Bacterial superantigen enhances cytokine production by T-helper lymphocyte subset-2 cells and modifies glomerular lesions in experimental immunoglobulin a nephropathy

Background The purpose of this study was to examine the effects of bacterial suporantigens, which can derange the immune response and contribute to the renal lesions of immunoglobulin A (lgA) nephropathy. Methods Twenty-five micrograms of a bacterial superantigen, staphylococcal enterotoxin B (SEB), was injected into IgA nephropathy-prone ddY mice intrathymically when they reached 6 weeks of age. Evaluation included measurement of albumin excretion in urine, immunoglobulin concentration, and lymphokine production in vitro, as well as analysis of T-cell receptor expression in splenic T-cell subsets and examination of renal histology by light and fluorescence microscopy. Results At 40 weeks of age, the serum level of IgA in these mice was substantially increased and the number of Vβ8⁺ CD4⁺splenic T-cells was significantly decreased compared with measurements in untreated controls. Both control and SEB-treated mice excreted less than 30 μg/mL of urinary albumin. In mice given SEB, the amount of interleukin 2 (IL-2) and tumor necrosis factor-α (T helper 1 [Th1]-type cytokines) produced by the in vitro-stimulated lymphocytes significantly decreased. whereas that of interleukin 4 (IL-4) and interleukin 6 (IL-6) (Th2-type cytokines) markedly increased compared with measurements in control mice. At 40 weeks of age, mice given SEB showed marked glomerular hypercellularity and enhanced glomerular C3 deposition by renal histology, compared with control mice. Conclusion These results suggest that bacterial superantigen SEB may modify glomerular lesions through activating Th2 cells, while inducing deletion of Th1 cells in this experimental model.     

The efficacy of fluconazole in treating prosthetic valve endocarditis caused byCandida glabrata: Report of a case

A case of active prosthetic valve infective endocarditis (PVE) due toCandida glabrata was successfully treated by the systemic administration of fluconazole. A 66-year-old Japanese man with infective endocarditis of unknown etiology underwent aortic and mitral valve replacement to treat severe aortic and mitral regurgitation associated with multiple organ failure. Postsurgical cultures of arterial blood were repeatedly positive forC. glabrata, and therefore fluconazole was administered either intravenously or orally at a dose of 400 mg/day for 46 days. During that time the signs of inflammation including fever such as an elevated white blood cell count and the presence of C-reactive protein (CRP) all improved while the blood cultures became negative. Fluconazole is thus considered to be effective in treating PVE caused byC. glabrata. When administering this treatment, it is also important to monitor the patient's renal and liver function.     

Benastatins A and B, new inhibitors of glutathione S-transferase, produced by Streptomyces sp. MI384-DF12. I. Taxonomy, production, isolation, physico-chemical properties and biological activities.

Benastatins have been isolated as part of a program designed to find microorganism-produced inhibitors of glutathione S-transferase from Streptomyces sp. MI384-DF12. They were purified by chromatography of reversed-phase silica gel, silica gel and Capcell Pak C18 (HPLC) followed by solvent extraction and then isolated as yellow powders. Benastatins A and B have the molecular formulae, C30H28O7 and C30H30O7, respectively. They were competitive with 3,4-dichloronitrobenzene as the substrate, and the inhibition constants (Ki) of benastatins A and B were 5.0 x 10(-6) and 3.7 x 10(-6), respectively.     

Nicotine applied by transdermal patch induced HSV-1 reactivation and ocular shedding in latently infected rabbits.

The identification of factors involved in herpes virus latency and reactivation is critical to a better understanding of the mechanisms essential to viral neuroinvasiveness and neurovirulence. Recurrent episodes of ocular herpes infections cause irreversible corneal scarring and are the primary cause of loss of vision due to an infectious agent in industrialized countries. In this study, we examined the ability of nicotine, a compound known to be involved in stress-associated immunomodulation and recognized as one of the most frequently used addictive agents, to induce ocular shedding in rabbits latently infected with herpes simplex virus type 1 (HSV-1) strain McKrae. New Zealand white rabbits latently infected with HSV-1 at 3-4 weeks post-inoculation were randomly divided into two groups. The corneas of all rabbits were free of lesions as verified by slit lamp biomicroscopy. One group received nicotine by transdermal patch (21 mg/day) for 20 days and the other group served as the control. Reactivation data were obtained by detection of virus in tear film collected by ocular swabbing performed concurrently with the administration of nicotine. Compilation of data from three separate experiments demonstrated that 16.5% (258/1560) of the swabs taken from rabbits treated with nicotine were positive for virus, compared with 8.3% (53/639) of swabs taken from controls. Rabbits receiving nicotine exhibited a significantly (P < 0.0001) higher rate of ocular shedding than controls. The concentration of nicotine in the serum was determined at various times (0-24 hrs) after new patch replacement. Peak (average) serum level of nicotine was obtained 8 hours after patch replacement and exhibited a broad range of values (0.233 microg/mL-6.21 microg/mL). These results suggest that an initial systemic exposure to nicotine significantly increases HSV-1 reactivation. Further studies are needed to reveal any effects of nicotine dependency and nicotine withdrawal on herpesvirus reactivation.     

Intraperitoneal high-dose cisplatinum chemotherapy (CDDP-ip) in patients with carcinomatous peritonitis

Immediately after CDDP-ip, the level of free Pt in ascites reached nearly 100 micrograms/ml, and the AUC (area under the curve) for ascites was 20-140 times greater than that for serum. The free Pt in serum following CDDP-ip administration was detected for several hours, and interestingly, the AUC for serum after ip therapy was 0.4-2.2 times greater than that after iv therapy. As a result, free Pt was found to act on cancer cells in the abdominal cavity directly at a high concentration. At the same time, the possibility of an antitumor effect from the vascular side of the tumor was also suggested. On the other hand, cases of ovarian cancer had various levels of peritoneal clearance (CLp), which depended on the severity of their carcinomatous peritonitis. The CLp had a great influence on the peak plasma concentration and on the AUC of free Pt in serum. In particular, the peak plasma concentration produced by CDDP-ip was 40-80% of the plasma concentration produced by CDDP-iv. These findings indicate that high-dose CDDP-ip is possibly effective and useful for advanced ovarian cancer, producing only very mild side effects.     

Pharmacokinetic and clinical studies with imipenem/cilastatin sodium in the pediatric field. Pediatric Study Group for Imipenem/Cilastatin Sodium

Pharmacokinetic and clinical studies of imipenem/cilastatin sodium (MK-0787/MK-0791), a new carbapenem antibiotic and a dehydropeptidase-I inhibitor, respectively, were carried out in a joint study in the pediatric field by a study group consisting of investigators at 16 institutions. The results were summarized below. Pharmacokinetic studies Peak plasma concentrations of MK-0787/MK-0791 were 27.7-190.0/28.3-216.4 micrograms/ml at doses of 10/10-50/50 mg/kg administered by a 30 or 60-minute drip infusion. The above findings proved that dose response was clearly observed. Over a period of 6 or 7 hours, the urinary excretion of MK-0787 and MK-0791 totaled 54.2-88.0% and 53.6-89.0% of the dose administered, respectively. Plasma half-lives of MK-0787 and MK-0791 in the beta-phase were 0.87-1.05 hours and 0.59-0.95 hour, respectively. The cerebrospinal fluid (CSF) levels of MK-0787 in patients with purulent meningitis were 2.0-14.4 micrograms/ml; however, the penetration rate of the drug into the CSF was relatively poor in patients with normal meninges. Clinical study Clinical efficacy was evaluated in 283 patients. In 112 patients the daily dosage ranged from 30/30 mg/kg to 59/59 mg/kg, and in 138 patients it ranged from 60/60 mg/kg to 99/99 mg/kg. The maximum dose administered was 222/222 mg/kg. The drug was administered either 3 or 4 times per day. The clinical efficacy rate was 92.5% among 187 patients with identified etiologic pathogens. The drug was effective in 3 out of 4 patients with purulent meningitis and in 7 out of 10 patients with septicemia. The clinical efficacy rate was 96.7% in 90 patients with respiratory tract infection (pneumonia, lung abscess, etc.), 96.5% in 57 patients with urinary tract infection, 90.9% in 11 patients with SSTI. The clinical efficacy rate in those with no identified etiologic pathogen was 97.0% among 101 patients. Bacteriologically, the eradication rate for S. aureus was 87.9% of 33 isolates. Comprehensively, the eradication rate for Gram-positive bacteria was 94.7% of 75 isolates. The eradication rate for P. aeruginosa was 87.5% of 8 isolates. Including these strains, the eradication rate for Gram-negative bacteria was 90.3% of 134 isolates. The MK-0787/MK-0791 exhibited an eradication rate of 91.9% among a total of 211 Gram-positive and Gram-negative bacteria including anaerobes.(ABSTRACT TRUNCATED AT 400 WORDS)     

Morphological characteristics, especially the malignant features, of chordoma in comparison with the notochord

Twelve cases of the chordoma, including 4 cases with metastases, have been examined by light and electron microscopy for a comparison with 5 cases of the human notochord. Observed similarities in the histological and ultrastructural characteristics of the chordoma with those of the notochord suggested the histogenetic origin of the chordoma from the remnant of notochord. A "diffuse pattern" that was seen in the histological appearance of 4 cases of the chordoma, including 2 cases with metastases, was not observed in the notochord and was considered to indicate the malignant nature of such chordoma. Electron microscopy of the physaliphorous cells characteristic of the chordoma demonstrated intracytoplasmic large vacuoles containing glycogen.     

Expression of the glutathione S-transferase placental form in human lung carcinomas

Expression of glutathione S-transferase placental form (GST-)in human lung carcinoma tissue taken at autopsy or biopsy wasinvestigated immunohistochemically. All of 34 cases of squamouscell carcinomas, including poorly, moderatelyand well-differentiatedexamples were shown to stain positively for GST-. Poorly differentiatedadenocarcinomas were, however, negatively stained (0/5 cases),while moderately and well differentiated adenocarcinomas werefound tostain with GST- at rates of 69% (9/13 cases) and 71%(5/7 cases), respectively. Six cases of small cell carcinomasexamined were all negative. The results indicate that GST- maybe a useful marker fornon-small cell type lung cancer, especiallysquamous cell carcinoma which is in agreement with findingsfor rat lung neoplastic lesions reported previously.     

Assembly of connectin (titin) in relation to myosin and α-actinin in cultured cardiac myocytes

Summary By using polyclonal and monoclonal antibodies against connectin (titin) which stain the A-I junctional area and the A-band domain (polyclonal anti-connectin and monoclonal 4C9) and the I-band domain (monoclonal SM1), the developmental relationship of this elastic protein with sarcomeric proteins, especially myosin and-actinin, was examined in embryonic chick cardiac myocytesin vitro under fluorescence microscopy. During premyofibril stages, I-Z-I proteins were detected first (-actinin dots and diffuse actin [phalloidin and anti-troponin C] staining), and later in these areas connectin and myosin dots appeared with nearly identical distribution. Somewhat later, phalloidin-positive nonstriated fibrils were observed in a straight course. They were always reactive with antibodies against a-actinin and troponin C, but unreactive or only weakly reactive with anticonnectin and anti-myosin. Initially,-actinin dots were aligned along these fibrils but did not form striations. As they aggregated to form Z-bands, connectin and myosin started to exhibit typical striations (doublets and A-bands, respectively). No difference in the staining pattern was observed with two kinds of monoclonal antibodies against different domains of connectin filaments (4C9 and SM1) at early phases. As myosin staining began to show clear A-bands, connectin epitopes became arranged in polarized positions. We conclude that primitive I-Z-I complexes appear prior to the assembly of connectin and myosin filaments and then connectin filaments, developing intimately and coordinately with myosin, become associated with the-actinin lines. Thus it appears that the putative elastic protein connectin plays some role in integrating myosin filaments with the preexisting I-Z-I brushes. The occasional absence of connectin and A-bands between two Z-bands, beyond both of which clear sarcomeres have been formed, indicates that connectin is not a preformed scaffold of myofibrils on which sarcomeric proteins accumulate.