPost hoc comparative effectiveness study within the Subtyping Primary Aldosteronism: A Randomized Trial Comparing Adrenal Vein Sampling and Computed Tomography Scan (SPARTACUS) trial.SettingTwelve Dutch hospitals and one Polish hospital.ParticipantsPatients with PA (n = 184).InterventionsADX or MRAs.Main Outcome MeasuresAt baseline and 6-month and 1-year follow-up, we assessed QoL by two validated questionnaires: RAND 36-Item Health Survey 1.0 (RAND SF-36) and European Quality of Life–5 Dimensions (EQ-5D).ResultsAt baseline, seven of eight RAND SF-36 subscales and both summary scores, as well as three of five EQ-5D dimensions and the visual analog scale, were lower in patients with PA compared with the general population, especially in women. The beneficial effects of ADX were larger than for MRAs for seven RAND SF-36 subscales, both summary scores, and health change. For the EQ-5D, we detected a difference in favor of ADX in two dimensions and the visual analog scale. Most differences in QoL between both treatments exceeded the minimally clinically important difference. After 1 year, almost all QoL measures had normalized for adrenalectomized patients. For patients on medical treatment, most QoL measures had improved but not all to the level of the general population.ConclusionBoth treatments improve QoL in PA, underscoring the importance of identifying these patients. QoL improved more after ADX for suspected APA than after initiation of medical treatment for suspected BAH.
      PubDate: Wed, 01 Nov 2017 00:00:00 GMT
  • Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or
           Recurrent Pheochromocytoma or Paraganglioma
    • Authors: Noto R; Pryma D, Jensen J, et al.
      Abstract: AbstractContextNo therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States.ObjectiveTo determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL.DesignPhase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg.SettingThree centers.PatientsTwenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity.InterventionOpen-label use of high-specific-activity I-131 MIBG therapy.Main Outcome MeasuresDose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival.ResultsThe MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received >18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity.ConclusionsThese findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg.
      PubDate: Wed, 01 Nov 2017 00:00:00 GMT
  • Chylomicron-Derived Fatty Acid Spillover in Adipose Tissue: A Signature of
           Metabolic Health'
    • Authors: Piché M; Parry S, Karpe F, et al.
      Abstract: AbstractContext and ObjectivesSpillover of fatty acids (FAs) into the plasma nonesterified fatty acid (NEFA) pool, because of an inability of adipose tissue (AT) to accommodate sufficient fat uptake, has been suggested to contribute to obesity-related insulin resistance. Using specific labeling techniques, we compared the proportion of spillover-derived NEFA across a range of adiposity.Participants and MethodsSeventy-one healthy men and women were fed a mixed meal (40 g fat) containing [U13C]palmitate to assess the contribution of chylomicron-derived spillover FAs. To investigate subcutaneous abdominal-specific spillover, arteriovenous difference and stable-isotope methodologies were used in substudy (six men, six women).ResultsChylomicron-derived FA spillover was higher in individuals with a BMI <25 kg/m2 (n = 18) compared with those with a BMI ≥25 kg/m2 (n = 53) (22.2 ± 1.6% vs 18.6 ± 0.7%, P = 0.02). Women had higher chylomicron-derived FA spillover than age- and BMI-matched men (21.9 ± 1.1% vs 15.0 ± 1.6%, P = 0.001). Assessing spillover across subcutaneous abdominal AT showed higher proportions in women than in men (28.5 ± 6.1% vs 9.9 ± 1.3%, P = 0.01).ConclusionThere is a considerable degree of spillover FA into the systemic NEFA pool in the postprandial state; this process is greater and more dynamic in lean individuals and women. Contrary to general perception, spillover of chylomicron-derived FA into systemic circulation is a physiologically normal feature most easily observed in people with a higher capacity for clearance of plasma triglycerides, but does not appear to be a pathway providing excess NEFA in obesity.
      PubDate: Wed, 01 Nov 2017 00:00:00 GMT
  • PTH(1–34) for Surgical Hypoparathyroidism: A 2-Year Prospective,
           Open-Label Investigation of Efficacy and Quality of Life
    • Authors: Palermo A; Santonati A, Tabacco G, et al.
      Abstract: AbstractContextDaily parathyroid hormone (PTH) (1–34) administrations can reduce the required total daily dose of calcium and calcitriol and restore normocalcemia in refractory hypoparathyroidism. However, most PTH(1–34) trials have been conducted on small cohorts including subjects with hypoparathyroidism of various etiologies, and quality of life (QOL) was not investigated.ObjectiveTo investigate the effects of 24-month PTH(1–34) treatment in a homogeneous cohort of adult subjects with postoperative hypoparathyroidism and to evaluate QOL changes.DesignProspective open-label study.SettingItalian multicenter study.Participants42 subjects.InterventionTwice-daily PTH(1–34) 20 μg subcutaneous injection.Main Outcome MeasuresCalcium and vitamin D supplementation requirements, serum calcium, phosphate, and urinary calcium excretion (3, 6, 12, 18, 24 months). At baseline and at 6 and 24 months, QOL was evaluated by the RAND 36-Item Short Form (SF-36) Health Survey, covering eight domains of physical and mental health.ResultsMean serum calcium concentration significantly increased from baseline to 3 months (7.6 ± 0.6 vs 8.9 ± 1.1 mg/dL, P < 0.001) and remained stable until the end of the study, despite reductions in calcium and vitamin D supplementation. Phosphate levels gradually decreased from baseline to 6 months (4.3 ± 1.1 vs 3.9 ± 0.6 mg/dL, P < 0.019), remaining stable until 24 months. Serum alkaline phosphatase and calcium excretion gradually increased from baseline to 24 months. Data from SF-36 showed a significant improvement in the mean scores of all eight domains (P < 0.001).ConclusionThis study demonstrates the efficacy and safety of PTH(1–34) to treat adult patients with postsurgical hypoparathyroidism. PTH(1–34) may improve their mental and physical health.
      PubDate: Wed, 01 Nov 2017 00:00:00 GMT
  • Clinical Fractures Among Older Men With Diabetes Are Mediated by Diabetic
    • Authors: Lee R; Sloane R, Pieper , et al.
      Abstract: AbstractIntroductionType 2 diabetes mellitus among older women has been associated with increased bone mineral density, but paradoxically with increased fracture risk. Findings among older men have varied, and potential mechanisms have not been fully elucidated.MethodsA retrospective study of male veterans 65 to 99 years of age who received primary care in the Veterans Health Administration from 2000 to 2010, using administrative data from all 146 Veterans Health Administration medical centers linked to Centers for Medicare and Medicaid Services Medicare fee-for-service data. Potential mediating factors of the diabetes-associated risk were evaluated using negative binomial regression models with the outcomes of any clinical fracture and hip fracture.ResultsOf 2,798,309 Veterans included in the cohort, 900,402 (32.3%) had a diagnosis of diabetes. After adjusting for age, race, ethnicity, body mass index, alcohol and tobacco use, rheumatoid arthritis, and corticosteroid use, the risk of any clinical fracture associated with diabetes was 1.22 (95% confidence interval, 1.21 to 1.23) and that of hip fracture was 1.21 (95% confidence interval, 1.19 to 1.23). Significant mediating factors included peripheral neuropathy, cardiovascular disease, and congestive heart failure, with 45.5% of the diabetes-associated fracture risk explained by these diagnoses.ConclusionsOlder male Veterans with diabetes have a 22% increased risk of incident clinical fracture compared with those without. A significant portion of this risk is explained by diabetes-related comorbidities, specifically peripheral neuropathy and congestive heart failure. Identification of these mediating factors suggests possible mechanisms, as well as potential interventions.
      PubDate: Wed, 01 Nov 2017 00:00:00 GMT
  • Glucose-Dependent Insulinotropic Polypeptide (GIP) Inhibits Bone
           Resorption Independently of Insulin and Glycemia
    • Authors: Christensen M; Lund A, Calanna S, et al.
      Abstract: AbstractContextThe gut hormone glucose-dependent insulinotropic polypeptide (GIP) causes postprandial insulin release and inhibits bone resorption assessed by carboxy-terminal collagen crosslinks (CTX).ObjectiveTo study if GIP affects bone homeostasis biomarkers independently of insulin release and glycemic level.DesignRandomized, double-blinded, crossover study with 5 study days.PatientsTen male C-peptide-negative patients with type 1 diabetes.InterventionsOn 3 matched days with “low glycemia” (plasma glucose in the interval 3 to 7 mmol/L for 120 minutes), we administered intravenous (IV) GIP (4 pmol × kg−1 × min−1), glucagon-like peptide 1 (1 pmol × kg−1 × min−1), or placebo (saline), and on 2 matched days with “high glycemia” (plasma glucose 12 mmol/L for 90 minutes), we administered either GIP or saline.Main Outcome MeasuresCTX, procollagen type 1 N-terminal propeptide (P1NP), and parathyroid hormone (PTH).ResultsDuring low glycemia: GIP progressively suppressed CTX from baseline by up to 59 ± 18% compared with 24 ± 10% during saline infusion (P < 0.0001). Absolute values of P1NP and PTH did not differ between days. During high glycemia: GIP suppressed CTX from baseline by up to 59 ± 19% compared with 7 ± 9% during saline infusion (P < 0.0001). P1NP did not differ between days. GIP suppressed PTH after 60 minutes compared with saline (P < 0.01), but this difference disappeared after 90 minutes.ConclusionsShort-term GIP infusions robustly reduce bone resorption independently of endogenous insulin secretion and during both elevated and low plasma glucose, but have no effect on P1NP or PTH after 90 minutes.
      PubDate: Wed, 01 Nov 2017 00:00:00 GMT
  • An Unusual Case of Takotsubo Syndrome With Hyperaldosteronism as the
           Potential Cause
    • Authors: Ou Y; Zhao Z, Tsauo J, et al.
      Abstract: AbstractContextCatecholamine-related factors are the most popular explanation for the occurrence of Takotsubo syndrome. An aldosterone-related mechanism, however, has not been proposed.Case DescriptionA 45-year-old male patient presenting with ST-segment elevation myocardial infarction was diagnosed with primary aldosteronism, severe hypokalemia, and Takotsubo syndrome. After excluding the known conditions of apical ballooning and the factors of vasospasm, primary aldosteronism is considered as the major contributor to the development of Takotsubo syndrome. The potential mechanisms are discussed.ConclusionsThe case suggests a possible hyperaldosteronism-induced and vasoconstriction-mediated mechanism in the development of Takotsubo syndrome.
      PubDate: Tue, 31 Oct 2017 00:00:00 GMT
  • Current Recommended Vitamin D Prenatal Supplementation and Fetal Growth:
           Results From the China–Anhui Birth Cohort Study
    • Authors: Tao R; Meng D, Li J, et al.
      Abstract: AbstractContextMaternal vitamin D insufficiency has been associated with fetal growth restriction. However, the effect of maternal vitamin D supplementation on fetal growth has not been confirmed.ObjectiveTo assess the effect of maternal vitamin D supplementation recommended by the Institute of Medicine (IOM) during pregnancy on the neonatal vitamin D status and the risk of small for gestational age (SGA).Design and ParticipantsAs part of the China–Anhui Birth Cohort study, maternal sociodemographic characteristics, food intake, lifestyle, information on vitamin D supplementation, and birth outcomes were prospectively collected. For participants, 600 IU/d of vitamin D3 was routinely advised to take during pregnancy. Cord blood levels of 25-hydroxyvitamin D [25(OH)D], calcium, and phosphorus were measured in 1491 neonates who were divided into three groups based on the duration of maternal vitamin D supplementation during pregnancy.ResultsMean cord blood concentrations of 25(OH)D were 3.5 nmol/L higher [95% confidence interval (CI), 0.8, 6.2] in neonates (median, 37.9 nmol/L) whose mother took vitamin D supplementation for >2 months during pregnancy compared with those (median, 34.3 nmol/L) whose mother did not take any supplement. These significant differences on cord blood concentrations of 25(OH)D occurred regardless of the season of birth. The adjusted risk of SGA in pregnant women with vitamin D supplementation for >2 months was significantly decreased than that in women without any vitamin D supplementation (11.8% vs 6.9%; adjusted odds ratio = 0.53; 95% CI, 0.32, 0.87).ConclusionsThe findings from China suggest that maternal vitamin D supplementation recommended by the IOM results in a slight but significantly higher fetal level of 25(OH)D and improves fetal growth.
      PubDate: Tue, 31 Oct 2017 00:00:00 GMT
  • Dose-Dependent Effects of Intranasal Insulin on Resting-State Brain
    • Authors: Kullmann S; Veit R, Peter A, et al.
      Abstract: AbstractContextInsulin action in the human brain influences eating behavior, cognition, and whole-body metabolism. Studies investigating brain insulin rely on intranasal application.ObjectiveTo investigate effects of three doses of insulin and placebo as nasal sprays on the central and autonomous nervous system and analyze absorption of insulin into the bloodstream.Design, Participants, and MethodsNine healthy men received placebo or 40 U, 80 U, and 160 U insulin spray in randomized order. Before and after spray, brain activity was assessed by functional magnetic resonance imaging, and heart rate variability (HRV) was assessed from electrocardiogram. Plasma insulin, C-peptide, and glucose were measured regularly.SettingGeneral community.ResultsNasal insulin administration dose-dependently modulated regional brain activity and the normalized high-frequency component of the HRV. Post hoc analyses revealed that only 160 U insulin showed a considerable difference from placebo. Dose-dependent spillover of nasal insulin into the bloodstream was detected. The brain response was not correlated with this temporary rise in circulating insulin.ConclusionsNasal insulin dose-dependently modulated regional brain activity with the strongest effects after 160 U. However, this dose was accompanied by a transient increase in circulating insulin concentrations due to a spillover into circulation. Our current results may serve as a basis for future studies with nasal insulin to untangle brain insulin effects in health and disease.
      PubDate: Tue, 31 Oct 2017 00:00:00 GMT
  • Progesterone Suppression of Luteinizing Hormone Pulse Frequency in
           Adolescent Girls With Hyperandrogenism: Effects of Metformin
    • Authors: Lundgren J; Kim S, Burt Solorzano C, et al.
      Abstract: AbstractContextPolycystic ovary syndrome (PCOS) and adolescent hyperandrogenism (HA) are characterized by rapid luteinizing hormone (LH) pulse frequency. This partly reflects impaired gonadotropin-releasing hormone pulse generator (hypothalamic) sensitivity to progesterone (P4) negative feedback. We assessed whether metformin may improve P4 sensitivity in adolescent HA, for which it is prescribed widely.ObjectiveTo test the hypothesis that metformin improves hypothalamic P4 sensitivity in adolescent HA.DesignNonrandomized, interventional trial.SettingAcademic clinical research unit.ParticipantsTen adolescent girls with HA.InterventionThe girls underwent LH sampling every 10 minutes for 11 hours, at study baseline and after 7 days of oral P4 and estradiol (E2). Participants then took metformin (1 g twice daily) for 9.4 to 13.7 weeks, after which participants again underwent frequent LH sampling before and after 7 days of oral P4 and E2 (while continuing metformin). Total and free testosterone (T) and fasting insulin were assessed at each admission. At admissions 1 and 3, 2-hour oral glucose tolerance tests were performed.Main Outcome MeasureMetformin-related change in hypothalamic P4 sensitivity index [percent change in LH pulse frequency (before vs after P4 and E2) divided by day 7 P4 level].ResultsFree T levels decreased by 29% with metformin (P = 0.0137). Measures of hyperinsulinemia and P4 sensitivity index did not significantly change with metformin use.ConclusionShort-term metformin use improved biochemical hyperandrogenemia, but did not improve hypothalamic sensitivity to P4 suppression, in adolescent girls.
      PubDate: Tue, 31 Oct 2017 00:00:00 GMT
  • Increased Brain Glucose Uptake After 12 Weeks of Aerobic High-Intensity
           Interval Training in Young and Older Adults
    • Authors: Robinson M; Lowe V, Nair K.
      Abstract: AbstractContextAerobic exercise training can increase brain volume and blood flow, but the impact on brain metabolism is less known.ObjectiveWe determined whether high-intensity interval training (HIIT) increases brain metabolism by measuring brain glucose uptake in younger and older adults.DesignBrain glucose uptake was measured before and after HIIT or a sedentary (SED) control period within a larger exercise study.SettingStudy procedures were performed at the Mayo Clinic in Rochester, MN.ParticipantsParticipants were younger (18 to 30 years) or older (65 to 80 years) SED adults who were free of major medical conditions. Group sizes were 15 for HIIT (nine younger and six older) and 12 for SED (six younger and six older).InterventionParticipants completed 12 weeks of HIIT or SED. HIIT was 3 days per week of 4 × 4 minute intervals at over 90% of peak aerobic capacity (VO2peak) with 2 days per week of treadmill walking at 70% VO2peak.Main Outcome MeasuresResting brain glucose uptake was measured using 18F-fluorodeoxyglucose positron emission tomography scans at baseline and at week 12. Scans were performed at 96 hours after exercise. VO2peak was measured by indirect calorimetry.ResultsGlucose uptake increased significantly in the parietal-temporal and caudate regions after HIIT compared with SED. The gains with HIIT were not observed in all brain regions. VO2peak was increased for all participants after HIIT and did not change with SED.ConclusionWe demonstrate that brain glucose metabolism increased after 12 weeks of HIIT in adults in regions where it is reduced in Alzheimer’s disease.
      PubDate: Wed, 25 Oct 2017 00:00:00 GMT
  • Differential Impact of Genetic Loci on Age at Thelarche and Menarche in
           Healthy Girls
    • Authors: Busch A; Hagen C, Assens M, et al.
      Abstract: AbstractContextRecent genetic studies have identified genetic variants associated with age at pubertal onset. Whereas genome-wide association studies reported associations of several hundred genetic variants with timing of self-reported age at menarche, a recent clinical study focused on genetic variation affecting follicle-stimulating hormone action and clinically determined age at thelarche. The observations appear to be incongruent, as effect sizes varied substantially among the studies. Alternatively, this may point to a differential impact of specific genetic loci on distinct pubertal events.ObjectiveTo investigate whether top-candidate genetic variants exhibit a different impact on timing of thelarche vs menarche, respectively.DesignCross-sectional and longitudinal study of healthy girls.SettingPopulation-based study in the Copenhagen area.Patients or Other ParticipantsGirls (1478) were followed through puberty and genotyped for FSHB c.−211G>T (rs10835638), FSHR c.−29G>A (rs1394205), FSHR c.2039A>G (rs6116), LIN28B (rs7759938), INHA (rs4141153), MKRN3 (rs12148769), TMEM38B (rs10453225), and ZNF483 (rs10980921).Main Outcome MeasuresClinical pubertal staging and anthropometric data.ResultsWe observed an association of LIN28B (rs7759938) with age at thelarche (P < 0.001, effect size: 0.27 year, 95% confidence interval: 0.12 to 0.42) and age at menarche (P = 0.005, 0.17 year, 0.05 to 0.29). FSHB c.−211G>T (rs10835638) and FSHR c.−29G>A (rs1394205) minor allele count was associated with age at thelarche (P = 0.004, 0.19 year, 0.06 to 0.31) but not with age at menarche (P = 0.97; all adjusted for body mass index z scores).ConclusionOur results indicate a differential impact of specific genetic loci on age at thelarche and menarche in healthy girls.
      PubDate: Wed, 25 Oct 2017 00:00:00 GMT
  • Long-Term Survivorship in Multiple Endocrine Neoplasia Type 2B Diagnosed
           Before and in the New Millennium
    • Authors: Raue F; Dralle H, Machens A, et al.
      Abstract: AbstractContextRecent long-term outcomes and survival data are lacking for patients with multiple endocrine neoplasia type 2B (MEN2B).ObjectivesTo analyze long-term MEN2B outcomes and define prognostic factors.Design, Setting, and ParticipantsRetrospective comparative study of 75 patients with MEN2B from two German tertiary referral centers. Patients diagnosed and treated before and after 2000 were compared for demographic, biochemical, surgical, and outcome parameters.InterventionSurgery.Main Outcome measureLong-term survival.ResultsWe identified seven familial and 68 de novo cases of MEN2B; 61 exhibited the RET M918T genotype (2 others exhibited A883F and E768D/L790T mutations). Surgery was performed at a mean age of 16.4 ± 11.2 years. The tumor stages at diagnosis for 71 patients were stage I, 15%; stage II, 6%; stage III, 35%; and stage IV, 44%. The mean follow-up was 9.6 ± 9.0 years. The outcomes were 15 (20%) cured, 9 (12%) with minimal residual disease, 19 (25%) with metastatic disease, and 10 (13%) unknown. Medullary thyroid cancer (MTC) caused 22 deaths (29%) 7.3 ± 6.2 years after diagnosis (mean age, 22.9 ± 10.7 years). The overall survival rates at 5, 10, and 20 years were 85%, 74%, and 58%, respectively. After 2000 (vs before 2000), significantly more patients had stage I and II (32% vs 11%) and more were cured (43% vs 20%), with a higher survival trend (P = 0.058). The only prognostic factor was tumor stage at diagnosis.ConclusionsPatients with MEN2B developed MTC at an early age with wide ranging aggressiveness, but the outcome was generally better after 2000 than before 2000.
      PubDate: Wed, 25 Oct 2017 00:00:00 GMT
  • Thyroid State Regulates Gene Expression in Human Whole Blood
    • Authors: Massolt E; Meima M, Swagemakers S, et al.
      Abstract: AbstractContextDespite the well-recognized clinical features resulting from insufficient or excessive thyroid hormone (TH) levels in humans, it is largely unknown which genes are regulated by TH in human tissues.ObjectiveTo study the effect of TH on human gene expression profiles in whole blood, mainly consisting of T3 receptor (TR) α-expressing cells.MethodsWe performed next-generation RNA sequencing on whole blood samples from eight athyroid patients (four females) on and after 4 weeks off levothyroxine replacement. Gene expression changes were analyzed through paired differential expression analysis and confirmed in a validation cohort. Weighted gene coexpression network analysis (WGCNA) was applied to identify thyroid state-related networks.ResultsWe detected 486 differentially expressed genes (fold-change >1.5; multiple testing corrected P value < 0.05), of which 76% were positively and 24% were negatively regulated. Gene ontology (GO) enrichment analysis revealed that three biological processes were significantly overrepresented, of which the process translational elongation showed the highest fold enrichment (7.3-fold, P = 1.8 × 10−6). WGCNA analysis independently identified various gene clusters that correlated with thyroid state. Further GO analysis suggested that thyroid state affects platelet function.ConclusionsChanges in thyroid state regulate numerous genes in human whole blood, predominantly TRα-expressing leukocytes. In addition, TH may regulate gene transcripts in platelets.
      PubDate: Mon, 23 Oct 2017 00:00:00 GMT
  • Letter to the Editor: “Fibroblast Growth Factor 23, Mineral Metabolism,
           and Adiposity in Normal Kidney Function”
    • Authors: Remer T.
      Abstract: In a large cross-sectional study in adults with normal kidney function, Zaheer et al. (1) observed a significant positive relationship between serum concentrations of the bone-derived hyperphosphaturic hormone fibroblast growth factor 23 (FGF23) and different markers of adiposity. Unfortunately, the most probable metabolic cause for this observation, namely an increase in circulating insulin, regularly accompanying adiposity and insulin resistance, has not been considered by the authors. During usual insulin resistance, insulin receptor action remains widely preserved in parts of the kidney (2). Accordingly, as an antiphosphaturic hormone, insulin can directly induce proximal tubular phosphate transporters (2, 3), with the result that renal phosphate reabsorption is basically promoted in obesity and, in turn, higher FGF23 production is required to compensate for rising plasma phosphate.
      PubDate: Fri, 20 Oct 2017 00:00:00 GMT
  • Response to Letter to the Editor: “Fibroblast Growth Factor 23, Mineral
           Metabolism, and Adiposity in Normal Kidney Function”
    • Authors: Zaheer S; Vaidya A.
      Abstract: We thank Dr. Remer for his commentary on our recent publication that demonstrated an independent association between higher body adiposity and higher fibroblast growth factor 23 (FGF23) levels (1).
      PubDate: Fri, 20 Oct 2017 00:00:00 GMT
  • Cytokine Autoantibody Screening in the Swedish Addison Registry Identifies
           Patients With Undiagnosed APS1
    • Authors: Eriksson D; Dalin F, Eriksson G, et al.
      Abstract: AbstractContextAutoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features autoimmune Addison disease as a major component. Although APS1 accounts for only a small fraction of all patients with Addison disease, early identification of these individuals is vital to prevent the potentially lethal complications of APS1.ObjectiveTo determine whether available serological and genetic markers are valuable screening tools for the identification of APS1 among patients diagnosed with Addison disease.DesignWe systematically screened 677 patients with Addison disease enrolled in the Swedish Addison Registry for autoantibodies against interleukin-22 and interferon-α4. Autoantibody-positive patients were investigated for clinical manifestations of APS1, additional APS1-specific autoantibodies, and DNA sequence and copy number variations of AIRE.ResultsIn total, 17 patients (2.5%) displayed autoantibodies against interleukin-22 and/or interferon-α4, of which nine were known APS1 cases. Four patients previously undiagnosed with APS1 fulfilled clinical, genetic, and serological criteria. Hence, we identified four patients with undiagnosed APS1 with this screening procedure.ConclusionWe propose that patients with Addison disease should be routinely screened for cytokine autoantibodies. Clinical or serological support for APS1 should warrant DNA sequencing and copy number analysis of AIRE to enable early diagnosis and prevention of lethal complications.
      PubDate: Fri, 20 Oct 2017 00:00:00 GMT
  • A Lymph Node Ratio–Based Staging Model Is Superior to the Current
           Staging System for Pancreatic Neuroendocrine Tumors
    • Authors: Gaitanidis A; Patel D, Nilubol N, et al.
      Abstract: AbstractContextThe incidence of pancreatic neuroendocrine tumors (PNETs) is increasing. Current staging systems include nodal positivity, but the association of lymph node status and worse survival is controversial.ObjectiveThe study aim was to determine the prognostic significance of lymph node ratio (LNR) and compare it with nodal positivity for PNET.Design, Setting, Participants, and InterventionA retrospective analysis of the Surveillance, Epidemiology, and End Results database between 2004 and 2011 was performed in patients who underwent a pancreatectomy with lymphadenectomy. The primary outcome was disease-specific survival (DSS).ResultsOf the 896 patients analyzed, T stage, N stage, distant metastasis, grade, extent of resection, sex, and age ≥57 years were significantly associated with worse DSS on univariate analysis. On multivariate analysis, age ≥57 [hazard ratio (HR) 1.75, 95% confidence interval (CI), 1.12 to 2.74, P = 0.015], male sex (HR 1.58; 95% CI, 1.01 to 2.48; P = 0.046), grade (poorly differentiated/undifferentiated: HR 7.59; 95% CI, 4.71 to 12.23; P < 0.001), distant metastases (HR 2.45; 95% CI, 1.58 to 3.79; P < 0.001), and partial pancreatectomy (HR 2.55; 95% CI, 1.2 to 5.4; P = 0.015) were associated with worse DSS. Comparison between staging models constructed based on LNR cutoffs and the American Joint Committee on Cancer (AJCC) eighth edition staging system revealed that a model based on LNR ≥0.5 was superior.ConclusionsLNR ≥0.5 is independently associated with worse DSS. A staging system with LNR ≥0.5 was superior to the current AJCC eighth edition staging system.
      PubDate: Fri, 20 Oct 2017 00:00:00 GMT
  • Skeletal Microstructure and Estimated Bone Strength Improve Following
           Parathyroidectomy in Primary Hyperparathyroidism
    • Authors: Cusano N; Rubin M, Silva B, et al.
      Abstract: AbstractContextHigh-resolution peripheral quantitative computed tomography (HRpQCT) is a noninvasive imaging technology that can provide insight into skeletal microstructure and strength. In asymptomatic primary hyperparathyroidism (PHPT), HRpQCT imaging has demonstrated both decreased cortical and trabecular indices, consistent with evidence for increased fracture risk. There are limited data regarding changes in HRpQCT parameters postparathyroidectomy.ObjectiveTo evaluate changes in skeletal microstructure by HRpQCT in subjects with PHPT after parathyroidectomy.DesignWe studied 29 subjects with PHPT (21 women, 8 men) with HRpQCT at baseline and 6, 12, 18, and 24 months postparathyroidectomy.Main Outcome MeasuresVolumetric bone mineral density, microarchitectural indices, and finite element analysis at the distal radius and tibia.ResultsAt both the radius and tibia, there were significant improvements in total, cortical, and trabecular volumetric bone density as early as 6 months postparathyroidectomy (24-month values for total volumetric bone density, radius: +2.8 ± 4%, tibia: +4.4 ± 4%; P < 0.0001 for both), cortical thickness (radius: +1.1 ± 2%, tibia: +2.0 ± 3%; P < 0.01 for both), and trabecular bone volume (radius: +3.8 ± 5%, tibia: +3.2 ± 4%; P < 0.0001 for both). At both sites, by finite element analysis, stiffness and failure load were improved starting at 6 months postparathyroidectomy (24-month values for failure load, radius: +6.2 ± 6%, tibia: +4.8 ± 7%; P < 0.0001 for both).ConclusionsThese results provide information about skeletal microarchitecture in subjects with PHPT followed through 2 years after parathyroidectomy. Estimated bone strength is improved, consistent with data showing decreased fracture risk postparathyroidectomy.
      PubDate: Fri, 20 Oct 2017 00:00:00 GMT
  • A Prospective Cohort Study of Prenatal Diethylstilbestrol Exposure and
           Cardiovascular Disease Risk
    • Authors: Troisi R; Titus L, Hatch E, et al.
      Abstract: AbstractPurposePrenatal exposure to diethylstilbestrol (DES), a prototype endocrine-disrupting chemical, is associated with risk for adverse reproductive outcomes and cancer in women. We investigated whether cardiovascular disease (CVD) risk might also be greater in women prenatally exposed to DES.MethodsDES-exposed (n = 3941) and -unexposed (n = 1705) women participating in the Combined DES Cohort Follow-up Study were followed prospectively from 1994 to 2013. Prenatal DES exposure (or lack of exposure) was documented in the birth record or physician’s note. Participants reported by questionnaire any “serious medical conditions requiring hospitalization, surgery or long-term treatment,” including coronary artery disease (CAD), myocardial infarction (MI), and stroke. We sought physician’s verification of self-reports and identified CVD deaths from the National Death Index. Hazard ratios (HRs) with 95% confidence intervals (CIs) from Cox proportional hazard regression models estimated associations between DES exposure and CVD incidence, adjusted for birth year, original cohort, and potential confounders.ResultsIn comparison of the exposed to the unexposed women, the HRs for reported conditions were 1.74 (95% CI, 1.03 to 2.93) for CAD, 2.20 (95% CI, 1.15 to 4.21) for MI, 1.01 (95% CI, 0.54 to 1.90) for stroke, and 1.31 (95% CI, 0.93 to 1.86) for the combined conditions (i.e., total CVD). The HRs were similar for verified outcomes (CAD, 1.72; MI, 2.67; stroke, 0.92; and total CVD, 1.25) and with additional adjustment for hypertension, diabetes, and high cholesterol (HRs: CAD, 1.67; MI, 2.04; stroke, 0.96; and total CVD, 1.24).ConclusionsThese data demonstrate associations in women who have prenatal DES exposure with CAD and MI, but not with stroke, which appear to be independent of established CVD risk factors.
      PubDate: Fri, 20 Oct 2017 00:00:00 GMT
  • Ossifications in Albright Hereditary Osteodystrophy: Role of Genotype,
           Inheritance, Sex, Age, Hormonal Status, and BMI
    • Authors: Salemi P; Skalamera Olson J, Dickson L, et al.
      Abstract: AbstractContextAlbright hereditary osteodystrophy (AHO) is caused by heterozygous inactivating mutations in GNAS. Depending on the parental origin of the mutated allele, patients develop either pseudohypoparathyroidism type 1A (PHP1A), with multihormone resistance and severe obesity, or pseudopseudohypoparathyroidism (PPHP), without hormonal abnormalities or marked obesity. Subcutaneous ossifications (SCOs) are a source of substantial morbidity in both PHP1A and PPHP.ObjectiveThis study investigated the previously undetermined prevalence of SCO formation in PHP1A vs PPHP as well as possible correlations with genotype, sex, age, hormonal resistance, and body mass index (BMI).DesignThis study evaluated patients with AHO for SCOs by physical examination performed by one consistent physician over 16 years.SettingAlbright Clinic, Kennedy Krieger Institute; Institute for Clinical and Translational Research, Johns Hopkins Hospital; Albright Center, Connecticut Children’s Medical Center.PatientsWe evaluated 67 patients with AHO (49 with PHP1A, 18 with PPHP) with documented mutations in GNAS.Main Outcome MeasuresRelationships of SCOs to genotype, sex, age, hormonal resistance, and BMI.ResultsForty-seven of 67 participants (70.1%) had SCOs. Patients with PHP1A and PPHP had similar prevalences and degrees of ossification formation. Patients with frameshift and nonsense mutations had much more extensive SCOs than those with missense mutations. Males were affected more than females. There was no correlation with hormonal status or BMI.ConclusionsThere is a similar prevalence of SCOs in PHP1A and PPHP, and the extent of SCO formation correlates with the severity of the mutation. Males are affected more extensively than females, and the SCOs tend to worsen with age.
      PubDate: Thu, 19 Oct 2017 00:00:00 GMT
  • Escitalopram Ameliorates Hypercortisolemia and Insulin Resistance in Low
           Birth Weight Men With Limbic Brain Alterations
    • Authors: Buhl C; Stødkilde-Jørgensen H, Videbech P, et al.
      Abstract: AbstractContextLow birth weight (LBW; <2500 g) is linked to the development of insulin resistance and limbic-hypothalamic-pituitary-adrenal (LHPA) axis hyperactivity.ObjectiveOur first aim was to study insulin action, LHPA axis function, and limbic brain structures in young, healthy LBW men vs normal birthweight (NBW) controls (part 1). Our second aim was to investigate the effects of escitalopram vs placebo in LBW men in the LHPA axis and insulin sensitivity (part 2).Design Setting, Participants, and InterventionThe maximal (Rdmax) and submaximal (Rdsubmax) rates of insulin-stimulated glucose turnover, LHPA axis, and brain morphology were examined in 40 LBW men and 20 matched NBW men using two-stage hyperinsulinemic euglycemic clamp, 24-hour hormone plasma profiles, and magnetic resonance imaging. Subsequently, all LBW subjects underwent randomized and double-blind treatment with escitalopram 20 mg/d or placebo for 3 months followed by a complete reexamination.Main Outcome Measures (Part 2)Changes in Rdmax/Rdsubmax and plasma-free cortisol 24-hour area under the curve.ResultsIn LBW vs NBW, Rdsubmax and Rdmax were ∼16% (P = 0.01) and ∼12% (P = 0.01) lower, respectively, and 24-hour free cortisol levels were ∼20% higher (P = 0.02), primarily driven by a ∼99% increase at 05:00 am (P < 0.001). Furthermore, these changes were related to structural alterations within left thalamus and ventromedial prefrontal cortex. However, in LBW men, exposure to escitalopram normalized the free cortisol levels and improved the Rdsubmax by ∼24% (P = 0.04) compared with placebo.ConclusionsLBW vs NBW displayed alterations in key brain structures modulating the LHPA axis, elevated free cortisol levels, and insulin resistance. Escitalopram administration ameliorated these defects, suggesting a potential for LHPA axis modulation compounds to improve insulin action in LBW subjects.
      PubDate: Wed, 18 Oct 2017 00:00:00 GMT
  • Associations Between Cellular Aging Markers and Metabolic Syndrome:
           Findings From the CARDIA Study
    • Authors: Révész D; Verhoeven J, Picard M, et al.
      Abstract: AbstractBackgroundMetabolic syndrome (MetS) is thought to promote biological aging, which might lead to cardiovascular and aging-related complications. This large-scale study investigated longitudinal relationships between MetS, its components, and cellular aging markers: leukocyte mitochondrial DNA copy number (mtDNAcn) and telomere length (TL).MethodsWe included 989 participants from the Coronary Artery Risk Development in Young Adults Study. MtDNAcn [study year (Y) 15, Y25] and TL (Y15, Y20, Y25) were measured via quantitative polymerase chain reaction. MetS components [waist circumference, triglycerides, high-density lipoprotein (HDL) cholesterol, systolic blood pressure, and fasting glucose] were determined (Y15, Y20, Y25). Generalized estimated equation and linear regression models, adjusting for sociodemographics and lifestyle, were used to examine associations between MetS and cellular aging at all time points, baseline MetS and 10-year changes in cellular aging, baseline cellular aging and 10-year changes in MetS, and 10-year changes in MetS and 10-year changes in cellular aging.ResultsMtDNAcn and TL were negatively associated with age [mtDNAcn unstandardized β (B) = −4.76; P < 0.001; TL B = −51.53; P < 0.001] and positively correlated (r = 0.152; P < 0.001). High triglycerides were associated with low mtDNAcn and low HDL cholesterol with short TL. Greater Y15 waist circumference (B = −7.23; P = 0.05), glucose (B = −13.29; P = 0.001), number of metabolic dysregulations (B = −7.72; P = 0.02), and MetS (B = −28.86; P = 0.006) predicted greater 10-year decrease in mtDNAcn but not TL. The 10-year increase in waist circumference was associated with 10-year telomere attrition (B = −27.61; P = 0.04).ConclusionsOur longitudinal data showed that some metabolic dysregulations were associated with mtDNAcn and TL decreases, possibly contributing to accelerated cellular aging but not the converse.
      PubDate: Wed, 18 Oct 2017 00:00:00 GMT
  • Systemic Inflammation Induced by microRNAs: Endometriosis-Derived
           Alterations in Circulating microRNA 125b-5p and Let-7b-5p Regulate
           Macrophage Cytokine Production
    • Authors: Nematian S; Mamillapalli R, Kadakia T, et al.
      Abstract: AbstractContextEndometriosis is characterized by aberrant inflammation. We previously reported increased levels of microRNA (miRNA) 125b-5p and decreased levels of miRNA Let-7b-5p in serum of patients with endometriosis.ObjectiveDetermine the regulatory function of miRNAs 125b-5p and Let-7b-5p on production of proinflammatory cytokines in endometriosis.DesignCase-control study.SettingUniversity hospital.PatientsWomen with (20) and without (26) endometriosis; human U937 macrophage cell line.InterventionSera were collected from surgically diagnosed patients and differentiated U937 cells that were transfected with miRNAs 125b-5p and Let-7b-5p mimics and inhibitor.Main Outcome MeasuresEnzyme-linked immunosorbent assay for tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and IL-1β levels and quantitative real-time polymerase chain reaction for expression of miRNAs 125b-5p and Let-7b-5p in sera of patients with and without endometriosis. Transfected macrophages were evaluated for expression of inflammatory cytokines, intracellular production, and secretion of these cytokines.ResultsWe noted substantial elevation of TNF-α, IL-1β, and IL-6, marked upregulation of miRNA 125b, and considerable downregulation of Let-7b in sera of patients with endometriosis vs control. There was a positive correlation between miRNA 125b levels and TNF-α, IL-1β, and IL-6 and a negative correlation between miRNA Let-7b levels and TNF-α in sera of patients with endometriosis. Transfection experiments showed a noteworthy upregulation of TNF-α, IL-1β, IL-6, and IL-8 in macrophages transfected with miRNA 125b mimic or Let-7b inhibitor. The secreted cytokine protein levels and intracellular imaging studies closely correlate with the messenger RNA changes.ConclusionsEndometriosis-derived miRNAs regulate macrophage cytokine production that contributes to inflammation associated with this condition.
      PubDate: Thu, 12 Oct 2017 00:00:00 GMT
  • Ratio of Endogenous Secretory Receptor for Advanced Glycation End Products
           to Pentosidine Predicts Fractures in Men
    • Authors: Tamaki J; Kouda K, Fujita Y, et al.
      Abstract: AbstractContextAlthough the endogenous secretory receptor for advanced glycation end products (esRAGE) has been associated with reduced activity of pentosidine (PEN), the association between PEN, esRAGE, and fracture is poorly understood.ObjectivesTo evaluate the ability of serum PEN and esRAGE levels to predict fragility fractures.MethodsA cohort of 1285 Japanese men aged ≥65 years old participated in a 2007 to 2008 Fujiwara-kyo Osteoporosis Risk in Men study baseline survey, as part of the Fujiwara-kyo prospective cohort study. Those participants provided information regarding any fractures they experienced during 5 years. The baseline bone mineral density (BMD) was measured. Hazard ratios (HRs) per one standard deviation increase of log-transformed serum levels of PEN, esRAGE, and esRAGE-to-PEN ratio were estimated at baseline.ResultsTwenty-five participating men suffered incident clinical fragility fractures. The crude HRs (95% confidence interval) for PEN, esRAGE, and esRAGE-to-PEN ratio were 1.56 (1.05 to 2.31), 0.79 (0.54 to 1.15), and 0.65 (0.44 to 0.95), respectively. HRs for PEN adjusted for age, esRAGE, and T score of BMD at femoral neck (FN) and lumbar spine (LS) were 1.48 (1.00 to 2.18) and 1.51 (1.03 to 2.21), respectively. The marginal significance adjusted for BMD at FN and the statistical significance adjusted for BMD at LS were attenuated after additional adjustment for glycated hemoglobin A1c level (P = 0.111 and 0.072, respectively). The HRs for esRAGE-to-PEN ratio adjusted for age, glycated hemoglobin A1c, and T-score of BMD at FN and LS were 0.67 (0.45 to 0.98) and 0.64 (0.43 to 0.95).ConclusionsHigher esRAGE-to-PEN ratios were associated with decreased risk of fragility fractures independent of BMD among elderly Japanese men.
      PubDate: Thu, 12 Oct 2017 00:00:00 GMT
  • Neurokinin B Regulates Gonadotropin Secretion, Ovarian Follicle Growth,
           and the Timing of Ovulation in Healthy Women
    • Authors: Skorupskaite K; George J, Veldhuis J, et al.
      Abstract: AbstractContextNeurokinin B (NKB) is obligate for human puberty, but its role in adult female gonadotropin secretion and ovarian follicle growth is unknown.ObjectiveTo investigate antagonism of NKB on pulsatile gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion and ovarian follicle development in healthy women.DesignOpen investigation of the effects of a neurokinin-3 receptor (NK3R) antagonist (NK3Ra) vs a no-treatment control cycle.SettingClinical research facility.Patients or other participantsHealthy women with regular menses (n = 13).Intervention(s)NK3Ra MLE4901 40 mg taken orally twice daily from cycle day 5 to 6 for 7 days.Main outcome measure(s)LH secretion, ovarian follicle growth, and timing of ovulation.ResultsNK3Ra administration reduced basal LH secretion without a change in pulse frequency and delayed the LH surge by 7 days, the duration of treatment [mean cycle day ± standard error of the mean (SEM), 22 ± 1 days vs 15 ± 1 days in control cycles; P = 0.0006]. Follicle growth (mean diameter at the end of administration of NK3Ra administration ± SEM, 9.3 ± 0.4 mm vs 15.1 ± 0.9 mm in control cycles; P < 0.0001) and rising estradiol concentrations (mean ± SEM, 166 ± 29 pmol/L vs 446 ± 86 pmol/L in control cycles; P < 0.0001) were prevented. After treatment, follicle development resumed and normal preovulatory follicle diameter and estradiol concentrations were demonstrated. Postovulatory progesterone rise was similarly delayed (peak cycle day, 30 ± 2 vs 22 ± 1; P = 0.002) and cycle length was prolonged (35 ± 1 days vs 29 ± 1 days in control cycles; P = 0.0003) but luteal progesterone excretion was unaffected by the NK3Ra (LH surge day +7 mean urinary progesterone levels ± SEM, 58 ± 10 pmol/mol vs 48±7 pmol/mol creatinine in control cycles; nonsignificant).ConclusionThese data demonstrate the involvement of NKB-NK3R signaling in the physiological regulation of GnRH/LH secretion, determining normal follicle development in women.
      PubDate: Thu, 12 Oct 2017 00:00:00 GMT
  • Statins Affect Skeletal Muscle Performance: Evidence for Disturbances in
           Energy Metabolism
    • Authors: Allard N; Schirris T, Verheggen R, et al.
      Abstract: AbstractContextStatin myopathy is linked to disturbances in mitochondrial function and exercise intolerance.ObjectivesTo determine whether differences exist in exercise performance, muscle function, and muscle mitochondrial oxidative capacity and content between symptomatic and asymptomatic statin users, and control subjects.DesignCross-sectional study.SettingDepartment of Physiology, Radboud University Medical Center.ParticipantsLong-term symptomatic and asymptomatic statin users, and control subjects (n = 10 per group).InterventionsMaximal incremental cycling tests, involuntary electrically stimulated isometric quadriceps-muscle contractions, and biopsy of vastus lateralis muscle.Main Outcomes MeasuredMaximal exercise capacity, substrate use during exercise, muscle function, and mitochondrial energy metabolism.ResultsPeak oxygen uptake, maximal work load, and ventilatory efficiency were comparable between groups, but both statin groups had a depressed anaerobic threshold compared with the control group (P = 0.01). Muscle relaxation time was prolonged in both statin groups compared with the control group and rate of maximal force rise was decreased (Ptime×group < 0.001 for both measures). Mitochondrial activity of complexes II and IV was lower in symptomatic statin users than control subjects and tended to be lower for complex (C) III (CII: P = 0.03; CIII: P = 0.05; CIV: P = 0.04). Mitochondrial content tended to be lower in both statin groups than in control subjects.ConclusionStatin use attenuated substrate use during maximal exercise performance, induced muscle fatigue during repeated muscle contractions, and decreased muscle mitochondrial oxidative capacity. This suggests disturbances in mitochondrial oxidative capacity occur with statin use even in patients without statin-induced muscle complaints.
      PubDate: Mon, 09 Oct 2017 00:00:00 GMT
  • Decreased Homocysteine Trans-Sulfuration in Hypertension With
           Hyperhomocysteinemia: Relationship With Insulin Resistance
    • Authors: Tessari P; Cecchet D, Vettore M, et al.
      Abstract: AbstractContextHomocysteine is an independent cardiovascular risk factor and is elevated in essential hypertension. Insulin stimulates homocysteine catabolism in healthy individuals. However, the mechanisms of hyperhomocysteinemia and its relationship with insulin resistance in essential hypertension are unknown.ObjectiveTo investigate whole body methionine and homocysteine kinetics and the effects of insulin in essential hypertension.Design and SettingEight hypertensive male subjects and six male normotensive controls were infused with l-[methyl-2H3,1-13C]methionine for 6 hours. In the last 3 hours a euglycemic, hyperinsulinemic clamp was performed. Steady-state methionine and homocysteine kinetics were determined in postabsorptive and hyperinsulinemic conditions.ResultsPostabsorptive hypertensive subjects had elevated homocysteine concentrations (+30%, P = 0.035) and slightly (by 15% to 20%) but insignificantly lower methionine rates of appearance (Ras) (P = 0.07 to P = 0.05) and utilization for protein synthesis (P = 0.06) than postabsorptive normotensive controls. Hyperinsulinemia suppressed methionine Ra and protein synthesis, whereas it increased homocysteine trans-sulfuration, clearance, and methionine transmethylation (the latter only in the normotensive subjects). However, in the hypertensive subjects trans-sulfuration was significantly lower (P < 0.05) and increased ~50% less [by +1.59 ± 0.34 vs +3.45 ± 0.52 µmol/kg lean body mass (LBM) per hour, P < 0.005] than in normotensive controls. Homocysteine clearance through trans-sulfuration was ~50% lower in hypertensive than in normotensive subjects (P < 0.005). In the hypertensive subjects, insulin-mediated glucose disposal was ~45% lower (460 ± 44 vs 792 ± 67 mg/kg LBM per hour, P < 0.0005) than in normotensive controls and was positively correlated with the increase of trans-sulfuration (P < 0.0015).ConclusionsIn subjects with essential hypertension, hyperhomocysteinemia is associated with decreased homocysteine trans-sulfuration and probably represents a feature of insulin resistance.
      PubDate: Fri, 29 Sep 2017 00:00:00 GMT
  • Iatrogenic Cushing Syndrome in a Child With Congenital Adrenal
           Hyperplasia: Erroneous Compounding of Hydrocortisone
    • Authors: Barillas J; Eichner D, Van Wagoner R, et al.
      Abstract: AbstractContextPatients with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) require lifelong treatment with glucocorticoids. In growing children, the drug of choice is hydrocortisone. Commercially available hydrocortisone tablets do not conform to very low doses prescribed to infants and toddlers, and compounded hydrocortisone is often dispensed to meet therapeutic needs. However, safety, efficacy, and uniformity of compounded products are not tested. We report a case of Cushing syndrome in a child with CAH who was inadvertently receiving excessive hydrocortisone in compounded form.DesignA 20-month-old girl with CAH developed growth deceleration, excessive weight for length, irritability, increased facial fat, plethora, and excess body hair while receiving hydrocortisone from a local compounding pharmacy. The signs and symptoms persisted despite decreasing hydrocortisone dose. Iatrogenic Cushing syndrome was suspected. The prescribed hydrocortisone capsules were sent for analysis to the Sports Medicine Research & Testing Laboratory, where testing revealed that each 1-mg hydrocortisone capsule contained five to 10 times the dose prescribed and listed on the label.ConclusionPhysicians must be aware that errors in compounded medications may lead to unanticipated adverse effects. Iatrogenic Cushing syndrome should be suspected in any child receiving compounded glucocorticoid treatment who develops growth arrest and excess weight gain.
      PubDate: Thu, 28 Sep 2017 00:00:00 GMT
  • Expression of Contactin 4 Is Associated With Malignant Behavior in
           Pheochromocytomas and Paragangliomas
    • Authors: Evenepoel L; van Nederveen F, Oudijk L, et al.
      Abstract: AbstractContextPheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine, usually benign, tumors. Currently, the only reliable criterion of malignancy is the presence of metastases.ObjectiveThe aim of this study was to identify genes associated with malignancy in PPGLs.DesignTranscriptomic profiling was performed on 40 benign and 11 malignant PPGLs. Genes showing a significantly different expression between benign and malignant PPGLs with a ratio ≥4 were confirmed and tested in an independent series by quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemistry was performed for the validated genes on 109 benign and 32 malignant PPGLs. Functional assays were performed with hPheo1 cells.SettingThis study was conducted at the Department of Pathology of the Erasmus MC University Medical Center Rotterdam Human Molecular Genetics laboratory of the de Duve Institute, University of Louvain.PatientsPPGL samples from 179 patients, diagnosed between 1972 and 2015, were included.Main outcome measuresAssociations between gene expression and malignancy were tested using supervised clustering approaches.ResultsTen differentially expressed genes were selected based on messenger RNA (mRNA) expression array data. Contactin 4 (CNTN4) was overexpressed in malignant vs benign tumors [4.62-fold; false discovery rate (FDR), 0.001]. Overexpression at the mRNA level was confirmed using qRT-PCR (2.90-fold, P = 0.02; validation set: 4.26-fold, P = 0.005). Consistent findings were obtained in The Cancer Genome Atlas cohort (2.7-fold; FDR, 0.02). CNTN4 protein was more frequently expressed in malignant than in benign PPGLs by immunohistochemistry (58% vs 17%; P = 0.002). Survival after 7 days of culture under starvation conditions was significantly enhanced in hPheo1 cells transfected with CNTN4 complementary DNA.ConclusionCNTN4 expression is consistently associated with malignant behavior in PPGLs.
      PubDate: Thu, 17 Aug 2017 00:00:00 GMT
  • Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal
           Variants in KCNJ11, HNF1A, GATA6, and LMNA
    • Authors: Sanyoura M; Jacobsen L, Carmody D, et al.
      Abstract: AbstractContextMonogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes.ObjectiveRetrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology.MethodsWe selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation−targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed.ResultsForty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates.ConclusionsFour cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.
      PubDate: Wed, 16 Aug 2017 00:00:00 GMT
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