Biomedical subjects
Z Varga
Publications and source records attributed to Z Varga.
[Acute tubulointerstitial nephritis in HIV infection].
We report about a patient with human immunodeficiency virus infection who developed acute renal failure after therapy with atazanavir. Renal biopsy showed acute interstitial nephritis. After discontinuing medication with atazanavir serum creatinine level decreased spontaneously without steroids. The different etiologies of acute renal failure in patients with human immunodeficiency infection are discussed.
Monitoring in a Lotka-Volterra model.
The problem of monitoring arises when in an ecosystem, in particular in a system of several populations, observing some components, we want to recover the state of the whole system as a function of time. Due to the difficulty to construct exactly this state process, we look for an auxiliary system called an observer. This system reproduces this process with a certain approximation. This means that the solution of the observer tends to that of the original system. An important concept for this work is observability. This means that from the observation it is possible to recover uniquely the state process, however, without determining a constructive method to obtain it. If observability holds for the original system, it guarantees the existence of an auxiliary matrix that makes it possible to construct an observer of the system. The considered system of populations is described by the classical Lotka-Volterra model with one predator and two preys and the construction of its observer is illustrated with a numerical example. Finally, it is shown how the observer can be used for the estimation of the level of an abiotic effect on the population system.
Intrapleural topical application of cisplatin with the surgical carrier Vivostat increases the local drug concentration in an immune-competent rat model with malignant pleuromesothelioma.
OBJECTIVE: We sought to investigate whether intrapleural topical application of cisplatin with a surgical carrier has a prolonged local tissue level in comparison with cisplatin solution while reducing systemic toxicity. METHODS: Forty immune-competent Fischer rats were inoculated with 10(6) mesothelioma cells. Ten days later, left pneumonectomy with tumor debulking was performed. Twenty animals underwent local application of cisplatin solution (100 mg/m2), whereas the same quantity of cisplatin was topically applied as a gel with the Vivostat (Vivolution) system in 20 other animals. In each group 5 subgroups of 4 animals were defined according to the harvesting time of blood and tissue samples (2, 4, 24, and 72 hours and 1 week) after local therapy. Platinum concentrations in serum and tissue and systemic toxicity were analyzed. RESULTS: Platinum concentrations in tissue were significantly higher in the gel group (group 1) than in the solution group (group 2) at 1, 3, and 7 days after therapy (1510, 1224, and 1069 pg/mg for group 1 vs 598, 382, and 287 pg/mg for group 2; P = .007, P = .005, and P = .0002, respectively). Laboratory findings showed renal insufficiency in the animals of the solution group at 1 week, with values of 98 mmol/L versus 7.7 mmol/L for urea and 410 mumol/L versus 43 mumol/L for creatinine (P = .02 and P = .01, respectively), which was confirmed by means of pathologic analysis. CONCLUSIONS: Intrapleural administration of cisplatin with the carrier Vivostat significantly provides sustained higher platinum concentrations up to 1 week in tissue in comparison with application of cisplatin solution without conferring systemic toxicity in this model.
Hemodialysis reduces inhibitory effect of plasma ultrafiltrate on LDL oxidation and subsequent endothelial reactions.
Oxidative modification of low-density lipoprotein (LDL) and its deleterious effect on endothelium is implicated in the pathogenesis of atherosclerosis. Endothelium responds to such an insult by upregulating the synthesis of heme oxygenase-1 (HO-1) and ferritin. Endothelial cell damage and dysfunction have been observed in patients with chronic kidney disease (CKD) on maintenance hemodialysis (HD). We studied the effect of low-molecular-weight components of uremic plasma on LDL oxidation and LDL-oxidation-provoked endothelial cell reactions, such as the induction of cytotoxicity and the upregulation of cell-protective HO-1 and ferritin. Plasma ultrafiltrate (molecular weight<5000 Da) from CKD patients on HD or when treated conservatively exhibited a pronounced inhibition on heme-mediated oxidative modification of LDL. Endothelial cell cytotoxicity provoked by LDL oxidation was also attenuated by plasma ultrafiltrate from CKD patients. During HD treatment, a dramatic drop occurred in the retardation of oxidative reactions, and a loss of endothelial cytoprotection exerted by plasma ultrafiltrate was noted. The upregulation of HO-1 and ferritin in response to oxidative stress of LDL was blunted by uremic plasma ultrafiltrate that was released by the end of HD. The decreased antioxidant capacity of ultrafiltrate after HD occurred as a consequence of the intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol. Intradialytic removal of L-ascorbic acid, uric acid, bilirubin, 3-indoxyl sulfate, indoxyl-beta-D-glucuronide, p-cresol, and phenol increases the risk of LDL oxidation and subsequent endothelial cell damage, which underlines the importance of activation of cytoprotective HO-1 and ferritin in endothelium.
[Second-line thalidomide/IL-2 therapy in metastatic kidney cancer--results of a pilot study].
PURPOSE: On the basis of promising first-line data we have evaluated the safety and efficacy of a combination therapy comprising interleukin-2 (IL-2) and thalidomide in patients with metastatic renal cell carcinoma (RCC) refractory to both immuno- and chemotherapy. PATIENTS AND METHODS: 14 patients with progressive metastatic RCC, in whom prior immunochemotherapy had failed but who desired further active therapy, were enrolled in this study. Oral thalidomide was started at 200 mg/d and escalated after two days to 400 mg/d at week 0. IL-2 at 7 MIU/m (2) was given by subcutaneous injection, starting at week 1, days 1 to 5, weeks 1 to 4, with no IL-2 at weeks 5 and 6. The response was assessed every other therapy cycle. RESULTS: 12 patients were evaluable for response. There was no objective response; 4 patients showed stable disease for 21, 15, 13 and 9 months, respectively. Toxicities were predominantly grade 1 - 3 and included somnolence and constipation, as well as flu-like symptoms associated with IL-2. However, one patient developed serious constipation which led to a paralytic ileus and discontinuation of treatment. Another patient left the study after seven weeks due to increasing confusion. 11 patients required IL-2 dose reduction. Time on therapy ranged from 3 - 44 weeks (median, 19 weeks). Median overall survival was 22 months. Up to date, all patients have discontinued treatment. CONCLUSIONS: We conclude that outpatient administration of thalidomide/IL-2 is feasible in patients with heavily pretreated and progressive RCC who desire further active treatment. However, toxicity and costs are considerable and the clinical benefit is uncertain. Therefore thalidomide/IL-2 may not represent a promising therapeutic approach for this subgroup of patients.
Comparing the biomechanical response of human and porcine kidneys to blunt trauma.
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K+ channel blockers: novel tools to inhibit T cell activation leading to specific immunosuppression.
During the last two decades since the identification and characterization of T cell potassium channels great advances have been made in the understanding of the role of these channels in T cell functions, especially in antigen-induced activation. Their limited tissue distribution and the recent discovery that different T cell subtypes carrying out distinct immune functions show specific expression levels of these channels have made T cell potassium channels attractive targets for immunomodulatory drugs. Many toxins of various animal species and a structurally diverse array of small molecules inhibiting these channels with varying affinity and selectivity were found and their successful use in immunosuppression in vivo was also demonstrated. Better understanding of the topological differences between potassium channel pores, detailed knowledge of toxin and small-molecule structures and the identification of the binding sites of blocking compounds make it possible to improve the selectivity and affinity of the lead compounds by introducing modifications based on structural information. In this review the basic properties and physiological roles of the voltage-gated Kv1.3 and the Ca2+-activated IKCa1 potassium channels are discussed along with an overview of compounds inhibiting these channels and approaches aiming at producing more efficient modulators of immune functions for the treatment of diseases like sclerosis multiplex and type I diabetes.
Second-line strategies for metastatic renal cell carcinoma: classics and novel approaches.
OBJECTIVES: Renal cell carcinoma is an aggressive malignancy with a high propensity for both early and metachronous regional and distant metastasis. While surgical resection is the mainstay of therapy for patients with localized disease, the prognosis for patients with distant metastasis is poor with a 5-year survival rate of less than 10%. Response rates to first-line immunotherapy or immunochemotherapy range from 10-35%; responses achieved are predominantly partial remissions of short duration. Until today, there is no standard therapeutic procedure for the growing number of patients who relapse following first-line therapy and desire further active treatment. MATERIALS AND METHODS: This article reviews classic and recent publications about second- and third-line approaches, their potential efficacy and toxicity. RESULTS: Several novel approaches have raised well-founded hope. Especially the application of monoclonal antibodies targeting VEGF signalling as well as different receptor tyrosine kinase inhibitors have the potential to change the face of second-line treatment of patients with metastatic RCC. Both groups of agents are focused in current phase III trials, either as mono- and/or combination therapy. CONCLUSIONS: Until today, second-line treatment of patients with metastatic RCC progressing under therapy with biological response modifiers remains an unresolved issue. The results of ongoing clinical trials evaluating novel targeted approaches can be expected with suspense.
Immunostimulatory CpG oligonucleotides reduce tumor burden after intravesical administration in an orthotopic murine bladder cancer model.
Bacillus Calmette-Guérin is established in the prophylaxis of recurrent intermediate and high-risk superficial bladder cancer and induces an unspecific, Th1-biased local immune response. Small CpG oligonucleotides (CpG ODN) containing a central unmethylated CpG motif are able to mimic the immunostimulatory activity of bacterial DNA. The purpose of the present study was to evaluate the antineoplastic properties of intravesically administered CpG ODN in an orthotopic murine bladder cancer model. MB49 tumor cell suspension was instilled transurethrally in female C57/BL6 mice on day 0. Mice were divided in three groups of 12 animals. Four mice in each group received either stimulative CpG ODN, non-stimulative GpC ODN or PBS intravesically: group I on day 3, group II on day 5, group III on day 7. After sacrifice 7 days after treatment, bladders were removed and histological examinations were performed. Single instillation of CpG ODN revealed antineoplastic effects in every group demonstrated by significantly lower bladder weight compared with non-stimulative GpC ODN- and PBS-treated mice. Histological examination showed extensive infiltration of macrophages and lymphocytes in CpG ODN-treated mice, whereas PBS- and GpC ODN-treated mice showed solid tumor growth with only few leucocytes. Intravesically applied immunostimulative DNA demonstrated antitumoral activity in an orthotopic murine bladder cancer model. A single instillation seems to be sufficient to reduce tumor load.
Equilibrium, observability and controllability in selection-mutation models.
In this paper we shortly discuss the problem of the equilibrium in the well-known Fisher type selection-mutation model, also providing a formula for particular three-allele models. The considered continuous-time dynamics is a known extension of the classical model of natural selection given by Fisher. We also extend the existing investigation of the observability of Fisher's model to the case when another evolutionary factor, mutation is also present. Moreover, we prove a result of technical character, which makes it possible to apply the methodology of nonlinear systems with invariant manifold, to models of artificial selection. For an illustration, a class of three-allele systems is presented in which the controllability into equilibrium is guaranteed without any condition on the biological parameters.
Intussusception of bladder neck improves early continence after radical prostatectomy: results of a prospective trial.
OBJECTIVES: To evaluate the impact of intussusception of the bladder neck on post-radical prostatectomy incontinence. METHODS: A total of 272 men with organ-confined prostate cancer who had undergone radical retropubic prostatectomy were studied. Of the 272 men, 139 underwent bladder neck intussusception and 133 did not. Patients completed validated questionnaires IIQ-7 and a symptom inventory. Continence was defined as the use of no or only one pad daily. RESULTS: Of the 272 men, 100%, 98.5%, and 96% answered the questionnaire and urinary symptom inventory at baseline and 3 and 12 months postoperatively, respectively. According to the protective pad requirement, 100%, 60%, and 86% of patients without intussusception and 100%, 77%, and 83% of the patients with intussusception were continent at baseline and 3 and 12 months postoperatively, respectively. Univariate logistic regression analysis revealed a statistically significant impact of intussusception on postprostatectomy incontinence at 3 months (P = 0.009), although continence at 12 months did not differ significantly (P = 0.5). CONCLUSIONS: Intussusception of the bladder neck had a significant effect on regaining continence at 3 months, although continence at 12 months was not affected.
Nongenomic effect of thyroid hormone on free-radical production in human polymorphonuclear leukocytes.
Over the past few years increasing evidence has suggested the nongenomic effects of thyroid hormone, such as the activation of the signal transduction pathways and the activation of nuclear factor-kappaB by the induction of oxidative stress. The present study was undertaken to investigate the effect of thyroid hormone on human polymorphonuclear leukocytes (PMNLs) which are known as important sources of reactive oxygen species in the circulation. The production of superoxide anion (O2-) and the activity of myeloperoxidase were determined in the presence and absence of several inhibitors of the signalling pathway. L-thyroxine (T4) l-3,5,3'-tri-iodothyronine (T3) and L-3,5-di-iodothyronine (T2) stimulated O2- production in PMNLs in a dose-dependent manner within a few minutes of addition to cells. Thyroid hormone-stimulated O2- production was partially inhibited by pertussis toxin, an inhibitor of GTP-binding G protein, and was completely abolished by the protein kinase C inhibitors calphostin C and Ro-32-0432, and by a calcium chelator (BAPTA; bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid). Thyroid hormone stimulated myeloperoxidase activity and induced 125I- incorporation into PMNLs. Furthermore, thyroid hormone pre-incubation enhanced O2- production for n-formyl-methionyl-leucyl- phenylalanine (FMLP) stimulation. In conclusion, novel nongenomic actions of thyroid hormone, the induction of superoxide anion production and the stimulation of myeloperoxidase activity in PMNLs were demonstrated. The induction of O2- production requires calcium and is mediated by a pertussis toxin-sensitive G protein via stimulation of protein kinase C(s). These results suggest the existence of a membrane-bound binding site for thyroid hormone in PMNLs and a physiological role for thyroid hormone in the cellular defence mechanisms by stimulating free-radical production.
Oxidative stress and non-enzymatic glycation in IgA nephropathy.
AIM: Approximately 20-50% of IgA nephropathy patients develop end-stage renal disease. We have previously found enhanced oxidative stress and decreased antioxidant capacity in red blood cells of IgA nephropathy patients. In this study we assess oxidative stress, non-enzymatic glycation, oxidative resistance of low-density lipoprotein and its alpha-tocopherol content in these patients. PATIENTS AND METHODS: Non-enzymatic glycation and oxidative stress were assessed in 88 IgA nephropathy patients by measuring advanced glycation end products, Nepsilon-carboxymethyl-lysine, thiobarbituric acid reactive substances, oxidative resistance of low-density lipoprotein and its alpha-tocopherol content. RESULTS: Advanced glycation end products (2659 +/- 958 a.u.) and Nepsilon-carboxymethyl-lysine (563 +/- 215 ng/ml) were significantly higher in IgA nephropathy patients with decreased renal function compared to those with normal renal function (p < 0.002) or controls (p < 0.001). Thiobarbituric acid-reactive substances in plasma and associated with low-density lipoprotein were significantly elevated and oxidative resistance of low-density lipoprotein was significantly reduced in all groups of IgA nephropathy patients. There was no significant difference in circulating fluorescent advanced glycation end products, Nepsilon-carboxymethyl-lysine, thiobarbituric acid-reactive substances levels, oxidative resistance of low-density lipoprotein and its alpha-tocopherol content between patients with normal vs. impaired glucose metabolism. Low alpha-tocopherol content of low-density lipoprotein was accompanied with decreased oxidative resistance, depletion in polyunsaturated fatty acids, elevated saturated fatty acids and thiobarbituric acid-reactive substances within low-density lipoprotein suggesting enhanced lipid peroxidation. CONCLUSIONS: Decreased oxidative resistance of low-density lipoprotein and enhanced oxidative stress are common features in IgA nephropathy, while increased non-enzymatic glycation occurs as renal function declines.
Infection rates of perennial ryegrass seeds (Lolium perenne L.) with different fungi.
Authors made investigations to map occurrence of different fungal pathogens on seeds of varieties from different grass species. This work presents data on three cultivars of perennial ryegrass (Lolium perenne L.). When seeds were germinated, eight genuses of fungi were identified belonging to the Deuteromycota. Alternaria was the most frequently occurred genus. Drechslera, Bipolaris, Cladosporium, Stemphylium, and Epicoccum spp. has also been found in the seed samples. Two genus of fungal pathogens (Embellisia and Septonema) were identified which were not mentioned in Hungary so far.
A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients.
Chimeric monoclonal antibody G250 (WX-G250) binds to a cell surface antigen found on >90% of renal cell carcinoma (RCC). A multicentre phase II study was performed to evaluate the safety and efficacy of WX-G250 in metastatic RCC (mRCC) patients. In all, 36 patients with mRCC were included. WX-G250 was given weekly by intravenous infusion for 12 weeks. Patients with stable disease (SD) or response were eligible to receive additional treatment for 8 weeks. None of the 36 enrolled patients experienced any drug-related grade III or IV toxicity. Only three patients had grade II toxicity possibly related to the study medication. In all, 10 patients had SD and received extended treatment. One complete response and a significant regression was observed during the follow-up of the treatment. Five patients with progressive disease at study entry were stable for more than 6 months after study entry. The median survival after treatment start was 15 months. The weekly schedule of WX-G250 was well tolerated. With a median survival of 15 months after the start of this treatment and two late clinical responses, WX-G250 seems to be able to modulate mRCC. To improve the activity of WX-G250-specific antibody-dependent cellular cytotoxicity and the clinical response rate, currently combinations of WX-G250 with cytokines are in phase II trials.
Kv1.3 potassium channels are localized in the immunological synapse formed between cytotoxic and target cells.
Membrane proteins of cytotoxic T cells specifically reorganize to form an immunological synapse (IS) on interaction with their specific target. In this paper, we investigated the redistribution of Kv1.3 channels, which are the dominant voltage-gated potassium channels, in the plasma membrane of allogen-activated human cytotoxic T lymphocytes (CTLs) on interacting with their specific target cells. Kv1.3 channels bearing a FLAG epitope were expressed in the CTLs and the cell-surface distribution of fluorescently labeled ion channels was determined from confocal laser-scanning microscopy images. FLAG epitope-tagged Kv1.3 channels showed a patchy distribution in CTLs not engaged with target cells, whereas the channels were accumulated in the IS formed between CTLs and specific target lymphocytes. Localization of Kv1.3 channels in the IS might open an unrevealed possibility in the regulation of ion channel activity by signaling molecules accumulated in the IS.
Ileocolic anastomotic ulcer after surgery in adulthood: case report and review of the literature.
Anastomotic ulcer is a rare complication after ileocolic resection, especially in adults without evidence of inflammatory bowel disease or tumor recurrence. We report the case of a 63-year-old male patient who presented 6 years after ileocolic resection, and also review the data of six similar cases described in the literature. The markedly reduced bile acid absorption found in our case raises the possibility of an etiological role of bile acids in the development of ileocolic anastomotic ulcers.