PPARs: Molecular Targets in the Pharmacogenomics Era

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Šeda, O. ^{1, 2, 3,} Šedová, L.¹
1. Institute of Biology and Medical Genetics of the First Faculty of Medicine, Charles University in Prague, Czech Republic;
2. Department of Metabolism and Diabetes of the Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic;
3. Research Centre, Centre Hospitalier de l’Université de Montréal, Quebec, Canada
 
Abstract:
The recent global increase in prevalence of diseases like obesity, type 2 diabetes and hypertension in westernized societies is unfortunately not paralleled by our full understanding of the causative mechanisms. It is now firmly established that the interacting genetic and environmental (diet, smoking) components together determine the development and severity of the particular condition, which makes detailed dissection of such complex traits even more complicated. In effect, there is an unmet urgent need for molecular targets so we can directly modulate the causative factors and devise effective preventive and therapeutic algorithms. Among the most promising molecular targets for treatment of metabolic syndrome-related conditions identified so far, the group of three lipid-sensors, the peroxisome proliferator-activated receptors (PPARs) clearly stands out. The review focuses on pharmacogenetic aspects of recent developments in PPAR biology.
Key words: PPAR - Systems biology – Pharmacogenetics -  Thiazolidinediones - cd36
 
Mailing Address: Ondřej Šeda, MD., PhD., Institute of Biology and Medical Genetics of the First Faculty of Medicine, Charles University, Albertov 4,
128 00 Prague 2, Czech Republic, Phone + 420 224 968 154,
Fax + 420 224 918 666, e-mail: oseda(zavináč)lf1.cuni.cz
 

ANCA –Associated Renal Vasculitis – Epidemiology, Diagnostics and Treatment

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Říhová Z., Jančová E., Merta M., Tesař V.
Nephrology Department of the First Faculty of Medicine, Charles University in Prague, Czech Republic
 
Abstract:
The pauciimmune small-vessel vasculitides are multisystem diseases with frequent renal involvement. They are strongly associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA).
In this review we have focused on the ethiopathogenesis and the role of ANCA, clinical presentation and histopathologic findings of different ANCA – associated vasculitides (AAV). Current treatment strategies and the overall and renal outcome of patients with AAV are also discussed.
Key words: ANCA – Cyclophosphamide – Vasculitis – Wegener´s granulomatosis
 
Mailing Address: Zuzana Říhová, MD., Nephrology Department of the First Faculty of Medicine and General Teaching Hospital, U Nemocnice 2, 128 08 Praha 2, Czech Republic, Phone: +420 224 962 663, Fax: +420 224 962 696,
e-mail.: zrihova(zavináč)seznam.cz 
 
 
New Immunosuppressive Agents in Chronic Progressive Glomerulopathies: an Update
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Bloudíčková S., Viklický O.
Department of Nephrology, Transplant Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
 
Abstract:
The etiology of chronic glomerulopathies is not yet clear, however the impairment of immune system is supposed to play a decisive role. Thus, immunosuppressants are often used to slow the activity and/or progression of the disease. Usually the patients are treated either by corticosteroids alone or by the combination of corticosteroids with other immunosuppressive agents. Recently, immunosuppressants successfully applied in the transplantation medicine have been also tested in the therapy of chronic glomerulopathies. Cyclosporine A, a potent calcineurin inhibitor, has been used as a second line therapy. The place of CsA in lupus nephritis and especially in IgA nephropathy is not defined so well as it is in idiopathic nephrotic syndrome. The newer calcineurin inhibitor tacrolimus is already widely used in the transplantation medicine while its effectiveness in clinical nephrology has to be tested. Mycophenolate mofetil in monotherapy or with concomitant low-dose steroids can be regarded as an alternative therapeutical approach in case of standard regimens´ failure. Sirolimus just entered clinical transplant medicine and its role in slowing the progression of chronic glomerulopathies is not yet clear.
Key words: Immunosuppression – Chronic nephropathy – Glomerulonephritis
 
Mailing Address: Ondřej Viklický, M.D., Department of Nephrology, Transplant Centre, Institute for Clinical and Experimental Medicine, Vídeňská 1958/9, Prague 4 – Krč, 140 21, Czech Republic, Phone/Fax: +420 261 366 070, e-mail: ondrej.viklicky(zavináč)medicon.cz
 
 
Surgical contribution to the management of primary hyperparathyroidism

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Libánský P.¹, Adámek S.¹, Broulík P.², Pafko P.¹, Tvrdoň. J.¹
1. Third Department of Surgery of the First Faculty of Medicine and Teaching Hospital Motol, Czech Republic;
2. Third department of Medicine of the First Faculty of Medicine, Charles University in Prague and General Teaching Hospital in Prague, Czech Republic
 
Abstract:
Surgical management of primary hyperparathyroidism is a very effective method. The target is to cure primary hyperparathyroidism and to reach normal calcium levels. This results in an improvement of health condition and resolution or at least moderation of symptoms. Complications are infrequent and mortality is very low. Surgical management is definite, safe and effective. Authors of this article address the diagnosis of primary hyperparathyroidism, clarify bone, metabolic and biochemical syndromes and present series of 151 patients that have been operated on at the 3rd Department of Surgery of the Motol University Hospital, Prague, with the diagnosis of primary hyperparathyroidism. The survey is focused on the primary hyperparathyroidism concomitant diseases and on the possible sequelae in the postoperative period.
Key Words: Primary hyperparathyroidism – Bone syndrome - Metabolic syndrome - Biochemical syndrome – Surgical treatment
 
Mailing address: Petr Libánský. MD., Ke Karlovu 8, 120 00 Praha 2,
Phone: +420 224 438 030, e-mail: libanskyp.III.chir.kl.FNM(zavináč)seznam.cz
 
 
Effects of Intracarotid Injection of Methylprednisolone on Cellular Oedema after Osmotic Opening of the Blood-Brain Barrier in Rats

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Kozler P.¹, Pokorný J.^2
1Department of Neurosurgery of the Central Military Hospital and the First Faculty of Medicine, Charles University in Prague, Czech Republic;
²Institute of Physiology of the First Faculty of Medicine, Charles University in Prague, Czech Republic
 
Abstract:
In our work we studied methylprednisolone (MP) for its effects on the permeability of cytoplasmatic membranes of neuronal populations in the rat. We used a standard model of cellular oedema induced by water intoxication, applying MP selectively into the internal carotid (ICA) after opening the blood-brain-barrier (BBB) with mannitol. The results were assessed under fluorescence microscopy in keeping with the Intracellular Distribution Index of Evans Blue (IDI) in the neocortical field (Cortex) and in hippocampal areas CA1, CA3 and GD. Evans blue (EB) was applied similarly as MP. Three different experiments were carried out. In experiment 1 - EB alone and no MP was applied. In experiment 2 - 5.4 mg/kg MP and EB were applied. In experiment 3 - 54 mg/kg MP and EB were applied. In experiment 1 the IDI values were high (>1), indicating the presence of large quantities of EB in the cells. In experiments 2 and 3 the IDI values were low (<1), indicating more EB outside than inside cells. IDI differences between experiments 2 and 1 and experiments 3 and 1 were statistically significant (p<0.05). This morphological evidence sufficiently proved the possibility to restore the cell membrane integrity by means of MP administration.
­­­­­­­­­­Key words: Cellular oedema - Methylprednisolone - Blood-brain-barrier - Intracarotid injection - Fluorescence microscopy
 
Mailing address: Petr Kozler, MD., PhD., Department of Neurosurgery of the Central Military Hospital, U vojenské nemocnice 1200, 169 02 Prague 6, Czech Republic, Phone-fax +420 973 202 963, e-mail: petr.kozler(zavináč)uvn.cz
   

Hypoxia-induced Long-term Increase of Dopamine and Tyrosine Hydroxylase mRNA Levels

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Leclere N.¹, Andreeva N.², Fuchs J.¹, Kietzmann T.³, Gross J.^1
1Department of Otorhinolaryngology, Charité Hospital, Humboldt University, Berlin, Germany;
²Brain Research Institute, Academy of Medical Sciences, Moscow, Russia;
³Institute of Biochemistry and Molecular Cell Biology, Georg August University, Göttingen, Germany
 

Abstract:
The aim of the present study was to determine hypoxia-induced changes in dopamine (DA) levels in rat mesencephalic cell cultures. The cultures were exposed to expression were determined on day in vitro (DIV) 14. Hypoxic exposure of 5-day-old cultures resulted in increased DA (control 89.9 ± 8.9, hypoxia 135.8 ± 23.7 pg/µg protein) and TH mRNA (control 37.3 ± 4.7, hypoxia 143,1 ± 49.4 pg/µg RNA) levels. To analyze the involvement of hypoxia-inducible factor-1 (HIF-1) in these changes, we studied its activation using reporter gene. Hypoxia caused a 3-fold increase in HIF-1 activity. Our data suggest that hypoxia/ischemia during the putative critical developmental period of neurons may determine the tyrosine hydroxylase gene expression and, consequently, the development of the dopaminergic system.

Key words: Dopamine – Hypoxia inducible factor – mRNA – Mesencephalic neuron – Quantitative reverse-transcription polymerase chain reaction – Rat – Tyrosine hydroxylase
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Mailing address: Prof. J. Gross, MD., Humboldt University Medical Faculty Charité, Molecular Biological Research Laboratory, Department of Otorhinolaryngology, Spandauer Damm 130, Haus 31, 14050 Berlin, Germany, Phone  +030 450 555 311; Fax +030 450 555 908; e-mail: johann.gross(zavináč)charite.de
 
 
Markers of Inflammation in Preeclampsia

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Fialová L.¹, Kalousová M.^1,2, Soukupová J.², Malbohan I.^1,2, Madar J.³, Frisová V.³, Štípek S.¹, Zima T.^2
1Institute of Medical Biochemistry of the First Faculty of Medicine, Charles University in Prague, Czech Republic;
²Institute of Clinical Chemistry and Laboratory Diagnostics of the First Faculty of Medicine, Charles University in Prague and General Teaching Hospital, Czech Republic;
³Institute for the Care of Mother and Child, Prague, Czech Republic 
  
Abstract:
Advanced oxidation protein products (AOPP) represent terminal products of proteins exposure to free radicals. The aim of this study was to estimate the serum AOPP levels in preeclamptic patients together with ultrasensitive C-reactive protein and anticardiolipin antibodies (ACA) IgG and IgM. 21 women in the third trimester of pregnancy were included in the study - 10 women with preeclampsia and 11 women with normal outcome of pregnancy. AOPP levels in preeclampsia were higher than those in normal pregnant women in the third trimester, but not statistically significantly. The comparison with AOPP levels in non-pregnant women has shown a significant increase (P<0.0001). CRP in preeclampsia was significantly increased in comparison with third trimester levels in normal pregnancy (P<0.001) as well as with non-pregnant women (P<0.0001). In preeclampsia, the ACA IgG levels were even significantly lower than in normal pregnant women in the same gestation age, but significantly higher than in non-pregnant women (P<0.001). No difference was found in ACA IgM in preeclampsia and normal third trimester pregnancy and non-pregnant women. A statistically significant negative correlation was found between AOPP and ACA IgG (r= - 0.708, P<0.05). The results indicate enhanced oxidative and inflammatory reaction of maternal organism to pregnancy, which is more pronounced in preeclampsia than in uncomplicated pregnancy.

Key words: Advanced oxidation protein products - C-reactive protein – Anticardiolipin antibodies – Preeclampsia – Oxidative stress – Pregnancy - Inflammation
 
Mailing address: Lenka Fialová, MD., PhD., Institute of Medical Biochemistry of the First Faculty of Medicine, Charles University, Kateřinská 32,
121 08 Prague 2, Czech Republic, Phone +420 224 964 282,
fax +420 224 964 280, e-mail: lfial(zavináč)lf1.cuni.cz
 
 
Thrombelastography Monitoring of Platelet Substitution Therapy and rFVIIa Administration in Haemato-oncological Patients with Severe Thrombocytopenia

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Salaj P., Marinov I., Marková M., Pohlreich D., Cetkovský P., Hrachovinová I.
Institute of Haematology and Blood Transfusion, Prague Czech Republic
 
Abstract:
Thrombocytopenic patients refractory to platelet concentrates (PC) could be treated during bleeding episodes with the recombinant activated FVII (rFVIIa). However, monitoring of administration of the rFVIIa or a response to platelet substitution therapy in thrombocytopenia patients is not well documented so far. Using of whole blood ROTEG® analysis we monitored the changes in haemostatic parameters following in vivo platelet concentrate administration compared to ex vivo rFVIIa administration in patients with a severe to mild thrombocytopenia secondary to haemato-oncological disease. We use non-activated thrombelastography (NATEG) and a mild intrinsic activation thrombelastography (INTEG). NATEG analysis was sufficiently sensitive to monitor changes following PC and rFVIIa administration. Both, platelet infusion and rFVIIa treatment induced significant shortening of clotting time (CT) and clot formation time (CFT) parameters (p<0.05). When we compared the effect of platelet vs. rFVIIa treated whole blood by NATEG analysis we did not found any significant difference. Analysis with INTEG system was less sensitive and changes in CT and CFT were not significant. The monitoring with thrombelastography could enable efficient application of platelet concentrate and furthermore the using of rFVIIa as an alternative treatment of patients refractory to platelet infusion or with allergic reactions.
Key words: Thrombelastography – Platelet substitution – rFVIIa – Thrombocytopenia
 
Mailing address: Peter Salaj, MD., Institute of Haematology and Blood Transfusion, U nemocnice 1, 128 20 Prague 2, Czech Republic, Phone: +420 221 977 284, Fax: +420 221 977 249, e-mail: salaj@uhkt.cz
 
 
Microphthalmia Transcription Factor: a Specific Marker for Malignant Melanoma

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Vachtenheim J.¹, Borovanský J. ^2 
 
1Laboratory of Molecular Biology of the University Hospital Na Bulovce, Charles University in Prague, Czech Republic, ²Institute of  Biochemistry and Exprimental Oncology of the First Faculty of Medicine, Charles University in Prague, Czech Republic
 
Abstract: 
The transcription factor microphthalmia (MITF) is required for the formation of normal melanocytes during embryonic development and for the expression of pigment cell-specific markers, which are the downstream transcriptional targets of MITF. It also seems to be crucial for the survival of malignant melanocytes. The special interest of this review is the possible utility of MITF as a marker of malignant melanoma. Melanocyte-specific isoform of MITF appears to be a unique molecule in the differential diagnosis of melanocytic tumors.
Key words: MITF – Melanoma – Melanocyte – Microphthalmia – Transcription
 
Mailing address: Jiří Vachtenheim, MD., Laboratory of Molecular Biology, Clinic of Pneumology, Third Faculty of Medicine, Charles University and University Hospital Na Bulovce, Budínova 2, 180 00 Prague 8, Czech Republic, Phone +420 266 082 272, Fax: +420 284 840 840, e-mail: jivach(zavináč)upn.anet.cz 

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Marešová D., Pokorný J., Langmeier M.

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