Risk factors for postoperative bleeding and early death in percutaneous endoscopic gastrostomy: A multicenter retrospective study.

BACKGROUND AND AIM: Comprehensive reports on the risk factors for bleeding and early death after percutaneous endoscopic gastrostomy (PEG) are limited. In this multicenter study, we retrospectively investigated the risk factors for bleeding and early death after PEG. METHODS: Patients (n = 1234) who underwent PEG between 2015 and 2020 at Osaka Medical and Pharmaceutical University and its affiliated hospitals (11 institutions in total) were evaluated for postoperative bleeding and early death (within 60 days) after PEG according to patient characteristics, construction method, medical history, medications, preoperative hematological findings, and perioperative adverse events. Multivariate logistic regression was performed to identify independent predictors of bleeding and early death after PEG. RESULTS: The risk factors for bleeding after PEG were PEG tube insertion using the modified introducer method (odds ratio [OR], 4.37; P = 0.0003), low platelet count (OR, 0.99; P = 0.014), antiplatelet therapy (OR, 2.11; P = 0.036), and heparinization (OR, 4.50; P = 0.007). Risk factors for early death were low body mass index (BMI) (OR, 0.89; P = 0.015), low serum albumin levels (OR, 0.50; P = 0.035), and comorbidity of active cancer (OR, 4.03; P < 0.0001). There was no significant association between bleeding and early death after PEG. CONCLUSIONS: We identified several risk factors for bleeding and early death after PEG. Risk factors for bleeding were PEG tube insertion using the modified introducer method, low platelet count, antiplatelet therapy, and heparinization. Risk factors for early death were low BMI, low serum albumin levels, and comorbidity of active cancer.

Newborn screening for congenital adrenal hyperplasia in Tokyo, Japan from 1989 to 2013: a retrospective population-based study.

BACKGROUND: Congenital adrenal hyperplasia (CAH) cause life-threatening adrenal crisis. It also affects fetal sex development and can result in incorrect sex assignment at birth. In 1989, a newborn screening program for congenital adrenal hyperplasia (CAH) was introduced in Tokyo. Here we present the results of this screening program in order to clarify the efficiency of CAH screening and the incidence of CAH in Japan. METHOD: From 1989 to 2013, a total of 2,105,108 infants were screened for CAH. The cutoff level for diagnosis of CAH was adjusted for gestational age and birth weight. RESULTS: A total of 410 infants were judged positive, and of these, 106 patients were diagnosed with CAH, indicating a positive predictive value (PPV) of 25.8 %. Of the 106 patients, 94 (88.7 %) were diagnosed with 21-OHD. Of these 94 patients, 73 were diagnosed with the salt wasting form, 14 with the simple virilising form and 7 with the nonclassical form (NC21OHD). The mean birth weight and gestational age were 3192 ± 385 g and 38.9 ± 1.38 weeks. 11 out of 44 female patients were assigned as female according to their screening result. CONCLUSIONS: These data suggest that the newborn screening in Tokyo was effective, especially for sex assignment and preventing fatal adrenal crisis. The incidence of CAH was similar to that measured in previous Japanese screening studies, and it was also similar to that of western countries. The incidence of NC21OHD in Japan in the present study was lower than that in western countries as previous studies reported. The screening program achieved higher PPV than previous CAH screening studies, which might be due to the use of variable cutoffs according to gestational age and birth weight. However, most of the neonates born at 37 weeks or less that were referred to hospital were false-positives. Further changes are needed to reduce the number of false positive preterm neonates.

Urinary calcium to creatinine ratio: a potential marker of secondary hyperparathyroidism in patients with vitamin D-dependent rickets type 1A.

Patients with vitamin D-dependent rickets type 1A (VDDR1A) are usually treated with alfacalcidol, an analog of vitamin D. Around puberty, an increased dose of alfacalcidol is recommended for these patients to avoid hypocalcemia and secondary hyperparathyroidism. However, no indicators of secondary hyperparathyroidism except for PTH are presently known. The aim of this study is to evaluate whether urinary calcium to creatinine ratio (U-Ca/Cr) is useful as a biomarker of secondary hyperparathyroidism in VDDR1A patients in order to determine the proper dose of alfacalcidol. Two brothers with VDDR1A were recruited who had null mutations of CYP27B1 which encodes 1-alpha-hydroxylase of vitamin D. We investigated the relationship between U-Ca/Cr and intact-PTH around puberty when the brothers showed hypocalcemia with secondary hyperparathyroidism. The results were compared to those of five patients with vitamin D deficiency (VDD). As a result, high intact-PTH levels were observed when U-Ca/Cr decreased to less than 0.1 (mg/mg) in both VDDR1A brothers. This relationship was also observed in the VDD patients. However, it is necessary to take into account body calcium status, either in depletion or in excess, to accurately evaluate the relationship between U-Ca/Cr and secondary hyperparathyroidism. First, low U-Ca/Cr was detected in situations with calcium depletion without hyperparathyroidism in the VDDR1A patients. Second, high U-Ca/Cr with hyperparathyroidism could be detected theoretically in a condition of excess calcium supply. In conclusion, a U-Ca/Cr ratio of less than 0.1 (mg/mg) in VDDR1A patients is useful to accurately evaluate calcium depletion and secondary hyperparathyroidism.

Longitudinal analysis of growth and body composition of Japanese 21-OHD patients in childhood.

Substitution therapy of glucocorticoid is a major part of the treatment for 21-OHD (21-hydroxylase deficiency). However, the therapy causes two major adverse effects, impairment of linear growth and obesity, so that collecting precise growth data is essential for optimizing the therapy. We longitudinally evaluated the linear growth and the body composition of Japanese 21-OHD patients during childhood. For the present study, we chose 16 patients (eight of each sex) who were diagnosed during the newborn period, and continuously observed them in our institute until they were at least 15 years old. All patients were treated according to the guidelines from The Japanese Society for Pediatric Endocrinology. The final height standard deviation score (Ht-SDS) of all the patients was -1.18 ± 0.85 SD, and no significant differences were observed between males and females or between the simple virilizing form and the salt wasting form. As previously reported, in spite of nearly normal height at the onset of puberty, the pubertal height gains were severely impaired, resulting in reduced final heights. Body composition of the patients was evaluated with BMI-SDS. Our longitudinal data showed that BMI was increased up to +1.23 SD in males and up to +1.75 SD in females, and that adiposity rebound was precipitated. Our study should alert physicians to the risk of metabolic syndrome and provide a framework for further studies of metabolic syndrome in 21-OHD patients.

Initial high dose hydrocortisone (HDC) treatment for 21-hydroxylase deficiency (21-OHD) does not affect linear growth during the first three years of life.

An initial high-dose treatment of glucocorticoid has been proposed to prevent chronic androgen excess, improving the final height prognosis of 21-hydroxylase deficiency (21-OHD) patients. In Japan, it is recommended to use an extremely high-dose of hydrocortisone (HDC) (100-200 mg/m(2)/day) for initial treatment by the Japanese Society for Pediatric Endocrinology. However, a precise evaluation of the treatment has not been carried out. In this study, we retrospectively analysed the effects of initial high-dose HDC therapy on the linear growth of classical 21-OHD patients discovered by newborn screening. Thirty patients (14 females) were eligible for this study, all of whom were initiated with high dose HDC therapy. The height standard deviation score (Ht-SDS) was 0.76 ± 0.65 at birth, and decreased to -1SD or less until the age of 12 months, subsequently catching up by 3 years of age (-0.56 ± 0.76). The growth pattern and the height at the age of two years were very similar to those previously observed in patients without initial high dose HDC therapy. We did not find any significant difference in growth retrospectively between the high- or low-dose HDC group (initial treatments of ≥150 mg/m(2)/day and 100 mg/m(2)/day, respectively). Bone ages did not exceed chronological ages at the ages of three and six years. Our data suggest that an initial high-dose HDC treatment does not profoundly affect linear growth during first three years of life and that the treatment could be a valuable option for 21-OHD patients without having an obvious adverse effect on linear growth.

Liquid chromatography-tandem mass spectrometric method for determination of salivary 17alpha-hydroxyprogesterone: a noninvasive tool for evaluating efficacy of hormone replacement therapy in congenital adrenal hyperplasia.

A sensitive liquid chromatography-electrospray ionization-tandem mass spectrometric (LC-ESI-MS-MS) method for the quantification of 17alpha-hydroxyprogesterone (17OHP) in human saliva has been developed and validated. The saliva was deproteinized with acetonitrile, purified using a Strata-X cartridge, derivatized with a highly proton-affinitive reagent, 2-hydrazinopyridine, and subjected to LC-MS-MS. Quantification was based on the selected reaction monitoring, and deuterated 17OHP was used as the internal standard. This method allowed the reproducible and accurate quantification of the salivary 17OHP using a 200-mul sample, and the limit of quantitation was 5.0 pg/ml. The developed method was applied to clinical studies. A linear relationship was found to be positive (r(2)=0.975) between the blood 17OHP level and the salivary 17OHP level measured using the proposed method. The result from the salivary 17OHP measurement in patients with congenital adrenal hyperplasia demonstrated that the proposed method is very useful for monitoring of the therapeutic efficacy during hormone replacement therapy.

Clinical course of patients with nonclassical 21-hydroxylase deficiency (21-OHD) diagnosed in infancy and childhood.

We report four cases of nonclassical 21-hydroxylase deficiency (21-OHD) diagnosed in neonate or early childhood. The four patients comprised a 6-year, 5-month-old male (case 1); a 3-year, 10-month-old female (case 2); a 13-year, 11-month-old female (case 3) and a 17-year, 1-month-old male (case 4). Cases 3 and 4 were siblings. None had any signs of virilization or salt wasting at birth. 21-OHD was diagnosed using ACTH loading test and other adrenal steroid evaluations. Mutations of the CYP21 gene were detected in all patients. Three patients (cases 1, 3 and 4) had positive results in neonatal mass screening. Cases 1 and 2 showed no apparent signs of virilization and were observed without conventional treatment. In cases 3 and 4, because of increased growth velocity and accelerated bone maturation, hydrocortisone administration was initiated from their late infantile period. In spite of hydrocortisone treatment, in case 4, the final height of 159.7 cm was less than his predicted final height. Besides he revealed adrenal insufficiency at the age of 9 years and 2 months old caused by viral infection. Hydrocortisone supplementation therapy may cause adrenal insufficiency in nonclassical patients due to suppression of the hypothalamus-pituitary-adrenal axis. The clinical courses in these cases were various, and it was difficult to predict the appearance of any symptoms of virilization. Careful observation is necessary.

In Vitro Enzyme Assay of CYP21A2 Mutation (R483Q) by A Novel Method Using Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry (LC-ESI-MS/MS).

Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive disorders in humans, and 21-hydroxylase deficiency (21-OHD) accounts for 90 to 95% of all cases of CAH. Approximately 95% mutations are a consequence of recombination between the CYP21A2 and its highly homologous pseudogene CYP21A1P. Recently, other rare mutations have been identified, increasing the number of reported mutations to more than eighty. The in vitro enzyme assay for the detection of mutated 21-hydroxylase is a well-established method. In this study, we report the characterization of the R483Q mutation using a novel in vitro enzyme assay, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). With this system, we evaluated the activity of the R483Q mutation. The enzyme activities of 21-hydroxylase in the convertion of progesterone to deoxycorticosterone (DOC), and 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol (11-DOF), were measured as 2.00 ± 0.25% and 1.89 ± 0.30% of the wild type, respectively. This result was in agreement with that of a previous report, which measured the activities using the (3)H labeled steroid assay. Our results suggest that the R483Q mutation is compatible with the simple virilizing form of 21-OHD and that the LC-ESI-MS/MS assay using picolinoyl derivatives is an alternative to the existing (3)H-labeled steroid assay for the characterization of the CYP21A2 mutation.

A boy with "transient" growth hormone deficiency in prepubertal stage despite normal growth hormone secretion in childhood and after puberty.

Transient growth hormone deficiency (GHD) is occasionally found in prepubertal individuals, and this phenomenon has been variously interpreted. Sex steroids enhance GH secretion; however, the cut-off values of provocative GH tests are not modified according to the physiological changes. Physiological changes in sex steroid levels are thought to cause the image of transient GHD. In addition, the reproducibility of provocative GH tests makes the interpretation complicated. We experienced a case of a boy with short stature who had undergone provocative GH tests at three different times: childhood (5 and 7 years old), before puberty (12 years old), and in adolescence (15 years old). Although the responses of GH in his childhood and adolescence were within the normal range, his prepubertal GH response was extremely low, as if he had "complete" GHD (peak GH: insulin test, 0.60 ng/ml; clonidine test, 0.78 ng/ml). No morphological changes were observed in the pituitary gland or hypothalamus on MRI. The level of insulin-like growth factor 1 was in the normal range for his age at this time. Here, we report the clinical course and endocrinological data of this case, and suggest that transient GHD is caused not only by the physiological effects of sex steroids but also by certain mechanisms that actively reduce GH secretion.

Molecular loops in the galactic center: evidence for magnetic flotation.

The central few hundred parsecs of the Milky Way host a massive black hole and exhibit very violent gas motion and high temperatures in molecular gas. The origin of these properties has been a mystery for the past four decades. Wide-field imaging of the (12)CO (rotational quantum number J = 1 to 0) 2.6-millimeter spectrum has revealed huge loops of dense molecular gas with strong velocity dispersions in the galactic center. We present a magnetic flotation model to explain that the formation of the loops is due to magnetic buoyancy caused by the Parker instability. The model has the potential to offer a coherent explanation for the origin of the violent motion and extensive heating of the molecular gas in the galactic center.

Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 patients with Noonan syndrome.

We report on PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutation analysis and clinical assessment in 45 patients with Noonan syndrome. Sequence analysis was performed for all of the coding exons 1-15 of PTPN11, revealing a novel 3-bp deletion mutation and 10 recurrent missense mutations in 18 patients. Clinical assessment showed that 1) the growth pattern was similar in mutation-positive and mutation-negative patients, with no significant difference in birth length [-0.6 +/- 2.2 sd (n = 10) vs. -0.6 +/- 1.4 sd (n = 21); P = 0.95], childhood height [-2.6 +/- 1.1 sd (n = 14) vs. -2.1 +/- 1.6 sd (n = 23); P = 0.28], or target height [-0.4 +/- 0.9 sd (n = 14) vs. -0.2 +/- 0.7 sd (n = 17); P = 0.52]; 2) pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients (10 of 18 vs. 6 of 27; P = 0.02), as was atrial septal defect (10 of 18 vs. 4 of 27; P = 0.005), whereas hypertrophic cardiomyopathy was present in five mutation-negative patients only; and 3) other features were grossly similar in the prevalence between mutation-positive and mutation-negative patients, but hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007). The results suggest that PTPN11 mutations account for approximately 40% of Noonan syndrome patients, as has been reported previously. Furthermore, assessment of clinical features, in conjunction with data reported previously, implies that the type of cardiovascular lesions and the occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients, whereas the remaining findings are similar in the two groups of patients.

Simple new technique for sonographic measurement of the thyroid in neonates and small children.

PURPOSE: The aim of this study was to determine whether the ratio of the thyroid width (Th) to the trachea width (Tr) is a useful technique for sonographic estimation of thyroid size in neonates and small children. METHODS: We prospectively performed sonographic examination of the thyroid gland in 30 pediatric subjects ranging in age from 1 week to 12 years. The sum of the maximum width of the left thyroid lobe and the maximum width of the right lobe was considered the Th. Each subject's thyroid was classified as small, normal sized, or large on the basis of the Th value in reference to the subject's body height. The ratios of the Th to the Tr were then calculated and compared among the 3 groups by 1-way analysis of variance. Correlation and regression analyses were performed to determine the correlation between body height and Tr. A p value of less than 0.05 was considered significant. RESULTS: The mean Th/Tr ratios (+/- standard deviations) for the 3 groups were as follows: small, 1.25 +/- 0.19; normal sized, 2.09 +/- 0.19; and large, 4.10 +/- 2.42. The difference in the Th/Tr ratios between the 3 groups was statistically significant (p < 0.0001). A significant positive correlation was found between Tr and body height (p < 0.001; r = 0.85). CONCLUSIONS: The Th/Tr ratio is a simple, practical parameter for estimating the size of the thyroid gland in neonates and small children.

RMRP mutations in Japanese patients with cartilage-hair hypoplasia.

We examined 12 Japanese patients with metaphyseal chondrodysplasia (MCD) for mutations in the ribonuclease mitochondrial RNA processing gene (RMRP), and identified four novel mutations in two patients with typical and atypical cartilage-hair hypoplasia (CHH), a form of MCD characterized by extra-skeletal manifestations including hypoplastic hair and defective immunity. A patient with typical CHH had a 17-bp duplication at +3 and a de novo 182G > A. The other patient with atypical CHH had a 17-bp insertion at -20 and a 218A > G. Expression analysis revealed that the allele with this insertion mutation in the promoter region silenced the gene. Spectrum analysis of the mutations and polymorphisms in RMRP showed marked difference between the Japanese and other ethnic groups. Such ethnic and phenotypic difference should be taken into account in mutation analysis of the gene.

A highly specific heterologous enzyme immunoassay for 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide (androstanediol-17G) and developmental patterns of urinary androstanediol-17G excretions.

We established a highly specific enzyme immunoassay (EIA) for 5 alpha-androstane-3 alpha, 17 beta-diol 17-glucuronide (androstanediol-17G). Rabbit antisera raised against 5 alpha-androstane-3 alpha, 11 alpha, 17 beta-triol 17-glucuronide 11-glutaryl bovine serum albumin and a heterologous tracer of androstanediol-17G conjugated with horseradish peroxidase at the glucuronic acid group were used. The EIA showed excellent specificity: there were no remarkable cross-reactivities with related androgens. The assay range for urine samples was 0.3-30 ng/ml. Recoveries of standards added to samples were 100-108%. Intra-assay and inter-assay coefficients of variation were 2.9-4.4% and 5.7-7.9%, respectively. The EIA was applied to urine samples of 407 males and 322 females to determine developmental patterns and normal ranges of androstanediol-17G excretions in 11 age groups (0 y, 1 y, 2-3 y, 4-5 y, 6-7 y, 8-9 y, 10-11 y, 12-13 y, 14-15 y, 16-17 y, and over 18 y). Urinary androstanediol-17G/creatinine (androstanediol-17G/Cre) ratios in both sexes were high in infancy, tended to decrease during childhood, and began to increase near adolescence. While androstanediol-17G/Cre ratio in girls increased at 8-9 y and reached a plateau during adolescence, that in boys increased at 10-11 y and continued to increase throughout adolescence. Androstanediol-17G/Cre ratios in girls were higher than those in boys at 6-7 y (P < 0.05) and at 8-9 y (P < 0.01). Androstanediol-17G/Cre ratios in boys were higher than those in girls at 12-13 y and at older ages (P < 0.01). These developmental patterns are parallel to age-related changes in androgenicity and serum androstanediol-17G, suggesting that urinary androstanediol-17G/Cre ratio could be a good marker for androgenicity in childhood.