Diagnosis of growth hormone deficiency in childhood. On behalf of the Growth Hormone Research Society.
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Child↗
Biomedical subjects
P Cohen
Publications and source records attributed to P Cohen.
New paradigms for growth hormone therapy in children.
Much has been learned over the last two decades regarding the management of growth hormone (GH) deficiency (GHD) in children and adolescents. However, significant divergence and debate continue to exist on the ideal approach to the management of GHD. Despite active controversy, several paradigms have recently emerged which should guide the treatment of GHD patients as we head into the new millennium. The primary objectives of GH therapy remain the normalization of height in childhood and the attainment of normal adult height, but the recognition of the metabolic roles of GH define additional therapeutic benefits. A daily subcutaneous injection of recombinant human GH in a dose range of 25-50 microg/kg/day has been established as the mainstay of therapy. Alternative modes of treatment including GH-releasing hormone (GHRH), GH secretagogues and depot GH have been developed, but evaluation of their clinical utility remains incomplete. Careful monitoring and follow-up of pediatric GHD patients by a pediatric endocrinologist are essential. Accurate determination of height velocity and interval height increases (expressed as the change in height z score) continue to be the most important parameters in monitoring the response to treatment. Monitoring serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 has gained utility in the assurance of compliance and safety, but does not always correlate well with the growth response. A clear role for a biochemical as well as an auxological monitoring approach has nonetheless been established. The comparison of attained growth response to that which has been calculated by various modeling approaches is also becoming a valuable monitoring tool. Significant side effects of GH therapy are quite rare and are easily identified and addressed during close follow-up. Despite previous concerns, it now appears that in the absence of additional risk factors there is no evidence that long-term recipients of GH are at any increased risk of developing diabetes, slipped capital femoral epiphysis, brain tumor recurrence or leukemia. Although GHD may or may not persist into adult life, adult GHD diagnostic criteria and the importance of GH therapy in adult GHD patients have recently been established. Therefore, the pediatric endocrinologist now has a crucial role in guiding the transition to adult GHD management in collaboration with the adult endocrinologist. In the years to come, with the continued investigation and collaborationof experts from around the world, the approach to GH treatment will undoubtedly continue to evolve and improve.
Adult↗
Insulin-like growth factor binding protein-6 inhibits the growth of human bronchial epithelial cells and increases in abundance with all-trans-retinoic acid treatment.
Retinoids are potent inhibitors of human bronchial epithelial (HBE) cell growth. Retinoids initiate signaling through activation of nuclear receptors, but the signal transduction pathways that mediate growth inhibition have not been defined. In this study, we investigated the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-6 as a potential mediator of retinoid actions. IGFBP-6 is a secreted glycoprotein that inhibits the bioavailability of IGFs, which are potent mitogens of HBE cells. IGFBP-6 was detected by immunohistochemical staining in the basal epithelial layer of human bronchial organ cultures, and all-trans-retinoic acid (t-RA) treatment increased the intensity of IGFBP-6 immunostaining. In primary cultures of HBE cells treated with t-RA, IGFBP-6 messenger RNA and protein levels increased within 6 and 24 h, respectively, and IGFBP-6 was detected in the conditioned media at 48 h. The effect of IGFBP-6 on HBE cell growth was investigated with a recombinant adenoviral vector, Ad5CMV-BP6, which expresses IGFBP-6 under the control of a cytomegalovirus promoter. IGFBP-6 overexpression induced a proliferative arrest of HBE cells with no evidence of apoptosis. These findings provide the first evidence that IGFBP-6 is expressed in the bronchial epithelium and that IGFBP-6 may contribute to the biologic effects of retinoids on HBE cells.
Adenoviridae↗
Associations between bipolar disorder and other psychiatric disorders during adolescence and early adulthood: a community-based longitudinal investigation.
OBJECTIVE: The study investigated cross-sectional and longitudinal associations between bipolar disorder and other psychiatric disorders during adolescence and early adulthood. METHOD: Psychiatric interviews were administered to a representative community sample of 717 youths and their mothers in 1983 (mean age of youths=14 years) and again in 1985-1986, and 1991-1993. RESULTS: A wide range of psychiatric disorders co-occurred with bipolar disorder during adolescence and early adulthood. Adolescent anxiety disorders were uniquely associated with increased risk for early adulthood bipolar disorder after adolescent bipolar disorder was accounted for. Manic symptoms during adolescence were associated with increased risk for anxiety and depressive disorders during early adulthood after adolescent anxiety and depressive disorders were accounted for. CONCLUSIONS: Adolescents with anxiety disorders may be at increased risk for bipolar disorder or clinically significant manic symptoms during early adulthood. Adolescents with manic symptoms may be at increased risk for anxiety and depressive disorders during early adulthood.
Adolescent↗
Nonaffective psychosis after prenatal exposure to rubella.
OBJECTIVE: The authors' goal was to investigate the suggestion of previous investigations that prenatal viral exposures might increase the later risk of psychotic disorders. METHOD: They conducted a follow-up study in young adulthood of a birth cohort that was previously documented, by clinical examination and serological testing, to have in utero rubella exposure during the 1964 rubella epidemic. Data were also obtained from an unexposed birth cohort and from the Epidemiological Catchment Area survey. Young adult subjects were administered a standard psychiatric diagnostic interview. The authors compared the proportions of subjects with nonaffective psychosis in the exposed and unexposed cohorts. RESULTS: The rubella-exposed subjects, most of whom were exposed in the first trimester, demonstrated a substantially greater risk for nonaffective psychosis than the subjects who were not exposed to rubella (relative risk=5.2). CONCLUSIONS: There is an association between clinically and serologically diagnosed prenatal viral infection and nonaffective psychosis in adulthood.
Adult↗
Adolescent personality disorders associated with violence and criminal behavior during adolescence and early adulthood.
OBJECTIVE: A community-based, longitudinal prospective study was conducted to investigate whether personality disorders during adolescence are associated with elevated risk for violent behavior during adolescence and early adulthood. METHOD: A community-based sample of 717 youths from upstate New York and their mothers were interviewed in 1983, 1985-1986, and 1991-1993. Axis I and II disorders were assessed in 1983 and 1985-1986. Antisocial personality disorder was not assessed because most participants were less than 18 years of age in 1983 and 1985-1986. Violent behavior was assessed in 1985-1986 and 1991-1993. RESULTS: Adolescents with a greater number of DSM-IV cluster A or cluster B personality disorder symptoms were more likely than other adolescents in the community to commit violent acts during adolescence and early adulthood, including arson, assault, breaking and entering, initiating physical fights, robbery, and threats to injure others. These associations remained significant after controlling for the youths' age and sex, for parental psychopathology and socioeconomic status, and for co-occurring psychiatric disorders during adolescence. Paranoid, narcissistic, and passive-aggressive personality disorder symptoms during adolescence were independently associated with risk for violent acts and criminal behavior during adolescence and early adulthood after the covariates were controlled. CONCLUSIONS: Cluster A and cluster B personality disorders and paranoid, narcissistic, and passive-aggressive personality disorder symptoms during adolescence may increase risk for violent behavior that persists into early adulthood.
Adolescent↗
Genetics, chemistry, and function of the IGF/IGFBP system.
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Acromegaly↗
Role of insulin-like growth factor monitoring in optimizing growth hormone therapy.
Much has been learned over the past two decades regarding the management of growth hormone (GH) deficiency in children and adolescents. Current GH therapy under ideal circumstances enables children to attain a final height within the normal range and close to their target height. However, such a successful outcome is not always achieved and the necessity to individualize treatment according to the specific needs of each GH-deficient child is now well recognized. Consensus does not currently exist as to how to formulate individualized treatment plans. Nonetheless, a clear role for a biochemical, as well as an auxological, monitoring approach has been established. Accurate determinations of height velocity and interval height increase (expressed as the change in height Z-score) continue to be the most important parameters in monitoring the response to treatment. The importance of routinely monitoring serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 is an emerging paradigm. Firm roles have been established for this approach in the assurance of compliance and safety (particularly to avoid long-term theoretical risks). IGF monitoring also has important potential utility as a tool to assess and optimize the response to GH therapy through dose adjustments. In years to come, we expect the development of multiple GH treatment optimization strategies, including approaches such as prediction modeling, as well as serum IGF monitoring and dose adjustments, to evolve and improve.
Body Height↗
Associations between four types of childhood neglect and personality disorder symptoms during adolescence and early adulthood: findings of a community-based longitudinal study.
Data from a community-based longitudinal study were used to investigate the association between childhood neglect and personality disorder (PD) symptom levels during adolescence and early adulthood. Psychosocial and psychiatric interviews were administered to a representative sample of 738 youths and their mothers from upstate New York in 1975, 1983, 1985-1986, and 1991-1993. Evidence of childhood cognitive, emotional, physical, and supervision neglect was obtained from the maternal interviews that were conducted in 1975, 1983, and 1985-1986, and from New York State records. PDs were assessed among the youths in 1985-1986, when they were adolescents, and in 1991-1993, when they were young adults. Findings indicated that childhood emotional, physical, and supervision neglect were associated with increased risk for PDs and with elevated PD symptom levels during adolescence and early adulthood, after age, sex, childhood physical or sexual abuse, other types of childhood neglect, and cooccurring PD symptoms were controlled statistically. Childhood emotional neglect was associated with increased risk for avoidant PD and with paranoid and Cluster A PD symptom levels during adolescence and early adulthood. Childhood physical neglect was associated with increased risk for schizotypal PD and with Cluster A PD symptom levels during adolescence and early adulthood. Childhood supervision neglect was associated with increased risk for passive-aggressive and Cluster B PDs and with borderline, paranoid, and passive-aggressive PD symptom levels during adolescence and early adulthood. The present findings suggest that childhood emotional, physical, and supervision neglect may play a role in the etiology of some PDs.
Adolescent↗
Transforming growth factor-beta induces growth inhibition and IGF-binding protein-3 production in prostatic stromal cells: abnormalities in cells cultured from benign prostatic hyperplasia tissues.
The IGF axis has been implicated in the pathogenesis of benign prostatic hyperplasia (BPH) via the paracrine action of IGFs and IGF-binding proteins (IGFBPs). In this study, we examined the regulation of cell growth and IGFBP-3 secretion by transforming growth factor-beta (TGF-beta) in prostatic stromal cell (PC-S) cultures from histologically normal tissues and tissues from BPH. PC-S cultures were treated with varying doses of TGF-beta1. Forty-eight hour conditioned media (CM) from these cultures were subjected to Western immunoblotting and ligand blotting for detection and quantification of IGFBPs. IGFBPs-2, -3 and -4 were detected in the CM from normal PC-S cultures. In CM from BPH PC-S, IGFBP-3 levels were 2-fold lower at baseline than in the normal PC-S CM, in addition to the differences in IGFBPs-2 and -5 which we have previously reported. In response to TGF-beta1, a 15-fold increase in the levels of IGFBP-3 was observed in normal PC-S CM, while a mere 2-fold increase was observed in BPH PC-S CM (P<0.001). These findings were confirmed by specific immunoblotting and immunocytochemistry. IGFBP-3 mRNA levels detected by Northern blotting of total RNA extracted from similar cultures showed the induction of IGFBP-3 expression by TGF-beta1 in normal PC-S and its lack of induction in BPH PC-S. Cell growth inhibition in response to TGF-beta1 correlated with the IGFBP-3 concentrations found in CM. Normal PC-S showed a 60% decrease in cell number after 10 days in media with 1 ng/ml TGF-beta1, compared with the untreated control. The decrease in proliferation observed in comparably treated BPH cells was only 20% (P<0.001). In conclusion, BPH PC-S had a reduced IGFBP-3 response to TGF-beta1 and demonstrated decreased TGF-beta1-induced growth inhibition relative to normal PC-S. We hypothesize that in normal PC-S, TGF-beta exerts its anti-proliferative effects by stimulating the production of IGFBP-3, which acts as an inhibitory factor, either by inhibiting IGFs or directly by interacting with cells, and that this process is altered in BPH PC-S.
Blotting, Western↗
Cancer risk estimates for family members of a population-based family registry for breast and ovarian cancer.
Population-based breast and ovarian cancer family registries can facilitate studies to evaluate genetic and environmental factors in the etiology of these malignancies. The purpose of this study is to describe what is, as far as we know, the first population-based breast and ovarian cancer family registry and to estimate breast and ovarian cancer risk in relatives of breast and ovarian cancer probands. Population-based consecutive incident cases of breast and ovarian cancer were invited to participate in the University of California, Irvine breast and ovarian family registry. In this study, we report data on 1567 breast cancer and 328 ovarian cancer probands. The operational components of this family registry include enrollment of probands, family history interviewing, confidentiality, pathology, verification and review, biospecimen bank, statistical/genetic analysis, and special studies on positional cloning of known genes. All of the components are tracked through the University of California, Irvine Genetic Research Information System. In non-Hispanic-white breast cancer probands, relative risk (RR) of breast cancer in mothers and sisters is significantly elevated [RR = 1.7 and 95% confidence interval (CI) = 1.4-2.0 and RR = 2.8 and 95% CI = 2.3-3.3, respectively]. In families of ovarian cancer probands, mothers are at increased risk of ovarian cancer (RR = 4.6; 95% CI, 2.1-8.7). RR of breast cancer in mothers of Hispanic breast cancer probands is significantly elevated (RR = 4.9; 95% CI, 2.6-8.5). No elevation of breast or ovarian cancer risk was observed among relatives of Asian probands. In general, there is a decrease in RR among mothers and sisters with increase in age of onset of probands. In second-degree relatives and first cousins, the breast cancer hazards ratios increase with increase in the number of affected first-degree relatives and decrease with increase in age at onset of the proband.
Adult↗
[Polyarteritis nodosa: clinical, prognostic and therapeutic features].
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Adult↗
How to optimize the treatment of systemic vasculitides.
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Humans↗
Whose rights are they anyway?
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Genetic Research↗
Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway.
STAT1 is an essential transcription factor for macrophage activation by IFN-gamma and requires phosphorylation of the C-terminal Ser727 for transcriptional activity. In macrophages, Ser727 phosphorylation in response to bacterial lipopolysaccharide (LPS), UV irradiation, or TNF-alpha occurred through a signaling path sensitive to the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 whereas IFN-gamma-mediated Ser727 phosphorylation was not inhibited by the drug. Consistently, SB203580 did not affect IFN-gamma-mediated, Stat1-dependent transcription but inhibited its enhancement by LPS. Furthermore, LPS, UV irradiation, and TNF-alpha caused activation of p38 MAPK whereas IFN-gamma did not. An essential role for p38 MAPK activity in STAT1 Ser727 phosphorylation was confirmed by using cells expressing an SB203580-resistant p38 MAPK. In such cells, STAT1 Ser727 phosphorylation in response to UV irradiation was found to be SB203580 insensitive. Targeted disruption of the mapkap-k2 gene, encoding a kinase downstream of p38 MAPK with a key role in LPS-stimulated TNF-alpha production and stress-induced heat shock protein 25 phosphorylation, was without a significant effect on UV-mediated Ser727 phosphorylation. The recombinant Stat1 C terminus was phosphorylated in vitro by p38MAPKalpha and beta but not by MAPK-activated protein kinase 2. Janus kinase 2 activity, previously reported to be required for IFN-gamma-mediated Ser727 phosphorylation, was not needed for LPS-mediated Ser727 phosphorylation, and activation of Janus kinase 2 did not cause the appearance of STAT1 Ser727 kinase activity. Our data suggest that STAT1 is phosphorylated at Ser727 by a stress-activated signaling pathway either through p38 MAPK directly or through an unidentified kinase downstream of p38MAPK.
Animals↗
Alternative splicing regulates the production of ARD-1 endoribonuclease and NIPP-1, an inhibitor of protein phosphatase-1, as isoforms encoded by the same gene.
ARD-1 is an endoribonuclease identified initially as the product of a human cDNA that complements mutations in rne, a gene that encodes Escherichia coli ribonuclease E. NIPP-1 was identified in bovine nuclear extracts as an inhibitor of protein phosphatase-1. Earlier work has shown that the protein-coding sequence of ARD-1 is identical to the carboxy-terminal third of NIPP-1. However, whether ARD-1 is present in eukaryotes as a distinct entity has been unclear, as neither ARD-1-specific transcripts nor ARD-1 protein were detected in mammalian cells in earlier studies. Here we show that ARD-1 exists in human cells as a discrete protein, and that the ARD-1 and NIPP-1 peptides are isoforms encoded by a single gene and the same alternatively spliced precursor RNA. A retained intron containing multiple translation stop codons that are configured to terminate translation and initiate nonsense-mediated decay, limits the production of cellular ARD-1 protein. Our results establish the process by which functionally disparate ARD-1 and NIPP-1 peptides are generated from the protein-coding sequence of the same gene in human cells.
Alternative Splicing↗
Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase.
The catalytic domain of serum- and glucocorticoid-induced protein kinase (SGK) is 54% identical with protein kinase B (PKB) and, like PKB, is activated in vitro by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and in vivo in response to signals that activate phosphatidylinositol (PI) 3-kinase. Here we identify two novel isoforms of SGK, termed SGK2 and SGK3, whose catalytic domains share 80% amino acid sequence identity with each other and with SGK (renamed SGK1). Like SGK1, the mRNA encoding SGK3 is expressed in all tissues examined, but SGK2 mRNA is only present at significant levels in liver, kidney and pancreas and, at lower levels, in the brain. The levels of SGK2 mRNA in H4IIE cells and SGK3 mRNA in Rat2 fibroblasts are not increased by stimulation with serum or dexamethasone, whereas the level of SGK1 mRNA is increased greatly. SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively, the residues equivalent to the Thr in the 'activation loop' of PKB that is targeted by PDK1. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB. Like SGK1, SGK2 and SGK3 are activated 5-fold via a phosphorylation mechanism when cells are exposed to H(2)O(2) but, in contrast with SGK1, activation is only suppressed partially by inhibitors of PI 3-kinase. SGK2 and SGK3 are activated to a smaller extent by insulin-like growth factor-1 (2-fold) than SGK1 (5-fold). Like PKB and SGK1, SGK2 and SGK3 preferentially phosphorylate Ser and Thr residues that lie in Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr motifs.
Amino Acid Sequence↗
Role of protein kinase B and the MAP kinase cascade in mediating the EGF-dependent inhibition of glycogen synthase kinase 3 in Swiss 3T3 cells.
Epidermal growth factor (EGF), insulin-like growth factor 1 (IGF1) and phorbol myristate acetate (PMA) induce the inhibition of glycogen synthase kinase 3 (GSK3) by stimulating the phosphorylation of an N-terminal serine. Here, we show that protein kinase B (PKB) plays a key role in mediating EGF-induced inhibition of GSK3alpha and that the classical MAP kinase (MAPK) cascade has two functions in this process. Firstly, it makes a transient contribution to EGF-induced inhibition of GSK3alpha. Secondly, it shortens the duration of PKB activation and GSK3alpha inhibition. In contrast, PKB alone mediates the IGF1-induced inhibition of GSK3alpha, while the MAPK cascade mediates the inhibition of GSK3alpha by PMA.
3T3 Cells↗