Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone.

STUDY QUESTION: Does treatment of constitutional delay of growth and puberty (CDGP) in boys with aromatase inhibitor letrozole (Lz) or conventional low-dose testosterone (T) have differing effects on developing seminiferous epithelium? SUMMARY ANSWER: Anti-Müllerian hormone (AMH) declined similarly in both treatment groups, and the two Sertoli cell-derived markers (AMH and inhibin B (iB)) exhibited differing responses to changes in gonadotrophin milieu. WHAT IS KNOWN ALREADY: Boys with CDGP may benefit from puberty-inducing medication. Peroral Lz activates gonadotrophin secretion, whereas intramuscular low-dose T may transiently suppress gonadotrophins and iB. STUDY DESIGN, SIZE, DURATION: Sera of 28 boys with CDGP who participated in a randomised, controlled, open-label trial at four paediatric centres in Finland between August 2013 and January 2017 were analysed. The patients were randomly assigned to receive either Lz (2.5 mg/day) (n = 15) or T (1 mg/kg/month) (n = 13) for 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 28 patients were at least 14 years of age, showed first signs of puberty, wanted medical attention for CDGP and were evaluated at 0, 3, 6 and 12 months of visits. AMH levels were measured with an electrochemiluminescence immunoassay and Lz levels with liquid chromatography coupled with tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: AMH levels decreased in both treatment groups during the 12-month follow-up (P < 0.0001). Between 0 and 3 months, the changes in gonadotrophin levels (increase in the Lz group, decrease in the T group) correlated strongly with the changes in levels of iB (FSH vs iB, r = 0.55, P = 0.002; LH vs iB, r = 0.72, P < 0.0001), but not with the changes in AMH (P = NS). At 12 months, AMH levels did not differ between the groups (P = NS). Serum Lz levels (range, 124-1262 nmol/L) were largely explained by the Lz dose per weight (at 3 months r = 0.62, P = 0.01; at 6 months r = 0.52, P = 0.05). Lz levels did not associate with changes in indices of hypothalamic-pituitary-gonadal axis activity or Sertoli cell markers (in all, P = NS). LIMITATIONS, REASONS FOR CAUTION: The original trial was not blinded for practical reasons and included a limited number of participants. WIDER IMPLICATIONS OF THE FINDINGS: In early puberty, treatment-induced gonadotrophin stimulus was unable to counteract the androgen-mediated decrease in AMH, while changes in iB levels were associated with changes in gonadotrophin levels. AMH decreased similarly in both groups during the treatment, reassuring safety of developing seminiferous epithelium in both treatment approaches. Since a fixed dose of Lz induced variable serum Lz levels with a desired puberty-promoting effect in all boys, more research is needed to aim at a minimal efficient dose per weight. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Academy of Finland, the Foundation for Pediatric Research, the Emil Aaltonen Foundation, Sigrid Juselius Foundation and Helsinki University Hospital Research Funds. The authors have nothing to disclose. TRIAL REGISTRATION NUMBER: NCT01797718.

Impacts of Caregiving for Individuals with Autism in Low-Resource Settings, a Report from the Kurdistan Region of Iraq.

Caring for children with different developmental trajectories brings various challenges, which are often exacerbated in low-resource settings. International research has shown that raising a child with autism strongly impacts family caregivers, particularly mothers. There is a dearth of information regarding caregiving for individuals with autism in the Kurdistan Region of Iraq (KRI) and for fathers as well as mothers. This study examined the similarities and differences in caregiving for mothers and fathers of a child with autism in KRI using validated rating scales to measure various aspects of their general well-being. Over two years, a sample of 118 parents of individuals with autism (81 mothers and 37 fathers) self-completed the rating scales, which were further discussed through individual interviews with service personnel mainly known to them. The findings indicated that mothers and fathers were similarly impacted. Although there were no statistically significant differences in the ratings of their general health, sources of stress, family functioning, and satisfaction with caregiving, the majority of parents had elevated ratings on all the measures. In addition, parents who rated their children higher on the Aberrant Behavior Checklist had significantly higher scores on their general health issues and were less satisfied with their caregiving role. Parents of female individuals with autism were also significantly more stressed compared to the male individuals with autism and parents of children who received a diagnosis before three years of age, reported fewer behavioral problems with their child compared to the parents who received a diagnosis when the child was older. In this sample, mothers and fathers seem to be similarly impacted by caring for a child with autism, which is contrary to findings from other countries. However, in this region, family bonds between couples and the wider family may have had an influence which further cross-cultural research in low-resource settings could help elucidate, notwithstanding the challenges this poses. The findings have policy implications for health authorities in the KRI to improve the support provided to both mothers and fathers who care for children with autism, which presently is rarely available to them.

Bone mineral density, body composition and bone turnover in patients with congenital hypogonadotropic hypogonadism.

Patients with congenital hypogonadotropic hypogonadism (HH) may have reduced peak bone mass in early adulthood, and increased risk for osteoporosis despite long-term hormonal replacement therapy (HRT). To investigate the relationship between HRT history and measures of bone health in patients with HH, we recruited 33 subjects (24 men, nine women; mean age 39.8 years, range: 24.0-69.1) with congenital HH (Kallmann syndrome or normosmic HH). They underwent clinical examination, were interviewed and medical charts were reviewed. Twenty-six subjects underwent dual-energy X-ray absorptiometry for evaluation of BMD of lumbar spine, hip, femoral neck and whole body; body composition and vertebral morphology were evaluated in 22 and 23 subjects, respectively. Circulating PINP, ICTP and sex hormone levels were measured. HRT history clearly associated to bone health: BMDs of lumbar spine, femoral neck, hip and whole body were lower in subjects (n = 9) who had had long (≥5 years) treatment pauses or low dose testosterone (T) treatment as compared to subjects without such history (n = 17; all p-values < 0.05). In addition, fat mass and body mass index (BMI) were significantly higher in men with deficient treatment history (median fat mass: 37.5 vs. 23.1%, p = 0.005; BMI: 32.6 vs. 25.2 kg/m(2), p < 0.05). Serum PINP correlated with ICTP (r(s) = 0.61; p < 0.005) in men, but these markers correlated neither with circulating T, nor with serum estradiol levels in women. In conclusion, patients with congenital HH require life-long follow-up to avoid inadequate HRT, long treatment pauses and further morbidity.

Disorders of sex development: timing of diagnosis and management in a single large tertiary center.

BACKGROUND: We describe the phenotypic spectrum and timing of diagnosis and management in a large series of patients with disorders of sexual development (DSD) treated in a single pediatric tertiary center. METHODS: DSD patients who had visited our tertiary center during the survey period (between 2004 and 2014) were identified based on an ICD-10 inquiry, and their phenotypic and molecular genetic findings were recorded from patient charts. RESULTS: Among the 550 DSD patients, 53.3% had 46,XY DSD; 37.1% had sex chromosome DSD and 9.6% had 46,XX DSD. The most common diagnoses were Turner syndrome (19.8%, diagnosed at the mean age of 4.7 ± 5.5 years), Klinefelter syndrome (14.5%, 6.8 ± 6.2 years) and bilateral cryptorchidism (23.1%). Very few patients with 46,XY DSD (7%) or 46,XX DSD (21%) had molecular genetic diagnosis. The yearly rate of DSD diagnoses remained stable over the survey period. After the release of the Nordic consensus on the management of undescended testes, the age at surgery for bilateral cryptorchidism declined significantly (P < 0.001). CONCLUSIONS: Our results show that (i) Turner syndrome and Klinefelter syndrome, the most frequent single DSD diagnoses, are still diagnosed relatively late; (ii) a temporal shift was observed in the management of bilateral cryptorchidism, which may favorably influence patients' adulthood semen quality and (iii) next-generation sequencing methods are not fully employed in the diagnostics of DSD patients.

Effect of acute decreases of perfusion pressure on choroidal blood flow in humans.

PURPOSE: To investigate the relationship between choroidal blood velocity (ChBVel), blood volume (ChBVol) and blood flow (ChBF) in the foveal region of the human ocular fundus and ocular perfusion pressure and to determine whether the choroidal circulation has some autoregulatory capacity. METHODS: Measurements of ChBVel, ChBVol and ChBF were obtained by laser Doppler flowmetry in healthy subjects (age range, 21 to 57 years) with normal eye examination results. Measurements were performed at normal intraocular pressure (IOP) and during successive step increases in IOP induced by scleral suction. In experiment 1, in six eyes (five subjects), the IOP was increased rapidly, in steps of 50 to 100 mm Hg of suction pressure, which each lasted approximately 10 seconds to a level above diastolic ophthalmic artery blood pressure (IOP = approximately 72 mm Hg). In experiment 2, in 14 eyes (seven subjects), the IOP was increased slowly in four successive steps at 2-minute intervals to a level of approximately 42 mm Hg. We also determined the pulsatility of the flow parameters during the heart cycle, pulsatility = 1 - diast value/syst value. RESULTS: For both rates of suction cup increase, the relationship between ChBFm (mean ChBF over the heart cycle) and mean perfusion pressure was not linear. At high pressure, ChBFm was less affected by decreases in the pressure than expected from a passive vascular system. In some cases, no change in ChBFm was detectable, although significant changes in PChBF occurred. Further decreases in perfusion pressure resulted in a proportional decrease in ChBFm. On release of suction, a significant increase in ChBFm over baseline value was detectable in experiment 1. CONCLUSIONS: The relationship between ChBFm and ocular mean perfusion pressure appears to be bilinear and reveals some autoregulation for moderate step decreases in perfusion pressure. The temporal characteristics of the ChBFm-response suggest a neural or passive hemodynamical process rather than a myogenic or metabolic compensatory mechanism.

Choroidal blood flow during isometric exercises.

PURPOSE: To investigate the response of choroidal blood flow in the foveal region of the human eye to increases in mean perfusion pressure (PPm = mean ophthalmic artery pressure - intraocular pressure; IOP) induced by isometric exercises. METHODS: Using laser-Doppler flowmetry, changes in velocity (ChBVel), number (ChBVol), and flux (ChBF) of red blood cells in the choroidal vascular system in the foveal region of the fundus were measured in both eyes of 11 normal subjects (ages 18 to 57 years) during isometric exercises. RESULTS: During 90 seconds of squatting, PPm increased by an average of 67%, from 46 to 77 mm Hg. This resulted in a significant increase of 12% in ChBFm (the mean of ChBF during the heart cycle), mainly caused by an increase in ChBVelm. A further increase in PPm to a value approximately 85% above baseline resulted in a 40% increase in ChBFm. A significant negative correlation was found between the changes in ChBVelm and ChBVolm, during squatting. CONCLUSIONS: Previous studies have demonstrated that during isometric exercise, blood pressures in the ophthalmic and brachial arteries rise in parallel. These observations and the current results indicate that an increase in PPm up to 67% induces an increase in choroidal vascular resistance that limits the increase in choroidal blood flow to approximately 12%. This regulatory process fails when PPm is further increased.

Internal right atrial cardioversion of chronic atrial fibrillation: effects of low-energy biphasic shocks.

This study evaluates the efficacy and safety of internal right atrial cardioversion of atrial fibrillation using a defibrillation right atrial catheter and 2 thoracic patches with low-energy biphasic shocks.

Intrauterine creation and repair of pulmonary artery stenosis in the fetal lamb. Weight and ultrastructural changes of the ventricles.

Fetal lamb experimental models were employed for intrauterine creation and repair of pulmonary artery stenosis. The study group was composed of 51 fetal lambs including 29 models of pulmonary artery stenosis and 22 control lambs. Gestational age was 89 days at creation of pulmonary artery stenosis. Fourteen fetal lambs (Group A) were studied after creation of the stenosis at 131 days of gestation and compared to normal age-matched control lambs. The systolic right ventricular pressure was significantly higher after creation of pulmonary artery stenosis (76.6 +/- 17.8 versus 50.3 +/- 23.5 mm Hg), but the systolic pulmonary artery pressure was unchanged. The mean right ventricular weight and the mean right ventricular/left ventricular weight ratio were significantly greater after pulmonary artery stenosis than in normal control animals. The transverse myocyte diameter was not modified by pulmonary artery stenosis, but on electron microscopic study the myocytes appeared mature. Ten lambs (Group B) underwent intrauterine repair of pulmonary artery stenosis at 131 days of gestation without cardiopulmonary bypass. The pulmonary artery was clamped and patched. Immediately after repair the right ventricular pressure fell significantly from 85.8 +/- 18.9 to 62.2 +/- 14.6 mm Hg. At birth, 7 +/- 6 days after repair, Group B was compared to Group C (unrepaired pulmonary artery stenosis, five fetuses) and to normal control lambs. The mean right ventricular weight and the mean right ventricular/left ventricular weight ratio were not statistically different in Group B and in the control group. There were no ultrastructural changes after intrauterine repair. We conclude that intrauterine creation of pulmonary artery stenosis causes right ventricular hypertrophy with more mature myocytes. Intrauterine repair of pulmonary artery stenosis is feasible without cardiopulmonary bypass and rapidly abolishes the preponderance of right ventricular weight over left ventricular weight.

Photographic and angiographic characterization of the retina of Kenyan children with severe malaria.

OBJECTIVE: To investigate retinal lesions in children with severe falciparum malaria. METHODS: Color photography and fluorescein angiography were performed in consecutive children admitted to a pediatric high-dependency unit in Kenya during 1 malaria season. The presence and category of retinal lesion was compared with disease severity, clinical outcome, anemia, lactic acidosis, and parasite count. RESULTS: Twenty-six patients with cerebral malaria and 14 patients who were prostrate were studied. Thirty-one of the patients had clinical features of ocular disease, including round, flame-shaped, and white-centered hemorrhages; peripheral and foveal retinal opacification; peripheral vascular occlusion; venous dilation; disc edema with hyperemia; and arterial pulsatility. Of 8 patients with retinal opacification, only 2 showed small, infrequent zones of capillary nonperfusion on fluorescein angiography; the leakage of dye at sites of opacification was not seen. Retinal opacification was significantly associated with a higher parasite count (P < .02). White-centered hemorrhages were significantly associated with a higher parasite count (P < .05), severe disease (p < .05), and severe anemia (P < .02). CONCLUSIONS: The blood-retina barrier and retinal vascular flow remain substantially normal despite widespread pathological features. Retinal features in children with severe malaria are consistent with cellular hypoxia, nutritional deficiency, or both rather than with vascular occlusion; they support the concept of metabolic steal by parasites.

Intraindividual variability of infant whole-body plethysmographic measurements: effects of age and disease.

The intraindividual variability of whole-body plethysmographic measurements was studied in a large series of consecutive infants (N = 144), divided into two groups: a group of infants born very prematurely (PM, N = 63), with (N = 28) or without (N = 35) a history of bronchopulmonary dysplasia (BPD), and a group of infants with persistent respiratory symptoms (PRS, N = 81), i.e., wheezing (N = 53) or cough (N = 28). The intraindividual variability was determined within each test and between tests, separated by a 10-min interval. In both study groups, the between-test variability was significantly larger than that within tests. Expressed as the median coefficient of variation (CV), the between-test repeatabilities in the PRS group were 8.0% for thoracic gas volume (TGV), 17.5% for airway resistance (Raw), and 18.4% for specific airway conductance (sGaw), and in the PM group, 8.9% for TGV, 20.4% for Raw, and 20.7% for sGaw. However, the individual range of CVs was large, ranging from 3 to 19% for TGV and from 5 to 55% for sGaw. With respect to TGV, the difference between the groups was statistically significant (P = 0.03). In infants with a history of BPD, there was also a significant negative age dependency in CVs of sGaw (r = -0.50, P = 0. 009), showing larger variation among younger individuals. The presenting symptom (wheezing or cough) in the PRS group did not influence the measurement variability significantly, and neither did the degree of bronchial obstruction. We conclude that on a group basis, the repeatability of infant body plethysmographic measurements may be satisfactory for scientific studies demonstrating pharmacodynamic effects; however, the intraindividual measurement variability should be reported for each test conditions and for infant groups in each study. Due to the large range in individual variation and the influence of age and disease processes on the variation, for an individual child there is only questionable benefit from a given measurement, unless the intrasubject, between-test variability is assessed individually before interventions, such as a bronchodilation test.

[Action of trimethyl 3,3-N-hexene-5-lactam on the mechanical properties of the longitudinal fibers of the rat colon. An in vitro study]. / Action du triméthyl-3,3-N-hexène-5-lactame (T.H.L.) sur les propriétés mécaniques des fibres longitudinales du colon de rat. Etude "in vitro".

The effects of trimethyl 3,3-N-hexene-5-lactam (T. H. L.) on the mechanical properties of longitudinal muscle strips of the distal rat colon were investigated through stretching, electrical stimulation and addition of pharmacologic agents. T. H. L. abolished the contraction induced by electrical stimulation and decreased amplitude of contractions induced by carbamoylcholine and serotonin. It further reduced the relaxation induced by adrenaline.

Experimental cardioplasty using the latissimus dorsi muscle flap.

This study was undertaken to examine the possibility of using the latissimus dorsi muscular flap, divided in two parts thus covering the surfaces of the heart, and inserting it into the thoracic cavity by means of a segmental resection of the second rib. After cadaver case studies, 15 operations were performed on 5 Beagle dogs. The first group of 5 operations consisted of a latissimus dorsi flap graft over the heart. The second group and third group of operations (3 and 6 months later) consisted of reoperating for muscular and cardiac biopsies and electrical stimulation tests on the heart-muscle complex. The latissimus dorsi flap provided a sizable mass of contractile tissue. The haemodynamic studies showed no compressive or constrictive phenomenon of the muscle on the heart and revealed the preservation of an appropriate cardiac output for short intervals of time (2 hours), through phasic electrostimulation of the flap. The histopathological studies showed conserved muscular structure. The technical feasibility, histological adaptability and electrophysiological properties of this muscular flap makes it appropriate to develop a functional stimulation programme and perhaps adequate for the treatment of dysplasic, ischemic, tumoral and other acquired or congenital myocardial diseases.

Indirect trauma causing dislocation of the crystalline lens--a case report.

PURPOSE: To report a case of indirect trauma causing dislocation of the crystalline lens in a patient with no underlying risk factors. METHODS: Case report. RESULTS: A 76-year-old woman fell injuring her right temple area. She complained of blurring of vision in her right eye. Her vision was reduced to 6/60. Ocular examination revealed right aphakia associated with complete posterior dislocation of the crystalline lens into the vitreous cavity. No predisposing factors as pigment dispersion or pseudoexfoliation material was found on gonioscopy. CONCLUSIONS: Dislocation of the crystalline lens has been reported following direct trauma. It is known to occur spontaneously in mature and hypermature cataracts and in cases of weak zonules. Our case shows that indirect trauma can cause complete dislocation of the crystalline lens in the absence of any predisposing factors.

Anti-tumor necrosis factor treatment in cherubism--clinical, radiological and histological findings in two children.

Cherubism is a rare and disfiguring genetic disorder with excessive bone resorption and multilocular lesions in the mandible and/or maxilla. The disease-causing gain-of-function mutations in the SH3-binding protein 2 (SH3BP2) gene result in increased myeloid cell responses to macrophage colony stimulating factor and RANK ligand, formation of hyperactive osteoclasts (giant cells), and hyper-reactive macrophages that produce excessive amounts of the inflammatory cytokine tumor necrosis factor α (TNF-α). Recent findings in the cherubism mouse model suggest that TNF-α plays a major role in disease pathogenesis and that removal of TNF-α prevents development of the bone phenotype. We treated two children with cherubism with the TNF-α antagonist adalimumab for approximately 2.5 years and collected extensive clinical, radiological and histological follow-up data during the treatment. Histologically the treatment resulted in a significant reduction in the number of multinucleated giant cells and TNF-α staining positivity in both patients. As evaluated by computed tomography and magnetic resonance imaging, the lesions in Patient 1 showed either moderate enlargement (mandibular symphysis) or remained stable (mandibular rami and body, the maxilla). In Patient 2, the lesions in mandibular symphysis showed enlargement during the first 8 months of treatment, and thereafter the lesions remained unchanged. Bone formation and resorption markers remained unaffected. The treatment was well tolerated. Based on our findings, TNF-α antagonist may decrease the formation of pathogenic giant cells, but does not result in lesion regression or prevent lesion expansion in active cherubism. TNF-α modulator treatment thus does not appear to provide sufficient amelioration for patients suffering from cherubism.

Progressive obtundation in a young woman with bilateral corpus striatum infarction: a case report.

BACKGROUND: Bilateral ischemic infarction involving the corpus striatum is a rare event which usually results from global cerebral hypoxia, intoxications, and drug abuse. CASE PRESENTATION: We report a 28 year old Caucasian woman who presented with progressive obtundation and later development of severe expressive dysphasia and Parkinsonism after sustaining ischemic stroke of both corpora striata. Hemorrhagic transformation developed on day four of admission. CONCLUSION: This is a rare case of bilateral basal ganglia infarction with hemorrhagic transformation in a young patient. Our patient's work up did not reveal any cause behind this stroke; however, advanced investigations (such as genetic testing and conventional angiography) were not done. The damage resulted in motor dysphasia and Parkinsonism. Neither dystonia nor other involuntary movements developed, and cognitive function was not assessed because of the language disorder.

Cognitive effects of aromatase inhibitor therapy in peripubertal boys.

OBJECTIVE: Aromatase inhibitors, blockers of oestrogen biosynthesis, have emerged as a new potential treatment modality for boys with short stature. The cognitive effects of such therapy are unknown. In this study, we explored the effects of aromatase inhibition on cognitive performance in peripubertal boys. DESIGN: Prospective, double-blind, randomised, placebo-controlled clinical study. METHODS: Twenty-eight boys, aged 9.0-14.5 years, with idiopathic short stature were treated with the aromatase inhibitor letrozole (2.5 mg/day) or placebo, for 2 years. During the treatment, the progression of physical signs of puberty and the concentrations of sex hormones were followed up. A selection of cognitive tests, focusing on memory function, was administered to the participants at entry, at 12 months and at 24 months after the start of the treatment. RESULTS: Letrozole effectively inhibited the conversion of androgen to oestrogen, as indicated by high serum testosterone and low serum oestradiol concentrations in letrozole-treated boys who progressed into puberty. In both the groups, there was a gain in performance during the follow-up period in tests of verbal performance, in most of the tests of visuospatial performance and in some tests of verbal memory. No significant differences between the letrozole- and placebo-treated boys in development of cognitive performance were found in any of the tests during the follow-up period. CONCLUSIONS: Our results suggest that blockade of oestrogen biosynthesis with an aromatase inhibitor does not influence cognitive performance in peripubertal males.

The striatocapsular infarction and its aftermaths.

Ischaemic stroke syndromes in the vascular territory of middle cerebral artery may have atypical presentation and radiographic findings because of the variable anatomy of that artery. Therefore, misdiagnosis of these syndromes as neoplastic or infectious processes is not uncommon. This case describes a 69-year-old comatose woman who was referred to us as having 'a brain tumour with massive surrounding oedema.' Further work-up revealed that she had a large left-sided lenticular nuclear infarction with some extension into the surrounding areas-the striatocapsular infarction.