An inconspicuous insect bite as the cause of sepsis in a patient treated with infliximab due to rheumatoid arthritis.

The monoclonal antibody against TNFa (infliximab) suppresses cytokines involved in inflammatory reaction. Consequently, infliximab is a potent agent in treating refractory rheumatoid arthritis (RA). There is also evidence showing beneficial anti-TNFα therapy effect on RA-related amyloidosis AA. TNFα inhibition may, however, lead to leucopenia and, eventually, severe sepsis. We discuss a case of RA with RA-related AA amyloidosis and renal impairment which was refractory to disease-modifying anti-rheumatic drug (DMARD). The treatment led to inflammatory complications of two distinct phases: immediately after drug administration and six weeks later. Both phases were linked to an innocuous skin infection.

Glomerular lesion and increased cytokine gene expression in renal tissue in patients with decompensated nephrotic syndrome due to chronic GvHD.

The nephrotic syndrome is a rare complication of allogeneic stem cell transplantation (alloHSCT). We present two cases of nephrotic syndrome during chronic graft-versus-host disease (GvHD) involving altered cytokine gene expression in renal tissue. A patient with acute lymphatic leukemia demonstrated nephrotic syndrome due to minimal change disease as a marker of chronic GvHD. A patient with acute lymphoblastic leukemia suffered from severe nephrotic syndrome due to membranous glomerulopathy. In the two presented cases of GvHD-linked nephrotic syndrome, increased cytokine gene expression [tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta), interferon gamma (IFN-gamma), interleukin 2 (IL-2), IL-6, and IL-10] assessed using semiquantitative evaluation with reverse transcriptase polymerase chain reaction (RT-PCR) in situ on renal biopsy was observed.

Successful revascularisation of a thrombosed renal artery aneurysm in a young man with solitary kidney and history of severe hypertension.

Case report of a 18-year-old patient with long lasting hypertension, who developed acute renal failure, in course of an antihypertensive therapy modification, backgrounded by undiagnosed aneurysm of the solitary kidney renal artery. The acute renal function decrease was caused by single dose of ACE inhibitor causing an equivalent drop in serum ACE activity. Aneurysm excision followed by implantation of a venous bypass normalized restored renal function and blood pressure for over 24 months of observation.

Kidney graft function in long-term cyclosporine and tacrolimus treatment: comparative study with nephrotoxicity markers.

Calcineurin inhibitors improve kidney allograft survival in the posttransplantation period; however, they may cause nephrotoxicity. The objective of this study was to compare the effect of cyclosporine (CsA) and tacrolimus (Tac) treatment on the transplanted kidney. The study included 219 patients aged 21 to 65 years. Of these, 120 (39 women and 81 men) were treated with CsA and 99 (38 women and 61 men) were treated with Tac. Patients were divided into 4 groups depending on the time since kidney transplantation. We evaluated urine markers of nephrotoxicity: proximal tubular cells lysosomal enzymes (N-acetyl-beta-d-glucosaminidase [NAG] and its isoform NAG-B, beta-d-galactosidase, and beta-glucouronidase) and brush border enzymes (alanyl aminopeptidase and gamma-glutamyl transpeptidase). Urine activities of nephrotoxicity markers were compared in CsA- and Tac-treated patients groups depending on the duration of treatment and allograft function as measured by serum creatinine concentration. Correlation studies between CsA and Tac levels and enzyme activities were performed in both groups and in the entire patient cohort. NAG and its isoform NAG-B seemed to be the most reliable markers of nephrotoxicity. Despite the significant correlation between NAG urine activity and serum creatinine concentration in the CsA group, there were no significant differences in NAG or NAG-B activities between CsA- and Tac-treated graft recipients.

Kidney transplantation and enzyme alpha-galactosidase A therapy in patient with Fabry disease: a case report.

Fabry disease, an X-linked recessive glycolipid storage disease, is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A), which cleaves a fatty substance called globotriaosylceramide (GL3). The abnormal storage of GL3 in blood vessel walls leads to ischemia and necrosis, particularly in blood vessels of the skin, kidneys, heart, brain, and nervous system. The aim of our study was to present the results of cadaveric kidney transplantation with enzyme alpha-Gal A therapy in a patient with Fabry disease. The patient was diagnosed with Fabry disease at the age of 33 years, based on enzymatic tests. Renal manifestations occurred a year later as proteinuria. At the age of 35 years, the glomerular filtration rate (GFR) was within the normal range. The patient received supplemental enzyme treatment with alpha-Gal (1 mg/kg every 2 weeks). At 3 months after starting supplementation, renal function worsened with serum creatinine levels at 1.7 to 1.8 mg/dL. The following months of supplementation (alpha-Gal 1 mg/kg) concurred with progressive renal dysfunction. After 27 months of supplementation at 37 years, with a creatinine value of 5.5 mg/dL, hemodialysis began and months later the patient received a cadaveric kidney graft. The patient no longer required dialysis. On postoperative day 5 the serum creatinine was 3.9 mg/dL; on day 7, 2.2 mg/dL; on day 14, 1.5 mg/dL. Enzyme supplementation began on posttransplant day 13. Renal graft function has been good during 5 months of observation with creatinine levels at 1.2 to 1.3 mg/dL. The treatment does not interfere with tacrolimus metabolism. Simultaneous chronic enzyme supplementation is the optimal treatment in the fifth stage of end-stage renal disease in Fabry disease.

Dissecting aneurysm of the thoracic aorta in a patient with nephrotic syndrome and brucellosis.

We report the case of a 61-year-old man with nephrotic syndrome due to glomerulonephritis and chronic brucellosis complicated by dissecting aortic aneurysm. The patient worked as a veterinarian and was diagnosed for chronic but non-active brucellosis with positive serum test for Brucella melitensis in the past. Administration of cyclosporine in combination with low dose prednisone resulted at least in proteinuria reduction and partial remission for 3 years. Dissecting aortic aneurysm was treated by insertion of a stent-graft, that resulted in canalization of blood flow and retraction of aneurysm wall later in the course in our patient.

Evaluation of drug toxicity in clinical trials.

An increasing number of drugs removed from the market because of unacceptable toxicity raises concerns regarding pre-approval testing of drug safety. In the present paper it is postulated that the non-inferiority type of trial should be abandoned in favor of the superiority trial with active controls and less stringent (p<0.1, both for efficacy and toxicity) statistics. This approach will increase sensitivity of detection of drug-induced adverse effects at the expense of increasing false positive results regarding the difference in efficacy between the tested and reference drug. Such a move will increase the protection of future patients. In addition, the proposed design is far more acceptable from the clinical (e.g. no need to specify the statistically expected "unimportant" number of deaths) and ethical points of view, as well as being favored by the strong incentive of involved parties. In the second part of this paper arguments are presented in favor of the hypothesis that placebo (still used in some superiority trials) does not induce adverse effects. The assertion that placebo may induce adverse effects is probably biased by the nature of the clinical experiment. Such a conclusion is supported by studies indicating that placebo-induced adverse effects are disease -- and treatment -- specific. The modification of clinical trials according to the proposed changes may increase the trials' sensitivity at detecting adverse effects of drugs.

Bioequivalence of two preparations of ticlopidine evaluated using a pharmacodynamic end point.

OBJECTIVE: To evaluate the bio-equivalence of 2 ticlopidine preparations, 250 mg Iclopid tablets (Pabianickie Zaklady Farmaceutyczne, Polfa, Poland; test formulation) and 250 mg Ticlid tablets (Sanofi, France; reference formulation) using a pharmacodynamic end point, i.e the platelet aggregation test ex vivo. SUBJECTS, MATERIALS AND METHODS: The study was open, randomized, multiple-dose, two-period, crossover with a four-week washout interval. Volunteers were screened for sensitivity towards the platelet aggregation (ex vivo) effect of ADP (30 micromol/l) and sensitivity to the antiplatelet activity of ticlopidine (250 mg daily, for 3 consecutive days). Only those responding to 30 micromol/l of ADP with aggregation in the range of 40 - 75% of control (0.9% NaCI), and those responding to ticlopidine within 40 - 75% of inhibition of platelet aggregation to ADP ex vivo were randomized to the study. The dose of ticlopidine in each phase was 250 mg daily for four days. Blood samples were taken on Day 0 and Days 2, 4 (last day of ticlopidine administration), 5, 6, 9, 11 and 16 in order to follow platelet recovery. The pharmacodynamic parameter measured was expressed as the percentage inhibition of ex vivo platelet aggregation calculated from the number of platelets in the sample of whole blood remaining after ADP (30 micromol/l) compared to the control sample. The following values were calculated: area under the inhibition curve of platelet aggregation (AUC(inh 1-16)), maximal inhibition of platelet aggregation (Max(inh)) and time at which maximal inhibition of aggregation occurred (T(max inh)). RESULTS: The ratios (90% confidence intervals) of Iclopid/Ticlid for AUC(inh 1-16), Max(inh), and T(max inh) were: 1.008 (0.973 - 1.044), 1.009 (0.991 - 1.028) and 1.015 (0.988 - 1.043), respectively, satisfying the bioequivalence criteria. CONCLUSIONS: The test and the reference products are bioequivalent on the basis of the ex vivo platelet aggregation test. Our study has shown that the bioequivalence of two different preparations can be assessed by measuring a pharmacodynamic end point in a suitably selected group of subjects.

Oxidative stress and coenzyme Q10 supplementation in renal transplant recipients.

Recently some reports about the oxidative stress in renal transplant recipients have been published. The role of coenzyme Q10 (CoQ10) as radical scavanger is largely known. The aim of our study was to evaluate the protective role of CoQ10 in renal transplant recipients on lipid peroxidation and lipids parameters, as well as its influence on antioxidant enzymes, neutrophils chemiluminescence and urinary enzymes. The study was performed in 11 long term allograft recipients treated additionally with CoQ10 90 mg/day in three doses, 30 mg each for four weeks. The malonyldialdehyde (MDA) and 4-hydroxynonenal (4-HNE), superoxide dismutase (SOD) and glutathione peroxidase (GPx) and the basic parameters of lipid metabolism such as total cholesterol (TC), high and low density lipoproteins (HDL, LDL), triglycerides (TG), atherogenicity indicators [LDL/HDL; (TC-HDL)/HDL] were evaluated. The chemiluminescence of neutrophils (luminol, fLMP-method) were mesured and the activity of N-acetyl-beta-D-glucosaminidase (NAG), alanylaminopeptidase (AAP), elastase, alpha-1-antitrypsin. All parameters were estimated before and after CoQ10 treatment. Statistically significant changes were noticed with the LDL and atherogenicity indicators (p < 0.01) (decrease) as well as HDL level (p < 0.001) (increase). Also the significant decrease of fMLP stimulated PMNL chemiluminescence (p < 0.05) confirms the antioxidative properties of CoQ10. The significant increase of NAG activity (p < 0.05) can't be the result of nephrotoxic effect, because NAG-B is unchanged. Serum concentration of creatinine and cyclosporine A in renal allograft recipients was unchanged after CoQ10 treatment. The presented date shows that further study with CoQ10 treatment in renal transplant in larger numbers and over longer periods should be considered.

Enzymuria and beta2-mikroglobulinuria in the assessment of the influence of proteinuria on the progression of glomerulopathies.

The important role of the tubulo-interstitial system for the progression of glomerulonephritis (GN), is the cause of a continuous search for the proper markers of kidney tubules damage, which can be applied in clinical diagnosis. In the present work the activity of N-acetyl-beta-D-glucosamidase (NAG), its isoenzyme NAG-B, alanylaminopeptidase (AAP), gamma-glutamyltransferase (GGT), concentration of beta2-microglobulin (beta2M) and daily protein excretion in the urine of 37 patients with morphologically different glomerulopathies were measured. The serum creatinine was also controlled. The obtained results suggest that activity of NAG in the patients with GN has an intermediate connection with proteinuria and could be a cause of the inflammatory process of the kidney, but the activity of AAP is directly dependent on urine protein concentration. Systemic analysis of both partial and multiple correlation coefficients of the examined indicators creates new, additional possibilities in the estimation of activity and progress of GN.

Enzymatic markers of cyclosporine nephrotoxicity in patients after renal transplantation.

Toxicity of cyclosporine (CsA), an immunosuppressive drug widely used in transplantation, to the transplanted kidney creates a serious side effect. Therefore, searching for sensitive indicators of nephrotoxic action is well worth the effort. In this work we describe the results of estimation of urine concentration of lysosomal enzymes widely present in the kidney: N-acetyl-beta-D-glucosaminidase (NAG), its isoenzyme NAG-B and beta-glucuronidase (beta-Gr). The studies were conducted in various periods after transplantation of kidneys, on patients under various treatments and receiving different doses of CsA. The results indicate a substantial dependence of the activity of NAG and NAG-B on CsA doses and the period after transplantation. The enzyme proved to be also a sensitive indicator of graft rejection. No such dependence was observed in the case of beta-Gr.

[A case of cylindroma of the parapharyngeal space]. / Przypadek oblaka przestrzeni przygardlowej.

The authors show a case of parapharyngeal space cylindroma paying attention to large diagnostic difficulties. This tumor has been characterized by a slow local growth but after five years disease involved many organs with metastases.

Diagnostic application of AAP isoenzyme separation.

We describe the separation of alanylaminopeptidase (AAP) from urine into two isoenzymes: a particulate and a soluble form. The separation was accomplished using ion-exchange column chromatography on DEAE-52 cellulose. The purity of the isolated forms was confirmed electrophoretically. We attempted to create a method allowing the quantitative assessment of AAP isoenzymes in urine based on electrophoretic separation in 7.5% polyacrylamide gel with subsequent densitometric analysis. The content of AAP isoenzymes in examined urine was estimated using ultracentrifugation. The differences in the content of cytosolic and microsomal forms were observed suggesting the possibilities of using AAP isoenzymes in diagnostics. Furthermore, the effect of temperature on the activity of AAP separated on DEAE-52 cellulose was studied.

Enzymuria in antibiotic therapy of acute infections.

Activities of N-acetyl-beta-D-glucosaminidase (NAG), its isoenzyme NAG-B, alanylaminopeptidase (AAP), elastase and trypsin inhibitor (alpha 1 PI) were evaluated as markers of nephrotoxicity and inflammation in acute infections treated with various antibiotics (vancomycin, netilmicin, pefloxacine, cefoperazone and imipenem).

The efficacy and potency of antiplatelet activity of ticlopidine is increased by aspirin.

Concomitant therapy with ticlopidine (T) and aspirin (ASA) profoundly increases spectrum of antiplatelet activities of both drugs. It was hypothesized that in addition to increased spectrum of activity (efficacy) each drug may potentiate the specific antiplatelet activity (potency) of the other. In 32 volunteers whole blood platelet aggregation (PA) in response to ADP, collagen, and arachidonic acid was evaluated ex vivo following 10-day treatments with normal or subthreshold doses of T or ASA with addition of second drug on the 5th day of administration of the first. PA was measured before, on day 5 and 10 of treatment. The results indicate that ASA increased spectrum of activity of T, i.e. T and ASA in combination, were significantly more effective against collagen-induced PA than either drug alone. This increased efficacy was retained when subthreshold dose of T (100 mg, qd) was used. T was without effect on AA-induced and ASA on ADP-induced PA. However, ASA potentiated effect of T on ADP-induced PA; the subthreshold dose of T (100 mg, qd) in presence of ASA (100 mg, qd) exerted powerful inhibition. Thus, combination therapy increases both efficacy and potency of T allowing for reduction of the dose.

Pharmacodynamics of ticlopidine: relation between dose and time of administration to platelet inhibition.

In spite of long clinical experience with ticlopidine (T) knowledge of its pharmacodynamics is limited. In this study relation between dose and time of administration of T to platelet inhibition was investigated in 62 healthy volunteers ex vivo in whole blood and platelet rich plasma. Gender-related sensitivity of platelets to ticlopidine was also evaluated. Inhibition of ADP-induced platelet aggregation by T, 500 mg, daily, was almost identical in both sexes. 100 mg daily did not inhibit ADP-induced platelet aggregation even after 14 days of administration. 250 mg daily induced strong inhibition on day 5 of administration comparable to the inhibition obtained with 500 mg daily dose. The antiplatelet (ADP) effect of T (500 mg, daily) was present on day 2-3 and full inhibitory effect on day 4 of administration. T1/2 of antiplatelet (ADP) activity of T was 5.3 days and full recovery of platelets activity 11-13 days. No rebound phenomenon was present. T (regardless the dose) inhibited platelet aggregation induced by small but not high concentrations of collagen and was without effect on arachidonic acid-induced platelet aggregation. Therefore, T is not suitable for treatment of acute event, 250 mg daily dose should be used especially for combination with other drugs and 11 days washout interval seems necessary to change the treatment or to perform surgery.

[Influence of vapours of paint and toxic dusts on mucous membranes of the upper airways in paint and varnish factory workers]. / Wplyw par rozpuszczalników i pylów toksycznych na blony sluzowe górnych dróg oddechowych pracowników fabryki farb i lakierów.

Macroscopic, cytologic and bacteriologic conditions of mucous membranes of the upper airways in workers (n = 146) of the Polifarb Factory, Wroclaw, exposed to dusts and solvent vapours used in the paint and varnish production was estimated. In 89% of the workers, pathologic changes in throat mucous membranes were observed. Three types of macroscopic changes were distinguished. In workers with the shortest period of employment, laryngeal oedema congestion alteration was diagnosed, and atrophic changes with medium intensity were observed in workers employed for a long period. It was found that cytologic changes in the nose mucous membrane depended on the duration of exposure. Inflammation cytograms appeared during the first period of exposure to the substances discussed. The longer period of exposure, the more clear features of metaplasia squamous epithelium. The composition of the nose and throat bacterial flora changed according to the length of employment. An increased growth of G(-) genera Enterobacter, Klebsiella, Proteus, Escherichia and Candida fungi was found in workers with long period of employment.

N-acetyl-B-D-glucosaminidase isoenzymes in the diagnosis of poisoning and kidney diseases.

Damaged lysosomes from renal tubular cells are, to the greatest degree, the source of activity of NAG in urine. Besides this, the enzyme can appear as a result of degranulation of granulocytes (PMN), active infection of the urinary system as also from serum as a result of glomerular filtration during damage to the glomerular basement membrane. For the purpose of explaining the source of origin of the enzyme in urine, NAG was separated into isoenzymes from the kidneys, granulocytes and serum for comparison with isoenzymes in physiological and pathological urines after ethylene glycol poisoning, and glomerulonephritis, respectively. The separation was made by column ion-exchange chromatography on DEAE-52 cellulose and by electrophoresis in 7% polyacrylamide gel. In addition, the thermostability of isolated isoenzymes was compared.

The variety of clinical and histopathologic presentations of glomerulonephritis associated with latent syphilis.

Glomerulonephritis is a well established but rather uncommon complication of latent secondary syphilis. We present three cases of glomerulopathies associated with luetic infection, observed and managed in our institutions in the past three years. They illustrate a variety of clinicopathologic presentations of this nephropathy, from acute nephrotic syndrome through membranous glomerulopathy up to rapidly progressive glomerulonephritis. Regardless of the clinical course and histologic type, they were all characterized by strongly positive results of serologic tests for syphilis. Our observations suggest the necessity of eliminating luetic infection in aetiologic considerations of each newly diagnosed case of nephrotic syndrome.