Gonadal Function in Boys with Bilateral Undescended Testes.

Background: Bilateral undescended testes (BUDT) may be a marker of an underlying condition that affects sex development or maturation. Aims: To describe the extent of gonadal dysfunction in cases of BUDT who had systematic endocrine and genetic evaluation at a single tertiary pediatric center. Methods: A retrospective review was conducted of all boys with BUDT who had endocrine evaluation between 2008 and 2021 at the Royal Hospital for Children, Glasgow (RHCG). Continuous variables were analyzed using Mann-Whitney U and non-continuous variables using Fisher's exact, via Graphpad Prism v 8.0. Multivariable logistic regression was used to identify any associations between groups. A P < .05 was considered statistically significant. Results: A total of 243 bilateral orchidopexies were performed at RHCG between 2008 and 2021. Of these 130 (53%) boys were seen by the endocrine team. The median (range) age at first orchidopexy was 1 year (0.2, 18.0) with 16 (12%) requiring re-do orchidopexy. The median External Masculinization Score of the group was 10 (2, 11) with 33 (25%) having additional genital features. Of the 130 boys, 71 (55%) had extragenital anomalies. Of the 70 who were tested, a genetic abnormality was detected in 38 (54%), most commonly a chromosomal variant in 16 (40%). Of the 100 who were tested, endocrine dysfunction was identified in 38 (38%). Conclusion: Genetic findings and evidence of gonadal dysfunction are common in boys who are investigated secondary to presentation with BUDT. Endocrine and genetic evaluation should be part of routine clinical management of all cases of BUDT.

Serum Anti-Müllerian Hormone in the Prediction of Response to hCG Stimulation in Children With DSD.

INTRODUCTION: The relationship between serum anti-Müllerian hormone (AMH) and the testosterone response to human chorionic gonadotropin (hCG) stimulation test is unclear. METHODS: Children who had hCG stimulation tests in one tertiary centre from 2001 to 2018 were included (n = 138). Serum testosterone was measured before (day 1 [D1]) and after 3 days (D4) of hCG stimulation. Sixty-one of these children also had prolonged hCG stimulation for 2 more weeks and serum testosterone measured after 21 days (D22). All children had a serum AMH measured on D1. RESULTS: Of the 138 children, D4 testosterone was normal in 104 (75%). AMH was low in 24/138 (17%) children, and 16 (67%) of these had a low D4 testosterone. Median AMH in those who had a normal vs low D4 testosterone was 850 pmol/L (24, 2280) and 54 pmol/L (0.4, 1664), respectively (P < 0.0001). An AMH > 5th centile was associated with a low D4 testosterone in 18/118 (13%; P < 0.0001). Of the 61 children who had prolonged hCG stimulation, D22 testosterone was normal in 39 (64%). AMH was low in 10/61(16%) children and 9 (90%) of these had a low D22 testosterone. Median AMH in children who responded and did not respond by D22 was 639 pmol/L (107, 2280) and 261 pmol/L (15, 1034) (P < 0.0001). CONCLUSION: A normal AMH may provide valuable information on overall testicular function. However, a low AMH does not necessarily predict a suboptimal testosterone response to hCG stimulation.

A retrospective analysis of longitudinal changes in bone mineral content in cystic fibrosis.

BACKGROUND: We aimed to describe the longitudinal changes in bone mineral content and influencing factors, in children with cystic fibrosis (CF). METHODS: One hundred children (50 females) had dual X-ray absorptiometry (DXA) performed. Of these, 48 and 24 children had two to three scans, respectively over 10 years of follow-up. DXA data were expressed as lumbar spine bone mineral content standard deviation score (LSBMCSDS) adjusted for age, gender, ethnicity and bone area. Markers of disease, anthropometry and bone biochemistry were collected retrospectively. RESULTS: Baseline LSBMCSDS was >0.5 SDS in 13% children, between -0.5; 0.5 SDS, in 50% and ≤-0.5 in the remainder. Seventy-eight percent of the children who had baseline LSBMCSDS >-0.5, and 35% of the children with poor baseline (LSBMCSDS<-0.5), showed decreasing values in subsequent assessments. However, mean LS BMC SDS did not show a significant decline in subsequent assessments (-0.51; -0.64; -0.56; p=0.178). Lower forced expiratory volume in 1 s percent (FEV1%) low body mass index standard deviation scores (BMI SDS) and vitamin D were associated with reduction in BMC. CONCLUSIONS: Bone mineral content as assessed by DXA is sub-optimal and decreases with time in most children with CF and this study has highlighted parameters that can be addressed to improve bone health.

A prospective longitudinal study of growth and pubertal progress in adolescents with inflammatory bowel disease.

BACKGROUND: Puberty and growth may be affected in inflammatory bowel disease (IBD) but the extent is unclear. METHODS: We performed a prospective study over 12 months in 63 adolescents (Crohn's disease, CD, n = 45; ulcerative colitis/IBD unclassified, UC, n = 18) with a median age of 13.4 years (range 10-16.6). Assessment included anthropometry, biochemical markers of growth and puberty and an assessment of quality of life by IMPACT-III. RESULTS: Compared to the normal population, boys with CD were shorter, with a median height SDS (HtSDS) of -0.13 (-2.52 to 1.58; p < 0.05). In addition, the study cohort had a lower median IGF-1 SDS of -0.29 (-4.53 to 2.96; p = 0.008) and a higher median IGFBP3 SDS of 0.45 (-3.15 to 2.55; p = 0.002). Over the study period, the median Ht velocity (HV) was 5 cm/year (0.2-8.7) and the change in HtSDS was 0.06 (-0.48 to 0.57). The median difference between the chronological and bone age was 0.3 years (-2.5 to 3.0) and pubertal examination was not delayed. In the whole group, the erythrocyte sedimentation rate (ESR) showed an inverse association with HV (r = -0.29; p = 0.025) and IGF-1:IGFBP3 (r = -0.34; p = 0.016). The score in the body image domain, IMPACT-III, was inversely associated with HtSDS (r = -0.31; p = 0.03). CONCLUSION: Despite no evidence of pubertal delay, adolescents with IBD display growth retardation which may be associated with raised ESR, adverse quality of life measures and an abnormality of IGF-1 bioavailability.

Urinary gonadotrophins: a useful non-invasive marker of activation of the hypothalamic pituitary-gonadal axis.

BACKGROUND: Non-invasive screening investigations are rarely used for assessing the activation and progression of the hypothalamic-pituitary gonadal axis through puberty. This study aimed to establish a normal range for urinary gonadotrophins in children progressing through puberty. METHODS: Urine samples were collected from 161 healthy school children (76 boys, 85 girls) aged 4-19 yrs. Height and weight were converted to standard deviation score. Pubertal status, classified by Tanner staging, was determined by self-assessment. Urinary gonadotrophins were measured by chemiluminescent microparticle immunoassay. Results were grouped according to pubertal status (pre-pubertal or pubertal). RESULTS: Of the 161 children, 50 were pre-pubertal (28 boys; 22 girls) and 111 were pubertal (48 boys; 63 girls). Overall, urinary gonadotrophins concentrations increased with pubertal maturation. All pre-pubertal children had a low urinary LH:Creatinine ratio. LH:Creatinine ratios were significantly higher in pubertal compared to pre-pubertal boys (p<0.001). In girls, FSH:Creatinine ratios were significantly higher in the pubertal group (p = 0.006). However, LH:FSH ratios were a more consistent discriminant between pre-pubertal and pubertal states in both sexes (Boys 0.45 pubertal vs 0.1 pre-pubertal; girls 0.23 pubertal vs 0.06 pre-pubertal). CONCLUSION: Urinary gonadotrophins analyses could be used as non-invasive integrated measurement of pubertal status which reflects clinical/physical status.

Use of preoperative natriuretic peptides and echocardiographic parameters in predicting new-onset atrial fibrillation after coronary artery bypass grafting: a prospective comparative study.

BACKGROUND: Atrial fibrillation (AF) is a common complication after coronary artery bypass grafting (CABG). We prospectively compared the ability of echocardiographic parameters and the cardiac neurohormones, brain natriuretic peptide (BNP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) to predict AF in this setting. METHODS: We recruited 275 patients undergoing nonemergency CABG. Patients undergoing valve surgery or with prior atrial dysrhythmia (based on clinical history and review of medical records) were excluded. Echocardiography was performed, and natriuretic peptide levels were measured, 24 hours before surgery. The primary end point was postoperative AF lasting >30 seconds. RESULTS: The only significant echocardiographic predictors of postoperative AF (n = 107, 39%) were the transmitral E to A-wave ratio and the early mitral annulus velocity. Levels of BNP and NT-proBNP were higher in patients who developed AF. Both natriuretic peptides, but none of the echocardiographic parameters, remained independently predictive in multivariable analysis. The optimum cut points for predicting AF were 31 pg/mL for BNP (odds ratio [OR] 2.74, P = .001) and 74 pg/mL for NT-proBNP (OR 2.74, P = .003). CONCLUSION: Levels of BNP and NT-proBNP are independent, though modestly effective, predictors of AF after isolated CABG. In contrast, none of the echocardiographic parameters assessed, including measures of LV systolic function and filling pressure, were independently predictive.

Uric acid levels and outcome from coronary artery bypass grafting.

OBJECTIVE: Elevated uric acid levels have been associated with an adverse cardiovascular outcome in several settings. Their utility in patients undergoing surgical revascularization has not, however, been assessed. We hypothesized that serum uric acid levels would predict the outcome of patients undergoing coronary artery bypass grafting. METHODS: The study cohort consisted of 1140 consecutive patients undergoing nonemergency coronary artery bypass grafting. Clinical details were obtained prospectively, and serum uric acid was measured a median of 1 day before surgery. The primary end point was all-cause mortality. RESULTS: During a median of 4.5 years, 126 patients (11%) died. Mean (+/- standard deviation) uric acid levels were 390 +/- 131 micromol/L in patients who died versus 353 +/- 86 micromol/L among survivors (hazard ratio 1.48 per 100 micromol/L; 95% confidence interval, 1.25-1.74; P < .001). The excess risk associated with an elevated uric acid was particularly evident among patients in the upper quartile (>or=410 micromol/L; hazard ratio vs all other quartiles combined 2.18; 95% confidence interval, 1.53-3.11; P < .001). After adjusting for other potential prognostic variables, including the European System for Cardiac Operative Risk Evaluation, uric acid remained predictive of outcome. CONCLUSION: Increasing levels of uric acid are associated with poorer survival after coronary artery bypass grafting. Their prognostic utility is independent of other recognized risk factors, including the European System for Cardiac Operative Risk Evaluation.

Soluble transition metals cause the pro-inflammatory effects of welding fumes in vitro.

Epidemiological studies have consistently reported a higher incidence of respiratory illnesses such as bronchitis, metal fume fever (MFF), and chronic pneumonitis among welders exposed to high concentrations of metal-enriched welding fumes. Here, we studied the molecular toxicology of three different metal-rich welding fumes: NIMROD 182, NIMROD c276, and COBSTEL 6. Fume toxicity in vitro was determined by exposing human type II alveolar epithelial cell line (A549) to whole welding fume, a soluble extract of fume or the "washed" particulate. All whole fumes were significantly toxic to A549 cells at doses >63 microg ml(-1) (TD 50; 42, 25, and 12 microg ml(-1), respectively). NIMROD c276 and COBSTEL 6 fumes increased levels of IL-8 mRNA and protein at 6 h and protein at 24 h, as did the soluble fraction alone, whereas metal chelation of the soluble fraction using chelex beads attenuated the effect. The soluble fraction of all three fumes caused a rapid depletion in intracellular glutathione following 2-h exposure with a rebound increase by 24 h. In addition, both nickel based fumes, NIMROD 182 and NIMROD c276, induced significant reactive oxygen species (ROS) production in A549 cells after 2 h as determined by DCFH fluorescence. ICP analysis confirmed that transition metal concentrations were similar in the whole and soluble fractions of each fume (dominated by Cr), but significantly less in both the washed particles and chelated fractions. These results support the hypothesis that the enhanced pro-inflammatory responses of welding fume particulates are mediated by soluble transition metal components via an oxidative stress mechanism.