IgA nephropathy--human disease and animal model

IgA nephropathy is one of the most common chronic glomerulonephritides worldwide. Since the first publication on IgA nephropathy, a number of clinical and pathological investigations have revealed that the clinical course of patients with IgA nephropathy is extremely diverse, with approximately 10-20% of the patients developing end-stage chronic renal failure. Glomerular changes similar to IgA nephropathy have also been observed in patients with Schoenlein-Henoch purpura, and with other diseases such as liver cirrhosis and chronic inflammatory diseases of the lung. The broad spectrum of clinical and pathological features of IgA nephropathy encompasses a syndrome which includes both primary and secondary IgA nephropathy. The common etiology and pathogenesis of primary and secondary IgA nephropathy appear to be closely related to immunological abnormalities in the production of IgA induced by antigenic stimulation of the common mucosal immune system. IgA is one of the most important humoral factors of the mucosal immune defense system and functions as an antibody against various extrinsic and intrinsic substances. This review describes the Arthus type of IgA immune complex deposition in the glomeruli which can result from persistent or repeated increases in circulating IgA immune complexes. The latter occurs as a consequence of overproduction of IgA antibodies and/or impairment in clearance of IgA immune complexes by the mononuclear phagocytic system. The present review also focuses on the biology of the IgA-mediated immune system and on the etiology, pathogenesis, and animal models of IgA nephropathy.     

In vitro transformation of ochratoxin A by animal microbioal floras

Ochratoxin A is hydrolysed to ochratoxin alpha by the centrifugal pellet of rat caecal contents containing the microbial flora. The supernatant liquid is however, completely lacking in detoxifying enzymatic activity. The large proportion of toxin lost suggest that degradation of the active principe to non-fluorescent metabolites occurs. The rumen fluid of cows and sheep obtained at a slaughterhouse can hydrolyse the toxin and also, in certain cases, esterifies it to the equally toxic ochratoxin C. Cow rumen fluid obtained by oesophageal sounding does not have the latter activity but hydrolyses more intensively ochratoxin A. In this case the fraction responsible for this transformation contains mainly protozoa.     

In vitro MR microscopy of the hippocampus in Alzheimer''s disease

In prepubertal children, teratoma is a benign tumor, whereas in adolescents and adults, it behaves as a malignant neoplasm. Adult patients without evidence of metastases may be candidates for surveillance after orchiectomy, and those with low-volume or borderline retroperitoneal metastases thought to contain teratoma might best be managed by surgery, as teratomatous deposits do not respond to chemotherapy. Patients with larger retroperitoneal metastases may be given chemotherapy before surgery to reduce or eliminate other germ-cell elements. Teratomatous masses persisting after chemotherapy are excised by most clinicians, in part to obtain a pathologic diagnosis. In childhood tumors, inguinal orchiectomy or enucleation is sufficient if one is certain the lesion contains only teratoma.     

E. L. Thorndike and the origins of animal psychology: On the nature of the animal in psychology.

E. L. Thorndike's deliberate use of the experimental method and rejection of anthropomorphism and anecdotalism place him squarely at the beginning of a century of animal research in psychology. The authors examine Thorndike's critique of the extant research of his day and the development of his methods, including the important way in which animals and children were often taken as interchangeable sources of data for the new functional psychology. Thorndike's research clearly altered the relationship between psychologist and animal, as is demonstrated by his own studies and those that were published in the decade that followed. The authors review this body of work in the early 20th century for (a) the manner in which it exchanges anthropomorphism for mechanicotheriomorphism and (b) its constitution of the animal as a conflation between organism and technology. The authors conclude by noting the importance of debates concerning anthropomorphism in psychology for the century-long question of consciousness. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Leukocyte counts in patients with Kawasaki disease: from the results of nationwide surveys of Kawasaki disease in Japan

In the latest survey of Kawasaki disease in Japan, questionnaires on maximal leukocyte counts of the patients were included to clarify whether leukocyte counts could be of value for the diagnosis and prediction of outcome. A questionnaire form and diagnostic guidelines for Kawasaki disease were sent to all pediatric departments of hospitals with > or = 100 beds throughout Japan, and information including maximal leukocyte counts was obtained on patients with Kawasaki disease diagnosed during the 2-y period from January 1993 to December 1994. Of the 11,458 patients diagnosed during the 2-y period, maximal leukocyte counts were reported in 11,062 patients (96.5%). The mean value and the distribution of maximal leukocyte counts were lower in the age group under 1 y. The mean values and the distribution of leukocyte counts were lowest in suspected cases among three diagnostic categories: typical cases of Kawasaki disease, atypical cases, and suspected cases. The mean values of maximal leukocyte counts of the patients with cardiac sequelae were significantly higher than those without cardiac sequelae in each age group. The proportion of patients with cardiac sequelae increased with leukocyte counts in each age group. The Receiver/Response Operating Characteristic (ROC) curve for maximal leukocyte counts in Kawasaki disease revealed that the accuracy of maximal leukocyte counts for prediction of cardiac sequelae was highest in the age group < 6 months, and the most accurate cut-off point was 16 x 10(9)/l. The strongest association between higher leukocyte counts (> or = 16 x 10(9)/l) and cardiac sequelae was observed in the age group < 6 M. A large-scale analysis of leukocyte counts in patients with Kawasaki disease revealed age-dependent relationship between maximal leukocyte counts, diagnostic categories and outcome. Maximal leukocyte counts may be helpful for the prediction of outcome with the consideration of age.     

In vitro and animal validation of bromine-76-bromodeoxyuridine as a proliferation marker

The potential of 76Br-bromodeoxyuridine as a PET tracer for characterizing proliferation potential was investigated in multicellular tumor aggregates and in healthy rats and pigs. METHODS: Bromine-76-bromide was produced by proton irradiation of a 76Se-enriched target using a 17-MeV cyclotron and recovered by thermal diffusion. Bromine-76-BrdU was prepared from the corresponding trimethylstannate by an oxidative bromination. Multicellular aggregates from a carcinoid cell line and two bladder cancer cell lines were co-incubated with 76Br-BrdU and 3H-thymidine and the uptake and DNA incorporation analyzed. About 0.5 MBq 76Br-BrdU were injected in the tail vein of unanaesthetised Sprague-Dawley rats. Two to 36 hr later they were decapitated and the radioactivity concentration and fraction of radioactivity incorporated into DNA determined in five different organs and the blood. Parallel studies were performed in animals pretreated with hydroxyurea. In separate experiments, rats were given an injection of 76Br-bromide and organ uptake was evaluated after 20 hr. PET studies were performed in two pigs and the uptake in different organs was investigated after injection of 76Br-BrdU. In these studies, diuresis was induced by furosemide and mannitol and radioactivity in blood and organs was followed during 10 hr. RESULTS: In the cell aggregates, 30%-90% of the radioactivity was extracted in the DNA fraction. A good correlation was found between 76Br-BrdU and 3H-thymidine with respect to total uptake and DNA fraction. The DNA fraction increased from 2-10 hr after incubation. With in vivo injection in the rat, relatively high uptake of radioactivity was found in all organs, unrelated to the degree of DNA synthesis. However, inhibition by hydroxyurea occurred only in the spleen and intestines, organs which also showed a high degree of incorporation of 76Br-BrdU into DNA. In the pig, the highest in vivo uptake was observed in the red bone marrow and the intestines. In these organs, 70%-80% of the radioactivity was recovered in the DNA fraction. The concentration of radioactivity in the heart, liver and kidney was 3-10 times lower, and here the DNA fraction accounted for 10%-20% of the radioactivity. The decay-corrected radioactivity in blood and nonproliferating organs decreased with diuresis with a half-life of 13 and 16 hr, respectively. CONCLUSION: It is suggested that the radioactivity uptake as seen after the administration of 76Br-BrdU, is constituted by two parts: one relating to incorporation into DNA and one existing as free 76Br- or metabolites of 76Br-BrdU. If sufficient time has passed, 76Br- dominates other metabolites. A correct assessment of DNA-incorporated radioactivity using PET with 76Br-BrdU is not trivial and can only be made with due correction for 76Br-, using either a complementary investigation after hydroxyurea pretreatment (in animal studies) or a separate 76Br-bromide investigation. Alternatively, the free bromide can be eliminated partially through forced diuresis.     

Cardiovascular abnormalities in Kawasaki disease. An Italian prospective study

We report a prospective study performed over a 9 year period in 96 children with Kawasaki disease (mean age 35 +/- 29 months), 84 of whom < 5 years of age. The male/female ratio was 1.5 (57/39). A total of 38 patients had cardiac involvement, including flattened T waves in the ECG (10 patients), pericardial effusion (6 patients), myocarditis (1 patient), and coronary artery aneurysms (25 patients; frequency of aneurysms: 26%). All patients were evaluated during the acute phase (first month) of the illness. The first echocardiographic examination was performed 15 days (range 4.30 days) from the appearance of fever, and coronary aneurysms were observed in 23 patients; in 2 patients, however, aneurysms appeared later (2 and 6 months). Aneurysms were small (< or = 4.5 mm) in 12, medium (4.5-7 mm) in 11, and large (> 7 mm) in 12 patients. Male sex (p = 0.02), age < 12 months (p = 0.005), ESR (p = 0.001), platelet count (p = 0.009), and pericardial effusion (p = 0.02) were significantly related to the presence of aneurysm. Among females, incidence of aneurysms was significantly higher in infants < 12 months than in older patients (60 vs 6%, p < 0.001). Intravenous immunoglobulin treatment was started early (within 10 days) in 61 patients and late (> 10 days) in 22. Compared to late treatment, early i.v. immunoglobulin treatment was associated with smaller aneurysms and higher regression rate (67 vs 28%, p < 0.05). No difference was observed concerning frequency and number of dilated vessels as related to therapeutical regimens. Total i.v. immunoglobulin dose (2 g/kg) was administered over 1-2 days in 26 patients (scheme I) or over 4-5 days in 58 (scheme II). Frequency of aneurysms was significantly lower in patients treated early (p = 0.02). No myocardial infarctions or deaths occurred at short- or long-term follow-up.     

In vitro evaluation of the antigenotoxic activity of a strain of L. bulgaricus isolated from commercial yogurt

Sequential oxidations at the arylamine moiety of the procainamide molecule leading to the formation of N-hydroxyprocainamide and its nitroso derivative may be responsible for lupus erythematosus observed in patients treated with the drug. The objective of the present study was to characterize major cytochrome P450 isozyme(s) involved in the N-hydroxylation of procainamide. Firstly, incubations were performed with microsomes from either lymphoblastoid cells or yeast transfected with cDNA encoding for specific human cytochrome P450 isozymes. Experiments performed with these enzyme expression systems indicated that the highest formation rate of N-hydroxyprocainamide was observed in the presence of CYP2D6 enriched microsomes. Additional experiments demonstrated that the formation rate of N-hydroxyprocainamide by CYP2D6 enriched microsomes was decreased from 45 +/- 4% to 93 +/- 1% by quinidine at concentrations ranging from 30 nM to 100 microM (all p < 0.05 vs control) and by approximately 75% by antibodies directed against CYP2D6. Secondly, incubations were performed with microsomes prepared from 15 human liver samples. Using this approach, an excellent correlation was observed between the formation rate of N-hydroxyprocainamide and dextromethorphan O-demethylase activity (CYP2D6; r = 0.9305; p < 0.0001). In contrast, no correlation could be established between N-hydroxyprocainamide formation rate and caffeine N3-demethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), S-mephenytoin N-demethylase (CYP2B6), tolbutamide methlhydroxylase (CYP2C9), S-mephenytoin 4'-hydroxylase (CYP2C19), chlorzoxazone 6-hydroxylase (CYP2E1), dextromethorphan N-demethylase (CYP3A4), testosterone 6 beta-hydroxylase (CYP3A4/5) or lauric acid 12-hydroxylase (CYP4A11) activities. Furthermore, formation rate of N-hydroxyprocainamide was decreased in a concentration-dependent manner by quinidine (300 nM to 100 microM) and by antibodies directed against CYP2D6 but not by furafylline 20 microM (CYP1A2), ketoconazole 1 microM (CYP3A4), sulfaphenazole 10 microM (CYP2C9) or antibodies directed against CYP1A1/1A2, CYP2C, CYP2A6, CYP2E1 or CYP3A4/3A5. In conclusion, the results obtained in the present study demonstrate that CYP2D6 is the major human cytochrome P450 isozyme involved in the formation of the reactive metabolite of procainamide, namely N-hydroxyprocainamide.     

An animal model for the behavioral effects of interferon.

Interferon, which is produced during viral infections, has cognitive and neurological effects in humans. A dose of 1600 U/g of mouse interferon-alpha significantly depressed horizontal activity, head pokes into a food chamber, and food intake in mice 10 hr and 24 hr after injection. An 800 U/g dose had only slight effects on horizontal activity and food intake, whereas a 400 U/g dose had no effect. There was no evidence of sensitization to interferon when a second 400 U/g dose was given after the 1600 U/g dose. The results imply that mouse interferon-alpha can be used in mice as a model for studying the fatigue and anorexia produced by interferon. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A new placental enzyme in the metabolism of cocaine: an in vitro animal model

OBJECTIVE: The aim of this study was to analyze placental metabolism in a genetically controlled in vitro animal model. STUDY DESIGN: Placentas from Sprague-Dawley rats were centrifuged, and microsomes were isolated. Four treatment groups were incubated with cocaine over four time periods: placental microsomes + cocaine, placental microsomes + diisopropyl fluorophosphate (an anticholinesterase) + cocaine, placental microsomes + cocaine + butyrylcholinesterase, and a blank (cocaine only). Gas chromatography was used to quantify cocaine (Limit of quantitation = 19 ng/ml) and metabolites. Gas chromatography/mass spectrometry was used to verify the identity of the metabolites. RESULTS: Butyrylcholinesterase enhanced cocaine metabolism to ecgonine methyl ester. More than 40% of cocaine was metabolized to norcocaine by rat placental when diisopropyl fluorophosphate suppressed cocaine. Norcocaine is produced by hepatic N-demethylase action on methyl-bearing nitrogen in cocaine, suggesting that placenta and liver have this capacity. Gas chromatography/mass spectrometry was essential to the identification of norcocaine, because norcocaine is frequently not identified. CONCLUSIONS: This biotransformation of cocaine to norcocaine may be a primary metabolic pathway induced in the cholinesterase-deficient placenta. This has clinical implications because norcocaine is ninefold more active physiologically than cocaine or ecgononine methylesterase.     

In vitro training model for endovascular embolization of cerebral aneurysms

We present a new in vitro model for the training of endovascular embolizations of cerebral aneurysms. The technique and laboratory set-up described allow the embolization of thin-walled, transparent silicone aneurysm models under "semi-physiologic" conditions, i.e., in a closed circulation with pulsatile flow and pressure, simulating the hemodynamic conditions encountered in biologic systems.     

The endothelium in Kawasaki disease: the next frontier

A 24-mo study of the laboratory life cycle of the tick Ixodes woodi Bishopp was conducted. No other such study of any species in the subgenus Ixodiopsis Filippova has been reported. Three generations of I. woodi were examined. Larvae and nymphs fed for an average of 4 d; approximately 8-9 d were required for females to engorge. Females laid approximately 900 eggs that required an average of 37.33 d to hatch.     

Hospital facilities available to patients with Kawasaki disease: results of a national survey of Kawasaki disease in Japan

Since 1970, thirteen nationwide epidemiologic surveys of Kawasaki disease have been conducted, and questions on the current situation of hospitals and their facilities have been included in the survey form to assess the care available to patients with Kawasaki disease. To clarify the characteristics of medical care for Kawasaki disease, this paper summarizes the present condition of hospital facilities available to patients with Kawasaki disease. A questionnaire form including questions about the situation of hospital facilities was sent to all pediatric departments of hospitals with 100 or more beds throughout Japan. The proportion of hospitals in which successive observations with echocardiography (UCG) is available (UCG available hospital) was significantly increased compared with the ninth survey (1985-86), whereas that of the hospitals in which coronary angiography (CAG) is available (CAG available hospital) was significantly decreased. Almost all (96.2%) of the patients were reported from the UCG available hospitals. The proportion of patients reported from hospitals with a set policy for intravenous gamma globulin (IVGG) therapy was 74.5%. The proportion of UCG available and CAG available hospitals and that of hospitals with a set policy for IVGG therapy correlated with the increase in the number of patients. In conclusion, hospital facilities available to patients with Kawasaki disease in Japan have satisfactory capability for diagnosis and management of Kawasaki disease.