Publications by authors named "Angela Delaney"

16 Publications

  • Page 1 of 1

Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants.

Genet Med 2021 Jan 13. Epub 2021 Jan 13.

Harvard Reproductive Sciences Center, The Reproductive Endocrine Unit and The Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.

Purpose: SOX10 variants previously implicated in Waardenburg syndrome (WS) have now been linked to Kallmann syndrome (KS), the anosmic form of idiopathic hypogonadotropic hypogonadism (IHH). We investigated whether SOX10-associated WS and IHH represent elements of a phenotypic continuum within a unifying disorder or if they represent phenotypically distinct allelic disorders.

Methods: Exome sequencing from 1,309 IHH subjects (KS: 632; normosmic idiopathic hypogonadotropic hypogonadism [nIIHH]: 677) were reviewed for SOX10 rare sequence variants (RSVs). The genotypic and phenotypic spectrum of SOX10-related IHH (this study and literature) and SOX10-related WS cases (literature) were reviewed and compared with SOX10-RSV spectrum in gnomAD population.

Results: Thirty-seven SOX10-associated IHH cases were identified as follows: current study: 16 KS; 4 nIHH; literature: 16 KS; 1 nIHH. Twenty-three IHH cases (62%; all KS), had ≥1 known WS-associated feature(s). Moreover, five previously reported SOX10-associated WS cases showed IHH-related features. Four SOX10 missense RSVs showed allelic overlap between IHH-ascertained and WS-ascertained cases. The SOX10-HMG domain showed an enrichment of RSVs in disease states versus gnomAD.

Conclusion: SOX10 variants contribute to both anosmic (KS) and normosmic (nIHH) forms of IHH. IHH and WS represent SOX10-associated developmental defects that lie along a unifying phenotypic continuum. The SOX10-HMG domain is critical for the pathogenesis of SOX10-related human disorders.
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http://dx.doi.org/10.1038/s41436-020-01051-3DOI Listing
January 2021

Kisspeptin deficiency leads to abnormal adrenal glands and excess steroid hormone secretion.

Hum Mol Genet 2020 Dec;29(20):3443-3450

Section on Endocrinology and Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), Bethesda, MD 20892, USA.

Knockout mice for the kisspeptin receptor, Kiss1r (Kiss1r-/-) and its ligand kisspeptin, Kiss1 (Kiss1-/-) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology in Kiss1-/- mice that do not go through normal puberty. Two fetal markers were expressed in eosinophilic cells potentially derived from the X-zone that should disappear at puberty in male mice and during the first pregnancy in female animals. Although the hypercorticosteronism observed in Kiss1-/- females corrected overtime, hyperaldosteronism persisted at 14 months and correlated with the overexpression of Star. To determine if KISS1 and KISS1R genes are involved in the development of primary aldosteronism (PA) and hypercortisolism [Cushing's syndrome (CS)] in humans, we sequenced these 2 genes in 65 patients with PA and/or CS. Interestingly, a patient with CS presented with a germline KISS1 variant (p.H90D, rs201073751). We also found three rare variants in the KISS1R gene in three patients with PA: p.C95W (rs141767649), p.A189T (rs73507527) and p.R229R (rs115335009). The two missense variants have been previously associated with IHH. Our findings suggest that KISS1 may play a role in adrenal function in mice and possibly adrenocortical steroid hormone secretion in humans, beyond its recently described role in human fetal adrenocortical development.
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http://dx.doi.org/10.1093/hmg/ddaa215DOI Listing
December 2020

Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women with Hypothalamic Amenorrhea.

J Clin Endocrinol Metab 2020 Sep 1. Epub 2020 Sep 1.

National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC.

Context: Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility.

Objective: We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls.

Design: We compared patients with HA to control women.

Setting: The study was conducted at secondary referral centers.

Patients And Other Participants: Women with HA (n=106) and control women (ClinSeq study; n=468).

Interventions: We performed exome sequencing in all patients and controls.

Main Outcome Measure(s): The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests.

Results: RSVs were overrepresented in women with HA compared with controls (P = 0.007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%).

Conclusions: Women with HA are enriched for RSVs in genes that cause IHH suggesting that variation in genes associated with GnRH neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise and/or stress.
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http://dx.doi.org/10.1210/clinem/dgaa609DOI Listing
September 2020

Pubertal timing predicts adult psychosexuality: Evidence from typically developing adults and adults with isolated GnRH deficiency.

Psychoneuroendocrinology 2020 09 6;119:104733. Epub 2020 Jun 6.

Department of Anthropology, Pennsylvania State University, Carpenter Building, University Park, PA, 16802, USA. Electronic address:

Evidence suggests that psychosexuality in humans is modulated by both organizational effects of prenatal and peripubertal sex steroid hormones, and by activational effects of circulating hormones in adulthood. Experimental work in male rodents indicates that sensitivity to androgen-driven organization of sexual motivation decreases across the pubertal window, such that earlier puberty leads to greater sex-typicality. We test this hypothesis in typically developing men (n = 231) and women (n = 648), and in men (n = 72) and women (n = 32) with isolated GnRH deficiency (IGD), in whom the precise timing of peripubertal hormone exposure can be ascertained via the age at which hormone replacement therapy (HRT) was initiated. Psychosexuality was measured with the Sexual Desire Inventory-2 (SDI-2) and Sociosexual Orientation Inventory-Revised (SOI-R). In both sexes, earlier recalled absolute pubertal timing predicted higher psychosexuality in adulthood, although the magnitude of these associations varied with psychosexuality type and group (i.e., typically developing and IGD). Results were robust when controlling for circulating steroid hormones in typically developing participants. Age of initiation of HRT in men with IGD negatively predicted SOI-R. We discuss the clinical implications of our findings for conditions in which pubertal timing is medically altered.
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http://dx.doi.org/10.1016/j.psyneuen.2020.104733DOI Listing
September 2020

Heterozygous Deletions in MKRN3 Cause Central Precocious Puberty Without Prader-Willi Syndrome.

J Clin Endocrinol Metab 2020 08;105(8)

Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland.

Context: Loss-of-function mutations in the imprinted genes MKRN3 and DLK1 cause central precocious puberty (CPP) but whole gene deletions have not been reported. Larger deletions of the chromosome 15q11-13 imprinted locus, including MKRN3, cause Prader-Willi syndrome (PWS). CPP has been reported in PWS but is not common, and the role of MKRN3 in PWS has not been fully elucidated.

Objective: To identify copy number variants in puberty-related, imprinted genes to determine their role in CPP.

Methods: Probands with idiopathic CPP had chromosomal microarray (CMA) and targeted deletion/duplication testing for MKRN3 and DLK1.

Results: Sixteen female probands without MKRN3 or DLK1 variants identified by Sanger sequencing were studied. Whole gene deletions of MKRN3 were identified in 2 subjects (13%): a complete deletion of MKRN3 in Patient A (pubertal onset at 7 years) and a larger deletion involving MAGEL2, MKRN3, and NDN in Patient B (pubertal onset 5.5 years). Both were paternally inherited. Patient B had no typical features of PWS, other than obesity, which was also present in her unaffected family.

Conclusions: We identified 2 cases of whole gene deletions of MKRN3 causing isolated CPP without PWS. This is the first report of complete deletions of MKRN3 in patients with CPP, emphasizing the importance of including copy number variant analysis for MKRN3 mutation testing when a genetic diagnosis is suspected. We speculate that there is a critical region of the PWS locus beyond MKRN3, MAGEL2, and NDN that is responsible for the PWS phenotype.
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http://dx.doi.org/10.1210/clinem/dgaa331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324050PMC
August 2020

DLG2 variants in patients with pubertal disorders.

Genet Med 2020 Aug 28;22(8):1329-1337. Epub 2020 Apr 28.

Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Purpose: Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions.

Methods: Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH.

Results: We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH.

Conclusion: The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.
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http://dx.doi.org/10.1038/s41436-020-0803-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510947PMC
August 2020

Timing of peripubertal steroid exposure predicts visuospatial cognition in men: Evidence from three samples.

Horm Behav 2020 05 18;121:104712. Epub 2020 Feb 18.

Department of Anthropology, Pennsylvania State University, Carpenter Building, University Park, PA 16802, USA. Electronic address:

Experiments in male rodents demonstrate that sensitivity to the organizational effects of steroid hormones decreases across the pubertal window, with earlier androgen exposure leading to greater masculinization of the brain and behavior. Similarly, some research suggests the timing of peripubertal exposure to sex steroids influences aspects of human psychology, including visuospatial cognition. However, prior studies have been limited by small samples and/or imprecise measures of pubertal timing. We conducted 4 studies to clarify whether the timing of peripubertal hormone exposure predicts performance on male-typed tests of spatial cognition in adulthood. In Studies 1 (n = 1095) and 2 (n = 173), we investigated associations between recalled pubertal age and spatial cognition in typically developing men, controlling for current testosterone levels in Study 2. In Study 3 (n = 51), we examined the relationship between spatial performance and the age at which peripubertal hormone replacement therapy was initiated in a sample of men with Isolated GnRH Deficiency. Across Studies 1-3, effect size estimates for the relationship between spatial performance and pubertal timing ranged from. -0.04 and -0.27, and spatial performance was unrelated to salivary testosterone in Study 2. In Study 4, we conducted two meta-analyses of Studies 1-3 and four previously published studies. The first meta-analysis was conducted on correlations between spatial performance and measures of the absolute age of pubertal timing, and the second replaced those correlations with correlations between spatial performance and measures of relative pubertal timing where available. Point estimates for correlations between pubertal timing and spatial cognition were -0.15 and -0.12 (both p < 0.001) in the first and second meta-analyses, respectively. These associations were robust to the exclusion of any individual study. Our results suggest that, for some aspects of neural development, sensitivity to gonadal hormones declines across puberty, with earlier pubertal hormone exposure predicting greater sex-typicality in psychological phenotypes in adulthood. These results shed light on the processes of behavioral and brain organization and have implications for the treatment of IGD and other conditions wherein pubertal timing is pharmacologically manipulated.
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http://dx.doi.org/10.1016/j.yhbeh.2020.104712DOI Listing
May 2020

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

J Clin Endocrinol Metab 2020 05;105(5)

Clinical Research Branch, National Institute of Environmental Health Sciences, Durham, North Carolina.

Context: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.

Objective: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.

Methods: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.

Results: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient.

Conclusions: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.
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http://dx.doi.org/10.1210/clinem/dgaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108682PMC
May 2020

Evaluating the impact of national education in pediatric palliative care: the Quality of Care Collaborative Australia.

Adv Med Educ Pract 2018 14;9:927-941. Epub 2018 Dec 14.

Western Australia Paediatric Palliative Care Service, Perth Children's Hospital, Perth, WA, Australia.

Purpose: The Quality of Care Collaborative Australia (QuoCCA) provided pediatric palliative care education across Australia with the aim of improving the quality of services. The education was delivered through a collaboration of six tertiary pediatric palliative care services, through funding for Nurse Educators, Medical Fellows, a National Allied Health Educator, and national project staff.

Methods: Pre- and post-education surveys were completed by participants immediately following the education, and confidence and knowledge were measured along nine domains related to the care of the child and family, including managing a new referral, symptom management, medications, preparing the family, and using local agencies.

Results: Education was provided to over 5,500 health and human service professionals in 337 education sessions across Australia between May 2015 and June 2017. Paired pre- and post-surveys were completed by 969 participants and showed a significant improvement in all the domains measured. Those with no experience in caring for children receiving palliative care showed greater improvement following QuoCCA education compared to those with experience, although the latter had higher scores both before and after education. Similarly, those with no previous education showed greater improvement, but those with previous education showed higher scores overall. Participants in full-day and half-day sessions showed greater improvement than those in short day sessions. Thus, the dosage of education in the length of the sessions and prior attendance impacted knowledge and confidence. Topics requested by the participants were analyzed. Educator learnings were that education was more effective when tailored to the needs of the audience, was interactive, and included story-telling, case studies, and parent experiences.

Conclusion: These results encouraged the continuation of the provision of education to novice and experienced professionals who care for children with a life-limiting condition, leading to higher levels of confidence and knowledge. The learnings from this evaluation will be transferred into the second round of funding for the national QuoCCA education project. The next stage will focus on developing simulation and interactive training, accessible training modules, and videos on a national website.
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http://dx.doi.org/10.2147/AMEP.S180526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298873PMC
December 2018

Assessing Sex Steroid Influence on Kisspeptin Responsiveness in Idiopathic Hypogonadotropic Hypogonadism.

J Endocr Soc 2018 Nov 20;2(11):1293-1305. Epub 2018 Sep 20.

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts.

Context: Individuals with idiopathic hypogonadotropic hypogonadism (IHH), even those with evidence of some hypothalamic reproductive endocrine activity, fail to complete puberty and fail to respond to physiologic doses of kisspeptin.

Objective: This case series examined whether treatment with sex steroids could stimulate kisspeptin responsiveness in patients with IHH.

Design: This was a case series.

Setting: This study was conducted at an academic medical center.

Participants: Seven patients with IHH were studied.

Interventions: Participants, both on and off sex steroid therapy, underwent frequent blood sampling to measure LH at baseline, in response to kisspeptin and GnRH.

Main Outcome Measures: The main outcome measure was LH responses to kisspeptin on and off sex steroids.

Results: All participants responded to exogenous GnRH, but no participant responded to exogenous kisspeptin. Sex steroid treatment did not modify responsiveness to kisspeptin.

Conclusions: The functional impairment of the GnRH neuronal network in patients with IHH, as evidenced by their inability to respond to a physiologic dose of kisspeptin, is observed in both sex steroid- deficient and sex steroid-replete states. In this case series, a normalized sex steroid milieu does not appear capable of overcoming the kisspeptin resistance of these patients.
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http://dx.doi.org/10.1210/js.2018-00183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223246PMC
November 2018

Kisspeptin Responsiveness Signals Emergence of Reproductive Endocrine Activity: Implications for Human Puberty.

J Clin Endocrinol Metab 2016 08 23;101(8):3061-9. Epub 2016 May 23.

Harvard Reproductive Sciences Center and Reproductive Endocrine Unit (M.F.L., Y.-M.C., D.R.-M., S.B.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology (Y.-M.C.), Department of Medicine, Boston Children's Hospital, and Division of Sleep Medicine (J.P.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Unit on Genetics of Puberty and Reproduction (A.D.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland 20892.

Context: Some patients with idiopathic hypogonadotropic hypogonadism (IHH) undergo spontaneous activation of their hypothalamic-pituitary-gonadal axis resulting in normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal.

Objective: To assess the responsiveness of the GnRH neuronal network to exogenous kisspeptin administration in IHH patients who have undergone reversal.

Participants: Six men with congenital IHH and evidence for reversal.

Intervention: Subjects underwent q10 min blood sampling to measure GnRH-induced LH secretion at baseline and in response to iv boluses of kisspeptin (0.24-2.4 nmol/kg) and GnRH (75 ng/kg).

Results: Individuals with sustained reversal of their hypogonadotropism (spontaneous LH pulses) responded to exogenous kisspeptin with a GnRH-induced LH pulse. Individuals who had reversal but then subsequently suffered relapse of their IHH (loss of spontaneous LH pulsatility) did not respond to kisspeptin.

Conclusions: The ability of kisspeptin to stimulate a GnRH-induced LH pulse correlates with the presence of endogenous LH pulses. These data suggest that reversal of hypogonadotropism, and by extension sexual maturation, may be due to the acquisition of kisspeptin responsiveness.
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http://dx.doi.org/10.1210/jc.2016-1545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971332PMC
August 2016

Expression profile of heat shock response factors during hookworm larval activation and parasitic development.

Mol Biochem Parasitol 2015 Jul 18;202(1):1-14. Epub 2015 Aug 18.

Research Center for Neglected Diseases of Poverty, Department of Microbiology, Immunology and Tropical Medicine, George Washington University Medical Center, Washington, District of Columbia, United States. Electronic address:

When organisms are exposed to an increase in temperature, they undergo a heat shock response (HSR) regulated by the transcription factor heat shock factor 1 (HSF-1). The heat shock response includes the rapid changes in gene expression initiated by binding of HSF-1 to response elements in the promoters of heat shock genes. Heat shock proteins function as molecular chaperones to protect proteins during periods of elevated temperature and other stress. During infection, hookworm infective third stage larvae (L3) undergo a temperature shift from ambient to host temperature. This increased temperature is required for the resumption of feeding and activation of L3, but whether this increase initiates a heat shock response is unknown. To investigate the role of the heat shock in hookworm L3 activation and parasitic development, we identified and characterized the expression profile of several components of the heat shock response in the hookworm Ancylostoma caninum. We cloned DNAs encoding an hsp70 family member (Aca-hsp-1) and an hsp90 family member (Aca-daf-21). Exposure to a heat shock of 42°C for one hour caused significant up-regulation of both genes, which slowly returned to near baseline levels following one hour attenuation at 22°C. Neither gene was up-regulated in response to host temperature (37°C). Conversely, levels of hsf-1 remained unchanged during heat shock, but increased in response to incubation at 37°C. During activation, both hsp-1 and daf-21 are down regulated early, although daf-21 levels increase significantly in non-activated control larvae after 12h, and slightly in activated larvae by 24h incubation. The heat shock response modulators celastrol and KNK437 were tested for their effects on gene expression during heat shock and activation. Pre-incubation with celastrol, an HSP90 inhibitor that promotes heat shock gene expression, slightly up-regulated expression of both hsp-1 and daf-21 during heat shock. KNK437, an inhibitor of heat shock protein expression, slightly down regulated both genes under similar conditions. Both modulators inhibited activation-associated feeding, but neither had an effect on hsp-1 levels in activated L3 at 16h. Both celastrol and KNK437 prevent the up-regulation of daf-21 and hsf-1 seen in non-activated control larvae during activation, and significantly down regulated expression of the HSF-1 negative regulator Aca-hsb-1 in activated larvae. Expression levels of heat shock response factors were examined in developing Ancylostoma ceylanicum larvae recovered from infected hosts and found to differ significantly from the expression profile of activated L3, suggesting that feeding during in vitro activation is regulated differently than parasitic development. Our results indicate that a classical heat shock response is not induced at host temperature and is suppressed during larval recovery and parasitic development in the host, but a partial heat shock response is induced after extended incubation at host temperature in the absence of a developmental signal, possibly to protect against heat stress.
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http://dx.doi.org/10.1016/j.molbiopara.2015.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605861PMC
July 2015

Evolutionary conservation and modulation of a juvenile growth-regulating genetic program.

J Mol Endocrinol 2014 Jun 28;52(3):269-77. Epub 2014 Apr 28.

Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development Microarray Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, MSC-1103; Building 10, Room 1-3330, Bethesda, Maryland 20892, USA Department of Pediatrics and the Reproductive Sciences Program, The University of Michigan, Ann Arbor, Michigan, USA.

Body size varies enormously among mammalian species. In small mammals, body growth is typically suppressed rapidly, within weeks, whereas in large mammals, growth is suppressed slowly, over years, allowing for a greater adult size. We recently reported evidence that body growth suppression in rodents is caused in part by a juvenile genetic program that occurs in multiple tissues simultaneously and involves the downregulation of a large set of growth-promoting genes. We hypothesized that this genetic program is conserved in large mammals but that its time course is evolutionarily modulated such that it plays out more slowly, allowing for more prolonged growth. Consistent with this hypothesis, using expression microarray analysis, we identified a set of genes that are downregulated with age in both juvenile sheep kidney and lung. This overlapping gene set was enriched for genes involved in cell proliferation and growth and showed striking similarity to a set of genes downregulated with age in multiple organs of the juvenile mouse and rat, indicating that the multiorgan juvenile genetic program previously described in rodents has been conserved in the 80 million years since sheep and rodents diverged in evolution. Using microarray and real-time PCR, we found that the pace of this program was most rapid in mice, more gradual in rats, and most gradual in sheep. These findings support the hypothesis that a growth-regulating genetic program is conserved among mammalian species but that its pace is modulated to allow more prolonged growth and therefore greater adult body size in larger mammals.
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http://dx.doi.org/10.1530/JME-13-0263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051439PMC
June 2014

Pitfalls in the measurement of the nocturnal blood pressure dip in adolescents with type 1 diabetes.

Diabetes Care 2009 Jan 4;32(1):165-8. Epub 2008 Nov 4.

Division of Pediatric Endocrinology, Schneider Children's Hospital, North-Shore Long Island Jewish Health System, New Hyde Park, New York, USA.

Objective: The purpose of this study was to screen adolescents with type 1 diabetes using ambulatory blood pressure monitoring (ABPM) to 1) test the hypothesis that using a preset sleep time results in an overdiagnosis of abnormal nocturnal dipping in systolic blood pressure and 2) assess the reproducibility of an abnormal nocturnal systolic blood pressure dip.

Research Design And Methods: For aim 1, ABPM from 53 adolescent patients with type 1 diabetes was reviewed. Nocturnal dips in systolic blood pressure calculated by actual sleep time were compared with those from a preset sleep time. For aim 2, blood pressure monitoring from 98 patients using actual reported sleep time was reviewed. Reproducibility of the nocturnal dip in systolic blood pressure was assessed in a subset of "nondippers."

Results: For aim 1, the actual mean +/- SE decline in nocturnal systolic blood pressure was 11.6 +/- 4.7%, whereas the mean decline in nocturnal systolic blood pressure calculated using the preset sleep time was 8.8 +/- 4.9% (P < 0.0001). For aim 2, 64% of patients had a normal nocturnal decline in systolic blood pressure (14.9 +/- 3.1% mmHg), whereas 36% had an abnormal dip (5.7 +/- 2.8% mmHg). Repeat ABPM performed in 22 of the 35 nondippers revealed that only 36% had abnormal systolic dipping confirmed on the repeat ABPM.

Conclusions: The use of actual reported sleep time is required to accurately determine the nocturnal dip in systolic blood pressure. Repeating ABPM in nondippers is essential to confirm this abnormality.
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http://dx.doi.org/10.2337/dc08-1319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2606854PMC
January 2009

Cloning and characterisation of an aspartyl protease inhibitor (API-1) from Ancylostoma hookworms.

Int J Parasitol 2005 Mar 8;35(3):303-13. Epub 2005 Jan 8.

Department of Microbiology and Tropical Medicine, The George Washington University Medical Center, 725 Ross Hall, 2300 Eye Street North West, Washington, DC 20037, USA.

Hookworm infection persists as a public health problem in developing nations. Vaccine-based strategies offer the best chance of long-term control. Aspartyl protease inhibitors from parasitic nematodes are highly immunogenic, and have been suggested as potential vaccine antigens. An aspartyl protease inhibitor, API-1, was cloned and characterised from the hookworms Ancylostoma caninum and Ancylostoma ceylanicum. Using sequence from the hookworm expressed sequence tag project, specific primers were designed and used to amplify Ac-api-1 from A. caninum infective L3 cDNA by PCR. Amplicons from the 5' and 3' ends were cloned, sequenced, and combined to create an 874-bp full-length composite sequence of the Ac-api-1 gene. The A. ceylanicum api-1 cDNA of 878 bp was cloned from L3 cDNA using the A. caninum primers. The amino acid sequences of hookworm orthologues were nearly identical, and database searching indicated they belonged to the aspin family, a group of nematode specific aspartyl protease inhibitors that includes the Ascaris pepsin inhibitor PI-3. Ac-api-1 mRNA was detected by reverse transcriptase PCR in eggs, L1, L3 and adult life cycle stages. A polyclonal antiserum against Escherichia coli expressed recombinant Ac-API-1 detected the protein in adult A. caninum excretory/secretory products, but not in those from activated infective larvae. Immunolocalisation experiments using the antiserum indicated that Ac-API-1 is present primarily in the pseudocoelomic fluid in adult hookworms. Soluble, yeast-expressed Ac-API-1 failed to inhibit pepsin or a hookworm gut aspartyl protease in vitro, but inhibited approximately 30% of the proteolytic activity of adult excretory/secretory products. The pseudocoleomic location, presence in all life cycle stages, lack of inhibitory activity against pepsin, and inhibitory activity against excretory/secretory products suggest that Ac-API-1 inhibits an unidentified, putative aspartyl protease secreted by adult hookworms, and may be released as an enzyme-inhibitor complex. The highly immunogenic properties of nematode aspins suggest that Ac-API-1 represents a promising target for a recombinant hookworm vaccine.
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http://dx.doi.org/10.1016/j.ijpara.2004.11.014DOI Listing
March 2005

Effect of vaccinations with recombinant fusion proteins on Ancylostoma caninum habitat selection in the canine intestine.

J Parasitol 2002 Aug;88(4):684-90

Department of Microbiology and Tropical Medicine, Sabin Vaccine Institute, George Washington University Medical Center, 2300 Eye Street NW, Washington, D.C. 20037, USA.

Laboratory dogs were vaccinated subcutaneously with 3 different recombinant fusion proteins, each precipitated with alum or calcium phosphate. The vaccinated dogs were then challenged orally with 400 third-stage infective larvae (L3) of the canine hookworm, Ancylostoma caninum. The 3 A. caninum antigens selected were Ac-TMP, an adult-specific secreted tissue inhibitor of metalloproteases; Ac-AP, an adult-specific secreted factor Xa serine protease inhibitor anticoagulant; and Ac-ARR-1, a cathepsin D-like aspartic protease. Each of the 3 groups comprised 6 male beagles (8 +/- 1 wk of age). A fourth group comprised control dogs injected with alum. All of the dogs vaccinated with Ac-TMP or Ac-APR-1 exhibited a vigorous antigen-specific antibody response, whereas only a single dog vaccinated with Ac-AP developed an antibody response. Dogs with circulating antibody responses exhibited 4.5-18% reduction in the numbers of adult hookworms recovered from the small intestines at necropsy, relative to alum-injected dogs. In contrast, there was a concomitant increase in the number of adult hookworms recovered from the colon. The increase in colonic hookworms was as high as 500%, relative to alum-injected dogs. Female adult hookworms were more likely to migrate into the colon than were males. Anti-enzyme and anti-enzyme inhibitor antibodies correlated with an alteration in adult hookworm habitat selection in the canine gastroinntestinal tract.
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http://dx.doi.org/10.1645/0022-3395(2002)088[0684:EOVWRF]2.0.CO;2DOI Listing
August 2002