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At least 1,063 records · Page 59Linked to original sources
PubMed2005

Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis.

The fundamental role of telomerase is to protect telomere ends and to maintain telomere length during replication; hence, telomerase expression is high in stem cells but reduced upon differentiation. Recent studies indicate that telomerase might play other roles besides telomere maintenance. We have investigated the role of telomerase in cellular differentiation and death. Here, we show that ectopic expression of mouse telomerase catalytic subunit (mTERT) does not affect embryonic stem (ES) cell proliferation or differentiation in vitro, but protects ES cells against cell death during differentiation. Ectopic mTERT expression also confers resistance to apoptosis induced by oxidative stress and other genotoxic insults. This resistance depends on the catalytic activity of mTERT. Stress-signal-induced p53 accumulation and consequent p53-dependent apoptotic target gene expression was not affected by mTERT overexpression. However, although chemical inhibition of p53 by alpha-pifithrin reduced stress-induced apoptosis in vector-expressing cells, it did not significantly affect apoptosis in mTERT-expressing cells. Moreover, overexpression of mTERT in p53-/- ES cells did not confer further resistance to genotoxic insults, suggesting that mTERT might exert its protective effect by antagonizing the p53 pathway. Altogether, our findings indicate that ectopic mTERT expression in ES cells does not affect differentiation but confers resistance to apoptosis, and suggest that this strategy might be used in improving the efficiency of stem-cell therapies.

Animals↗
PubMed1998

Haptoglobin polymorphism, iron metabolism and mortality in HIV infection.

BACKGROUND: Three phenotypes of the antioxidant protein haptoglobin are known: Hp 1-1, Hp 2-1 and Hp 2-2. OBJECTIVES: To investigate the outcome of HIV infection according to haptoglobin type. DESIGN AND METHODS: Haptoglobin phenotypes were determined using starch gel electrophoresis in serum obtained from 653 HIV-infected Caucasians in the AIDS reference centers of Gent (n = 184), Antwerp (n = 309), and Luxembourg (n = 160). Survival was compared between haptoglobin types using Kaplan-Meier curves. Plasma HIV-1 RNA was quantified by reverse transcriptase PCR. Serum iron, transferrin saturation, ferritin, and vitamin C were assayed to evaluate iron-driven oxidative stress in 184 HIV-infected patients and 204 controls. RESULTS: The haptoglobin type distribution amongst the patients (17.6% Hp 1-1, 49.9% Hp 2-1, 32.5% Hp 2-2) corresponded to that of the controls. Kaplan-Meier curves showed a higher mortality for the Hp 2-2 group (P = 0.0001; adjusted mortality risk ratio, 1.78; 95% confidence interval, 1.25-2.54). Median survival time was 11.0 years (Hp 1-1 and Hp 2-1) versus 7.33 years (Hp 2-2). Plasma HIV-1 RNA levels prior to antiviral therapy and their increase over 1 year were highest in Hp 2-2 patients (P = 0.03 and 0.003, respectively). The Hp 2-2 type was associated with higher serum iron, transferrin saturation, and ferritin levels and with low vitamin C concentrations. Furthermore, ferritin concentrations were higher in HIV-infected patients than in controls (P < 0.0001). CONCLUSION: HIV-infected patients carrying the Hp 2-2 phenotype show a worse prognosis, which is reflected by a more rapid rate of viral replication (in the absence of antiviral treatment). They also accumulate more iron and oxidize more vitamin C, suggesting that less efficient protection against haemoglobin/iron-driven oxidative stress may be a direct mechanism for stimulating viral replication.

Adult↗
PubMed1995

Does peace prevent homosexuality?

This study attempted to replicate a series of investigations by Gunter Dörner and his associates that concluded that more homosexual men are born in wartime than in times of peace. That conclusion is based on Dörner's belief that war induces stress in pregnant women and that stress causes a drop in fetal androgen levels which in turn leads to the development of a homosexual "orientation". The replication not only failed to support the Dörner conclusion but also found that even those cities that suffered the most severe bombing during World War II showed no evidence of increased numbers of homosexuals. The authors conclude that homosexual men can go on loving peace and getting involved in the peace movement.

Adolescent↗
PubMed2001

Genetic architecture of thermal adaptation in Escherichia coli.

Elucidating the genetic basis of adaptation on a genomewide scale has evaded biologists, but complete genome sequences and DNA high-density array technology make genomewide surveys more tractable. Six lines of Escherichia coli adapted for 2,000 generations to a stressful high temperature of 41.5 degrees C were examined on a genomewide scale for duplication/deletion events by using DNA high-density arrays. A total of five duplication and deletion events were detected. These five events occurred in three of the six lines, whereas the remaining three lines contained no detectable events. Three of the duplications were at 2.85 Mb of the E. coli chromosome, providing evidence for the replicability of the adaptation to high temperature. Four candidate genes previously shown to play roles in stress and starvation survival were identified in the region of common duplication. Expression of the two candidate genes examined is elevated over expression levels in the ancestral lines or the lines without the duplication. In the two cases where the duplication at 2.85 Mb has been further characterized, the timing of the genome reorganization is coincident with significant increases in relative fitness. In both of these cases, the model for the origin of the duplication is a complex recombination event involving insertion sequences and repeat sequences. These results provide additional evidence for the idea that gene duplication plays an integral role in adaptation, specifically as a means for gene amplification.

Adaptation, Physiological↗
PubMed1999

Inorganic polyphosphate regulates responses of Escherichia coli to nutritional stringencies, environmental stresses and survival in the stationary phase.

The molecular mechanisms responsible for polyP accumulation in E. coli remain largely obscure. Based on the available data, a tentative model is proposed (Fig. 1; Ault-Riché et al. 1998). Inhibition by (p)ppGpp of PPX interrupts the dynamic balance between the synthesis of polyP by PPK and its hydrolysis by PPX, accounting for polyP accumulation. However, mutants lacking PhoB, the response regulator of the Pho regulon, fail to accumulate polyP even in the face of high levels of (p)ppGpp. Clearly, PhoB is required in some undefined manner. With regard to osmotic stress, the pathway to polyP accumulation is also distinct from the one identified with the activation of envZ and the associated changes in membrane functions. A tentative scheme attempting to describe the metabolic turnover of polyP is given in Fig. 4. [figure: see text] In adaptations to stress, cells must coordinate major changes in the rates of transcription, translation, and replication as well as make choices in the genes expressed (Kolter et al. 1993). PolyP could provide activated phosphates or coordinate an adaptive response by binding metals and/or specific proteins. Accumulation of polyP in E. coli and other organisms is commonly assumed to provide a reservoir of energy convertible to ATP. This seems implausible because of the turnover of ATP which consumes only a fraction of a second (Chapman and Atkinson 1977). Thus, other functions for polyP need to be considered, among them a regulatory role. PolyP, even at very low levels, is essential in E. coli for adaptations in stationary phase and for survival (Rao and Kornberg 1996). As a polyanionic polymer, polyP has chemical similarities to DNA and RNA in interactions with basic domains of proteins. Further investigation of the cellular location of polyP, its state of metabolic availability and identification of its binding partners are needed. In view of the ubiquity of polyP in eukaryotic cells (including dynamic turnover in the nuclei of some mammalian cells), studies similar to those undertaken in E. coli may reveal comparable functions.

Adaptation, Physiological↗
PubMed1992

Topoisomerase II: its functions and phosphorylation.

The gene encoding topoisomerase II in yeast is unique and essential, required for both mitotic and meiotic proliferation. The use of temperature-sensitive mutants in topoisomerase II have demonstrated roles in the relaxation of tortional stress, reduction of recombination rates, and in the separation of sister chromatids after replication. In vertebrate cells, topoisomerase II was shown to be the most abundant component of the metaphase chromosomal scaffold, and has been shown to play a role in chromosome condensation in vitro. The cell cycle control of chromosome condensation may well require phosphorylation of topoisomerase II, since the enzyme is more highly phosphorylated in metaphase than in G1. Recent studies have identified casein kinase II as the major enzyme phosphorylating topoisomerase II in intact yeast cells. The target sites of CKII are exclusively in the C-terminal 400 amino acids of topoisomerase II, the region that is most divergent among the eukaryotic type II enzymes and which is absent in the bacterial gyrase homologues.

Casein Kinase II↗
PubMed2002

Prevention of liver cancer.

Hepatocellular carcinoma (HCC) is among the most prevalent and deadly cancers worldwide. Prominent risk factors for HCC include viral hepatitis infection; dietary exposure to hepatotoxic contaminants such as aflatoxins; alcoholism; smoking; and male gender. This review highlights ongoing efforts in HCC prevention. Strategies include vaccination against, and treatment of, viral hepatitis infection. In addition to interferon alpha, an acyclic retinoid (all-trans-3,7,11, 15-tetramethyl-2,4,6,10,14-hexadecapentanoic acid), glycyrrhizin and ginseng are currently under clinical investigation for HCC prevention in Japanese hepatitis C patients. Several recent clinical studies in a Chinese region of pervasive aflatoxin contamination also support the approach of favorably altering aflatoxin metabolism and excretion using the chemopreventive agents oltipraz or chlorophyllin. Agents exhibiting chemopreventive efficacy in preclinical HCC models include vitamins A, D, and E, herbal extracts, a 5alpha-reductase inhibitor, green tea, and D-limonene. Efforts to elucidate the molecular lesions and processes underlying HCC development have identified several putative molecular targets for preventive interventions. These include genes and gene products controlling viral replication, carcinogen metabolism, signal transduction, cell-cycle arrest, apoptosis, proliferation, and oxidative stress.

Animals↗
PubMed2005

Cyclical mitochondrial deltapsiM fluctuations linked to electron transport, F0F1 ATP-synthase and mitochondrial Na+/Ca+2 exchange are reduced in Alzheimer's disease cybrids.

Reduced complex IV, increased oxidative stress and beta amyloid peptide secretion in Alzheimer's disease (AD) can be replicated in cybrid models. We characterized cyclical mitochondrial deltapsiM fluctuations ('flickering') in neuroblastoma cells and AD/CTL cybrids. Flickering was blocked by ATP-synthase inhibition, was not observed in rho0 cells and was not blocked by antioxidant treatment. Flickering was not affected by the Ca(+2) uniporter antagonist Ru360 but was eliminated by BAPTA or CGP37137 blockade of the mitochondrial Na(+)/Ca(+2) exchanger. AD cybrid mitochondria showed reduced flickering. Flickering seems to represent coupling of deltapsiM to F0F1 ATP-synthase; reduction of flickering in AD cybrids suggests dysfunction of this coupling.

Alzheimer Disease↗
PubMedDate not supplied

The RAS genes: a homeostatic device in Saccharomyces cerevisiae longevity.

The genetic analysis of the yeast replicative life span has revealed the importance of metabolic control and resistance to stress. It has also illuminated the pivotal role in determining longevity that the RAS genes play by the maintenance of homeostasis. This role appears to be performed by the coordination of a variety of cellular processes. Metabolic control seems to occupy a central position among these cellular processes that include stress resistance. Some of the features of metabolic control in yeast resemble the effects of the daf pathway for adult longevity in Caenorhabditis elegans and the metabolic consequences of selection for extended longevity in Drosophila melanogaster, as well as some of the features of caloric restriction in mammals. The distinction between dividing and nondividing cells is proposed to be less important for the aging process than generally believed because these cell types are part of a metabolic continuum in which the total metabolic capacity determines life span. As a consequence, the study of yeast aging may be helpful in understanding processes occurring in the aging brain.

Animals↗
PubMed1996

The Clp ATPases define a novel class of molecular chaperones.

The Clp ATPases were originally identified as a regulatory component of the bacterial ATP-dependent Clp serine proteases. Proteins homologous to the Escherichia coli Clp ATPases (ClpA, B, X or Y) have been identified in every organism examined so far. Recent data suggest that the Clp ATPases are not only specificity factors which help to 'present' various protein substrates to the ClpP or other catalytic proteases, but are also molecular chaperones which can function independently of ClpP. This review discusses the recent evidence that the Clp ATPases are indeed molecular chaperones capable of either repairing proteins damaged during stress conditions or activating the initiation proteins for Mu, lambda or P1 DNA replication. A mechanism is suggested to explain how the Clp ATPases 'decide' whether to repair or destroy their protein substrates.

Adenosine Triphosphatases↗
PubMed1989

Allozyme-associated heterosis in Drosophila melanogaster.

Two large experiments designed to detect allozyme-associated heterosis for growth rate in Drosophila melanogaster were performed. Heterosis associated with allozyme genotypes may be explained either by functional overdominance at the allozyme loci, or closely linked loci; or by genotypic correlations between allozyme loci and loci at which deleterious recessive alleles segregate. Such genotypic correlations would be favored by consanguineous mating, small effective population size, population mixing and strong natural or artificial selection. D. melanogaster is outbred, has large effective population size and there is little evidence for genotypic disequilibria. Therefore it would be unlikely to show allozyme heterosis due to genotypic correlations. In the first experiment I estimated the genotypic values of 97 replicated genotypes. In the second experiment, 500 individuals were raised in a fluctuating, stressful environment. In neither experiment was there any consistent evidence for allozyme heterosis in size or development rate, fluctuating asymmetry for size or in tendency to deviate from the population mean. In the first experiment, heterosis explained less than 5.6% of the genetic variance in growth characters. In the second, heterosis explained less than 0.1% of the phenotypic variance in growth characters. Outside of the molluscs, species which show allozyme heterosis have population structures or histories which tend to promote genotypic correlations. There is little evidence that functional overdominance is responsible for observations of allozyme-associated heterosis.

Acid Phosphatase↗
PubMed2000

Biomechanical rationale for the pathology of rheumatoid arthritis in the craniovertebral junction.

STUDY DESIGN: A finite-element model of the craniovertebral junction was developed and used to determine whether a biomechanical mechanism, in addition to inflammatory synovitis, is involved in the progression of rheumatoid arthritis in this region of the spine. OBJECTIVES: To determine specific structure involvement during the progression of rheumatoid arthritis and to evaluate these structures in terms of their effect on clinically observed erosive changes associated with the disease by assessing changes in loading patterns and degree of anterior atlantoaxial subluxation. SUMMARY OF BACKGROUND DATA: Rheumatoid arthritis involvement of the occipito-atlantoaxial (C0-C1-C2) complex is commonly seen. However, the biomechanical contribution to the development and progression of the disease is neither well understood nor quantified. Although previous cadaver studies have elucidated information on kinematic motion and fusion techniques, the modeling of progressive disease states is not easily accomplished using these methods. The finite-element method is well suited for studying progressive disease states caused by the gradual changes in material properties that can be modeled. METHODS: A ligamentous, nonlinear, sliding-contact, three-dimensional finite-element model of the C0-C1-C2 complex was generated from 0.5 mm thick serial computed tomography scans. Validation of the model was accomplished by comparing baseline kinematic predictions with experimental data. Transverse, alar, and capsular ligament stiffness were reduced sequentially by 50%, 75%, and 100% (removal) of their intact values. All models were subjected to flexion moments replicating the clinical diagnosis of rheumatoid arthritis using full flexion lateral plane radiographs. Stress profiles at the transverse ligament-odontoid process junction were monitored. Changes in loading profiles through the C0-C1 and C1-C2 lateral articulations and their associated capsular ligaments were calculated. Anterior and posterior atlantodental interval values were calculated to correlate ligamentous destruction with advancement of atlantoaxial subluxation. RESULTS: Model predictions (at 0.3 Nm) fell within one standard deviation of experimental means, and range of motion data agreed with published in vitro and in vivo values. The model predicted that stresses at the posterior base of the odontoid process were greatly reduced with transverse ligament compromise beyond 75%. Decreases through the lateral C0-C1 and C1-C2 articulations were compensated by their capsular ligaments. Anterior and posterior atlantodental interval values indicate that the transverse ligament stiffness decreases beyond 75% had the greatest effect on atlantoaxial subluxation during the early stages of the disease (no alar and capsular ligament damage). Subsequent involvement of the alar and capsular ligaments produced advanced atlantoaxial subluxation, for which surgical intervention may be warranted. CONCLUSIONS: To the best of the authors' knowledge, this is the first report of a validated, three-dimensional model of the C0-C1-C2 complex with application to rheumatoid arthritis. The data indicate that there may be a mechanical component (in addition to enzymatic degradation) associated with the osseous resorption observed during rheumatoid arthritis. Specifically, erosion of the odontoid base may involve Wolff's law of unloading considerations. Changes through the lateral aspects of the atlas suggest that this same mechanism may be partially responsible for the erosive changes seen during progressive rheumatoid arthritis. Anterior and posterior atlantodental interval values indicate that complete destruction of the transverse ligament coupled with alar and/or capsular ligament compromise is requisite if advanced levels of atlantoaxial subluxation are present.

Arthritis, Rheumatoid↗
PubMed2000

General nonlinear framework for the analysis of gene interaction via multivariate expression arrays.

A cDNA microarray is a complex biochemical-optical system whose purpose is the simultaneous measurement of gene expression for thousands of genes. In this paper we propose a general statistical approach to finding associations between the expression patterns of genes via the coefficient of determination. This coefficient measures the degree to which the transcriptional levels of an observed gene set can be used to improve the prediction of the transcriptional state of a target gene relative to the best possible prediction in the absence of observations. The method allows incorporation of knowledge of other conditions relevant to the prediction, such as the application of particular stimuli or the presence of inactivating gene mutations, as predictive elements affecting the expression level of a given gene. Various aspects of the method are discussed: prediction quantification, unconstrained prediction, constrained prediction using ternary perceptrons, and design of predictors given small numbers of replicated microarrays. The method is applied to a set of genes undergoing genotoxic stress for validation according to the manner in which it points toward previously known and unknown relationships. The entire procedure is supported by software that can be applied to large gene sets, has a number of facilities to simplify data analysis, and provides graphics for visualizing experimental data, multiple gene interaction, and prediction logic.

DNA, Complementary↗
PubMed2002

Growth of Neisseria gonorrhoeae in the female mouse genital tract does not require the gonococcal transferrin or hemoglobin receptors and may be enhanced by commensal lactobacilli.

Neisseria gonorrhoeae is capable of utilizing a variety of iron sources in vitro, including human transferrin, human lactoferrin, hemoglobin, hemoglobin-haptoglobin complexes, heme, and heterologous siderophores. Transferrin has been implicated as a critical iron store for N. gonorrhoeae in the human male urethra. The demonstration that gonococci can infect the lower genital tracts of estradiol-treated BALB/c mice in the absence of human transferrin, however, suggests that other usable iron sources are present in the murine genital tract. Here we demonstrate that gonococcal transferrin and hemoglobin receptor mutants are not attenuated in mice, thereby ruling out transferrin and hemoglobin as essential for murine infection. An increased frequency of phase variants with the hemoglobin receptor "on" (Hg(+)) occurred in ca. 50% of infected mice; this increase was temporally associated with an influx of neutrophils and detectable levels of hemoglobin in the vagina, suggesting that the presence of hemoglobin in inflammatory exudates selects for Hg(+) phase variants during infection. We also demonstrate that commensal lactobacilli support the growth of N. gonorrhoeae in vitro unless an iron chelator is added to the medium. We hypothesize that commensal lactobacilli may enhance growth of gonococci in vivo by promoting the solubilization of iron on mucosal surfaces through the production of metabolic intermediates. Finally, transferrin-binding lipoprotein (TbpB) was detected on gonococci in vaginal smears, suggesting that although gonococci replicate within the genital tracts of mice, they may be sufficiently iron-stressed to express iron-repressible proteins. In summary, these studies support the potential role of nontransferrin, nonhemoglobin iron sources during gonococcal infection of the female genital tract.

Amino Acid Sequence↗
PubMed2005

PML bodies: a meeting place for genomic loci?

Promyelocytic leukemia (PML) bodies have been implicated in a variety of cellular processes, such as cell-cycle regulation, apoptosis, proteolysis, tumor suppression, DNA repair and transcription. Despite this, the function of PML bodies is still unknown. Direct and indirect evidence supports the hypothesis that PML bodies interact with specific genes or genomic loci. This includes the finding that the stability of PML bodies is affected by cell stress and changes in chromatin structure. PML bodies also facilitate the transcription and replication of double-stranded DNA viral genomes. Moreover, PML bodies associate with specific regions of high transcriptional activity in the cellular genome. We propose that PML bodies functionally interact with chromatin and are important for the regulation of gene expression.

Animals↗
PubMed2006

alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis.

alpha-1 Antitrypsin (A1AT) is an abundant circulating serpin with a postulated function in the lung of potently inhibiting neutrophil-derived proteases. Emphysema attributable to A1AT deficiency led to the concept that a protease/anti-protease imbalance mediates cigarette smoke-induced emphysema. We hypothesized that A1AT has other pathobiological relevant functions in addition to elastase inhibition. We demonstrate a direct prosurvival effect of A1AT through inhibition of lung alveolar endothelial cell apoptosis. Primary pulmonary endothelial cells internalized human A1AT, which co-localized with and inhibited staurosporine-induced caspase-3 activation. In cell-free studies, native A1AT, but not conformers lacking an intact reactive center loop, inhibited the interaction of recombinant active caspase-3 with its specific substrate. Furthermore, overexpression of human A1AT via replication-deficient adeno-associated virus markedly attenuated alveolar wall destruction and oxidative stress caused by caspase-3 instillation in a mouse model of apoptosis-dependent emphysema. Our findings suggest that direct inhibition of active caspase-3 by A1AT may represent a novel anti-apoptotic mechanism relevant to disease processes characterized by excessive structural cell apoptosis, oxidative stress, and inflammation, such as pulmonary emphysema.

Animals↗
PubMed2002

Cloning and characterization of Edwardsiella ictaluri proteins expressed and recognized by the channel catfish Ictalurus punctatus immune response during infection.

An Edwardsiella ictaluri expression library was screened for clones expressing antigenic E. ictaluri proteins using anti-E. ictaluri serum, which resulted in the isolation of 32 clones. The clones were partially characterized and 4 were selected for complete analysis. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), 2-dimensional PAGE, Western blotting, and DNA sequencing were used to analyze expressed antigenic proteins and encoded genes. Sequence analysis identified 4 putative open reading frames (ORFs) in the insert of Clone 4d6, which corresponded to antigenic acidic proteins of 55, 20 and 18 kDa expressed by both the clone and E. ictaluri cells. The predicted gene products of these ORFs were similar to several products of the imp locus of Rhizobium leguminosarum bv. trifolii. The imp locus of R. leguminosarum contains 14 genes that encode proteins involved in a putative temperature-dependent protein secretion system. In addition there was significant amino acid identity for a variety of hypothetical proteins from R. solanacearum, Ps. aeruginosa, A. tumefaciens, Y. pestis, and Salmonella typhimurium. Overlapping inserts of Clones 1.4, 5d2, and 5d3 encoded ORFs similar to Escherichia coli partial genes serA and pgk, and complete genes rpiA, iciA, yggE, yggB and fda. These genes encode D-3-phosphoglycerate dehydrogenase (serA), ribose 5-phosphate isomerase (rpiA), a specific inhibitor of chromosomal initiation of replication (iciA), a hypothetical protein (yggE), a protein involved in responses to osmotic stress (yggB), fructose 1,6-bisphosphate aldolase (fda), and phosphoglycerate kinase (pgk). Cloned antigenic E. ictaluri proteins of 33, 27, 35 and 45 kDa appeared to be products of the ORFs similar to yggE, rpiA, iciA, and fda respectively. All the cloned antigenic proteins were recognized by antiserum from catfish that had recovered from enteric septicemia of catfish (ESC), indicating that these antigens are expressed during the infectious process. The cloned antigenic proteins were subsequently evaluated as subunit vaccines for protection against wild-type E. ictaluri. All vaccine treatments were protective against E. ictaluri in catfish, but results were inconclusive due to high levels of cross-reactive protection afforded by the E. coli host strain of the cloning vector.

Animals↗
PubMed1993

Treatment of six patients with chronic active HCV hepatitis, with low dose natural human interferon alpha administered orally.

Following the widely accepted therapeutic standard of treatment of HCV infection with parenteral interferon alpha, and encouraged by the author's won good experience with orally administered natural human interferon alpha in low doses (leuHuIFN alpha (ldou)), applied to chronic active HBV hepatitis patients, this form of interferon was given to six randomly selected HCV infected patients (2 women, 4 men) aged 34-62 years. The diagnosis was made based on a clinical and histological evaluation and confirmed by anti-HCV antibodies detection. In 2 out of 6 patients, leuHuIFN alpha (ldou) was employed immediately after steroid discontinuation. Patients were instructed to take one lozenge daily, in the morning, on an empty stomach, and keep it in the mouth until fully dissolved. Observation period varies from 19 to 69 weeks. In 3 patients the therapy concluded, after 19, 61 and 62 weeks, respectively. One patient after 4 weeks of treatment reported increasingly troublesome small joints pain and swelling, which forced leuHuIFN alpha (ldou) discontinuation after 19 weeks. In no patient transaminases normalization was seen during treatment; biochemical and clinical remission after the drug discontinuation was observed in only one patient, in whom the treatment was interrupted due to articular adverse symptoms. With HCV RNA levels assessment being unavailable at the moment, the treatment impact on the virus replication remains difficult to evaluate objectively. The treatment was well tolerated. All patients stressed significant increase of drive and appetite as well as improvement of the exercise tolerance.

Administration, Oral↗