Testicular function in males with infantile nephropathic cystinosis.

STUDY QUESTION: Do males with the rare lysosomal storage disease infantile nephropathic cystinosis (INC) have a chance of biological fatherhood? SUMMARY ANSWER: Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval from the centre of the testes providing additional opportunities for fatherhood. WHAT IS KNOWN ALREADY: Biallelic mutations in the cystinosin (CTNS) gene in INC cause dysfunction in cystine transport across lysosomal membranes and cystine accumulation throughout the body. Spontaneous paternity in cystinosis has not been described, despite the availability of cysteamine treatment. Azoospermia has been diagnosed in small case series of males with INC. ART using ICSI requires few spermatozoa, either from semen or extracted surgically from the testes of azoospermic men. However, there is limited evidence to suggest this could be successful in INC. STUDY DESIGN, SIZE, DURATION: In this prospective cohort study performed between 2018 and 2019, we performed a cross-sectional investigation of 18 male patients with INC to delineate endocrine and spermatogenic testicular function. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum hormone levels, semen samples (according to World Health Organization 2010 standards), and testicular ultrasound images were analysed in 18 male patients aged 15.4-40.5 years. Surgical sperm extraction was performed in two, and their testicular biopsies were investigated by light and electron microscopy. Past adherence to cysteamine treatment was assessed from medical record information, using a composite scoring system. MAIN RESULTS AND THE ROLE OF CHANCE: Adherence to cysteamine treatment was high in most patients. Testicular volumes and testosterone levels were in the normal ranges, with the exception of two and three older patients, respectively. Serum LH levels were above the normal range in all subjects aged ≥20 years. FSH levels were elevated in all but four males: three with spermatozoa in semen and one adolescent. Inhibin B levels were shown to be lower in older men. Testicular ultrasound revealed signs of obstruction in 67% of patients. Reduced fructose and zinc seminal markers were found in 33%, including two patients with azoospermia who underwent successful surgical sperm retrieval. Histology identified fully preserved spermatogenesis in the centre of their testes, but also tubular atrophy and lysosomal overload in Sertoli and Leydig cells of the testicular periphery. LIMITATIONS, REASONS FOR CAUTION: Limitations of this study are the small number of assessed patients and the heterogeneity of their dysfunction in cystine transport across lysosomal membranes. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that testicular degeneration in cystinosis results from the lysosomal overload of Sertoli and Leydig cells of the testicular periphery, and that this can possibly be delayed, but not prevented, by good adherence to cysteamine treatment. Endocrine testicular function in INC may remain compensated until the fourth decade of life; however, azoospermia may occur during adolescence. Cryostorage of semen could be an option for approximately 20% of young males with INC, with surgical sperm retrieval providing additional opportunities for biological fatherhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Cystinosis Foundation Germany. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: n/a.

2-Methoxymethylestradiol: a new 2-methoxy estrogen analog that exhibits antiproliferative activity and alters tubulin dynamics.

An estradiol metabolite, 2-methoxyestradiol (2-MeOE(2)), has shown antiproliferative effects in both hormone-dependent and hormone-independent breast cancer cells. Previously, a series of 2-hydroxyalkyl estradiol analogs had been synthesized in our laboratories as potential probes for comparison of estrogen receptor (ER)-mediated versus non-ER-mediated effects in breast cancer cells. A methoxy derivative of 2-hydroxymethyl estradiol was prepared for biological evaluation and comparison with 2-MeOE(2). Estrogenic activity of the synthetic analogs was evaluated in two ways, one by examining affinity of the analogs for the estrogen receptor in MCF-7 cells and the other by examining the ability of the analogs to induce estrogen-responsive gene expression. The analog, 2-methoxymethyl estradiol (2-MeOMeE(2)), demonstrated weak affinity for the estrogen receptor (0.9% of estradiol) and weak ability to stimulate estrogen-induced expression of the pS2 gene (0.02% of estradiol). Antitumor activity was evaluated both in vitro and in vivo. The steroidal nucleus seems to be an attractive target for developing novel tubulin polymerization inhibitors. Additionally, such steroidal compounds may have low toxicity compared to the natural products known to interact with tubulin. Interestingly, 2-MeOMeE(2) inhibited tubulin polymerization in vitro at concentrations of 1 and 3 microM and was more effective than 2-MeOE(2). In cells, 2-MeOMeE(2) was effective in suppressing growth and inducing cytotoxicity in MCF-7 and MDA-MB-231 breast cancer cells. The cytotoxic effects of 2-MeOMeE(2) are associated with alterations in tubulin dynamics, with the frequent appearance of misaligned chromosomes, a significant mitotic delay, and the formation of multinucleated cells. In comparison, 2-MeOE(2) was more effective than 2-MeOMeE(2) in producing cytotoxicity and altering tubulin dynamics in intact cells. Assessment of in vivo antitumor activity was performed in athymic mice containing human breast tumor xenografts. Nude mice bearing MDA-MB-435 tumor xenografts were treated i.p. with 50 mg/kg per day of 2-MeOMeE(2) or vehicle control for 45 days. Treatment with 2-MeOMeE(2) resulted in an approximate 50% reduction in mean tumor volume at treatment day 45 when compared to control animals and had no effect on animal weight. Thus, 2-MeOMeE(2) is an estrogen analog with minimal estrogenic properties that demonstrates antiproliferative effects both in vitro and in the human xenograft animal model of human breast cancer.

Prenatal diagnosis of neuroblastoma by sonography.

Herein we report the first case in the literature in which a neuroblastoma in a fetus was recognized before birth and its growth could be observed. The diagnosis was made by ultrasonography. Other helpful diagnostic procedures in prenatal diagnosis are: determination of catecholamines, sonographic examination of the placenta, and search for metastases. As more and more centers perform ultrasound examinations routinely in pregnancy, similar findings such as fetal tumors or congenital malformations are to be expected more frequently.

Use-effectiveness and client satisfaction in six centers teaching the Billings Ovulation Method.

Use-effectiveness of the Billings Ovulation Method (OM) is reported for 1139 clients from six centers who were followed for at least 24 months. Method failure rates were 1% when calculated by either Pearl formula or life table analysis. Combined method and user failure rates were 20% when calculated with the Pearl formula, and 16% at 12 months and 23% at 24 months by life table analysis. Pregnancy rates were higher for couples using OM alone, than for couples using OM in combination with additional fertility awareness methods or together with barrier methods. The difference was significant when estimated by the Pearl formula but not when analyzed by the life table. The emotional implications underlying the apparent contradiction between a desire to avoid pregnancy and the deliberate coital use of fertile days are reflected in the differences between method and user failure rates, the high client satisfaction levels reported with "user failure," and 56% continuation rate at 24 months. The will require in-depth exploration.

[Renal sonography--errors, pitfalls, and their sources (author's transl)]. / Nierensonographie--Fehlinterpretationen und ihre Ursachen.

Retrospective evaluation of sonographic diagnoses showed 14 false interpretations, proven by operation or renal angiogram. A classification of errors and pitfalls in renal sonography is attempted and the place of this method in the diagnostic plan in kidney diseases is discussed.

Body-surface-area related renal volume: a common normal range from birth to adulthood.

Renal volume is an important parameter of renal development. Deviations from normal volume may indicate pathologic conditions. Thus, during childhood, the ever changing renal volumes require the continuous referral to normal volume charts in order to classify actual volumes, which is rather inconvenient. In daily practice this is frequently disregarded and kidneys are evaluated by their appearance only. Therefore, we tested the hypothesis that body surface area (BSA) and renal volume grow proportionally from birth to adulthood. We divided the renal volume of a child by its BSA to get the BSA-related renal volume (BSARV) and found no differences between left and right kidneys and a normal distribution for all kidneys regardless of the patient's age. BSARV has a common normal range for all age groups with the 10th percentile of 45 and the 90th percentile of 85 mL/m(2). 80% of all kidneys do not exceed the volume of their counterparts by more than 20%. BSARV alleviates the correct evaluation of a child's renal volume regardless of age and reveals pathological influences by the simple observation that a kidney deviates from a former percentile or z-value. This is especially valuable in the followup of kidneys with chronic diseases.

Prevailing therapeutic regimes and predictive factors for prandial insulin substitution in 26 687 children and adolescents with Type 1 diabetes in Germany and Austria.

AIMS: To analyse current therapeutic strategies for prandial insulin substitution in a large number of children and adolescents with Type 1 diabetes in Germany and Austria, along with changes in therapeutic habits and outcome. METHODS: We classified the data of 26 687 patients, treated from 1995 to 2005 in 152 paediatric clinics, using a database established for quality control and scientific surveys in paediatric diabetology (DPV). RESULTS: Seventy-three per cent of all patients (mean age 13.6 years., mean duration of diabetes 5.4 years.) were treated with > or = 4 daily injections (intensified conventional treatment; ICT), 14% with continuous subcutaneous insulin infusion (CSII), 13% with 1-3 injections per day (conventional treatment). Frequency of daily injections increased with age, duration of diabetes and insulin dose. The insulin dose at breakfast was higher than for the evening meal or lunch, from diagnosis onwards. Individuals using insulin analogues received up to 11% higher insulin doses per day compared with patients treated with human insulin. The time of day, age, duration of diabetes, female gender, insulin analogues and ICT all had a significant influence on prandial insulin doses. Although the number of patients treated with ICT or CSII increased over the period of observation, mean glycated haemoglobin (HbA(1c)) was approximately 8.0% each year, and decreased by only 0.01%. CONCLUSIONS: Eighty-seven per cent of patients were treated with ICT or CSII. However, while this percentage increased over the observation period, mean HbA(1c) was almost constant. Longer duration of diabetes, increasing age, female gender, insulin analogues and ICT were associated with higher prandial insulin doses.

[Ultrasound screening of the infant hip]. / Sonographisches Screening der Säuglingshüfte.

The sonographic screening of the hip has led to a marked decrease in treatment of children with developmental dysplasia of the hip (ddh) as inpatients. The prognosis for this disorder has greatly improved in the past few years due to early diagnosis and correspondingly early beginning of therapy, in many cases by using simple therapeutic methods. This undisputed success has been achieved with a high treatment rate in comparison with international practice (6.4%). The expectancy of reducing the number of checks, and thus costs, by deciding on the 4th to 6th week of life as the time for screening has not been met.

[Pediatric sonography]. / Pädiatrische Sonographie.

Sonography has become the most important basic imaging method in pediatrics. It mainly differs from sonography in adults in having more unspecific causes for examination, other facets of application, and a wider range of applicability including newborns and infants. Sonography should precede x-ray examination, since its findings must determine the need for and the timing and type of x-ray examinations. The wide range of application justifies a distinction between general and special pediatric sonography. This distinction seems to be particularly relevant with regard to the requirements for optimal technical equipment.

[Moving-picture corss-sectional echocardiography in normal children]. / Ultraschall-Schnittbilduntersuchungen des kindlichen Herzens mit dem schnellen B-Bild

Using a parallel-scan B-mode ultrasonic system (Vidoson, Siemens) 200 children with clinically normal hearts were examined. Using a cross-section parallel to the left sternal border, rapid and easily reporducible multi-frame echocardiograms were obtained with simultaneous presentation of the aortic, pulmonary and mitral valves. Interpretation of this cross-section, with echos from the three valves, the aortic route, pulmonary artery, right and left ventricles and left atrium, was checked against post-mortem studies and in-vivo contrast studies with ultrasonic contrast medium (indocyanine-green). As the described method is not ECG-triggered, only important morphological changes are demonstrable.

[On the importance of B-scan-ultrasound for the diagnosis of nephrological and urological diseases in childhood (author's transl)]. / Zur Bedeutung des ultraschall-Schnittbildverfahrens für die nephrologisch-urologische Diagnostik im Kindesalter

Kidneys of 118 children of all age groups, and of 2 adults were investigated by means of senography. Normal kidneys could be identified on account of a typical echo-pattern. Deviations from this pattern were interpreted as evidence for pathological changes in the kidneys; they were correlated to the radiological and in some cases to the pathologic-anatomical findings. Typical deviations of the echo-pattern were found in cases of hydronephrosis, duplex kidneys, duplex kidneys in combination with hydronephrosis, polycystic renal diseases and other renal diseases. It was even possible to demonstrate decrease and increase of hydronephrosis by means of sonography. Indications for the application of this method are pointed out. In addition its accuracy and importance in relation to other diagnostics methods are discussed.

[Diagnosis of pancreatic insufficiency with fluorescein dilaurate in patients with cystic fibrosis (author's transl)]. / Diagnose der exokrinen Pankreasinsuffizienz mit Fluorescein-Dilaurat bei Patienten mit cystischer Fibrose.

The tubeless pancreas-function test with fluorescein dilaurate, which is based on the saponification of the test substance by pancreas-specific arylesterases, and which has proved itself in adults, was given to children for the first time. After reduction of the size of the test dose and the amount of liquid to be drunk, there were no difficulties in carrying out the test. Elimination of the fluorescein released from the flourescein dilaurate and excreted via the kidneys was clearly less in patients with cystic fibrosis than in normal subjects. Thus, the test in its modified form for children can provide adequate differentiation between normal and pathological pancreas function.

[Ultrasonic examinations of Wilms' tumors stage II-V during preoperative therapy (author's transl)]. / Ultraschalluntersuchungen von Wilms-Tumoren Stadium II-V während der präoperativen Therapie.

Ultrasonic examinations were performed at weekly intervals in 8 patients with Wilms tumors Stage II-V during the period of preoperative therapy. Measurements of the maximum expansion of the tumors were made and expressed in an ellipsoid formula. The tumor volume was thus calculated. A description of the compactness of the tumor as well as the bordering of the tumor were done. This was followed by a photographic documentation. The mean value of the initial tumor volume in the 8 patients was 551 ml. At the end of the preoperative therapy, an average volume of 305,1 ml was recorded. One week after beginning the therapy, 25-40% diminution of the initial tumor volume was noted in 5 patients. The diminution in volume till tumor extirpation was in all 49%. In 3 patients, the reduction of tumor mass through therapy was only 27,8%. The histological examinations revealed a fetal rhabdomyomatic nephroblastoma in one case. The second case was massive tumor haemorrhage and in the third case a considerable formation of cysts.

[Sonographic visualization and size determination of the abdominal organs in healthy newborn infants]. / Sonographische Darstellbarkeit und Grössenbestimmung von Abdominalorganen bei gesunden Neugeborenen.

The determination of organ size is another important criterium in ultrasound examination. There are only few investigations in the neonatal group. Therefore in a prospective study the abdominal organs of 85 neonates were examined with a 7.5 MHz small part scanner. These organs were measured in standardized sections in order to establish normal values]

[Ultrasound imaging of the bile ducts and assessment of gallbladder kinetics in healthy newborn infants]. / Sonographische Darstellbarkeit der Gallenwege und Beurteilbarkeit der Gallenblasenkinetik bei gesunden Neugeborenen.

The gallbladder and the biliary tract of 85 neonates were sonographically examined, in the fasting state. The gallbladder was detectable in all neonates and showed a measurable contraction. Two types of biliary contraction could be observed: a concentric contraction of length, depth and width (concentric type) or a contraction of depth and width (collapse type). The grade of postprandial contraction was independent of the level of serum bilirubin. Furthermore, sonographic criteria were established allowing the differentiation of the bile ducts and their discrimination from hepatic arteries.

[Comparative studies of the use of linear array, curved array and sector technique in sonography of the infant hip]. / Vergleichende Untersuchungen zur Anwendung von Linear Array-, Curved Array- und Sektortechnik in der Sonographie der Süglingshüfte.

In an experimental study, the sonographic speed in the hyaline cartilage of the hip of the newborn is measured. With 1549 m/s it lies in the intermediate range of the equipment's pre-set calculation basis. By comparing large groups the study shows that the accuracy of the measurements of the angle alpha is independent of the technology used in the production of the hip sonogram. On the other hand, the image scale has a clear influence. The image scale of 1:1 is inadequate for a reliable repeated cross-sectional presentation and for measurements. The study shows that there are no statistically demonstrable differences when measuring hip sonograms regardless of whether they have been produced using linear array or sector scanning. This is shown both by repeated presentation of the respective cross-section by one and the same researcher and by measurement of identical sonograms by different researchers.

Differential spindle assembly checkpoint response in human lung adenocarcinoma cells.

CI-980 is an antimicrotubule agent that binds the colchicine site on tubulin. We examined CI-980 cytotoxicity in two lung adenocarcinoma cell lines, A549 and A427. Depolymerization of microtubules following CI-980 treatment resulted in a mitotic arrest in the A549 population, but not in the A427 population. Similar responses were obtained following treatment with Taxol and nocodazole. Drug-treated A427 cells exited mitosis, generating a population dominated by multinucleated cells, while both multinucleated and apoptotic cells were present in the A549 population after extended drug treatment. CI-980-induced microtubule depolymerization was only partially reversible. However, regrowth of some microtubules in mitotic A549 cells following drug washout resulted in multinucleation of the population in the absence of apoptosis. These results show that A427 cells have a defective spindle assembly checkpoint. Levels of the MAD2 and BUB1 checkpoint proteins were similar in both A549 and A427 cells, suggesting that the checkpoint defect in the A427 cells is downstream of these proteins. In addition, induction of apoptosis in response to CI-980 correlates with the presence of a functional mitotic checkpoint and the extent of microtubule depolymerization.

The anatomy of the heart in the sonogram. A comparison between anatomic and ultrasonic cross-section.

Cardiac sonography has only recently been introduced as a diagnostic procedure. In order to facilitate the interpretation and evaluation of the ultrasonic cardiac cross-section displayed by this two-dimensional technique, we performed anatomic cross-sections corresponding to ultrasonic cross-sections. The ultrasonic cross-sectional images were taken from children with a real-time-motion scanner. The anatomic cross-sections were taken from adult hearts. Two ultrasonic transverse cross-sections are compared with the two corresponding anatomic cross-sections and three ultrasonic longitudinal cross-sections with one corresponding anatomic cross-section. The direct comparison between anatomic and ultrasonic cross-sections best promotes the understanding of the latter: such a comparison shows certain gaps of information in the ultrasonic display, mostly due to the physical prerequisites of the technique. Morphological details, therefore, should be interpreted with great care. In spite of these disadvantages, sonography is the only non-invasive method that provides an exact analysis of the heart's structure. In addition to this, the real-time-motion technique allows observation of the movements of cardiac structures.