Low-dose chemotherapy in combination with COX-2 inhibitors and PPAR-gamma agonists in recurrent high-grade gliomas - a phase II study.

OBJECTIVES: Combined treatment approaches targeting tumor as well as other cells contributing to tumor progression may control chemorefractory malignancies. METHODS: A phase II trial was initiated to analyze the activity of continuously administered pioglitazone and rofecoxib combined with low-dose chemotherapy (capecitabine or temozolomide) in patients with high-grade gliomas (glioblastoma or anaplastic glioma). RESULTS: Fourteen patients were evaluable for response and toxicity. Major side effects were palmoplantar erythema, edema and motor neuropathy grade 3. Disease stabilizations lasting longer than 3 months were noted in 4 of 14 patients (29%). Clinical responses did not correspond to immunohistochemical staining for cyclooxygenase 2, peroxisome proliferator-activated receptor-gamma and CD31. DISCUSSION: The study demonstrates that this novel regimen is moderately active and well tolerated in patients with high-grade gliomas. As a comparably small proportion of patients responded, the regimen might only be suitable for a subset of highly selected patients.

Tackling the climate targets set by the Paris Agreement (COP 21): Green leadership empowers public hospitals to overcome obstacles and challenges in a resource-constrained environment.

The healthcare sector itself contributes to climate change, the creation of hazardous waste, use of toxic metals such as mercury, and water and air pollution. To mitigate the effect of healthcare provision on the deteriorating environment and avoid creating further challenges for already burdened health systems, Global Green Hospitals was formed as a global network. Groote Schuur Hospital (GSH), as the leading academic hospital in Africa, joined the network in 2014. Since then, several projects have been initiated to reduce the amount of general waste, energy consumption and food waste, and create an environmentally friendlier and more sustainable hospital in a resource-constrained public healthcare setting. We outline the various efforts made to reduce the carbon footprint of GSH and reduce waste and hazardous substances such as mercury and polystyrene, and elaborate how obstacles and resistance to change were overcome. The hospital was able to halve the amount of coal and water used, increase recycling by 50% over 6 months, replace polystyrene cups and packaging with Forest Stewardship Council recyclable paper-based products, reduce the effect of food wastage by making use of local farmers, and implement measures to reduce the amount of expired pharmaceutical drugs. To improve commitment from all involved roleplayers, political leadership, supportive government policies and financial funding is mandatory, or public hospitals will be unable to tackle the exponentially increasing costs related to climate change and its effects on healthcare.

Growth retardation in Turner syndrome: aneuploidy, rather than specific gene loss, may explain growth failure.

The etiology of short stature (SST) in Turner syndrome (TS) is still a subject of speculation. A variety of hypotheses have been put forward, from SST as a result of increased intrauterine tissue pressure after fetal lymphedema to haploinsufficiency of a specific growth gene(s). These hypotheses have various statistical-auxological implications on the growth distribution in TS. Empirical research has provided no clear evidence for any of these theories, but the well known correlation between patients' and midparental height (MPH) could be established. The influence of undetected mosaic status has often been cited as a major problem in the investigation of growth in TS. However, an assessment of mosaic status (simultaneous analysis of karyotype and phenotype) and its effect on growth with inclusion of MPH has been not yet carried out for a large sample. The aim of this study was to evaluate growth and its complex relationship to mosaic status and MPH in TS. In a mixed cross-sectional and longitudinal study we retrospectively analyzed the auxological and clinical data of 447 patients with a pure loss of X-chromosomal material (n = 381 with 45,X0; n = 66 mosaics). The 447 patients were selected from a series of 609 consecutive patients with TS. To assess the effect of mosaic status on growth, we computed a bifactorial analysis of variance (phenotype, karyotype), including MPH as a covariate. In line with the mosaic hypothesis, we found a correlation between individual loss of X-chromosomal material and phenotypical expressivity. In contrast, no correlation was found with respect to growth. With respect to MPH, we found growth retardation (GR) even in those patients with "normal" height above the third percentile (-2 or more SD score). The interindividual variance of GR in TS (comparable to growth variance in the normal population) seems to be unrelated to other TS-specific factors (e.g. mosaic status or single gene loss). Instead, both interindividual variance and the global growth shift distribution are best explained by the presence of an unspecific aneuploidic effect. Furthermore, consideration of patient height in relation to MPH should lead to a better understanding of the nature of GR in TS than the commonly used, strictly qualitative definition of SST.

Prolactin blocks glucocorticoid induced cell death by inhibiting the disruption of the mitochondrial membrane.

Prolactin (PRL) has been reported to inhibit dexamethasone (Dex) induced cell death. Nevertheless, the mechanism through which PRL exerts its protective effect is still not unravelled. Here, we analyse the effect of PRL at different stages of the glucocorticoid (GC) apoptotic pathway in PRL dependent cells (Nb2 cells). PRL blocks completely the GC induced loss of the mitochondrial transmembrane potential (delta psi(m)) and consequently phosphatidylserine (PS) exposure and loss of DNA content. Although PRL promotes an upregulation of the bcl-2 expression, simultaneous addition of PRL to GC fails to maintain even the normal levels of this anti-apoptotic protein. This finding excludes a critical role for bcl-2 in the PRL protective effect against GC. GC induced delta psi(m) disruption can be inhibited by the ICE-like inhibitor zVAD-fmk but not by ICE inhibitor tetrapeptide acetyl-Tyr-Val-Ala-Asp.chloromethylketone (YVAD-cmk) nor by caspase-3 inhibitor zDEVD. It can be speculated that PRL blocks delta psi(m) disruption by inhibiting an unknown caspase activated by GC.

Prolactin: a hormone at the crossroads of neuroimmunoendocrinology.

Prolactin (PRL), secreted by the pituitary, decidua, and lymphoid cells, has been shown to have a regulatory role in reproduction, immune function, and cell growth in mammals. The effects of PRL are mediated by a membrane-bound receptor that is a member of the superfamily of cytokine receptors. Formation of a trimer, consisting of one molecule of ligand and two molecules of receptor, appears to be a necessary prerequisite for biological activity. The function of these receptors is mediated, at least in part, by two families of signaling molecules: Janus tyrosine kinases (JAKs) and signal transducers and activators of transcription (STATs). To study these receptors, we have used two approaches: mutational analysis of their cytoplasmic domains coupled with functional tests and inactivation (knockout) of the receptor gene by homologous recombination in mice. We have produced mice by gene targeting in embryonic stem cells carrying a germline null mutation of the prolactin receptor gene. Heterozygous (+/-) females show almost complete failure to lactate, following their first, but not subsequent pregnancies. Homozygous (-/-) females are infertile as a result of multiple reproductive abnormalities, including ovulation of premiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Half of the homozygous males are infertile or show reduced fertility. In view of the wide-spread distribution of PRL receptors, other phenotypes including those on the immune system, are currently being evaluated in -/- animals. This study establishes the prolactin receptor as a key regulator of mammalian reproduction and provides the first total ablation model to further study the role of the prolactin receptor and its ligands.

Early determination of the reproductive number for vector-borne diseases: the case of dengue in Brazil.

OBJECTIVE: To evaluate a new method of deriving the reproductive number for vector-borne diseases from the early epidemic curves for vector-borne diseases with incubations in the vectors and in the hosts. METHOD: We applied the model to several dengue epidemics in different climatic regions of Brazil: Brasilia, Belém, Fortaleza, Boa Vista. RESULTS: The new method leads to higher estimates of the reproductive number than previous models. CONCLUSION: At present, Aedes aegypti densities, the meeting of more compatible strains of viruses and mosquitoes, may lead to re-emergence of urban yellow fever epidemics.

Clinical management of nipple discharge in neonates and children.

Bloody nipple discharge is a rare but distressing finding in neonates and infants. We report an 8-month-old boy who showed bilateral bloody nipple discharge for 5 months without signs of infection. Ultrasound examination revealed dilated mammary ducts. This benign phenomenon is most likely caused by mammary duct ectasia. On the background of the reviewed literature, intensive investigations should only be performed in neonates and infants if bloody nipple discharge is unilateral, continues, expands in size or shows signs of inflammation. We discuss the clinical management of nipple discharge during infancy and childhood.

Severe thrombosis during treatment with ethinylestradiol for tall stature.

High-dose estradiol therapy for reduction of final height may be complicated by severe side effects such as deep vein thrombosis. We report a 14.6-year-old girl with tall stature. In order to reduce final height she was treated with ethinylestradiol and medroxyprogesterone. After arthroscopy she suffered acute deep venous thrombosis of her left leg. Despite being monitored at short intervals, coagulation parameters such as AT III and protein C indicated no development of thrombosis. Medical height reduction with estrogen should be accompanied by heparinisation during longer-lasting periods of immobilisation.

[Principles and clinical significance of insulin-like growth factors/somatomedins]. / Grundlagen und klinische Bedeutung der Insulin-like Growth Factors/Somatomedine.

The Insulin-like Growth Factors (IGFs) or Somatomedins are polypeptide growth factors which are similar to insulin in respect to their aminoacid sequence, structure and biologic activities. The IGFs bind to high affinity receptors which are present on many cells and in many tissues. In the circulation the IGFs are bound to transport (binding) proteins (IGF-BPs). In this review the physiologic role, the basic chemistry and the gene expression of this family of growth factors is summarized systematically. The pathophysiology of growth disorders, diabetes mellitus, malnutrition, liver and kidney disease in relation to the IGFs as well as the therapeutic and diagnostic potentials of these peptides are discussed in detail.

[Acute acne fulminans et conglobata after the end of high-dose testosterone therapy for hereditary tall stature]. / Akute Akne fulminans et conglobata nach Beendigung einer hochdosierten Testosterontherapie bei konstitutionellem Hochwuchs.

We report on a 13.2 years old boy who was treated for tall stature (expected target height of 204.8 +/- 5.4 cm) with high dose of testosterone. Therapy for height reduction was started with testosterone injections (250 mg Testoviron Depot i.m.) once a week. There occurred no side effects during 6 months of treatment. Maximal blood testosterone concentration was 1209 ng/dl (norm: 300-1000 ng/dl). After six months height reduction was successful with a final height of 192.7 cm. Four weeks after cessation of therapy a severe acne conglobata et fulminans appeared in the face, the back and the breast lacking any familial predisposition for acne or other skin diseases. The exacerbation was accompanied by decreased endurance, nausea and indisposition. Leucocytosis with left shift, elevation of blood sedimentation rate and C-reactive protein in addition with an increase of immunglobulin G (IgG) were detectable. At that time testosterone concentration was 192 ng/dl. Systemic treatment was started with isoretretinoin therapy (retinoid 13-cis retinacid (Roaccutan) 0.3 mg/kg), 8 mg methylprednisolon (Urbason) and cefaclor (Panoral). Local therapy included external disinfectants. After 4 months of treatment infection parameters disappeared and the acne healed with visible skin defects and severe scars. This is the first case report on acne conglobata et fulminans that appeared after cessation of testosterone therapy. High testosterone treatment seems to trigger the outbreak of sex hormone related skin disorders such as acne fulminans. It can be presumed that testosterone leads to longer lasting induction of androgen receptors resulting in acne fulminans even four weeks after treatment. Patients asking for hormonal height reduction should be aware of this rare but serious side effect.

G-CSF, GM-CSF and IL-6 levels in cord blood: diminished increase of G-CSF and IL-6 in preterms with perinatal infection compared to term neonates.

AIM: The objectives of this study were 1) to clarify the physiologic regulation of cytokines such as IL-6, G-CSF and GM-CSF in preterm and term neonates and 2) to evaluate the influence of perinatal stress and infection on endogenous cytokine levels. METHOD: We examined cord blood levels of G-CSF, GM-CSF and IL-6 using a bioassay in 43 term and 44 preterm neonates. RESULTS: Compared to normal neonates (G-CSF: mean (m) = 97.6 +/- 16.3 pg/ml; IL-6: m = 20.2 +/- 4.6 pg/ml), we found elevated G-CSF levels in newborns with perinatal stress (m = 247.1 +/- 72.1 pg/ml; p = 0.003) and increased levels for G-CSF (m = 8980.9 +/- 4388 pg/ml; p = 0.0003) and IL-6 (m = 705 +/- 322.3 pg/ml; p = 0.025) in neonates with infection. Term newborns with infection had higher G-CSF levels than preterms (m = 15575 +/- 9374 pg/ml versus m = 5384.1 +/- 4470.9 pg/ml; p = 0.024). G-CSF levels of newborns with infection were correlated with birth weight (r = 0.50; p = 0.024) but not with gestational age (r = 0.40; p = 0.057). GM-CSF was only detectable in cord blood in 4 cases of normal healthy neonates. CONCLUSIONS: The response of G-CSF levels in preterms to infection is diminished. Body cell mass is more important than gestational age to provide high G-CSF levels during states of infection.

IL-6 and G-CSF levels in amniotic fluid during the second trimester in normal and abnormal pregnancies.

Activity levels of cytokines were measured by stimulation of the cell lines NFS-60, 7TD1, and TF-1. In 39 samples of amniotic fluid, levels of Granulocyte-Stimulating Factor (G-CSF) were 1434 +/- 2063 (mean +/- SD) and of Interleukin (IL-6) 546 +/- 1071 pg/ml; Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) was not detectable. IL-6 was correlated to G-CSF (r = 0.3; p = 0.003). G-CSF (p = 0.0002) and IL-6 (p = 0.006) were influenced by Alpha-Fetoprotein (AFP) and G-CSF by rhesus-incompatibility (p = 0.0004). These findings suggest that cytokines such as IL-6 and G-CSF play some role in physiological and pathological pregnancy.

Diabetes insipidus due to hypophysitis.

Central diabetes insipidus is a chronic disorder which in most patients occurs secondary to tumor, infection, trauma or other lesions. In about 20-30% of patients etiology is unclear, however a destructive autoimmune process in the hypophysis may play a role. We report the case of an 18-year-old girl with central diabetes insipidus. Vasopressin levels were typically decreased. Examinations performed 1.5 years after manifestation showed no pathologic changes on MRI and no additional endocrine disorder. MRI was repeated 1.5 years later whereon a thickening of the pituitary stalk as a typical sign of hypophysitis was apparent. No other reasons could be found for the vasopressin deficiency. The finding of hypophysitis in our patient 3 years after disease manifestation suggests that the characteristic MRI changes may take as long as 3 years to become apparent.

Peripubertal perturbations in elite gymnasts caused by sport specific training regimes and inadequate nutritional intake.

Low body fat masses of elite female gymnasts are favoured for the current aesthetic appeal required for complex movements performed by the gymnasts. Optimal nutritional intake relative to physical training regimes is essential for pubertal development. Here we evaluate how high intensity training in combination with nutritional intake affects pubertal development. Twenty-two female (13.6 +/- 1.0 years) and 18 male (12.4 +/- 1.6 years) elite gymnasts from national cadres were enlisted in this study. Skeletal maturation and hormonal levels of the hypophyseal, gonadal, and adrenal axes were estimated. Prepubertal and pubertal stages were determined, and body composition was measured using two indirect methods. Whereas female gymnasts showed bone retardation (1.7 years), reduced height potential, minimal fat mass (4.3 +/- 1.3 kg), no significant increase in pubertal oestradiol levels (17.6 +/- 4.2 pg/ml vs. 23.9 +/- 13.4 pg/ml), and delayed menarche (2.3 years), male gymnasts displayed virtually unaltered pubertal development due to different training regimes. Nutritional intake was insufficient in all gymnasts although to a lesser extent for male gymnasts. Intensive physical training of elite female gymnasts combined with inadequate nutritional intake can alter the normal pattern of pubertal development. In female gymnasts the onset of menarche can be influenced by keeping the amount of fat mass low. There is a peripubertal change favouring fat mass over muscle mass in females while there is a net gain of muscle mass during pubertal development in males.

Oestrogen treatment of constitutional tall stature: a risk-benefit ratio.

Oestrogens are given in high doses for the treatment of tall stature in girls. The aim of this study was to obtain data considering efficiency, side effects, and acceptance of the treatment of 50 constitutionally tall girls treated with conjugated oestrogens (7.5-11.25 mg/day). The mean (SD) adult height predictions were 188.3 (4.4) cm and the achieved height was 5.2 (3.3) cm less than the predicted height. A greater reduction from final predicted height occurred when treatment was started at an early bone age (< 13.0 years) and with a remaining growth potential of greater than 10 cm. Even postmenarcheal girls, however, had a mean reduction of 4.8 (3.2) cm. The main side effects were considerable weight gain (> 10 kg), an increase in triglyceride concentrations (37.5% of the patients), and increased platelet aggregation (60% of the patients). Altogether 84.6% of the patients were satisfied with the treatment and 15.4% regretted having had it.

[Effect of high performance sports on puberty development of female and male gymnasts]. / Auswirkungen des Hochleistungssports auf die Pubertätsentwicklung von Kunstturnerinnen und Kunstturnern.

High impact training may influence the pubertal development of athletes. The effects of high intensity training on pubertal development of female and male elite gymnasts are presented. 22 female and 18 male elite gymnasts were enlisted in this study. Prepubertal and pubertal stages were determined and hormonal levels regarding the hypophyseal, gonadal and adrenal axes were measured. The LH/FSH ratio necessary for the advancement of full pubertal maturation was assessed at 13.9 amd 13.0 years in female and male gymnasts, respectively. Female gymnasts demonstrated, on average, a delayed bone age of 1.7 years compared to their chronological age, whereas both bone and chronological age were identical in male gymnasts. There were no significant pubertal increase of estrogen levels in female gymnasts during their peripubertal development indicating a low amount of fat mass in female elite gymnasts. Intensive physical training of elite female gymnasts combined with inadequate nutritional intake markedly affect pubertal development. These peripubertal effects are not observable in male gymnasts due to different training regimes in male and female elite gymnast. Regular monitoring of female gymnast during their vulnerable growth phase is necessary to minimize life-long physiological and psychological side effects of high impact training.

[Nutritional behavior of female and male high performance gymnasts]. / Ernährungsverhalten bei weiblichen und männlichen Hochleistungsturnern.

Elite gymnasts pass through their whole physical and intellectual development with intensive physical training. In this period malnutrition can lead to delayed pubertal development with insufficient growth spurt and an increased incidence of stress fractures or osteoporoses. Different aspects about nutrition like body composition, objective and subjective eating-behaviour and sex-specific differences will be evaluated in our study. We examined 22 elite female gymnasts (age: median = 13.5 [12.0-16.1] years) und 19 elite male gymnasts (age: median = 12.3 [10.1-14.8] years). The following anthropometric measurements were carried out: weight, length, body mass index, upper arm circumference, arm muscle area, triceps skinfold, arm fat area. Eating diaries were compared with the recommendations of the German Federation of Nutrition and subjective eating behaviour was evaluated by questionnaires. Measurement of body composition showed an increase of musclemass at the cost of fatmass. The girls were smaller and leaner than the boys. Caloric intake in both groups was insufficient. Moreover the girls showed a tendency towards pathologic eating behaviour.

Hypoleptinaemia in patients with anorexia nervosa and in elite gymnasts with anorexia athletica.

Leptin, the product of the ob-gene, is specifically released by adipocytes. In addition to its metabolic function it seems to affect the feedback-mechanisms of the hypothalamic-pituitary-gonadal-axis. We studied 13 female juvenile elite gymnasts with anorexia athletica (AA) and 9 female patients with anorexia nervosa (AN) regarding the relation between leptin, fat stores, and the reproductive hormone levels. Leptin levels in females with anorexia nervosa (Tanner stage B4 [median]; mean age: 17.8 +/- 1.7 years) were low (2.9 +/- 2.7 microg/L), and were related to body mass index (BMI) (r = 0.71; p = 0.03) and percentage body fat mass (r = 0.78; p = 0.01). Leptin levels of the elite gymnasts were even more decreased (1.2 +/- 0.8 microg/L) caused by the low amount of fat stores. Leptin correlated with BMI (r= 0.77; p = 0.004) and the percentage body fat mass (r = 0.6; p = 0.04). In elite gymnasts leptin levels correlated with CA showing an age-dependent increase (r= 0.59; p = 0.04). Oestradiol was secreted at a low level in both groups (AN: 25.6 +/- 17.4 microg/L; AA: 24.4 +/- 13.5 microg/L). A delay in menarche and a retarded bone maturation occurred in AA. Our results clearly show that leptin levels are low in restrained eaters. Leptin levels represent the fat stores in the body and play a permissive role for female pubertal development. There is evidence that the mechanisms leading to a dysregulation of the reproductive-axis in patients with AN are comparable with those leading to delayed puberty in juvenile elite gymnasts with AA. This implies that AN and AA are overlapping groups and AA can lead to the development of AN.

Hypoleptinemia in female and male elite gymnasts.

BACKGROUND: Elite gymnasts favour low body fat mass as the current aesthetic ideal required for complex movements in this sports discipline. Pubertal development and growth are retarded in juvenile gymnasts. Leptin, the protein product of the ob-gene, is secreted by fat cells. Besides its role in regulation of body weight, leptin also stimulates the reproductive axis. We investigated various serum hormones including leptin, body composition and nutrition in cohorts of female and male elite gymnasts to elucidate if there is a relationship between leptin levels and delayed puberty in elite gymnasts. MATERIALS AND METHODS: Twenty-two female and 18 male elite gymnasts were enrolled in this study. Pubertal stage, various hormonal levels and body composition were determined and nutritional intake was assessed. Leptin was analysed using a specific RIA. RESULTS: Pubertal development and growth were delayed in the study group, especially in girls. The percentage of body fat was reduced as compared to a normal age-matched population: 14.4% versus 21.9% in girls and 10.4% versus 15.1% in boys. Serum leptin levels were decreased, especially in pubertal girls, and did not show the normal developmental pattern with a steady increase in girls and a peak in boys of pubertal stage 2. In all gymnasts leptin levels correlated with the amount of fat mass (r = 0.6, P = 0.005 in girls; r = 0.44, P = 0.038 in boys). When leptin levels were transformed into standard deviation scores (SDS) it became obvious that the gymnasts, especially pubertal females, had significantly lower values than normal controls of the same sex, pubertal stage and body mass index (BMI): leptin SDS (BMI) = -1.21 and -3.99 in prepubertal and pubertal girls, - 0.94 and -0.91 in prepubertal and pubertal boys, respectively. When leptin SDS were based on % body fat instead of BMI, mean values were still significantly decreased compared to normal controls: -1.05 in girls (P < 0.001) and -0.60 in boys (P = 0. 025). CONCLUSIONS: Adjustment of serum leptin levels in elite gymnasts for gender, pubertal stage and BMI or % body fat reveals inappropriately low values. The reason for this hypoleptinemia is most probably insufficient caloric intake. The data suggest that hypoleptinemia in turn causes delayed puberty and growth in this particular group of athletes.