Genetics of primary biliary cirrhosis

The primary biliary cirrhosis is a chronic cholestatic liver disease, which is characterised by non-suppurative destruction of interlobular bile ducts. The precise etiopathogenesis of primary biliary cirrhosis remains unknown. Evidence suggest that genetic and environmental factors seem to be important. It shows strong heritability according to familial occurrence and monozygotic twins concordance. There is an increase in the degree of monosomy of the X chromosome in female subjects with PBC. There is an association with HLA-DR8 (DR1*08) antigen at least in some populations. Correlation the PBC with polymorphisms of HLA class I, II, III alleles, genes encoding for molecules influencing immune tolerance, apoptosis, cytokine expression, will require additional studies.     

Presence and distribution of three calcium binding proteins in projection neurons of the adult rat cochlear nucleus

The presence and distribution of three cytoplasmic calcium binding proteins, calbindin, calretinin, and parvalbumin, have been investigated in the projection neurons of the cochlear nucleus complex in adult rats by using immunohistochemistry in free-floating slices. Identification of the individual cell types was carried out on the basis of their intranuclear localization, morphological characteristics, and (in the cases of pyramidal and bushy neurons) by retrograde labeling with rhodamine-dextran. The most important findings were confirmed by using confocal microscopy. The data obtained in these experiments are the first to demonstrate the presence of parvalbumin in pyramidal neurons and globular and spherical bushy cells of rat cochlear nucleus, whereas octopus and giant cells did not show positivity for parvalbumin. Calretinin was not present in either Purkinje-like cells or giant neurons. According to the double immunolabeling co-localization experiments, the pyramidal neurons, Purkinje-like cells, globular bushy cells, and octopus cells express two different calcium binding proteins in their cytoplasm (although in different combinations) whereas giant cells and spherical bushy cells contain solely calbindin and parvalbumin, respectively. The presence of calretinin in globular bushy cells provides a tool for distinguishing them from spherical bushy cells. The immunolabeling of the fibers and axonal endings of the acoustic nerve in the ventral part of the cochlear nucleus indicated that these structures are also parvalbumin positive. It is concluded that the heterogenous cell composition of the cochlear nucleus is accompanied by a rather complex expression pattern of the cytoplasmic calcium binding proteins.     

Gene therapy in pancreatic cancer

Pancreatic cancer is the fifth cause of cancer death in the developed world. It is a highly malignant disease, characterised by aggressive local spread and early locoregional and hepatic metastasis. Surgery offers the only prospect of long-term survival, but the resectability ratio is very low at the time of diagnosis. Conventional chemo- and radiotherapy are relatively ineffective, that is why development of newer therapeutic alternatives are encouraged. Gene therapy came into the limelight of interest. Authors discuss the fundamental scientific principle and clinical experience in connection with gene therapy of pancreatic cancer. Different targets include antisense strategies, gene-replacement, gene-directed prodrug activation therapy, promoter gene strategies, as well as oncolytic viruses.     

Prognosis for the fetus with congenital heart defects in the era of modern diagnostics and therapeutics

BACKGROUND: Prenatal detection of structural heart diseases and rhythm disturbance has become possible using echocardiography. Authors have already documented the high diagnostic accuracy of intrauterin diagnosis of heart diseases in our country as well. AIM OF THIS STUDY: To examine the prognosis of fetal cardiac diseases diagnosed by echocardiography in the institute between 1985-2001. METHODS: The prognosis of 223 (6.3%) cardiac anomalies found in 3468 fetal echocardiograms was assessed by postnatal echo/surgery/or autopsy. RESULTS: The authors detected cardiac anomalies in 153, rhythm disturbance in 70 fetuses. They could follow (mean 4.2 yrs) the 83% of patients by postnatal echo/surgery or autopsy. They lost 46 pts (36%) by elective termination, intrauterine death, or during the postnatal period. 83% of these pts had hypoplastic left heart syndrome, fibroeleastosis, or aortic stenosis. Right heart anomalies (tetralogy of Fallot, critical pulmonary stenosis etc.) showed good prognosis with early surgical or catheter intervention. Isolated fetal supraventricular tachycardias can be successfully treated prenatally, and fetal complete heart block by emergency postnatal permanent pacemaker implantation. CONCLUSIONS: Fetal echocardiography must be considered in our country also such a method which can influence the natural history of fetal heart diseases. The result of infant cardiac surgery also dramatically improved, so we think this knowledge is very important during the counselling.     

Photoreceptor death, trophic factor expression, retinal oxygen status, and photoreceptor function in the P23H rat

PURPOSE: To relate the oxygen environment of the retina to photoreceptor stability, protection, and function in the P23H rat. METHODS: Heterozygote P23H-3 (Line 3) rats were studied. Photoreceptor death rates were assessed with the TUNEL technique for detection of fragmenting DNA, in a developmental series from postnatal day (P)16 to P105 (adult). In adult retinas, trophic factor status was assessed with immunohistochemistry, intraretinal oxygen environment with O(2)-sensing electrodes, and photoreceptor function by the flash-evoked, dark-adapted electroretinogram (ERG), recorded in anesthetized animals. RESULTS: Photoreceptor death begins by P16; peaks at P25, when the frequency of TUNEL(+) profiles exceeds 70/mm of retina; and then declines to low (<5/mm) adult rates. Compared with that in nondegenerative Sprague-Dawley (SD) rats, the rate of photoreceptor death is abnormally high from P16 and remains several-fold higher than normal into young adulthood. In addition, the outer nuclear layer is reduced to approximately half of control thickness, and the levels of ciliary neurotrophic factor (CNTF), glial fibrillary acidic protein (GFAP), fibroblast growth factor (FGF)-2, and FGF-2/FGFR1 colocalization are markedly upregulated. O(2) tension and uptake are relatively normal in the inner retina, but uptake is considerably reduced, and O(2) tension is significantly raised in the outer retina. Surviving photoreceptors generate an a-wave with normal peak latency but sharply reduced amplitude. CONCLUSIONS: Excess photoreceptor degeneration in the P23H-3 retina begins just after eye opening, peaks in early postnatal life, and then slows, but persists into adulthood. In the adult retina, surviving photoreceptors operate in an environment that is chronically hyperoxic (and therefore toxic) and in which protective factors (CNTF, FGF-2) are chronically upregulated. The net result, slow degeneration and degraded function in an environment that is both toxic and protective, may be representative of adult photoreceptor status in a number of human retinal degenerations. Hyperoxia-induced photoreceptor death may be a self-reinforcing factor that increases oxidative stress in surviving photoreceptors.     

Selective sensory denervation by capsaicin aggravates adriamycin-induced cardiomyopathy in rats

Capsaicin-sensitive sensory nerves that contain calcitonin gene-related peptide (CGRP) contribute significantly to cardioprotective mechanisms. In this study, the possible role of capsaicin-sensitive afferent nerves in the development of congestive heart failure was examined in an established model of adriamycin-induced experimental cardiomyopathy in rats. Systemic treatment with capsaicin was utilized to deplete sensory neuropeptides from cardiac afferent nerves. Echocardiography was applied to assess the cardiac function in adriamycin-treated rats pretreated with capsaicin or its vehicle. In control rats, adriamycin treatment produced a reduction in the fractional shortening of the left ventricle and an increase in the ratio of the left atrial diameter and the aortic diameter, indicative of a decreased myocardial contractility and heart failure only at 3–4 weeks post-treatment. In contrast, in capsaicin-pretreated rats, a deterioration of the cardiac function was already evident 1 week after the cessation of adriamycin administration, while the clinical signs associated with cardiomyopathy were more severe and displayed a significantly more rapid progression. Immunohistochemistry revealed a complete depletion of calcitonin gene-related peptide from cardiac sensory nerves after systemic capsaicin treatment. This study has demonstrated that elimination of capsaicin-sensitive afferent nerves promotes the development and progression of adriamycin-induced myocardial dysfunction. The results suggest that interfering with capsaicin/vanilloid receptor function and/or perturbation of the myocardial CGRP metabolism may open up new perspectives concerning prevention and/or alleviation of the pathological changes that follow adriamycin treatment.     

Luminol-dependent chemiluminescence is related to the extracellularly released reactive oxygen intermediates in the case of rat neutrophils activated by formyl-methionyl-leucyl-phenylalanine

Luminol is a non-radical-specific amplifying molecule which produces light upon interaction with various reactive oxygen intermediates (ROIs). ROI production of rat peritoneal polymorphonuclear leukocytes (PMNLs) elicited by 2.3 microM formyl-methionyl-leucyl-phenylalanine (fMLP) results in a biphasic luminol-dependent chemiluminescence (LDCL) signal. Whereas ROIs are also produced intracellularly, as judged by flow cytometry, addition of non-membrane-permeable catalase reduces the first and second phases of the LDCL signal to around 3% and less than 3%, respectively. This suggests that in the case of fMLP-stimulated rat PMNLs, the LDCL signal is related to the ROIs in the extracellular medium and hydrogen peroxide has a key role in the formation of the LDCL signal. In the presence of the non-specific myeloperoxidase inhibitor Na-azide, the first phase of the LDCL signal decreases slightly (87+/-8%), while the second phase almost disappears (< 3%), indicating the myeloperoxidase dependence of the second phase. The hydroxyl radical scavenger histidine results in an 84+/-4% and a 71+/-4% decrease in the intensity of the first and second phases, respectively. Based on these data, it is concluded that hydrogen peroxide might be the source of hydroxyl radicals directly oxidizing luminol in the first phase of the LDCL signal, while in the second phase it serves as a substrate of myeloperoxidase in the peroxidation reaction of the luminol.     

Successful idebenone therapy of hypertrophic cardiomyopathy in Friedreich ataxia

Severe hypertrophic cardiomyopathy in a 15 years old child with Friedreich ataxia was treated with idebenone on the basis of a preliminary study reported in the literature. After 3 months of treatment the muscle thickness and mass and idices of diastolic function on echocardiogram and ischaemic signs on ECG changed significantly. IN CONCLUSION: Our data proves the preliminary results, so idebenobe treatment is very effective in the disease, where a deficiency of frataxin is involved in the regulation of mitochondral iron content which is responsible for myocardial injury. We suggest the widespread use of idebenone to treat patients with Friedreich ataxia and hypertrophic cardiomyopathy to improve the fatal prognosis of this type of cardiomyopathy.