Deeplasia: deep learning for bone age assessment validated on skeletal dysplasias.

BACKGROUND: Skeletal dysplasias collectively affect a large number of patients worldwide. Most of these disorders cause growth anomalies. Hence, evaluating skeletal maturity via the determination of bone age (BA) is a useful tool. Moreover, consecutive BA measurements are crucial for monitoring the growth of patients with such disorders, especially for timing hormonal treatment or orthopedic interventions. However, manual BA assessment is time-consuming and suffers from high intra- and inter-rater variability. This is further exacerbated by genetic disorders causing severe skeletal malformations. While numerous approaches to automate BA assessment have been proposed, few are validated for BA assessment on children with skeletal dysplasias. OBJECTIVE: We present Deeplasia, an open-source prior-free deep-learning approach designed for BA assessment specifically validated on patients with skeletal dysplasias. MATERIALS AND METHODS: We trained multiple convolutional neural network models under various conditions and selected three to build a precise model ensemble. We utilized the public BA dataset from the Radiological Society of North America (RSNA) consisting of training, validation, and test subsets containing 12,611, 1,425, and 200 hand and wrist radiographs, respectively. For testing the performance of our model ensemble on dysplastic hands, we retrospectively collected 568 radiographs from 189 patients with molecularly confirmed diagnoses of seven different genetic bone disorders including achondroplasia and hypochondroplasia. A subset of the dysplastic cohort (149 images) was used to estimate the test-retest precision of our model ensemble on longitudinal data. RESULTS: The mean absolute difference of Deeplasia for the RSNA test set (based on the average of six different reference ratings) and dysplastic set (based on the average of two different reference ratings) were 3.87 and 5.84 months, respectively. The test-retest precision of Deeplasia on longitudinal data (2.74 months) is estimated to be similar to a human expert. CONCLUSION: We demonstrated that Deeplasia is competent in assessing the age and monitoring the development of both normal and dysplastic bones.

Sperm capacitation as a predictor of boar fertility.

Prediction of a boar's fertility level has great economic importance for sow herds. After standard sperm morphology and motility metrics are met, approximately 25% of boars have less than 80% conception rates. Due in part to the many factors involved in the fertilization process, a multifactorial model incorporating multiple relevant sperm physiology factors will likely lead to increased understanding of boar fertility. Here we review the current literature on boar sperm capacitation as a predictor of boar fertility. While limited, several studies have provided correlations between the percentage of sperm in an ejaculate that are capable of undergoing sperm capacitation in a chemically defined media and artificial insemination field fertility as well as proteome and other methods. Work summarized here underscores the need for further understanding of boar fertility.

BRD4 degradation blocks expression of MYC and multiple forms of stem cell resistance in Ph+ chronic myeloid leukemia.

In most patients with chronic myeloid leukemia (CML) clonal cells can be kept under control by BCR::ABL1 tyrosine kinase inhibitors (TKI). However, overt resistance or intolerance against these TKI may occur. We identified the epigenetic reader BRD4 and its downstream-effector MYC as growth regulators and therapeutic targets in CML cells. BRD4 and MYC were found to be expressed in primary CML cells, CD34+ /CD38- leukemic stem cells (LSC), and in the CML cell lines KU812, K562, KCL22, and KCL22T315I . The BRD4-targeting drug JQ1 was found to suppress proliferation in KU812 cells and primary leukemic cells in the majority of patients with chronic phase CML. In the blast phase of CML, JQ1 was less effective. However, the BRD4 degrader dBET6 was found to block proliferation and/or survival of primary CML cells in all patients tested, including blast phase CML and CML cells exhibiting the T315I variant of BCR::ABL1. Moreover, dBET6 was found to block MYC expression and to synergize with BCR::ABL1 TKI in inhibiting the proliferation in the JQ1-resistant cell line K562. Furthermore, BRD4 degradation was found to overcome osteoblast-induced TKI resistance of CML LSC in a co-culture system and to block interferon-gamma-induced upregulation of the checkpoint antigen PD-L1 in LSC. Finally, dBET6 was found to suppress the in vitro survival of CML LSC and their engraftment in NSG mice. Together, targeting of BRD4 and MYC through BET degradation sensitizes CML cells against BCR::ABL1 TKI and is a potent approach to overcome multiple forms of drug resistance in CML LSC.

Platinum Nanoparticle Size and Density Impacts Purine Electrochemistry with Fast-Scan Cyclic Voltammetry.

We demonstrate the density and shape of platinum nanoparticles (PtNP) on carbon-fiber microelectrodes with fast-scan cyclic voltammetry (FSCV) directly impacts detection of adenosine. Previously, we showed that metal nanoparticle-modified carbon significantly improves adenine-based purine detection; however, how the size and shape of the particles impact electrochemical detection was not investigated. Electrochemical investigations of how the surface topology and morphology impacts detection is necessary for designing ultrasensitive electrodes and for expanding fundamental knowledge of electrode-analyte interactions. To change the density and shape of the PtNP's on the surface, we varied the concentration of K2PtCl6 and electrodeposition time. We show that increasing the concentration of K2PtCl6 increases the density of PtNP's while increasing the electrodeposition time impacts both the density and size. These changes manipulate the adsorption behavior which impacts sensitivity. Based on these results, an optimal electrodeposition procedure was determined to be 1.0 mg/mL of K2PtCl6 deposited for 45 s and this results in an average increase in adenosine detection by 3.5 ±0.3-fold. Interestingly, increasing the size and density of PtNPs negatively impacts dopamine detection. Overall, this work provides fundamental insights into the differences between adenosine and dopamine interaction at electrode surfaces.

Quality of life of patients following orthognathic surgery.

The aim of this study was to evaluate how patients with dentofacial deficiency who have undergone orthognathic surgery perceive their quality of life (QoL) with respect to functional, esthetic, and psychosocial issues. In an observational, cross-sectional, descriptive, and quantitative study, 10 patients who had undergone orthognathic surgery answered questionnaires used internationally for assessing QoL: the Short Form Health Survey (SF-36), Oral Health Impact Profile 14 (OHIP-14), and Orthognathic Quality of Life Questionnaire (OQLQ). In addition, the patients completed the Self-Perception Questionnaire of Esteem, Appearance, and Interpersonal Relationships (ASR-26), which explored the differences between their current self-esteem, appearance satisfaction, and interpersonal relationships and their memories of their presurgical feelings about those topics. The data were submitted to descriptive and multivariable statistical analyses. There was a statistically significant difference between the preoperative and postoperative periods regarding self-esteem, appearance satisfaction, and professional relationships (P < 0.05). The data collected with the SF-36, OHIP-14, and OQLQ questionnaires showed high internal consistency (Cronbach α coefficient). The index (mean) scores for the SF-36 (81.5), OHIP-14 (0.6), and OQLQ (5.0) were close to the conditions of high QoL. Principal component analysis revealed 3 distinct groups of patients, and 70% of patients composed a group with high QoL scores, showing no complaints of physical pain, functional limitation, psychological discomfort, social disability, or excessive concern about their oral condition. In this small sample of patients, orthognathic surgery resulted in improved health-related QoL with variations among patients regarding physical pain, psychological discomfort, oral function, facial esthetics, physical function, social function, and self-awareness of facial deformity. The results of this study indicate the importance of applying a questionnaire in individuals who have undergone orthognathic surgery to investigate their personal motivations for treatment and which physical, social, and psychological problems are limiting their QoL.

Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions.

Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between 'normal', pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.

Lab-on-a-Drone: Toward Pinpoint Deployment of Smartphone-Enabled Nucleic Acid-Based Diagnostics for Mobile Health Care.

We introduce a portable biochemical analysis platform for rapid field deployment of nucleic acid-based diagnostics using consumer-class quadcopter drones. This approach exploits the ability to isothermally perform the polymerase chain reaction (PCR) with a single heater, enabling the system to be operated using standard 5 V USB sources that power mobile devices (via battery, solar, or hand crank action). Time-resolved fluorescence detection and quantification is achieved using a smartphone camera and integrated image analysis app. Standard sample preparation is enabled by leveraging the drone's motors as centrifuges via 3D printed snap-on attachments. These advancements make it possible to build a complete DNA/RNA analysis system at a cost of ∼$50 ($US). Our instrument is rugged and versatile, enabling pinpoint deployment of sophisticated diagnostics to distributed field sites. This capability is demonstrated by successful in-flight replication of Staphylococcus aureus and λ-phage DNA targets in under 20 min. The ability to perform rapid in-flight assays with smartphone connectivity eliminates delays between sample collection and analysis so that test results can be delivered in minutes, suggesting new possibilities for drone-based systems to function in broader and more sophisticated roles beyond cargo transport and imaging.

Metal Nanoparticle Modified Carbon-Fiber Microelectrodes Enhance Adenosine Triphosphate Surface Interactions with Fast-Scan Cyclic Voltammetry.

Adenosine triphosphate (ATP) is an important rapid signaling molecule involved in a host of pathologies in the body. Historically, ATP is difficult to directly detect electrochemically with fast-scan cyclic voltammetry (FSCV) due to limited interactions at bare carbon-fibers. Systematic investigations of how ATP interacts at electrode surfaces is necessary for developing more sensitive electrochemical detection methods. Here, we have developed gold nanoparticle (AuNP), and platinum nanoparticle (PtNP) modified carbon-fiber microelectrodes coupled to FSCV to measure the extent to which ATP interacts at metal nanoparticle-modified surfaces and to improve the sensitivity of direct electrochemical detection. AuNP and PtNPs were electrodeposited on the carbon-fiber surface by scanning from -1.2 to 1.5 V for 30 s in 0.5 mg/mL HAuCl4 or 0.5 mg/mLK2PtCl6. Overall, we demonstrate an average 4.1 ± 1.0-fold increase in oxidative ATP current at AuNP-modified and a 3.5 ± 0.3-fold increase at PtNP-modified electrodes. Metal nanoparticle-modified surfaces promoted improved electrocatalytic conversion of ATP oxidation products at the surface, facilitated enhanced adsorption strength and surface coverage, and significantly improved sensitivity. ATP was successfully detected within living murine lymph node tissue following exogenous application. Overall, this study demonstrates a detailed characterization of ATP oxidation at metal nanoparticle surfaces and a significantly improved method for direct electrochemical detection of ATP in tissue.

A Novel Method for Adult Height Prediction in Children With Idiopathic Short Stature Derived From a German-Dutch Cohort.

Context: Prediction of adult height (AH) is important in clinical management of short children. The conventional methods of Bayley-Pinneau (BP) or Roche-Wainer-Thissen (RWT) have limitations. Objective: We aimed to develop a set of algorithms for AH prediction in patients with idiopathic short stature (ISS) which are specific for combinations of predicting variables. Methods: Demographic and auxologic data were collected in childhood (1980s) and at AH (1990s). Data were collected by Dutch and German referral centers for pediatric endocrinology. A total of 292 subjects with ISS (219 male, 73 female) were enrolled. The population was randomly split into modeling (n = 235) and validation (n = 57) cohorts. Linear multi-regression analysis was performed with predicted AH (PAH) as response variable and combinations of chronological age (CA), baseline height, parental heights, relative bone age (BA/CA), birth weight, and sex as exploratory variables. Results: Ten models including different exploratory variables were selected with adjusted R² ranging from 0.84 to 0.78 and prediction errors from 3.16 to 3.68 cm. Applied to the validation cohort, mean residuals (PAH minus observed AH) ranged from -0.29 to -0.82 cm, while the conventional methods showed some overprediction (BP: +0.53 cm; RWT: +1.33 cm; projected AH: +3.81 cm). There was no significant trend of residuals with PAH or any exploratory variables, in contrast to BP and projected AH. Conclusion: This set of 10 multi-regression algorithms, developed specifically for children with ISS, provides a flexible tool for AH prediction with better accuracy than the conventional methods.

Efficacy of Nx4 to Reduce Plasma Cortisol and Gastrin Levels in Norwegian Sled Dogs During an Exercise Induced Stress Response: A Prospective, Randomized, Double Blinded, Placebo-Controlled Cohort Study.

Introduction: An exercise induced stress response is commonly seen in high performance sled dogs, resulting in increased plasma cortisol. A stress induced rise of cortisol might result in increased prevalence of gastritis and gastric ulcers mediated by an increase of gastrin. Neurexan® (Nx4) is a medicinal product used for stress relief by reduction of cortisol. The aim of the study was to show that Nx4 reduces plasma cortisol and plasma gastrin in high performance sled dogs and to show tolerability of Nx4 in dogs. Material and Methods: First, a pilot study was done to validate the increase of cortisol by performance. The data from the pilot study was used for sample size estimation via an adapted power analysis as well as the identification of important variables. These were then used in the randomization procedure of the main study. Second, a prospective randomized, double blinded, placebo-controlled cohort study was conducted. The main study included 45 sled dogs, assigning 23 dogs to the Nx4 group, and 22 dogs to the placebo group, to analyze plasma cortisol and plasma gastrin at four time points: before, directly after and 30 and 120 min after performance. Results: For the main target variable, area under the curve (AUC) of plasma cortisol, a significantly lower adjusted mean value in the Nx4 group compared to the placebo group (p = 0.031) was found. Plasma gastrin was also significantly reduced in the Nx4 group 30 min after performance (p = 0.023), resulting in a significantly reduced plasma gastrin AUC in the Nx4 group compared to the placebo group (p = 0.049). Discussion: Within the limitation of the study, the results carry implications for the usefulness of Nx4 to reduce exercise induced plasma cortisol and gastrin levels. The reduction of the exercise induced stress response could help to improve the welfare of high-performance sled dogs. Since activation of the hypothalamic-pituitary-adrenal axis resulting in increased cortisol is similar for exercise induced stress and psychologic stress, the same might be true independent of the stressor, making Nx4 potentially useful in any stressful situation for dogs.

The influence of carbohydrate ingestion on peripheral and central fatigue during exercise in hypoxia: A narrative review.

Hypoxia impairs aerobic performance by accelerating fatiguing processes. These processes may originate from sites either distal (peripheral) or proximal (central) to the neuromuscular junction, though these are not mutually exclusive. Peripheral mechanisms include decrements in muscle glycogen or fluctuations in intramuscular metabolites, whereas central responses commonly refer to reductions in central motor drive elicited by alterations in blood glucose and neurotransmitter concentrations as well as arterial hypoxemia. Hypoxia may accelerate both peripheral and central pathways of fatigue, with the level of hypoxia strongly dictating the degree and primary locus of impairment. As more people journey to hypoxic settings for work and recreation, developing strategies to improve work capacity in these environments becomes increasingly relevant. Given that sea level performance improves with nutritional interventions such as carbohydrate (CHO) ingestion, a similar strategy may prove effective in delaying fatigue in hypoxia, particularly considering how the metabolic pathways enhanced with CHO supplementation overlap the fatiguing pathways upregulated in hypoxia. Many questions regarding the relationship between CHO, hypoxia, and fatigue remain unanswered, including specifics on when to ingest, what to ingest, and how varying altitudes influence supplementation effectiveness. Therefore, the purpose of this narrative review is to examine the peripheral and central mechanisms contributing to fatigue during aerobic exercise at varying degrees of hypoxia and to assess the role of CHO ingestion in attenuating fatigue onset.

Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a stem cell-derived neoplasm characterized by dysplasia, uncontrolled expansion of monocytes, and substantial risk to transform to secondary acute myeloid leukemia (sAML). So far, little is known about CMML-initiating cells. We found that leukemic stem cells (LSC) in CMML reside in a CD34+/CD38- fraction of the malignant clone. Whereas CD34+/CD38- cells engrafted NSGS mice with overt CMML, no CMML was produced by CD34+/CD38+ progenitors or the bulk of CD34- monocytes. CMML LSC invariably expressed CD33, CD117, CD123 and CD133. In a subset of patients, CMML LSC also displayed CD52, IL-1RAP and/or CLL-1. CMML LSC did not express CD25 or CD26. However, in sAML following CMML, the LSC also expressed CD25 and high levels of CD114, CD123 and IL-1RAP. No correlations between LSC phenotypes, CMML-variant, mutation-profiles, or clinical course were identified. Pre-incubation of CMML LSC with gemtuzumab-ozogamicin or venetoclax resulted in decreased growth and impaired engraftment in NSGS mice. Together, CMML LSC are CD34+/CD38- cells that express a distinct profile of surface markers and target-antigens. During progression to sAML, LSC acquire or upregulate certain cytokine receptors, including CD25, CD114 and CD123. Characterization of CMML LSC should facilitate their enrichment and the development of LSC-eradicating therapies.

STAT5 is Expressed in CD34+/CD38- Stem Cells and Serves as a Potential Molecular Target in Ph-Negative Myeloproliferative Neoplasms.

Janus kinase 2 (JAK2) and signal transducer and activator of transcription-5 (STAT5) play a key role in the pathogenesis of myeloproliferative neoplasms (MPN). In most patients, JAK2 V617F or CALR mutations are found and lead to activation of various downstream signaling cascades and molecules, including STAT5. We examined the presence and distribution of phosphorylated (p) STAT5 in neoplastic cells in patients with MPN, including polycythemia vera (PV, n = 10), essential thrombocythemia (ET, n = 15) and primary myelofibrosis (PMF, n = 9), and in the JAK2 V617F-positive cell lines HEL and SET-2. As assessed by immunohistochemistry, MPN cells displayed pSTAT5 in all patients examined. Phosphorylated STAT5 was also detected in putative CD34+/CD38- MPN stem cells (MPN-SC) by flow cytometry. Immunostaining experiments and Western blotting demonstrated pSTAT5 expression in both the cytoplasmic and nuclear compartment of MPN cells. Confirming previous studies, we also found that JAK2-targeting drugs counteract the expression of pSTAT5 and growth in HEL and SET-2 cells. Growth-inhibition of MPN cells was also induced by the STAT5-targeting drugs piceatannol, pimozide, AC-3-019 and AC-4-130. Together, we show that CD34+/CD38- MPN-SC express pSTAT5 and that pSTAT5 is expressed in the nuclear and cytoplasmic compartment of MPN cells. Whether direct targeting of pSTAT5 in MPN-SC is efficacious in MPN patients remains unknown.

High-sensitivity chemiluminescence immunoassays for detection of growth hormone doping in sports.

BACKGROUND: Recombinant human growth hormone (rhGH) is abused in sports, but adequate routine doping tests are lacking. Analysis of serum hGH isoform composition has been shown to be effective in detecting rhGH doping. We developed and validated selective immunoassays for isoform analysis with potential utility for screening and confirmation in doping tests. METHODS: Monoclonal antibodies with preference for pituitary hGH (phGH) or rhGH were used to establish 2 pairs of sandwich-type chemiluminescence assays with differential recognition of rhGH (recA and recB) and phGH (pitA and pitB). We analyzed specimens from volunteers before and after administration of rhGH and calculated ratios between the respective rec- and pit-assay results. RESULTS: Functional sensitivities were <0.05 microg/L, with intra- and interassay imprecision < or =8.4% and < or =13.7%, respectively. In 2 independent cohorts of healthy subjects, rec/pit ratios (median range) were 0.84 (0.09-1.32)/0.81 (0.27-1.21) (recA/pitA) and 0.68 (0.08-1.20)/0.80 (0.25-1.36) (recB/pitB), with no sex difference. In 20 recreational athletes, ratios (median SD) increased after a single injection of rhGH, reaching 350% (73%) (recA/pitA) and 400% (93%) (recB/pitB) of baseline ratios. At a moderate dose (0.033 mg/kg), mean recA/pitA and recB/pitB ratios remained significantly increased for 18 h (men) and 26 h (women). After high-dose rhGH (0.083 mg/kg), mean rec/pit ratios remained increased for 32 h (recA/pitA) and 34 h (recB/pitB) in men and were still increased after 36 h in women. CONCLUSIONS: Using sensitive chemiluminescence assays with preferential recognition of phGH or rhGH, detection of a single injection of rhGH was possible for up to 36 h.

Quality of Life of Short-Statured Children Born Small for Gestational Age or Idiopathic Growth Hormone Deficiency Within 1 Year of Growth Hormone Treatment.

Aside from clinical endpoints like height gain, health-related quality of life has also become an important outcome indicator in the medical field. However, the data on short stature and health-related quality of life is inconsistent. Therefore, we examined changes in health-related quality of life in German children with idiopathic growth hormone deficiency or children born small for gestational age before and after 12 months of human growth hormone treatment. Children with idiopathic short stature without treatment served as a comparison group. At baseline, health-related quality of life data of 154 patients with idiopathic growth hormone deficiency (n = 65), born small for gestational age (n = 58), and idiopathic short stature (n = 31) and one parent each was collected. Of these, 130 completed health-related quality of life assessments after 1-year of human growth hormone treatment. Outcome measures included the Quality of Life in Short Stature Youth questionnaire, as well as clinical and sociodemographic data. Our results showed that the physical, social, and emotional health-related quality of life of children treated with human growth hormone significantly increased, while untreated patients with idiopathic short stature reported a decrease in these domains. Along with this, a statistically significant increase in height in the treated group can be observed, while the slight increase in the untreated group was not significant. In conclusion, the results showed that human growth hormone treatment may have a positive effect not only on height but also in improving patient-reported health-related quality of life of children with idiopathic growth hormone deficiency and children born small for gestational age.

Identification of a leukemia-initiating stem cell in human mast cell leukemia.

Mast cell leukemia (MCL) is a highly fatal malignancy characterized by devastating expansion of immature mast cells in various organs. Although considered a stem cell disease, little is known about MCL-propagating neoplastic stem cells. We here describe that leukemic stem cells (LSCs) in MCL reside within a CD34+/CD38- fraction of the clone. Whereas highly purified CD34+/CD38─ cells engrafted NSGhSCF mice with fully manifesting MCL, no MCL was produced by CD34+/CD38+ progenitors or the bulk of KIT+/CD34- mast cells. CD34+/CD38- MCL cells invariably expressed CD13 and CD133, and often also IL-1RAP, but did not express CD25, CD26 or CLL-1. CD34+/CD38- MCL cells also displayed several surface targets, including CD33, which was homogenously expressed on MCL LSCs in all cases, and the D816V mutant form of KIT. Although CD34+/CD38- cells were resistant against single drugs, exposure to combinations of CD33-targeting and KIT-targeting drugs resulted in LSC-depletion and markedly reduced engraftment in NSGhSCF mice. Together, MCL LSCs are CD34+/CD38- cells that express distinct profiles of markers and target antigens. Characterization of MCL LSCs should facilitate their purification and should support the development of LSC-eradicating curative treatment approaches in this fatal type of leukemia.

Secular trends in body mass index in German children and adolescents: a cross-sectional data analysis via CrescNet between 1999 and 2006.

To assess secular trends in alterations in body mass index (BMI) in German children and adolescents between 1999 and 2006, we performed an analysis using data from a computerized database (CrescNet) and focusing on the data ranges above the 97th percentile (P97) and below the median (P50). This cross-sectional assessment of BMI data used a total of 143 495 single values (73 290 males and 70 205 females aged 0.5-17.5 years) from screening and/or consulting visits at 1 of the 294 participating German pediatricians. Body mass index data were calculated from standardized measurements of body weight and height entered into the CrescNet database. Individual percentiles were estimated according to German reference data sets. Across all age groups, the respective mean value of children with BMI above P97 increased from 5.32% to 7.02% in boys and from 5.70% to 7.18% in girls between 1999 and 2006, whereas those below P50 decreased from 48.52% to 43.71% in boys and from 47.48% to 42.57% in girls. The proportions of obese children (above the 97th percentile) were significantly higher than estimated by German reference values throughout the study period. The significant increase in childhood obesity between 1999 and 2006 was more pronounced in boys compared to girls. In conclusion, the cross-sectional study performed at a large cohort of German children and adolescents reveals an alarming increase in the number of obese children and adolescents and an accompanied shift toward higher BMI values. As the number of children below the 50th centile decreases accordingly, the shift in the distribution panel of the German reference percentile curves affecting the whole population can be observed.

Impact of weight status on the onset and parameters of puberty: analysis of three representative cohorts from central Europe.

It is controversial whether obesity in children is associated with earlier onset of puberty and advanced appearance of distinct parameters of pubertal development. To investigate the impact of obesity on markers of the onset and parameters representing stages of puberty, we analyzed auxological parameters and secondary sex characteristics in three representative cohorts of Caucasian children. Body weight, height, peak height velocity and pubertal stages were evaluated in two recent German cohorts (CrescNet and Leipzig Schoolchildren), and a historical Swiss cohort. According to body mass index (BMI), children were classified into three weight groups of lean, overweight, or normal weight with limits defined below -1.28 and above +1.28 BMI SDS. Peak height velocity (PHV) occurred significantly later in lean compared to normal weight children in the CrescNet and Swiss cohort, while there was no difference between obese and normal weight children. There was a trend towards acceleration of parameters of puberty onset and progression in obese children in all three cohorts. Height SDS was significantly higher in obese children compared to normal weight peers, but after completion of pubertal development it was similar in adolescents. The impact of overweight on the acceleration of puberty seems to be slightly stronger in boys. Once girls have reached a critical weight for entering the process of maturation, further increase in body weight does not seem to advance the onset of puberty.

A prismatic case: A 31-year old man who did not miss his pituitary.

Combined pituitary hormone deficiency (CPHD) is a rare disorder resulting from impaired production of several pituitary hormones. This report describes the 30-year history of a patient who has apparently lived without a pituitary. The patient, born in 1976, experienced recurrent episodes of hypoglycaemia (as low as 2.9 mg/dl) in early childhood and showed elevated liver enzymes up to the age of two years without specific diagnosis. At the age of approximately 13 years, he first presented at our Department of Paediatric Endocrinology (University Hospital for Children and Adolescents, Leipzig) with signs of hypopituitarism and a height SDS of - 5.4, a high pitched voice and hypogenitalism. Endocrine testing confirmed panhypopituitarism (GH 1.3 ng/mL, LH 0.8 mU/mL, FSH 0.1 mU/ml, ACTH <1.0 pmol/l, TSH 1.0 mU/l) and substitution therapy was initiated. Magnetic resonance imaging (MRI) of the sella turcica showed a planar, hypoplastic and empty sella with pituitary stalk aplasia and ectopic neurohypophysis. Currently nearly 31 years of age, though taking his medication irregularly or not at all, he claims to be in good mental and physical condition irrespective of compliance or non compliance with substitution therapy. This case illustrates the importance of continued follow-up in patients with hypopituitarism and a systemic transferral of adolescents with CPHD to the care of adult endocrinologists.

The JAK2/STAT5 signaling pathway as a potential therapeutic target in canine mastocytoma.

BACKGROUND: Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. MATERIALS AND METHODS: We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1. RESULTS: Activated JAK2 and STAT5 were detected in both cell lines. The drugs applied were found to inhibit proliferation and survival in these cells with the following rank-order of potency: R763 > TG101348 > AZD1480 > pimozide > ruxolitinib > piceatannol. Moreover, synergistic anti-neoplastic effects were obtained by combining pimozide with KIT-targeting drugs (toceranib, masitinib, nilotinib, midostaurin) in NI-1 cells. CONCLUSION: The JAK2/STAT5 pathway is a novel potential target of therapy in canine mastocytoma.