Pathogenesis of vestibular schwannoma in ring chromosome 22

<p>Abstract</p> <p>Background</p> <p>Ring chromosome 22 is a rare human constitutional cytogenetic abnormality. Clinical features of neurofibromatosis type 1 and 2 as well as different tumour types have been reported in patients with ring chromosome 22. The pathogenesis of these tumours is not always clear yet.</p> <p>Methods</p> <p>We report on a female patient with a ring chromosome 22 presenting with severe mental retardation, autistic behaviour, café-au-lait macules and facial dysmorphism. Peripheral blood lymphocytes were karyotyped and array CGH was performed on extracted DNA. At the age of 20 years she was diagnosed with a unilateral vestibular schwannoma. Tumour cells were analyzed by karyotyping, array CGH and <it>NF2 </it>mutation analysis.</p> <p>Results</p> <p>Karyotype on peripheral blood lymphocytes revealed a ring chromosome 22 in all analyzed cells. A 1 Mb array CGH experiment on peripheral blood DNA showed a deletion of 5 terminal clones on the long arm of chromosome 22. Genetic analysis of vestibular schwannoma tissue revealed loss of the ring chromosome 22 and a somatic second hit in the <it>NF2 </it>gene on the remaining chromosome 22.</p> <p>Conclusion</p> <p>We conclude that tumours can arise by the combination of loss of the ring chromosome and a pathogenic <it>NF2 </it>mutation on the remaining chromosome 22 in patients with ring chromosome 22. Our findings indicate that patients with a ring 22 should be monitored for NF2-related tumours starting in adolescence.</p

The effects of short - and long-term metformin therapy on cytokine levels in polycystic ovary syndrome

Introduction: Over a third of women with polycystic ovary syndrome (PCOS) display glucose intolerance and multiple risk factors for cardiovascular disease, including central obesity and insulin resistance. Cytokines like interleukin-6 (IL-6) and TNF-• and inflammatory markers like CRP and MCP-1 have recently been implicated as important links in the development of cardiovascular disease in human obesity and type 2 Diabetes. Metformin, an oral euglycaemic agent, is used as treatment for women with PCOS and provides a model to study cytokine regulation. Subjects and Methods: We determined circulating levels of inflammatory markers (hs-CRP and MCP-1) and Cytokines (IL-6, sTNFRI and sTNFRII, leptin and adiponectin) in 59 women (mean BMI: 26.9±5.9 kg/m²; age: 29±5.1 years) with PCOS of whom 37 were retested after receiving a therapeutic trial of Metformin (1500 mg/day) for 6 weeks and 6 months. In this way, we could study the response of adipose tissue-derived cytokines and inflammatory markers to weight loss and insulin sensitization. Fasting metabolic and hormone profiles were also recorded. Thirty six healthy women who were closely matched for BMI and age comprise the control group. Results: Lean women with PCOS had higher LH and Androstenedione and lower adiponectin levels (p=0.03) compared to lean controls. Obese women with PCOS had higher LH, Androstenedione and IL-6 levels (p=0.04) = 0.004) compared to obese controls. IL-6 levels correlated significantly with measures of adiposity (BMI r=0.55, p<0.001) and indices of insulin resistance (fasting insulin r=0.42, p=0.002; HOMA-R r=0.47 p<0.001). A very strong association was found between IL-6 and hs-CRP levels (r=0.59, p<0.001). However, adiposity as well as insulin resistance seems to account for most of the variability of IL-6 in women with PCOS. While there was a close association between CRP and BMI and HOMA-R, IL-6 was mainly regulated hs-CRP with the independent contribution of insulin resistance. In a subset of lean and obese patients (total n=37; Obese=25; Lean=12) 6 weeks of metformin therapy produced a significant reduction in BMI (p<0.001), waist (p<0.001), hs-CRP (p<0.01), MCP-1 (p=0.03) and leptin levels (p=0.03), but not in IL-6, sTNF-RI & sTNF-RII or adiponectin levels. Six months of metformin therapy compared to baseline produced reduction in BMI (p<0.001) and waist (p=0.001), HOMA-R (p=0.01), IL6 (p=0.002), sTNF-RII (p=0.05) and leptin levels (p=0.004), which were statistically significant, but not in hsCRP, MCP -1 or adiponectin levels. Conclusions: Our findings suggest that in women with PCOS obesity as well as insulin resistance is the main determinants of IL-6. The variability of hs-CRP is most strongly accounted with IL-6 levels with the independent contribution of insulin resistance. Metformin therapy facilitates weight loss, which is reflected by a reduction in hs-CRP, MCP-1 and leptin levels short-term and a reduction of IL-6, sTNFRII, HOMA-R and leptin levels long-term. It seems likely that fat mass reduction has to reach a particular level before changes in adipose tissue-derived cytokine levels become apparent. Metformin-induced reduction of hs-CRP levels prior to any significant changes in insulin resistance or IL-6 may involve different mechanisms of action. Finally, the anti-inflammatory properties of metformin may explain, at least in part, its cardio protective effects.Εισαγωγή: Η υψηλής ευαισθησίας C-αντιδρώσα πρωτεΐνη (hs-CRP) και οι κυτταροκίνες, όπως η Ιντερλευκίνη-6 (IL-6) και ο παράγοντας TNF-α, έχουν ενοχοποιηθεί ως σημαντικοί παράγοντες ανάπτυξης καρδιαγγειακής νόσου σε ασθενείς με παχυσαρκία και σε διαβητικούς τύπου 2 (ΣΔΤ2), με την CRP να υπερέχει ως προς την ικανότητα πρόβλεψης καρδιαγγειακών συμβαμάτων. Δεδομένα πρόσφατων μελετών έχουν δείξει ότι η θεραπεία με Μετφορμίνη -ενός αντιυπεργλυκαιμικού φαρμάκου- μπορεί να αποτρέψει τον καρδιαγγειακό κίνδυνο ασθενών με διαταραγμένη ανοχή στην γλυκόζη και ΣΔΤ2, ανεξάρτητα από την βελτίωση που επιφέρει στις μεταβολικές παραμέτρους, με άγνωστο μέχρι σήμερα μηχανισμό. Η Μετφορμίνη έχει επίσης χρησιμοποιηθεί επιτυχώς ως θεραπεία σε γυναίκες με Σύνδρομο Πολυκυστικών Ωοθηκών (ΣΠΩ), πάνω από το ένα τρίτο των οποίων εμφανίζει διαταραγμένη ανοχή στην γλυκόζη και πολλαπλούς παράγοντες κινδύνου για καρδιαγγειακή νόσο, όπως κεντρική παχυσαρκία και ινσουλινο-αντίσταση. Σκοπός-Μέθοδοι: Σκοπός της παρούσας μελέτης ήταν η εκτίμηση των επιπέδων στη συστηματική κυκλοφορία μιας σειράς φλεγμονωδών δεικτών και κυτταροκινών σε γυναίκες με ΣΠΩ (n=59), μέσος όρος BMI: 26.9±5.9 kg/m² και μέσος όρος ηλικίας: 29±5.1 χρόνια) και η αξιολόγηση της δράσης της Μετφορμίνης (μετά από έξι εβδομάδες και έξι μήνες θεραπείας) σε 37 από αυτές. Την ομάδα ελέγχου αποτέλεσαν 36 υγιείς γυναίκες της ίδιας ηλικίας και ΒΜΙ. Αποτελέσματα: Οι αδύνατες γυναίκες με ΣΠΩ παρουσίαζαν υψηότερα επίπεδα LH και Ανδροστενδιόνης και χαμηλότερα επίπεδα αδιπονεκτίνης (p=0.03) σε σύγκριση με τις υγιείς μάρτυρες. Οι παχύσαρκες γυναίκες με ΣΠΩ παρουσίαζαν υψηλότερα επίπεδα LH, Ανδροστενεδιόνης και IL-6 (p=0.04) και χαμηλότερα επίπεδα αδιπονεκτίνης (p=0.004) σε σύγκριση με την ομάδα ελέγχου. Τα επίπεδα της IL-6 παρουσίασαν σημαντική συσχέτιση με την hs-CRP (r=0.60, p<0.001), το BMI (r=0.70, p<0.001) και την αντίσταση στην ινσουλίνη (HOMA-R r=0.49, p=0.001). Τα επίπεδα της IL-6 καθόριζαν τόσο η παχυσαρκία όσο και η ινσουλινοαντίσταση, με την IL-6 να είναι ο κύριος καθοριστικός παράγοντας των επιπέδων της CRP με την ανεξάρτητη συμμετοχή και της ινσουλινοαντίστασης. Η θεραπεία με Μετφορμίνη για 6 εβδομάδες οδήγησε σε σημαντική μείωση του BMI της περιμέτρου μέσης και των επιπέδων στη συστηματική κυκλοφορία των hs-CRP (p=0.01), MCP-1 (p=0.03) και λεπτίνης (p=0.03), αλλά όχι των επιπέδων των IL-6, sTNF-RI & sTNF-RII ή αδιπονεκτίνης. Η θεραπεία Μετφορμίνη για 6 μήνες οδήγησε σε σημαντική μείωση του BMI (p<0.001), περιμέτρου μέσης (p=0.001), HOMA-R (p=0.01) και των επιπέδων της IL-6 (p=0.002), sTNF-RII (p=0.05) και λεπτίνης (p=0.004) αλλά όχι και σε στατιστικά σημαντική μείωση των hs-CRP, MCP-1 ή αδιπονεκτίνης σε σύγκριση με τη βασική φάση. Τέλος, τόσο η βραχυπρόθεσμη, όσο και η μακροπρόθεσμη θεραπεία με μετφορμίνη οδήγησε σε στατιστικά σημαντική βελτίωση (p<0.001) στο ρυθμό του καταμήνιου κύκλου των γυναικών με ΣΠΩ. Συμπεράσματα: Στις γυναίκες με ΣΠΩ τόσο η παχυσαρκία, όσο και η ινσουλινοαντίσταση αποτελούν τους κύριους καθοριστικούς παράγοντες των επιπέδων της IL-6, η οποία με τη σειρά τη ρυθμίζει τα επίπεδα της hs-CRP με την ανεξάρτητη συμμετοχή και της ινσουλινοαντίστασης. Η θεραπεία με Μετφορμίνη διευκολύνει την απώλεια βάρους, η οποία αντανακλάται στη μείωση των επιπέδων των CRP και MCP-1 βραχυπρόθεσμα, και των IL-6 και sTNF-RII μακροπρόθεσμα. Φαίνεται ότι η απώλεια του λιπώδους ιστού πρέπει να φτάσει σε κάποιο συγκεκριμένο επίπεδο πριν γίνου αντιληπτές οι αλλαγές στα επίπεδα των κυτταροκινών. Η μείωση των επιπέδων της hs-CRP χωρίς την πρηγούμενη σημαντική βελτίωση των επιπέδων της IL-6 ή της ινσουλινοαντίστασης συνηγορεί για τη συμμετοχή διαφορετικών μηχανισμών δράσης της Μετφορμίνης. Τέλος, τα παραπάνω μας οδηγούν στο συμπέρασμα ότι η μετφορμίνη παρουσιάζει αντιφλεγμονώδεις δράσεις που πιθανά εξηγούν τις καρδιοπροστατευτικές της ιδιότητες

A Greek Family with a Follicular Variant of Familial Papillary Thyroid Carcinoma: TCO, MNG1, fPTC/PRN, and NMTC1 Excluded as Susceptibility Loci

The familial form of nonmedullary thyroid carcinoma (FNMTC) has been recognized as a distinct clinical entity and is characterized by multifocality and a more severe phenotype than its sporadic counterpart. The majority of FNMTC pedigrees are small in size, show variable modes of inheritance, and may present with a variety of additional benign thyroid disorders. The existence of marked phenotypic differences between FNMTC families suggests that there is genetic heterogeneity. Recent studies have mapped a susceptibility locus for FNMTC at 2q21. This locus appears particular relevant to families with at least one case of the follicular variant of papillary thyroid cancer (fvPTC). We describe the clinical and pathologic characteristics of a large threegeneration fPTC kindred, with two of the four PTC patients presented with the follicular variant of PTC. It is of interest the occurrence of PTC in three siblings within a period of 3 years. In addition, multinodular goiter (MNG) was diagnosed in seven individuals, lymphocytic thyroiditis in four, while one diagnosed with a benign adenoma. From the PTC patients, one had MNG and fvPTC, one MNG, lymphocytic thyroiditis and papillary pattern of PTC, one lymphocytic thyroiditis and fvPTC, and one MNG and papillary pattern of PTC. The inheritance pattern was autosomal dominant with incomplete penetrance and women were affected more frequently than men. Considering all PTC-affected individuals, the limit of detection (LOD) score we got for this family on 2q21 was 0.5. The low LOD score is caused by a PTC patient who does not share the affected haplotype, suggesting that maybe a new locus for PTC predisposition is present in this kindred. Linkage analysis also excluded TCO, MNG, and fPTC/PRN as susceptibility loci to FNMTC in this family

Thyroid hemorrhage causing airway obstruction after intravenous thrombolysis for acute ischemic stroke

There are several life-threatening complications associated with intravenous thrombolysis after acute ischemic stroke such as symptomatic intracerebral hemorrhage, orolingual angioedema, or less frequent, bleedings of the mucosa or ecchymosis. Aside from these known critical incidents, rare and unfamiliar complications may be even more challenging, as they are unexpected and may mimic events that appear more frequently. We report a rare and unusual acute complication of intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) (0.9 mg/kg) administered for acute ischemic stroke.; Medical records, radiologic imaging, and pathologic specimens were reviewed.; A 86-year-old woman developed acute respiratory failure 20 h after thrombolysis with suspected angioedema triggered by intravenous rt-PA. The inspiratory stridor and dyspnea were unresponsive to bronchodilators, corticosteroids, and inhaled adrenaline. After endotracheal intubation, laryngoscopy showed no significant supraglottic narrowing. Thyroidal sonography and cervical computed tomography revealed a thyroidal mass causing a tracheal and vascular compression compatible with thyroidal hemorrhage. Sonography showed a nodular goiter of the right thyroid gland. A total thyroidectomy was performed and histologic analysis confirmed a hemorrhage of the right thyroidal lobe.; Acute airway obstruction with respiratory failure due to thyroidal hemorrhage after intravenous thrombolysis is an important life-threatening complication, mimicking an anaphylactic reaction or a more frequent orolingual angioedema

Drug-induced endocrinopathies and diabetes: a combo-endocrinology overview

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug-induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention

The Association of Serum Total Peptide YY (PYY) with Obesity and Body Fat Measures in the CODING Study

Background: PYY is an appetite suppressing hormone. Low circulating PYY has been linked to greater BMI. However data is controversial and this association has not been verified in large human populations. Objective: The purpose of this study was to investigate if fasting serum total PYY is associated with obesity status and/or adiposity at the population level. Design: A total of 2094 subjects (Male-523, Female-1571) participated in this investigation. Total PYY was measured in fasting serum by enzyme-linked immunosorbent assay. Obesity status (NW-normal-weight, OW-overweight and OB-obese) was determined by the Bray Criteria according to body fat percentage measured by dual-energy x-ray absorptiometry and the WHO criteria according to BMI. One-way ANOVA and multiple regression was used to assess the adiposity-specific association between PYY and the following; weight, BMI, waist-circumference, hip-circumference, waist-hip ratio, percent body fat (%BF), trunk fat (%TF), android fat (%AF) and gynoid fat (%GF). Results: PYY was not significantly different among NW, OW and OB groups defined by neither %BF nor BMI for both men and women. However among women, fasting PYY was positively associated with adiposity measures. Women with the highest (Top 33%) waist-circumference, %BF and %TF had significantly higher PYY (10.5%, 8.3% and 9.2% respectively) than women with the lowest (Bottom 33%). Age, smoking, medication use and menopause were all positively associated with PYY levels in women but not in men. Conclusion: To our knowledge this is the largest population based study, with the most comprehensive analysis and measures of confounding factors, to explore the relationship of circulating PYY with obesity. Contrary to initial findings in the literature we discovered that PYY was positively associated with body fat measures (waist-circumference, %BF and %TF) in women. Although the effect size of the positive association of PYY with obesity in women is small, and potentially negligible, it may in fact represent a protective response against significant weight gain