Gergely Lakatos

Role of Nox2 in elimination of microorganisms.

NADPH oxidase of the phagocytic cells (Nox2) transfers electrons from cytosolic NADPH to molecular oxygen in the extracellular or intraphagosomal space. The produced superoxide anion (O2·−) provides the source for formation of all toxic oxygen derivatives, but continuous O2·− generation depends on adequate charge compensation. The vital role of Nox2 in efficient elimination of microorganisms is clearly indicated by human pathology as insufficient activity of the enzyme results in severe, recurrent bacterial infections, the typical symptoms of chronic granulomatous disease. The goals of this contribution are to provide critical review of the Nox2-dependent cellular processes that potentially contribute to bacterial killing and degradation and to indicate possible targets of pharmacological interventions.

Macroprolactinemia associated with pituitary macroadenoma: treatment with quinagolide

According to current concept, macroprolactin is biologically inactive and, therefore, its accumulation in serum has little, if any, pathological significance. Authors present the history of a 80-year-old man who proved to have, among other associated disorders, an intra- and parasellar pituitary tumor measuring 21x12x12 mm in size which was revealed by pituitary MRI. His hormonal evaluation indicated a marked hyperprolactinemia mainly due to macroprolactinemia (total prolactin, 514 ng/ml; reference range, 1.6-10.7 ng/ml; macroprolactin 436 ng/ml, monomer prolactin 78.2 ng/ml). Tests for function of the pituitary-thyroid axis showed a mild subclinical primary hypothyroidism. The function of the pituitary-adrenal axis was normal, and other hormonal tests revealed low-normal serum gonadotropins and decreased testosterone level, whereas serum insulin-like growth factor I was normal. Although the majority of current guidelines state that dopamine-agonist treatment which is successfully used in prolactin-producing pituitary tumors and in other hyperprolactinemic disorders is unnecessary in patients with macroprolactinemia, the authors introduced a dopamine-agonist, quinagolide. During prolonged treatment, plasma prolactin returned close to the upper limit of normal (12.3 ng/ml) and 9 months after the beginning of treatment pituitary MRI showed a remarkable shrinkage of the pituitary tumor. Authors propose that in this patient the pituitary tumor secreted macroprolactin, and they recommend a treatment trial with dopamine-agonist in pituitary macroadenomas associated with macroprolactinemia.A jelenlegi általános nézet szerint a makroprolaktin biológiailag inaktív molekula, ezért szérumkoncentrációjának növekedése aligha bír patológiai jelentőséggel. A szerzők 80 éves férfi esetét ismertetik, akinél egyéb társbetegségek mellett sella-MR-vizsgálattal 21×12×12 mm-es intraés parasellaris hypophysisadenomát mutattak ki. A szérumprolaktin-vizsgálat jelentős mértékű macroprolactinaemiát igazolt (összes prolaktin: 514 ng/ml, referenciatartomány 1,6–10,7 ng/ml; makroprolaktin 436 ng/ml, monomer prolaktin 78,2 ng/ml). A hypophysis-pajzsmirigy tengely vizsgálata szubklinikai primer hypothyreosist mutatott ki, a hypophysis-mellékvese tengely működése normális volt. Egyéb hormonleletei a normális tartomány alsó harmadában levő gonadotrophormon-szintek mellett csökkent tesztoszteronszintet, valamint normális inzulinszerű növekedési faktor-1-szintet igazoltak. Bár a jelenlegi szakmai ajánlások többsége macroprolactinaemia esetén feleslegesnek tartja a prolaktintermelő hypophysisadenomákban és egyéb valódi hyperprolactinaemiás állapotokban kiváló hatású dopaminagonista kezelést, a szerzők dopaminagonista quinagolidkezelést alkalmaztak. A tartós gyógyszeres kezelés a prolaktinszintet csaknem normálisra csökkentette (12,3 ng/ml), és kilenc hónappal a kezelés megkezdése után elvégzett sella-MR-vizsgálat a hypophysisdaganat mintegy negyedére zsugorodását mutatta ki. A szerzők felvetik, hogy esetükben a prolaktintermelő adenoma makroprolaktint is termelt, és javasolják macroprolactinaemiával társuló hypophysismacroadenomák esetében a dopaminagonista kezelés megkísérlését.

Effects of imatinib and nilotinib on the whole transcriptome of cultured murine osteoblasts

Numerous clinical observations have confirmed that breakpoint cluster region-abelson fusion oncoprotein tyrosine kinase inhibitors used in leukemia treatment alter bone physiology in a complex manner. The aim of the present study was to analyze the whole transcriptome of cultured murine osteoblasts and determine the changes following treatment with imatinib and nilotinib using Sequencing by Oligonucleotide Ligation and Detection next generation RNA sequencing. This study also aimed to identify candidate signaling pathways and network regulators by multivariate Ingenuity Pathway Analysis. Based on the right-tailed Fishers exact test, significantly altered pathways including upstream regulators were defined for each drug. The correlation between these pathways and bone metabolism was also examined. The preliminary results suggest the two drugs have different mechanisms of action on osteoblasts, and imatinib was shown to have a greater effect on gene expression. Data also indicated the potential role of a number of genes and signaling cascades that may contribute to identifying novel targets for the treatment of metabolic bone diseases.

Az onkohematológiai betegségek kezelésében használt tirozinkináz-gátló imatinib és nilotinib csonthatásainak irodalmi áttekintése és a saját kutatási eredmények bemutatása

Absztrakt A tirozinkinaz-gatlok bizonyos onkohematologiai betegsegek kezeleseben elterjedten hasznalt gyogyszerek. Tobb klinikai tanulmany igazolta, hogy a BCR-ABL specifikus tirozinkinaz-gatlok alkalmazasa komplex es meg nem egyertelműen azonositott modon valtoztatja meg a csontszovet elettani folyamatait. Mivel a kezelesek egyre tobb beteget erintenek, illetve hosszu evtizedekig vagy akar elethosszig is tarthatnak, indokolt ezen mechanizmusok molekularis hatterenek reszletesebb megismerese. A szerzők osszefoglaljak az imatinibbel es a nilotinibbel vegzett, csontanyagcserehez kapcsolodo alapkutatasi eredmenyeket, human klinikai megfigyeleseket, kiegeszitve in vitro osteoblast-sejtkulturakon vegzett sajat kiserleteik eredmenyeivel. Az osszefoglalt kutatasi eredmenyek alapjan az imatinib es a nilotinib csontsejtekre gyakorolt hatasa fugg az alkalmazott hatoanyag-koncentraciotol, a sejtek erettsegi allapotatol, illetve az altaluk kotott receptor-tirozinkinaz utvonalak megoszlasi aranyatol. Jelen kozlemenyben elsőkent keszitettek a hazai szakirodalomban hianypotlo, atfogo irodalmi attekintest a tirozinkinaz-gatlok csontanyagcseret befolyasolo hatasaival kapcsolatban es vegeztek teljes transzkriptom-analizist osteoblastokon a sejtszintű hatasmechanizmus jobb megerteset szolgalva. Orv. Hetil., 2016, 157(36), 1429–1437. | Abstract Tyrosine kinase inhibitors are widely used for treatment of certain oncohematological diseases. Several clinical studies have confirmed that specific BCR-ABL tyrosine kinase inhibitors alter the physiological process of bone tissue in a complex and unclearly identified manner. Since these treatments are being given to more and more patients, and the therapy takes decades or lasts even lifelong, it is justifiable to obtain more detailed knowledge of the molecular background of these mechanisms. In this article the authors summarize preliminary research results and human clinical observations on imatinib and nilotinib which are related to bone metabolism, and present the results of their own experiments in in vitro osteoblast cultures. Based on the presented results, the effects of imatinib and nilotinib on bone cells depend on the concentration of imatinib and nilotinib, the maturation stage of the cells and the distribution ratio of receptor tyrosine kinase signaling pathways. In this study the authors firstly prepared a stop-gap, comprehensive review in the Hungarian literature, regarding the effects of tyrosine kinase inhibitors on bone metabolism. In addition they firstly performed whole transcriptome analysis on osteoblasts in order to obtain a better understanding of the cellular molecular mechanisms. Orv. Hetil., 2016, 157(36), 1429–1437.Tyrosine kinase inhibitors are widely used for treatment of certain oncohematological diseases. Several clinical studies have confirmed that specific BCR-ABL tyrosine kinase inhibitors alter the physiological process of bone tissue in a complex and unclearly identified manner. Since these treatments are being given to more and more patients, and the therapy takes decades or lasts even lifelong, it is justifiable to obtain more detailed knowledge of the molecular background of these mechanisms. In this article the authors summarize preliminary research results and human clinical observations on imatinib and nilotinib which are related to bone metabolism, and present the results of their own experiments in in vitro osteoblast cultures. Based on the presented results, the effects of imatinib and nilotinib on bone cells depend on the concentration of imatinib and nilotinib, the maturation stage of the cells and the distribution ratio of receptor tyrosine kinase signaling pathways. In this study the authors firstly prepared a stop-gap, comprehensive review in the Hungarian literature, regarding the effects of tyrosine kinase inhibitors on bone metabolism. In addition they firstly performed whole transcriptome analysis on osteoblasts in order to obtain a better understanding of the cellular molecular mechanisms. Orv. Hetil., 2016, 157(36), 1429-1437.

The “blue man”

The authors present the case of a 63-year-old man who was evaluated for symptoms of lung fibrosis, blue face and epithelopathy affecting both eyes. All these symptoms could be attributed to the adverse effects of amiodarone. Thyroid disorders, which are the most common side-effects of amiodarone treatment were absent. The authors want to draw attention to the potential side effects of amiodarone.

[Ectopic ACTH-secreting neuroendocrine tumor].

The authors report a case of an ectopic ACTH-syndrome that resulted in severe hypercortisolism, hypokalemia, diabetes mellitus and osteoporosis. The ACTH-secreting tumor tissue was localized in the lung. The tumor was removed by segmentectomy and histological evaluation revealed an ACTH-secreting neuroendocrine tumor. After surgery, however, plasma cortisol and ACTH levels failed to decrease significantly due to subtotal tumor removal. Long-acting somatostatin analogue therapy resulted in a normalization of both plasma cortisol and ACTH levels and the clinical symptoms improved significantly. Residual tumor was removed by repeat surgery and the patient was permanently cured.

Macroprolactinaemiával társuló hypophysismacroadenoma kezelése quinagoliddal@@@Macroprolactinemia associated with pituitary macroadenoma: treatment with quinagolide

According to current concept, macroprolactin is biologically inactive and, therefore, its accumulation in serum has little, if any, pathological significance. Authors present the history of a 80-year-old man who proved to have, among other associated disorders, an intra- and parasellar pituitary tumor measuring 21x12x12 mm in size which was revealed by pituitary MRI. His hormonal evaluation indicated a marked hyperprolactinemia mainly due to macroprolactinemia (total prolactin, 514 ng/ml; reference range, 1.6-10.7 ng/ml; macroprolactin 436 ng/ml, monomer prolactin 78.2 ng/ml). Tests for function of the pituitary-thyroid axis showed a mild subclinical primary hypothyroidism. The function of the pituitary-adrenal axis was normal, and other hormonal tests revealed low-normal serum gonadotropins and decreased testosterone level, whereas serum insulin-like growth factor I was normal. Although the majority of current guidelines state that dopamine-agonist treatment which is successfully used in prolactin-producing pituitary tumors and in other hyperprolactinemic disorders is unnecessary in patients with macroprolactinemia, the authors introduced a dopamine-agonist, quinagolide. During prolonged treatment, plasma prolactin returned close to the upper limit of normal (12.3 ng/ml) and 9 months after the beginning of treatment pituitary MRI showed a remarkable shrinkage of the pituitary tumor. Authors propose that in this patient the pituitary tumor secreted macroprolactin, and they recommend a treatment trial with dopamine-agonist in pituitary macroadenomas associated with macroprolactinemia.A jelenlegi általános nézet szerint a makroprolaktin biológiailag inaktív molekula, ezért szérumkoncentrációjának növekedése aligha bír patológiai jelentőséggel. A szerzők 80 éves férfi esetét ismertetik, akinél egyéb társbetegségek mellett sella-MR-vizsgálattal 21×12×12 mm-es intraés parasellaris hypophysisadenomát mutattak ki. A szérumprolaktin-vizsgálat jelentős mértékű macroprolactinaemiát igazolt (összes prolaktin: 514 ng/ml, referenciatartomány 1,6–10,7 ng/ml; makroprolaktin 436 ng/ml, monomer prolaktin 78,2 ng/ml). A hypophysis-pajzsmirigy tengely vizsgálata szubklinikai primer hypothyreosist mutatott ki, a hypophysis-mellékvese tengely működése normális volt. Egyéb hormonleletei a normális tartomány alsó harmadában levő gonadotrophormon-szintek mellett csökkent tesztoszteronszintet, valamint normális inzulinszerű növekedési faktor-1-szintet igazoltak. Bár a jelenlegi szakmai ajánlások többsége macroprolactinaemia esetén feleslegesnek tartja a prolaktintermelő hypophysisadenomákban és egyéb valódi hyperprolactinaemiás állapotokban kiváló hatású dopaminagonista kezelést, a szerzők dopaminagonista quinagolidkezelést alkalmaztak. A tartós gyógyszeres kezelés a prolaktinszintet csaknem normálisra csökkentette (12,3 ng/ml), és kilenc hónappal a kezelés megkezdése után elvégzett sella-MR-vizsgálat a hypophysisdaganat mintegy negyedére zsugorodását mutatta ki. A szerzők felvetik, hogy esetükben a prolaktintermelő adenoma makroprolaktint is termelt, és javasolják macroprolactinaemiával társuló hypophysismacroadenomák esetében a dopaminagonista kezelés megkísérlését.

Macroprolactinaemiával társuló hypophysismacroadenoma kezelése quinagoliddal

According to current concept, macroprolactin is biologically inactive and, therefore, its accumulation in serum has little, if any, pathological significance. Authors present the history of a 80-year-old man who proved to have, among other associated disorders, an intra- and parasellar pituitary tumor measuring 21x12x12 mm in size which was revealed by pituitary MRI. His hormonal evaluation indicated a marked hyperprolactinemia mainly due to macroprolactinemia (total prolactin, 514 ng/ml; reference range, 1.6-10.7 ng/ml; macroprolactin 436 ng/ml, monomer prolactin 78.2 ng/ml). Tests for function of the pituitary-thyroid axis showed a mild subclinical primary hypothyroidism. The function of the pituitary-adrenal axis was normal, and other hormonal tests revealed low-normal serum gonadotropins and decreased testosterone level, whereas serum insulin-like growth factor I was normal. Although the majority of current guidelines state that dopamine-agonist treatment which is successfully used in prolactin-producing pituitary tumors and in other hyperprolactinemic disorders is unnecessary in patients with macroprolactinemia, the authors introduced a dopamine-agonist, quinagolide. During prolonged treatment, plasma prolactin returned close to the upper limit of normal (12.3 ng/ml) and 9 months after the beginning of treatment pituitary MRI showed a remarkable shrinkage of the pituitary tumor. Authors propose that in this patient the pituitary tumor secreted macroprolactin, and they recommend a treatment trial with dopamine-agonist in pituitary macroadenomas associated with macroprolactinemia.A jelenlegi általános nézet szerint a makroprolaktin biológiailag inaktív molekula, ezért szérumkoncentrációjának növekedése aligha bír patológiai jelentőséggel. A szerzők 80 éves férfi esetét ismertetik, akinél egyéb társbetegségek mellett sella-MR-vizsgálattal 21×12×12 mm-es intraés parasellaris hypophysisadenomát mutattak ki. A szérumprolaktin-vizsgálat jelentős mértékű macroprolactinaemiát igazolt (összes prolaktin: 514 ng/ml, referenciatartomány 1,6–10,7 ng/ml; makroprolaktin 436 ng/ml, monomer prolaktin 78,2 ng/ml). A hypophysis-pajzsmirigy tengely vizsgálata szubklinikai primer hypothyreosist mutatott ki, a hypophysis-mellékvese tengely működése normális volt. Egyéb hormonleletei a normális tartomány alsó harmadában levő gonadotrophormon-szintek mellett csökkent tesztoszteronszintet, valamint normális inzulinszerű növekedési faktor-1-szintet igazoltak. Bár a jelenlegi szakmai ajánlások többsége macroprolactinaemia esetén feleslegesnek tartja a prolaktintermelő hypophysisadenomákban és egyéb valódi hyperprolactinaemiás állapotokban kiváló hatású dopaminagonista kezelést, a szerzők dopaminagonista quinagolidkezelést alkalmaztak. A tartós gyógyszeres kezelés a prolaktinszintet csaknem normálisra csökkentette (12,3 ng/ml), és kilenc hónappal a kezelés megkezdése után elvégzett sella-MR-vizsgálat a hypophysisdaganat mintegy negyedére zsugorodását mutatta ki. A szerzők felvetik, hogy esetükben a prolaktintermelő adenoma makroprolaktint is termelt, és javasolják macroprolactinaemiával társuló hypophysismacroadenomák esetében a dopaminagonista kezelés megkísérlését.