[Changes in serum ß2-microglobulin, retinol-binding protein, and cystatin C and their value in identifying early renal dysfunction in patients with chronic hepatitis B undergoing tenofovir or entecavir monotherapy: a comparative analysis].

Objective: To investigate the dynamic changes in serum ß2-microglobulin, retinol-binding protein, and cystatin C in chronic hepatitis B(CHB)patients treated with tenofovir or entecavir alone as the anti-HBV therapy, as well as their value in identifying early renal dysfunction. Methods: A total of 61 previously untreated CHB patients who were diagnosed and treated in the Department of Infectious Diseases in Henan Provincial People's Hospital from June 2013 to August 2015 were enrolled and divided into tenofovir group and entecavir group. The serum levels of ß2-microglobulin, retinol-binding protein, cystatin C, and creatinine and estimated glomerular filtration rate(eGFR)were compared between the two groups at baseline and 4, 8, 39, 52, 78, and 104 weeks after antiviral therapy. The independent samples t-test was used for comparison of continuous data, and the chi-square test was used for comparison of categorical data. P < 0.05 was considered statistically significant. Results: A total of 61 CHB patients were enrolled, with 31 in the tenofovir group and 30 in the entecavir group. The two groups had comparable serum levels of ß2-microglobulin, retinol-binding protein, and cystatin C at baseline, but there were significant differences in ß2-microglobulin and retinol-binding protein over time(both P < 0.05). There was a significant difference in cystatin C at 78 weeks(t = -2.062, P = 0.044), but there was no significant difference at 104 weeks(t = -1.544, P = 0.128). There were no significant differences in serum creatinine or eGFR at any time point between the two groups(P > 0.05). At 104 weeks, there were no significant differences in HBV-DNA clearance rate or the level of virologic breakthrough between the two groups(P > 0.05). Conclusion: Serum ß2-microglobulin, retinol binding protein, and cystatin C are more sensitive than eGFR in the monitoring of early renal dysfunction during the anti-HBV therapy with tenofovir or entecavir alone.

Drug-Disease Interaction and Time-Dependent Population Pharmacokinetics of Isatuximab in Relapsed/Refractory Multiple Myeloma Patients.

Isatuximab, a monoclonal antibody (mAb) of immunoglobulin G (IgG) isotype, specifically targets the cluster of differentiation 38 antigen overexpressed in malignant plasma cells. Isatuximab is used to treat multiple myeloma (MM), characterized by the excessive production of abnormal "myeloma proteins" (M-proteins) that may interact with therapeutic IgG mAb on the neonatal Fc receptor (FcRn)-mediated recycling pathway. The clinical pharmacology profile of isatuximab was investigated by population pharmacokinetics (PKs) modeling in 476 patients with MM who received 1-20 mg/kg isatuximab either as single agent or in combination with pomalidomide-dexamethasone in 4 clinical trials. Isatuximab PKs were characterized by a two-compartment model with parallel time-varying linear clearance (CL) and nonlinear elimination. Due to a mechanism-based drug-disease interaction, patients secreting IgG M-protein exhibited a twofold lower drug exposure compared with patients with non-IgG MM. No dose adjustment was required based on MM immunoglobulin type because efficacy and safety profiles were comparable between IgG and non-IgG MM subpopulations. ß2-microglobulin, body weight, sex, drug material, and race have a limited effect on drug exposure and do not require any dose adjustment. A typical 50% decrease in linear CL from initial treatment to steady-state was predicted, and this decrease correlated with the best overall response rate and was slower for patients with IgG MM. These findings suggest that the time-dependent effect of isatuximab is likely mediated by a combined factor of both disease state evolution and the perturbation of the FcRn-mediated recycling pathway.

N-Acetylcysteine prevents ifosfamide-induced nephrotoxicity in rats.

BACKGROUND AND PURPOSE: Ifosfamide nephrotoxicity is a serious adverse effect for children undergoing cancer chemotherapy. Our recent in vitro studies have shown that the antioxidant N-acetylcysteine (NAC), which is used extensively as an antidote for paracetamol (acetaminophen) poisoning in children, protects renal tubular cells from ifosfamide-induced toxicity at a clinically relevant concentration. To further validate this observation, an animal model of ifosfamide-induced nephrotoxicity was used to determine the protective effect of NAC. EXPERIMENTAL APPROACH: Male Wistar albino rats were injected intraperitoneally with saline, ifosfamide (50 or 80 mg kg(-1) daily for 5 days), NAC (1.2 g kg(-1) daily for 6 days) or ifosfamide+NAC (for 6 days). Twenty-four hours after the last injection, rats were killed and serum and urine were collected for biochemical analysis. Kidney tissues were obtained for analysis of glutathione, glutathione S-transferase and lipid peroxide levels as well as histology analysis. KEY RESULTS: NAC markedly reduces the severity of renal dysfunction induced by ifosfamide with a significant decrease in elevations of serum creatinine (57.8+/-2.3 vs 45.25+/-2.1 micromol l(-1)) as well as a reduced elevation of beta2-microglobulin excretion (25.44+/-3.3 vs 8.83+/-1.3 nmol l(-1)) and magnesium excretion (19.5+/-1.5 vs 11.16+/-1.5 mmol l(-1)). Moreover, NAC significantly improved the ifosfamide-induced glutathione depletion and the decrease of glutathione S-transferase activity, lowered the elevation of lipid peroxides and prevented typical morphological damages in renal tubules and glomeruli. CONCLUSIONS AND IMPLICATIONS: Our results suggest a potential therapeutic role for NAC in paediatric patients in preventing ifosfamide nephrotoxicity.

Beta-2-microglobulin is an androgen-regulated secreted protein elevated in serum of patients with advanced prostate cancer.

PURPOSE: A better understanding of secreted proteins may lead to the discovery of new biomarkers, which, along with prostate-specific antigen (PSA), may be useful in the diagnosis and treatment of prostate cancer patients. EXPERIMENTAL DESIGN: Conditioned medium was collected from LNCaP cells following stimulation with methyltrienolone (R1881), 17beta-estradiol (estradiol), or interleukin-6 and analyzed for differential protein expression with surface-enhanced laser desorption/ionization-time of flight mass spectrometry. Quantitative reverse transcription-PCR, immunoblots, and ELISA were used to measure beta-2-microglobulin (B2M) message and protein levels in cells, conditioned medium, and serum. RESULTS: Surface-enhanced laser desorption/ionization-time of flight revealed that many peaks were induced or repressed following stimulation with R1881 or estradiol. A peak of interest centered at 11.8 kDa was chosen for additional analysis. Immunodepletion identified the peak of interest as B2M. Reverse transcription-PCR and immunoblots confirmed that PSA and B2M were induced by R1881. However, unlike PSA, B2M was not increased on stimulation with estradiol or interleukin-6. Human B2M is identified in the serum of mice bearing human prostate cancer xenograft. B2M is expressed in human prostate cancer cell lines and tissues. Serum B2M levels are elevated in patients with metastatic, androgen-independent prostate cancer. CONCLUSIONS: B2M is a secreted protein expressed in prostate cancer, which is more specific for androgen stimulation than PSA under the conditions tested. Additional studies are warranted to explore if B2M is as useful marker for prostate cancer. Identification of proteins secreted from cancer cells in preclinical models may be a useful strategy for biomarker discovery.

Class-, gene-, and group-specific HLA silencing by lentiviral shRNA delivery.

HLA incompatibility is the most relevant immunologic barrier to cell-based therapies. Improvement of histocompatibility is essential to achieving better survival of allogeneic cells in the foreign organism. RNA interference technology can be used to selectively and stably reduce cellular HLA class I expression. In the present study, we designed small interfering RNA (siRNA) molecules that target either beta2-microglobulin (beta2m) or HLA-A heavy chain transcripts and identified sensitive sites on the target RNAs using an in vitro transcription/translation (IVTT) system. Transfection of siRNA into B-lymphocyte cell lines (B-LCLs) resulted in specific reduction of HLA class I or HLA-A antigen expression by 79% at the mRNA and protein levels. An allele-specific HLA silencing rate of 65% was achieved in a B-LCL heterozygous for HLA-A*24,*68 allospecificities using HLA-A*68-specific siRNA. Lentiviral delivery of short hairpin RNA into HeLa and B-LCL cells resulted in selective and permanent silencing of HLA class I or HLA-A by up to 90% even under inflammatory conditions. In cytotoxicity and proliferation assays, it was demonstrated that HLA class I knockdown was effective in preventing antibody-mediated cell lysis and CD8+ T cell response, while the residual HLA expression in HLA-silenced cells was protective against NK-cell-mediated lysis. The present data strongly suggest that silencing of HLA expression in a class-, gene-, and group-specific manner is an effective approach that may provide a new basis for developing new immunotherapies in the field of regenerative medicine.

Novel flutamide regulated genes in the rat ventral prostate: differential modulation of their expression by castration and flutamide treatments.

AIM: To identify flutamide regulated genes in the rat ventral prostate. METHODS: Total RNA from ventral prostates of control and flutamide treated rats were isolated. Differentially expressed transcripts were identified using differential display reverse transcriptase polymerase chain reaction. The effect of castration on the expression of flutamide-regulated transcripts was studied. RESULTS: We have identified beta2-microglobulin, cytoplasmic FMR1 interacting protein 2 and pumilio 1 as flutamide induced and spermine binding protein and ribophorin II as flutamide repressed targets in the rat ventral prostate. Although flutamide treatment caused an induction of pumilio 1 mRNA, castration had no effect. CONCLUSION: Castration and flutamide treatments exert differential effects on gene expression. Flutamide might also have direct AR independent effects, which might have implications in the emergence of androgen independent prostate cancer and the failure of flutamide therapy.

Mechanism of synergy of levamisole and fluorouracil: induction of human leukocyte antigen class I in a colorectal cancer cell line.

BACKGROUND: The use of the combination of fluorouracil (5-FU) and levamisole has been shown to improve the survival of patients with resected Dukes' stage C colon carcinoma. 5-FU is incorporated into RNA, which results in aberrant processing and turnover of RNA. Neither the mechanism of synergy between the two drugs nor the precise molecular mechanism of action of levamisole is known. Each drug has previously been shown to alter the expression of class I human leukocyte antigens (HLA class I) in colorectal cancer cell lines. PURPOSE: The purpose of this study was to explore the mechanism of interaction between 5-FU and levamisole by investigating the effect of this combination on HLA class I gene expression in the colorectal cancer cell line WiDr. METHODS: WiDr cells were treated either with 5-FU alone or with 5-FU and levamisole. Expression of HLA class I antigens was analyzed by flow cytometry using the monoclonal antibody W6/32. Specific DNA probes for HLA class I, beta 2-microglobulin, beta-actin, HLA class II, and p53 (also known as TP53) were used in Northern blot analysis of the steady-state level of messenger RNAs (mRNAs) and for "run-on" transcription analysis. RESULTS: 5-FU alone produced more than 50% increases in the expression of the HLA class I antigens, and levamisole caused a further 8%-18% increase. 5-FU caused the steady-state level of HLA class I mRNAs to increase by about 80%, and levamisole enhanced this effect of 5-FU by a further 70%. 5-FU did not increase the other mRNAs. In vitro run-on transcription revealed that 5-FU caused a 20%-57% reduction in RNA synthesis, while levamisole caused a 30%-190% increase in RNA synthesis. Levamisole therefore reversed the inhibition of RNA synthesis caused by 5-FU. Both drugs had a general effect on RNA synthesis that was not restricted to HLA class I transcription. CONCLUSIONS: The apparent synergy between levamisole and 5-FU is a result of the incorporation of 5-FU, which may stabilize HLA class I mRNAs, leading to their accumulation, while levamisole augments the accumulation of these stable mRNAs by increasing the rate of transcription. IMPLICATIONS: Levamisole reduces the toxicity of 5-FU caused by generalized inhibition of RNA synthesis, and at the same time augments the effects of 5-FU, which may be due to selective stabilization of certain mRNAs.

Effect of tibolone on cytochrome c oxidase I, beta-2-microglobulin and vascular endothelial growth factor gene expression in the lower urinary tract of castrated rats.

INTRODUCTION: The objective of this study was to evaluate the effect of tibolone on cytochrome oxidase I (COX I), beta-2-microglobulin (B2M) and vascular endothelial growth factor (VEGF) gene expression in the lower urinary tract of castrated rats. These genes are related to cell energy, cellular immunity and vascularization processes. METHODS: Fifty adult castrated rats remained at rest for 28 days. Thereafter they were randomly divided into two groups of 25 animals each. The lower urinary tract (bladder and urethra) was extracted in animals of one group and the other group received tibolone at a dose of 0.25 microg/animal/day for another 28 days followed by removal of the lower urinary tract. Total RNA was extracted from animals of both groups, forming two pools. After RT-PCR (reverse transcriptase polymerase chain reaction), expression of COX I, B2M and VEGF genes was evaluated by agarose gel electrophoresis, visualized by UV illumination. RESULTS: Expression of the three genes (COX I, B2M and VEGF) was greater in the group treated with tibolone. CONCLUSION: The use of tibolone increases the expression of COX, B2M and VEGF genes in the lower urinary tract as compared with that in castrated rats.

Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients.

BACKGROUND: Patients affected by end-stage renal disease (ESRD) demonstrate a very high cardiovascular risk mediated by traditional cardiovascular risk factors as well as abnormal mineral metabolism and a state of chronic inflammation. Sevelamer is a nonabsorbable non-calcium-based hydrogel with potential antiatherosclerotic properties. METHOD AND RESULTS: One hundred eight patients undergoing maintenance hemodialysis were randomized to sevelamer or calcium acetate as treatment for hyperphosphatemia. A coronary artery calcium score, as a measure of plaque burden, was calculated at baseline and 1 year, along with serial measurements of serum lipoproteins, beta2-microglobulin, and high-sensitivity C-reactive protein (hs-CRP). At 1 year, coronary artery calcium score progressed significantly from baseline in calcium acetate-treated subjects ( P < .001) but not in sevelamer-treated patients (P = NS). Total cholesterol (P < .0001), low-density lipoprotein cholesterol (P < .0001), apolipoprotein B (P < .0001), beta2-microglobulin (P = .018), and hs-CRP (P < .002) decreased, and high-density lipoprotein increased significantly (P = .036) from baseline in the sevelamer-treated subjects but not in subjects treated with calcium acetate despite the more frequent use of statins in the latter group (46% vs 22%, P < .05). The changes in total and low-density lipoprotein cholesterol, apolipoprotein B, and hs-CRP were significantly different between treatment groups (all P < .01). CONCLUSIONS: Sevelamer leads to favorable changes in lipids and inflammatory markers with potentially useful antiatherogenic effects in hemodialysis patients.

Immunoregulatory effects of interferon-beta and interacting cytokines on human vascular endothelial cells. Implications for multiple sclerosis autoimmune diseases.

The mechanism(s) of action responsible for the anti-inflammatory effects mediated by interferon (IFN)-beta are still elusive although suggestions include anti-viral effects, the enhancement of natural killer (NK) or suppressor T cell activity and opposition to the effects of inflammatory cytokines. As vascular endothelial cells are active participants in inflammatory and demyelinating processes, we decided to examine the effects of IFN-beta on the expression of major histocompatibility complex (MHC) gene products and intercellular adhesion molecule (ICAM)-1 on human vascular endothelial cells (ECs). Human umbilical ECs demonstrated constitutive expression of ICAM-1 and MHC class I molecules but did not express MHC class II molecules. Basal expression of ICAM-1 molecules was enhanced by TNF alpha and to a lesser extent by IFN-beta, but was not affected by IFN-gamma. MHC class I expression on ECs was enhanced by IFN-beta, IFN-gamma, and tumor necrosis factor (TNF)-alpha. Furthermore, a synergistic effect was observed to combinations of these interacting cytokines. Incubation of ECs with IFN-gamma, but not IFN-beta, induced class II expression in a dose dependent manner. Moreover, co-incubation of ECs with IFN-beta and IFN-gamma resulted in significant down-regulation of class II molecules expression which was directly dependent on IFN-beta concentration. Northern blot analysis of DR alpha and Beta 2-microglobulin mRNA expression suggested that cytokine-mediated regulation of MHC molecules is at the transcriptional level, while modulation of ICAM-1 expression appears to be at the transcriptional as well as post-transcriptional level. Thus, our study demonstrated that IFN-beta and interacting cytokines exert complex immunoregulatory effects on endothelial cells with differential modulatory effects on various cell surface markers. Understanding the biological significance of these immunomodulatory effects mediated by IFN-beta may have important implications for cytokine-based strategies in the treatment of inflammatory and autoimmune diseases.

HIV type 1-specific cytotoxic T lymphocytes stimulate HLA class I and intercellular adhesion molecule type 1 expression and increase beta 2-microglobulin levels in vitro.

Besides acting in a direct manner, cytolytic HIV-1-specific CTLs release a variety of cytokines. To assess the potential role of cytokines released by these CTLs we tested the ability of soluble products secreted by HIV-1-specific CTLs to induce HLA class I and ICAM-1 expression and to raise beta 2-microglobulin (beta 2M) concentrations in cell culture. To this end, supernatants were derived from HIV-1-specific CTLs incubated with autologous B lymphoblasts presenting either the cognate HIV-1 epitope or a control peptide. Cell lines and peripheral blood mononuclear cells (PBMCs) were incubated with these supernatants for 24-48 hr. Similarly, cells were cocultured with CTLs and their targets. This study demonstrates that in parallel with lysis of their cognate target, HIV-1-specific CTLs secreted products that stimulated HLA class I and ICAM-1 expression on cell lines and PBMCs. As few as 1000 CTLs significantly induced the expression of these molecules. In addition, secreted products of HIV-specific CTLs enhanced beta 2M release by PBMCs and Jurkat cells. These effects were mediated primarily by IFN-gamma and suggest that HIV-specific CTLs may contribute to increased HLA class I expression in infected tissue and elevated ICAM-1 and beta 2M concentrations in serum and cerebrospinal fluid of infected individuals.

Effects of alpha-interferon on serum beta-2-microglobulin.

Beta-2-microglobulin (B2M) forms the small invariable light chain subunit of class I HLA antigens on the cell membrane of all nucleated cells. During the continuous turnover of the HLA molecules, B2M is shed from the cell membrane into blood. Lymphocytes are the main source of serum free B2M. Serum B2M concentration is increased in renal diseases, various malignant diseases and some inflammatory and autoimmune disorders. In lymphatic malignancies serum B2M has significant prognostic value. Interferons (IFNs) have the ability to enhance the expression of class I and II histocompatibility antigens. Accordingly, IFNs cause a rise in formation and release of B2M. Currently, treatment with IFN alpha is used in diseases, like multiple myeloma, where serum B2M measurements are used to assess tumor burden. We have measured serum B2M levels during IFN alpha treatment in patients with both multiple myeloma and chronic myeloproliferative diseases, and IFN alpha caused a significant increase in serum B2M. It can be concluded that use of IFN alpha abolishes the value of serum B2M as an indicator of disease activity.

Formation of GSH-derivatives as a pathway for inactive intermediates in vinylidene chloride-treated rats.

The two conjugates, S-[N-(2-hydroxyethyl)carbamoylmethyl]glutathione (GSAAE), and its corresponding mercapturic derivative N-acetyl-S-[N-(2-hydroxyethyl)carbamoylmethyl]cysteine (NCySAAE) were administered to fasted Sprague-Dawley rats as putative metabolites of vinylidene chloride (VDC). Methylthioacetylaminoethanol (MAAE) was identified in the urine of GSAAE- or NCySAAE-treated rats (0.5-2.0 mmol/kg, i.p.), as well as in the urine of VDC-treated rats (0.5-2.0 mmol/kg, p.o.). The effects of VDC, GSAAE and NCySAAE on the kidney and liver were also examined using aspartate aminotransferase (ASAT). N-acetyl-beta-D-glucosaminidase (NAG) and beta 2-microglobulin (beta 2-m) as urinary parameters of nephrotoxicity, and glutamate dehydrogenase (GLDH), sorbitol dehydrogenase (SDH) and alanine aminotransferase (ALAT) as serum parameters of hepatotoxicity. Unlike treatment with VDC, treatment with both GSAAE and NCySAAE failed to cause kidney and liver toxicity. The results support the hypothesis that MAAE originates from the formation of GSAAE and further metabolization to NCySAAE, and that MAAE excretion does not reveal a pathway of reactive intermediates.

Alpha-interferon therapy increases serum beta2-microglobulin levels in hemodialysis patients.

BACKGROUND/AIMS: Beta2-microglobulin is the main component of dialysis-associated amyloid. Interferons (IFNs) have the ability to induce an increase in the formation and release of this protein. The aim of this study was to evaluate serum beta2-microglobulin levels in 11 hemodialysis patients with chronic hepatitis C treated with IFNalpha. METHODS: Eleven hemodialysis patients with chronic hepatitis C that received IFNalpha treatment were included in this study. No patient had residual renal function. High-flux membranes were used in 5 patients, and low-flux membranes in the remaining 6 patients. Beta2-microglobulin was analyzed at baseline, during IFNalpha treatment and after IFNalpha was stopped. RESULTS: Serum beta2-microglobulin concentration rose in all patients during the IFNalpha therapy. Compared with baseline values (43 mg/l, range 22-59) the median beta2-microglobulin levels increased significantly at one month (65 mg/l, range 37-142, p = 0.008) and at 12 months (59 mg/l, range 42-137, p = 0.003) after the beginning of IFN therapy. One month after IFNalpha was discontinued, beta2-microglobulin decreased significantly (median 48, range 34-75 mg/l, p = 0.05) in comparison with that obtained at the end of the therapy. The increase observed during IFN therapy was lower in patients treated with high-flux membranes than in those with low-flux membranes, although it was not statistically different. CONCLUSION: Our results show that IFNalpha therapy increases serum beta2-microglobulin levels in hemodialysis patients. Further studies are needed to clarify whether the use of high-flux membranes should be recommended in hemodialysis patients requiring IFN treatment.

Nephropathy of cyanotic congenital heart disease: clinical characteristics and effectiveness of an angiotensin-converting enzyme inhibitor.

AIMS: Nephropathy has long been recognized as a potential complication of cyanotic congenital heart disease (CCHD). There have been few large-scale studies or clinical reports on renal impairment in patients with CCHD; similarly, very few studies have examined the drug treatment of nephropathy in CCHD. We examined the clinical characteristics and effectiveness of enalapril, an angiotensin-converting enzyme inhibitor (ACE-I), in patients with CCHD complicated with significant proteinuria. MATERIALS AND METHODS: The clinical records of 37 patients with CCHD were evaluated; all were older than 10 years of age (median 19, range from 10 to 27) and had regular check-ups, including urinalysis. The treatment criteria for enalapril administration included significant proteinuria (urinary excretion > 1.0 g/24 h), stable cardiac condition and blood pressure within the normal range. RESULTS: Eleven patients (29.7%) had persistent proteinuria, 6 patients met the enalapril treatment criteria and 5 patients were treated for more than 12 months. Enalapril apparently reduced the urinary protein excretion in 4 of the 5 patients (80%). No consistent improvement of renal function, as evidenced in the glomerular filtration rate (GFR), renal plasma flow (RPF) or filtration fraction (FF) was found in these patients, but neither were any significant adverse effects noted. CONCLUSION: The incidence of nephropathy among patients with CCHD was about 30%, which was consistent with previous studies. It is worth considering the use of ACE-I when nephropathy accompanies CCHD.

Does occupational cobalt exposure determine early renal changes?

A cohort of workers occupationally exposed to cobalt (Co) dusts was examined to assess possible subclinical renal effects attributable to Co. Cross-sectional investigations involved 26 workers with a mean age of 34.2 (S.D., 8.3), chronically-exposed (median, 3.5 years; range, 0.9-11) to Co dusts in hard-metal manufacturing factories. Thirty-five healthy control workers, with a mean age of 32.4 (S.D., 4.6) were also examined. Individual interviews were used to exclude subjects with renal or systemic diseases, intake of nephrotoxic drugs, and exposure to known nephrotoxins. Exposure levels, assessed by ambient and biological monitoring, showed an estimated exposure approaching the ACGIH-recommended TLV of 50 micrograms/m3. Immunochemical methods were used to measure urinary albumin, retinol-binding protein (RBP), beta 2-microglobulin (beta 2m), and tubular brush-border antigens. The prevalence of abnormal values for early markers of renal dysfunction was similar in Co-exposed workers and in controls. However, within the reference interval, the cumulated frequency distribution for beta 2m was shifted towards higher values in the exposed group. No relationship was detected between renal markers and either intensity or duration of exposure. In spite of a limited number of observations, these findings suggest that the kidney is not a target organ during occupational exposure to Co.

[Monitoring of renal function in epileptic children and teenagers treated with valproic acid or carbamazepine in concomitant therapy with tiagabine]. / Monitorowanie czynnosci nerek u dzieci i mlodziezy chorych na padaczke leczonych kwasem walproinowym lub karbamazepina w terapii skojarzonej z tiagabina.

The aim of the study was the evaluation of the influence of 4-month concomitant tiagabine (TGB) and valproic acid (VPA) or carbamazepine (CBZ) therapy on renal function of epileptic children and teenagers. Initial parameter values, indicated on renal disfunction, were compared with these obtained after VPA and TGB or CBZ and TGB therapy and with values in healthy children and teenagers. Investigation group was composed of 22 children and teenagers with drug-resistant focal epilepsy. We observed that in the time of concomitant VPA and TGB therapy increased the NAG/g creatinine activity index. In spite the fact of statistical significance of these changes, they were not outside the normal range. beta 2-microglobulin concentrations in urine of epileptic children treated with VPA in monotherapy before concomitant therapy with TGB were higher than in control group. That difference was statistically significant. Addition of TGB to the therapy normalized this parameter. During concomitant VPA and TGB or CBZ and TGB therapy we didn't observe statistically significant changes of parameters indicating on glomerular disfunction. In the VPA therapy before concomitant treatment with tiagabine the disfunction of tubules and glomerules was observed. On the other side in the concomitant VPA and TGB therapy the disfunction of tubules and glomerules didn't occurred. We can conclude that concomitant therapy VPA or CBZ with tiagabine don't affect the renal function in clinical significant manner. Therapy with VPA could leads to minimal disfunction of tubules what is represented by increasing of beta 2-microglobulin level in urine.

[The dynamics of the humoral immunity indices and of the beta 2-microglobulin level in children with chronic hepatitis]. / Dynamika pokaznykiv humoral'noho imunitetu ta vmistu beta 2-mikrohlobulinu u ditei, khvorykh na khronichnyi hepatyt.

Studied in children with chronic hepatitis B (n = 38) were indices for humoral immunity, such as blood serum content of immunoglobulins A, G, M, and beta 2-microglobulin. The revealed increase in the level of the indices under study suggest to us an apparent tension of the humoral link of immunity. The polyenzymic drug preparation wobenzym in the complex of therapeutic measures instituted in the above children was found out to have a positive effect on humoral homeostasis.

Beta2-microglobulin: emerging as a promising cancer therapeutic target.

Beta2-microglobulin, a MHC class I subunit, is found to act similarly to a prototypical oncogenic factor capable of stimulating growth and progression of various cancers and plays a key regulatory role in stimulating cancer bone metastasis. Free beta2M in serum or urine has been regarded as an independent biomarker in several cancers. Specific antibodies to beta2M have remarkable tumoricidal activity for both solid tumors and blood malignancies and are shown to be selective to tumor cells, but caused no toxicity in normal cells. These surprising data strongly suggest that beta2M is a promising new therapeutic target for human cancers.