Immunohistochemical and molecular studies on the pathogenesis of pheochromocytomas and paragangliomas

Abstract In the last decades major progress has been made in discovering genes implicated in the syndromic occurrence of pheochromocytomas (PCC) and paragangliomas (PGL). It’s now well established that about 35% of all PCC/PGL are due to germline mutations in one of the genes: RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, PHD2, HIF2A, KIF1B, and FH. In addition, somatic mutations in RET, VHL, NF1, and HIF2A can also be detected in a subset of sporadic PCC/PGL. However, the pathogenesis of sporadic PCC and PGL is currently poorly understood. This issue has been investigated in the first part of this thesis (Chapters 2 and 3) by a candidate gene approach. SDHB and SDHA immunohistochemistry (IHC) is a valuable tool to identify PCC/PGL patients with mutations in one of the succinate dehydrogenase (SDH) genes. In the second part of this thesis we validated the reproducibility of this assessment method. Moreover, we determined if SDHA IHC could be a valuable tool to guide genetic testing in another tumor type from the SDH-associated tumor spectrum: gastrointestinal stromal tumors. In addition, we searched for new tools to validate SDH mutations. A major problem in PCC management remains the lack of predictive markers for malignancy and the lack of curative treatment options for progressive disease. In the last part of this thesis we focused on activation of intracellular pathways that could be targets for therapy and on validation of a prognostic tool for the distinction between benign and malignant PCC

Slow behavioral reorganization following experimental manipulation of caste ratios

Background-Fetal tachycardia may cause hydrops fetalis and lead to fetal death. No unanimity of opinion exists regarding the optimum treatment. This study evaluates our experience with transplacental sotalol therapy to treat fetal tachycardias in terms of safety and efficacy. Methods and Results-The charts of 21 patients who were treated with sotalol for fetal tachycardia were reviewed. Ten fetuses had atrial flutter (AF), 10 had supraventricular tachycardia (SVT), and I had VT. Hydrops fetalis was present in 9 fetuses. Drug treatment was successful in establishing sinus rhythm in 8 of 10 fetuses with AF and in 6 of 10 fetuses with SVT. The mortality rate in this study was 19% (4 of 21 fetuses 3 had SVT and 1 had AF); 3 deaths occurred just days after the initiation of sotalol therapy, and 1 occurred after a dosage increase. At birth, tachycardia was present in 6 infants. Two patients who converted to sinus rhythm in utero suffered from neurologic pathology postnatally. Conclusions-Fetal tachycardia is a serious condition in which treatment should be initiated, especially in the presence of hydrops fetalis, The high success rate in fetuses with AF suggests that sotalol should be considered a drug of first choice to treat fetal AF, The low conversion rate and the fact that 3 of the 4 deaths in this study occurred in fetuses with SVT indicate that the risks of sotalol therapy outweigh the benefits in this group and that sotalol should, therefore, be limited in the treatment of fetal SV

Early fecal calprotectin levels at week 8 may guide therapeutic decisions on Ustekinumab therapy in patients with Crohn’s disease

Background: Response evaluation after induction therapy with ustekinumab (UST) in Crohn’s disease (CD) is important for decisions on maintenance therapy. We aimed to assess the potential of fecal calprotectin (FC) levels to predict endoscopic response at week 16. Methods: CD patients with FC &gt;100 µg/g and endoscopic active disease (SES-CD&gt; 2, Rutgeerts’ score ≥ i2) at initiation of UST therapy were enrolled. FC was determined at weeks 0, 2, 4, 8 and 16 and patients underwent a colonoscopy at week 16. The primary outcome was an endoscopic response at week 16 (SES-CD score ≥50% decrease or a decrease of ≥1 points in Rutgeerts’ score). The optimal cut-off levels of FC and change in FC to predict endoscopic response were determined using ROC statistics. Results: 59 CD patients were included. Endoscopic response was observed in 21/59 (36%) patients. The diagnostic accuracy for FC levels at week 8 to predict endoscopic response at week 16 showed a predictive value of 0.71. A decrease in FC levels ≥500 µg/g between baseline at week 8 indicates endoscopic response (PPV = 89%), whereas absence of any decrease indicates endoscopic non-response after induction (NPV = 81%). Conclusions: Continuation of UST therapy without endoscopic response evaluation may be considered in patients with a decrease in FC levels of ≥500 µg/g at week 8. The decision on continuation of UST therapy or therapy optimization needs reconsideration in patients without a decrease of FC level. In all other patients, endoscopic response evaluation of induction therapy remains essential for therapeutic decisions.</p

The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes

Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry

The Role of Immunohistochemistry and Molecular Analysis of Succinate Dehydrogenase in the Diagnosis of Endocrine and Non-Endocrine Tumors and Related Syndromes

Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry

Risk of preterm birth after prior term cesarean

Peer reviewedPublisher PD

Феномен мастурбации: негативное или позитивное явление?

Рассмотрены разные взгляды на роль мастурбации в становлении сексуальности человека. Представлены результаты собственных исследований автора, проведенных с целью установить значение этого феномена для формирования сексуального поведения и сексуального здоровья.Various opinions about the role of masturbation in human sexuality development are discussed. The findings of the original research performed to evaluate the significance of this phenomenon in formation of sexual behavior and sexual health are reported