International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood.

This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.

Perioperative stress dose steroid management of children with classical congenital adrenal hyperplasia: Too much or too little?

BACKGROUND: Children with congenital adrenal hyperplasia (CAH) are at risk for adrenal crises in the perioperative period and require higher doses of glucocorticoids. However, there are no specific protocols detailing the appropriate stress dosing required for children with CAH undergoing surgery with anesthesia. OBJECTIVE: To evaluate CAH patients using our current hydrocortisone stress dose surgical protocol. We hypothesized that current clinical protocols may overestimate the endogenous response to perioperative stress. STUDY DESIGN: 14 children with CAH scheduled to have genital surgery and a control group of 10 unaffected children scheduled to have cardiac or urologic surgery (of a similar duration) were evaluated in a prospective observational study. Urinary free cortisol (UFC) and urinary 17-hydroxycorticosteroids (17-OHCS) per body surface area were measured in the postoperative period. RESULTS: UFC levels were significantly higher in CAH patients (115.8 ± 24.6 nmol/m2) than in controls (26.5 ± 12.2 nmol/m2), P < 0.05.17-OHCS levels were also higher in CAH patients than in controls (6.5 ± 0.5 nmol/m2 vs. 3.4 ± 0.5 nmol/m2), P < 0.05). CONCLUSION: In the immediate postoperative period, urinary cortisol and its metabolites are significantly higher in pediatric CAH patients receiving stress dose corticosteroids compared to controls. Results suggest that the amount of hydrocortisone given during our stress dose protocol may be higher than physiologic needs. Future dynamic studies are needed to determine appropriate perioperative and postoperative cortisol requirements in pediatric CAH patients in order to develop optimal stress dose regimens.

Long Non-Coding RNAs in Obesity-Induced Cancer.

Many mechanisms of obesity-induced cancers have been proposed. However, it remains unclear whether or not long non-coding RNAs (lncRNAs) play any role in obesity-induced cancers. In this article, we briefly discuss the generally accepted hypotheses explaining the mechanisms of obesity-induced cancers, summarize the latest evidence for the expression of a number of well-known cancer-associated lncRNAs in obese subjects, and propose the potential contribution of lncRNAs to obesity-induced cancers. We hope this review can serve as an inspiration to scientists to further explore the regulatory roles of lncRNAs in the development of obesity-induced cancers. Those findings will be fundamental in the development of effective therapeutics or interventions to combat this life-threatening adverse effect of obesity.

Congenital Adrenal Hyperplasia: Unresolved Issues.

Congenital adrenal hyperplasia (CAH) describes a family of disorders that comes from enzymatic deficiencies in cortisol production, with 21-hydroxylase deficiency causing ∼90% of cases. Distinction is made between the severe classical form and milder nonclassical form of CAH. Molecular genetic analysis is used to confirm the hormonal diagnosis. A high rate of genotype-phenotype disconcordance has been found in 21-hydroxylase deficiency. The goal of treatment is to replace with synthetic glucocorticoids and mineralocorticoids and suppress adrenal androgen production. The treatment of patients affected with nonclassical CAH, particularly males, remains controversial. Variable synthetic glucocorticoids are used and new modes of glucocorticoid delivery are under investigation. To improve height, growth hormone and other adjuvant therapies are employed. Long-term outcomes of genital surgery using modern techniques in females affected with classical CAH continue to be investigated. Prenatal treatment with dexamethasone is available to avoid ambiguous genitalia in these females. Although studies have shown its safety to mother and fetus, prenatal treatment is still regarded as experimental. Currently, prenatal diagnosis of CAH can only be obtained through invasive methods. Recently, the detection of cell-free fetal DNA in maternal plasma has made it possible to make this diagnosis earlier and noninvasively.

Ovarian carcinoma in a 14-year-old with classical salt-wasting congenital adrenal hyperplasia and bilateral adrenalectomy.

A 14-year-old female with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency underwent bilateral adrenalectomy at 6 years of age as a result of poor hormonal control. Because the patient was adrenalectomized, extra adrenal androgen production was suspected. Imaging studies including pelvic ultrasound and pelvic magnetic resonance imaging (MRI) were obtained to evaluate for adrenal rest tumors of the ovaries. Abdominal MRI was obtained to evaluate for residual adrenal tissue. A cystic lesion arising from her right ovary suspicious for ovarian neoplasm was noted on pelvic MRI. Right salpingo-oophorectomy was performed and histopathological examination revealed ovarian serous adenocarcinoma, low-grade, and well-differentiated. Tumor marker CA-125 was elevated and additional ovarian cancer staging workup confirmed stage IIIC due to one lymph node positive for carcinoma. The patient then developed a large left ovarian cyst, which led to a complete total abdominal hysterectomy and removal of the left ovary and fallopian tube. Pathology confirmed ovarian serous adenocarcinoma with microscopic focus of carcinoma in the left ovary. After numerous complications, the patient responded well to chemotherapy, CA-125 levels fell and no evidence of carcinoma was observed on subsequent imaging. To our knowledge, this is the first reported case of an ovarian serous adenocarcinoma in a patient with CAH. Although rare, we propose that the ovaries were the origin of androgen production and not residual adrenal tissue. The relationship between CAH and ovarian carcinomas has yet to be established, but further evaluation is needed given the poor survival rate of high-grade serous ovarian carcinoma.

Pitfalls in hormonal diagnosis of 17-beta hydroxysteroid dehydrogenase III deficiency.

Steroid 17ß-hydroxysteroid dehydrogenase III (17ß-HSD3) deficiency is a rare autosomal recessive disorder that usually presents in patients with a 46,XY karyotype with ambiguous genitalia at birth. The 17ß-HSD3 enzyme, which is encoded by the HSD17B3 gene, converts gonadal delta-4 androstenedione (Δ4) to testosterone (T). Such 17ß-HSD3 enzyme deficiency is expected to lead to an increased ratio of D4 to T when the patient undergoes a human chorionic gonadotropin stimulation (hCG) test. Two patients with 46,XY disorders of sexual differentiation were studied. Serum D4 and T levels were measured by HPLC tandem mass spectrometry. As one of the patients was born to consanguineous parents, we performed single nucleotide polymorphism (SNP) microarray to analyze regions of homozygosity (ROH). The HSD17B3 gene was sequenced using the Sanger method. Contrary to expectations, both patients demonstrated decreased D4/T ratio after hCG stimulation. Initial sequencing results for the androgen receptor or 5α-reductase were negative for mutations. ROH analysis identified HSD17B3 as a candidate gene that might cause the disease. Sanger sequencing of the HSD17B3 gene confirmed 17ß-HSD3 deficiency in both patients. Serum D4/T ratios are not reliable parameters for the diagnosis of 17ß-HSD3 deficiency. Molecular genetic analysis provides accurate diagnosis.

Superoxide anion is involved in the early apoptosis mediated by Gleditsia sinensis fruit extract.

Changes in the intracellular level of reactive oxygen species (ROS) including superoxide anion, hydroxyl radical, hydrogen peroxide and finally cellular acid-base equilibrium are reported to play an important role in the early step of apoptosis. All of which would precede the loss of mitochondrial membrane potential and releasing of those apoptotic inducing factors such as cytochrome c as well as caspases activation. Any potential chemotherapeutic agent that could drive such changes in ROS would be particularly attractive. Recently we have reported the potential use of Gleditsia sinensis extract (GSE) in cancer therapy including solid tumour and leukaemia cell lines as well as primary cultured leukaemia cells in vitro. We demonstrated that apoptotic activity is involved. Here we further showed that the mechanism of GSE induced apoptosis, including an early decreasing of intracellular superoxide anion as measured by nitroblue tetrazolium (NBT) reduction assay. This phenomenon readily occurred before any shrinkage of cancer cells including MDA-MB231 breast cancer, CNE-2 nasopharyngeal carcinoma, K-562 chronic myelogenous leukaemia and KG1-a, acute myelogenous leukaemia. Cell viability was determined by morphological investigation and the [3-(4,5-dimethyl-thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay. Furthermore, the superoxide dismutase activity from those cellular extracts after GSE treatment seemed to be increased. Taken together, we speculate that the GSE-induced apoptosis, via ROS pathway, involves an early decrease of intracellular superoxide anion.

Gleditsia sinensis fruit extract is a potential chemotherapeutic agent in chronic and acute myelogenous leukemia.

The anti-leukemia activity of the saponin rich Gleditsia sinensis Lam. fruit extract (GSE) was investigated on cancer cell lines and bone marrow cells obtained from consented patients with chronic myelogenous leukemia (CML) and acute myelogenous leukemia (AML) during presentation. The growth inhibitory activity of the extract was determined by [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay. Colony formation assay was performed to investigate the regeneration potential. Cellular morphology change was studied. Apoptosis was demonstrated by DNA electrophoresis, reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry. The mean concentration to inhibit the cell growth by 50% (MTS50) was 18+/-1.6 micro g/ml for K562 CML cell line and 12+/-1.3 micro g/ml for HL-60 acute promyelocytic leukemia cell line. Patient samples showed a mean MTS50 of 13-28 micro g/ml. Non-malignant hematological disorder bone marrow samples showed a mean MTS50 from 45 to 53 micro g/ml. Loss of regeneration property after treatment with GSE of these two cancer cell lines were confirmed by colony formation assay. GSE was able to induce cell shrinkage in K-562. DNA laddering was observed by incubating the leukemia cells with GSE. RT-PCR demonstrated that the pro-apoptic gene bax was induced while the anti-apoptic gene bcl-2 and cell cycle active gene PCNA were reduced. Flow cytometric analysis showed that the apoptotic effect of GSE on leukemia cell line was time- and dose-dependent. Thus GSE might be potentially used as a chemotherapeutic drug to treat patients with acute and chronic myelogenous leukemia.

Anti-angiogenic potential of Gleditsia sinensis fruit extract.

Blood supply plays a crucial role in solid tumour development and leukaemogenesis. It has been suggested that blocking of angiogenesis could be possible in cancer therapy. We have demonstrated the antiproliferative activity of Gleditsia sinensis fruit extract (GSE) on various human solid tumour cancer cell lines as well as leukaemia cell lines and primary cultured leukaemia cells obtained from leukaemia patients. However, the antiangiogenic potential of GSE has not been demonstrated. Here we demonstrated that GSE could reduce vascular endothelial growth factor (VEGF) mRNA expression in dose- and time course-dependently in MDA-MB231 breast cancer and HepG2 hepatoblastoma cell lines as measured by reverse transcriptase polymerase chain reaction. Enzyme-linked immunosorbent assay further showed that GSE could reduce the VEGF secretion from various cancer cell lines including MDA-MB231, HepG2, HL-60 (acute promyelocytic leukaemia) and eleven primary cultured leukaemia cells obtained from acute myelogenous leukaemia patients. In vivo chick chorioallantoic membrane assay illustrated that GSE could reduce the angiogenic activity of basic fibroblast growth factor. Taken together, the information suggested that GSE could be potentially used as an angiogenic inhibitor in both solid tumour and leukaemia therapy.

2[125I]Iodomelatonin binding sites in guinea pig platelets.

Using 2[125I]iodomelatonin as the radioligand, we characterized 2[125I]iodomelatonin binding sites in guinea pig platelet membrane preparations. Saturation radioreceptor studies indicated that these 2[125I]iodomelatonin binding sites were of picomolar affinity and femtomolar density. The dissociation constant (Kd) and maximum number of receptor sites (Bmax) were 42.5 +/- 1.79 pM and 11.8 +/- 0.8 fmol/mg protein (n = 6), respectively. 2[125I]Iodomelatonin competition studies with indoles or drugs indicate the following rank order of potency: 2-iodomelatonin > melatonin > 6-chloromelatonin > 6-hydroxymelatonin > N-acetylserotonin > 5-methoxytryptophol, whereas serotonin and its analogs had less than 20% inhibition at 0.1 mM. Guanosine 5'-O-(3-thiotriphosphate) significantly increased the Kd by twofold suggesting that these binding sites are coupled to the guanine nucleotide binding proteins. Immunoblotting studies using anti-MT(1) IgG demonstrated one peptide blockable band with an apparent molecular mass of 37 kDa. Melatonin had no effect on prostacyclin or forskolin-stimulated intracellular 3',5'-cyclic adenosine monophosphate accumulation. A diurnal variation in binding density, which was abolished after the animals were adapted to constant light conditions, was observed. Age related studies demonstrated that Bmax increased as the animal matured. Physiological melatonin concentrations potentiated whereas those at pharmacological levels inhibited adenosine diphosphate- or arachidonic acid-stimulated platelet aggregation. Our study demonstrated G-protein coupled, saturable, reversible and highly specific picomolar affinity 2[125I]iodomelatonin binding sites in guinea pig platelets. Pharmocological and physiological data indicate that they may be different from the nanomolar [3H]melatonin binding sites in human platelets previously reported.