Genetic disorders in the growth hormone-IGF-I axis

Growth is a complex process, regulated by multiple external and internal factors. Deviation from the normal growth pattern can be one of the first manifestations of an underlying disorder, disrupting the normal growth process. The growth hormone __ IGF-I axis plays a key role in regulating this growth process. This thesis focuses on growth disorders as a result of genetic defects in the GH-IGF-I axis. The aim of the thesis is to study the genotype-fenotype relationship in patients with a documented genetic defect in one of the components of the GH-IGF-I axis and to unravel the role of the GH-IGF-I axis in the complex process of growth and development throughout life. Two patients with a mutation in the GH releasing hormone receptor gene demonstrate that combined treatment of GH and gonadotropin-releasing hormone antagonists is very effective in increasing final height. The characteristics of the first male patient with a STAT5b mutation are described in detail. The fenotype of the first patient with an inactivating mutation of the IGF-I gene is described, as well as functional characteristics of the mutation. Finally the consequences of a genetic defect of the IGF-I receptor gene are discussed.LEI Universiteit LeidenNovo Nordisk Farma BV, Ipsen Farmaceutica BV, Pfizer BV, Ferring geneesmiddelen BV and Eli Lilly Nederland BVVroege ontwikkeling van hart, long en skele

Local corticosteroid injection versus Cyriax-type physiotherapy for tennis elbow

We performed a prospective, randomised trial on 106 patients to compare the effects of local corticosteroid injections with physiotherapy as advocated by Cyriax in the treatment of tennis elbow. The main outcome measures were the severity of pain, pain provoked by resisted dorsiflexion of the wrist, and patient satisfaction. At six weeks 22 of 53 patients in the injection group were free from pain compared with only three in the physiotherapy group. In the corticosteroid-treated group 26 patients had no pain on resisted dorsiflexion of the wrist compared with only three in the physiotherapy group. Thirty-five patients who had injections and 14 who had physiotherapy were satisfied with the outcome of treatment at six weeks. At the final assessment there were 18 excellent and 18 good results in the corticosteroid group and one excellent and 12 good results in the physiotherapy group. There was a significant increase in grip strength in both groups but those with injections had a significantly better result. After one year there were no significant differences between the two groups. Half of the patients, however, had received only the initial treatment, 20% had had combined therapy and 30% had had surgery. We conclude that at six weeks, treatment with corticosteroid injections was more effective than Cyriax physiotherapy and we recommend it because of its rapid action, reduction of pain and absence of side-effects

Recruitment of bone marrow derived cells during anti-angiogenic therapy in GBM:The potential of combination strategies

Glioblastoma (GBM) is a highly vascular tumor characterized by rapid and invasive tumor growth, followed by oxygen depletion, hypoxia and neovascularization, which generate a network of disorganized, tortuous and permeable vessels. Recruitment of bone marrow derived cells (BMDC) is crucial for vasculogenesis. These dells may act as vascular progenitors by integrating into the newly formed blood vessels or as vascular modulators by releasing pro-angiogenic factors. In patients with recurrent GBM, anti-vascular endothelial growth factor (VEGF) therapy has been evaluated in combination with chemotherapy, yielding improvements in progression-free survival (PFS). However, benefits are temporary as vascular tumors acquire angiogenic pathways independently of VEGF. Specifically, acute hypoxia following prolonged VEGF depletion induces the recruitment of certain myeloid cell subpopulations, which highly contribute to treatment refractoriness. Here we review the molecular mechanisms of neovascularization in relation to bevacizumab therapy with special emphasis on the recruitment of BMDCs and possible combination therapies for GBM patients. (C) 2014 Elsevier Ireland Ltd. All rights reserved

Cryptococcus neoformans

Cryptococcosis is the leading cause of life-threatening mycological disease of the central nervous system, with a high worldwide mortality and morbidity in immunocompromised patients.In the Netherlands from 1996 on incidence numbers are declining, in parallel with incidence numbers in the rest of the Western world. This decline is due to the introduction of highly active antiretroviral therapy (HAART). In countries that can not afford costs of HAART, like for example in Sub Saharan Africa and India, cryptococcal related infection are an enormous problem. C. neoformans enters the body by inhalation of poorly encapsulated yeast cells. In the lungs innate immune responses like phagocytosis of C. neoformans by resident macrophages (alveolar macrophages) take place. We developed a new, rapid and objective method to measure interaction between the yeast C. neoformans and adherent phagocytic cells. This method was used to investigate if surfactant proteins like surfactant protein A and D play a role in innate host defense against cryptococci.In contrast to many other micro-organisms like E. coli, M. tuberculosis and influenza A virus, pulmonary surfactant proteins do not support phagocytosis of C. neoformans. Cytokines that are present during the initiation ofresponse will determine whether CMI or B-cell development will take place. The time kinetics of cytokine release in PBMC of healthy donors stimulated with cryptococcal capsular polysaccharides indicate an autocrine-paracrine network regulation of the cytokines. Proinflammatory cytokines like TNF-aDPAF, IL-8 and fMLP. Another capsular component of C. neoformans Mannoprotein 4 (MP4) was found to potent inhibitor of PMN migration. Neutrophil infiltration into the central nervous system is a dual-edged sword in that it protects the tissue from infection and injury but can also be detrimental to the host. In diseases such as bacterial meningitis or cerebrovascular ischemia there is evidence that a high influx of PMN plays an adverse role in the pathogenesis of neurological damage Accordingly, it is now assumed that adjunctive therapeutic strategies with anti- inflammatory agents may favor neurological recovery. Therefore we will investigate the possibilities to use GXM and MP4 therapeutically

Multiple testing in orthopedic literature: a common problem?

BACKGROUND: Performing multiple tests in primary research is a frequent subject of discussion. This discussion originates from the fact that when multiple tests are performed, it becomes more likely to reject one of the null hypotheses, conditional on that these hypotheses are true and thus commit a type one error. Several correction methods for multiple testing are available. The primary aim of this study was to assess the quantity of articles published in two highly esteemed orthopedic journals in which multiple testing was performed. The secondary aims were to determine in which percentage of these studies a correction was performed and to assess the risk of committing a type one error if no correction was applied. METHODS: The 2010 annals of two orthopedic journals (A and B) were systematically hand searched by two independent investigators. All articles on original research in which statistics were applied were considered. Eligible publications were reviewed for the use of multiple testing with respect to predetermined criteria. RESULTS: A total of 763 titles were screened and 127 articles were identified and included in the analysis. A median of 15 statistical inference results were reported per publication in both journal A and B. Correction for multiple testing was performed in 15% of the articles published in journal A and in 6% from journal B. The estimated median risk of obtaining at least one significant result for uncorrected studies was calculated to be 54% for both journals. CONCLUSION: This study shows that the risk of false significant findings is considerable and that correcting for multiple testing is only performed in a small percentage of all articles published in the orthopedic literature reviewed

The immune tumour microenvironment of neuroendocrine tumours and its implications for immune checkpoint inhibitors

Immunotherapy in the form of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape in numerous types of advanced cancer. However, the majority of patients do not benefit from this treatment modality. Although data are scarce, in general, patients with low-grade neuroendocrine tumours (NETs) do not benefit from treatment with ICIs in contrast to patients with neuroendocrine carcinoma, in which a small subgroup of patients may benefit. Low- and intermediate-grade NETs predominantly lack factors associated with response to ICIs treatment, like immune cell infiltration and have an immunosuppressive tumour metabolism and microenvironment. In addition, because of its potential influence on the response to ICIs, major interest has been shown in the tryptophan-degrading enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). These enzymes work along the kynurenine pathway that deplete tryptophan in the tumour microenvironment. IDO and TDO are especially of interest in NETs since some tumours produce serotonin but the majority do not, which potentially deplete the precursor tryptophan. In this review we summarize the current knowledge on the immune tumour microenvironment of neuroendocrine tumours and implications for treatment with immune checkpoint inhibitors. We also discuss (targetable) factors in the NET tumour microenvironment that potentially modulate the anti-cancer immune response

Mixed Exocrine and Endocrine Carcinoma in the Stomach: A Case Report

We report a rare case of the coexistence of a gastric small cell neuroendocrine carcinoma with a gastric adenocarcinoma. A 62-year-old man presented with epigastric soreness for 1 month. Esophagogastroduodenoscopy revealed a Borrmann type I tumor at the lesser curvature of the lower body of the stomach. The patient underwent a distal gastrectomy with D2 lymph node dissection and the resected specimen exhibited a 3.5×3.5 cm sized, fungating lesion. Two separated, not intermingling, lesions with non-adenocarcinoma components encircled by well differentiated adenocarcinoma components were identified microscopically. The non-adenocarcinoma component showed neuroendocrine features, such as a solid and trabecular pattern, and the tumor cells showed a high nuclear grade with minimal cytoplasm, indistinct nucleoli, and positive response for synaptophysin, CD56. The final pathological diagnosis was a gastric mixed exocrine-endocrine carcinoma (MEEC) composed of an adenocarcinoma and small cell neuroendocrine carcinoma of the collision type