Thyroid lesions and dioxin accumulation in the livers of jungle crows (Corvus macrorhynchos) in urban and suburban Tokyo.

Wild jungle crows (Corvus macrorhynchos) captured from three different areas of Tokyo were examined to evaluate environmental contamination of dioxins. In addition to the pathologic examination of their whole body, accumulation of dioxins, mRNA expression of the aryl hydrocarbon receptor (AhR), and pentoxyresorufin-O-depenthylase (PROD) activity in the liver were determined. Marked histopathologic changes were observed in the thyroid glands, especially in the crows from the urban downtown area. Levels of dioxins and their toxic equivalents (TEQs) and AhR mRNA expression in the livers of the crows from the urban area were higher than those from the suburban area. There was a high correlation between the levels of TEQs and PROD activity. The results of the present study demonstrated that jungle crows possess AhR-mediated toxicologic pathways similar to those of mammals and suggest the possibility that the thyroidal changes observed in the adult crows from the urban areas are one of the toxic manifestations resulting from exposure to dioxins and other environmental chemicals.

Myocardial hamartoma of the right atrium in a dog.

A myocardial hamartoma of the right atrium is described in an 8-year-old dog that died from pneumonia. At necropsy, a firm, mottled, dark-brown right atrial appendage, of normal shape but slightly enlarged, was found incidentally. On section, the right atrial appendage was composed of a grey-tan, solid mass. Histological features of the mass were as follows: the component cells were mature cardiac muscle cells; the mass contained all of the components of the normal heart wall (i.e., epicardium, myocardium and endocardium), but the arrangement of the component tissues was disorganized; growth of the mass was non-invasive, and continuity of the component cells with adjacent normal myocardial cells was evident, suggesting a congenital origin. This appears to be the first report of congenital myocardial hamartoma in any animal other than man.

Pathologic and electrocardiographic findings in sudden cardiac death in racehorses.

Five racehorses in apparently normal condition succumbed to sudden cardiac death (SCD) during or shortly after intensive training exercise. Cardiopathologic examination was performed. In 1 of the 5 horses, the use of an electrocardiogram (ECG) recording taken continuously for 440 sec enabled us to analyze some of the arrhythmias in the terminal event of SCD. The ECG tracing exhibited the R-on-T phenomenon following a pair of ventricular premature contractions (VPCs). The phenomenon rapidly degenerated into ventricular fibrillation, which led to cardiac arrest. In all 5 horses cardiopathologic examination revealed the following lesions: (i) foci of myocardial fibrosis in the right atrium located close to the sinoatrial (SA) node, (ii) fibrotic and/or fibroplastic changes in the upper portion of the interventricular septum, including the atrioventricular (AV) conduction system, and (iii) arterio- and arteriolosclerosis of the SA and AV node vessels. Pathogenetically, the process by which the focal lesions of myocardial ischemia secondary to vascular sclerosis progressed into fibrosis and/or fibroplasia could play a major role in the genesis of arrhythmias. Presumably the fibrotic and/or fibroplastic changes in the area of the AV bundle and its bundle branches are closely related to the onset of fatal ventricular arrhythmias such as VPCs, deteriorating into ventricular fibrillation. SCD in training and racing Thoroughbred horses appears to be due to arrhythmia.

Characterization of fluoroquinolone-induced Achilles tendon toxicity in rats: comparison of toxicities of 10 fluoroquinolones and effects of anti-inflammatory compounds.

Fluoroquinolone antibacterial agents have been reported to induce tendon lesions in juvenile rats. In the present study, we characterized fluoroquinolone-induced Achilles tendon lesions by comparing the effects of 10 fluoroquinolones and examining the potential of one of these antimicrobial agents, pefloxacin, to induce tendon lesions when coadministered with one of nine anti-inflammatory compounds. Among the 10 fluoroquinolones tested, fleroxacin and pefloxacin were the most toxic, inducing lesions at a dose of 100 mg/kg of body weight or more, while lomefloxacin, levofloxacin, and ofloxacin or sparfloxacin and enoxacin induced lesions at 300 mg/kg or more and 900 mg/kg, respectively. In contrast, norfloxacin, ciprofloxacin, and tosufloxacin had no effect even at the high dose of 900 mg/kg. The severity of the Achilles tendon lesions appeared to correlate with the structure of the substituent at the seventh position. Furthermore, pefloxacin-induced tendon lesions were inhibited by coadministration with dexamethasone and N-nitro-L-arginine methyl ester. Phenidone (1-phenyl-3-pyrazolidinone) and 2-(12-hydroxydodeca-5,10-diynyl)3,5,6-trimethyl-1,4-benzoqui none (AA861) also decreased the incidence of tendon lesions. In contrast, catalase, dimethyl sulfoxide, indomethacin, pyrilamine, and cimetidine did not modify these tendon lesions. These results suggest that nitric oxide and 5-lipoxigenase products partly mediate fluoroquinolone-induced tendon lesions.

Possible involvement of nitric oxide in the quinolone-induced tendon lesions in rats.

Quinolone antibacterial agents have been reported to induce adverse effects on the tendon and the musculoskeletal system in humans. We have previously demonstrated that Achilles tendon lesions could be induced in juvenile rats by a single oral administration of quinolones at high doses with simultaneous induction of lesions in the muscle, synovial membrane and articular cartilage. In the present investigation, we examined the involvement of nitric oxide (NO) in pefloxacin (PFLX)-induced lesions of the Achilles tendon in juvenile rats. The incidence of lesions was diminished markedly by co-administration of a potent NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). Further, the urinary nitrate/nitrite excretion was decreased significantly by 4 h after administration, unchanged between 4 and 8 h, and significantly increased in the 8- to 24-h samples in the PFLX group, as compared to the control group. In contrast, the serum concentration of nitrate/nitrite was significantly higher in the PFLX group 4 h after administration, but there was no difference from controls was observed at 8 and 24 h. These results suggest that NO is involved in the induction of Achilles tendon lesions in juvenile rats by pefloxacin (PFLX) and may be similar to the tendon disorder of humans receiving quinolones.

Toxic effects of quinolone antibacterial agents on the musculoskeletal system in juvenile rats.

Quinolone antibacterial agents have adverse effects on the musculoskeletal system in humans, consisting mainly of myalgia and arthralgia, and additionally of tendon disorders and rhabdomyolysis. The present study was conducted to examine the toxic effects of quinolones on the musculoskeletal system in juvenile rats using light microscopy, 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry and electron microscopy. Single oral administration of 900 mg/kg pefloxacin (PFLX) or levofloxacin (LVFX) was found to induce lesions in the muscle + fascia, tendon + sheath, and synovial membrane, in addition to articular cartilage in the fore- and hindlimbs. Articular cartilage lesions were not necessarily associated with changes in the muscle, tendon, and synovial membrane, or the reverse. Among all lesions, the ankle and elbow showed the highest incidence and severity. Changes were more severe in the PFLX than in the LVFX group. Lesions in the muscle + fascia, tendon + sheath, and synovial membrane were similar and characterized by edema and increased number of mononuclear cells, many of which were positively stained with BrdU, as well as vascular endothelial cells in the Achilles tendon sheath and synovial membrane in the ankle. Electron microscopic examination revealed an increased number of fibroblasts and macrophages and collagen deposition in the matrix of the synovial membrane and tendon sheath. Capillary endothelial cells were hypertrophied, increased in number, and stratified. These results suggest that quinolones have toxic potentials in the muscle, tendon, and synovial membrane in addition to articular cartilage, and that local vascular hyperpermeability may contribute to the development of these lesions.

Examination of lesions in the urinary bladder and kidney of dogs induced by nefiracetam, a new nootropic agent.

Toxic lesions induced by nefiracetam, a nootropic drug, in the urinary bladder and kidney were examined by repeated oral administration of 300 mg/kg/day for 1, 2, 3, 4, or 11 wk to male and female beagle dogs. Each dog was sacrificed after each treatment period, and urinalysis and serum biochemistry were performed for surviving dogs at several time points. One male and 2 females died during week 10 or 11. Degeneration and desquamation of epithelial cells and edema and hemorrhage in the lamina propria were observed in the urinary bladder after 1 wk of treatment. These changes became severe as time progressed and were reflected in the clinical abnormalities of hematuria and increased protein excretion in urine. However, epithelial regeneration and hyperplasia were seen thereafter, and almost no change was seen in the urinary bladder after treatment for 11 wk. Instead of recovery as in the urinary bladder, the kidney showed epithelial degeneration and hyperplasia in the papilla and collecting duct and interstitial congestion and hemorrhage after treatment for 11 wk. Extensive hemorrhage and papillary necrosis were seen in animals that died during week 10 or 11 of dosing. These kidney changes were associated with increased urinary volume and decreased osmotic pressure. The lesions are thought to have a common etiopathogenesis and to be initiated by the epithelial damage with a time lag between expression of injury in the urinary bladder and the kidney.

Histological examination on Achilles tendon lesions induced by quinolone antibacterial agents in juvenile rats.

We examined the effects of the quinolone antibacterial agents pefloxacin (PFLX) and ofloxacin (OFLX) on the Achilles tendon of Sprague-Dawley rats. A single oral administration of PFLX 300 and 900 mg/kg or OFLX 900 mg/kg induced edema with mononuclear cell infiltration mainly in the inner sheath of the inner Achilles tendon just proximal to the tuber calcanei in rats killed on the next day. Cell infiltration was also seen in the adjacent synovial membrane and joint space. With progression of severity, the lesions extended to the surface tendon tissue, wherein irregularly arranged collagen bundles were detached from each other and nuclei of fibroblasts were pyknotic and fragmented. After 2-wk repeated administration, these lesions were replaced by fibrotic foci with regenerated tendon fibroblasts, and the incidence and severity were reduced in the OFLX but not PFLX groups. Coadministration of cyclosporin A with OFLX 300 mg/kg induced these lesions despite the fact that neither induced lesions alone. The tendon lesions were induced in juvenile rats (4 wk of age) but not in young adults (12 wk). The articular cartilage of juvenile rats showed focal degeneration and/or cavitation in the tarsal joints after a single and 2-wk administration of PFLX or OFLX. Hydrocortisone slightly increased the incidence of OFLX-induced lesions in both the tendon and cartilage after a 2-wk administration. The occurrence of the tendon lesions is different from that of the Achilles tendon disorders reported in older humans, but they are thought to be a useful model for them.

Role of Candida albicans in chronic hypersensitivity pneumonitis.

An autopsy was performed on a patient who had chronic hypersensitivity pneumonitis that was observed for 9 years. The patient was a farmer who developed symptoms every March through July during the use of moist hay that was infected heavily with Candida. Precipitins and an inhalation challenge test to C albicans were positive. We interpret the role of C albicans in this case.

[Case report of Farmer's lung disease in siblings in Kagoshima Prefecture].

Two cases of farmer's lung disease in siblings are reported. A 54-year-old male farmer, who had been engaged in stock work for 20 years, presented to our clinic for the second episode of fever, productive cough and shortness of breath. Chest roentgenogram revealed diffuse micronodular pattern, and mild hypoxemia was recognized on arterial blood gas analysis. Cytology obtained from BALF showed lymphocytosis, with especially increased OKT3, OKT4 positive cells and OKT4/8 ratio. The diagnosis was confirmed by highly positive reaction of precipitins to Thermoactinomyces vulgaris and granulomatous interstitial pneumonitis on histopathological examination. The second case was a 51-year-old female patient, the sister of the first case, who also worked as a stock farmer of another farm for 20 years. She presented with an episode of similar symptoms to the first case, one and a half years after the onset of her brother's symptoms. The findings of roentgenogram, BALF analysis, precipitins to T. Vulgaris and pathology were similar to those of the first case. The finding of high OKT4/8 ratio on BALF analysis in both cases is characteristic of formers lung disease, in contrast to the summer-type hypersensitivity pneumonitis which usually shows low OKT4/8 ratio in BALF. To our knowledge, this is the first report of farmer's lung disease in an area other than the northern part of Japan. Thus we conclude that farmer's lung disease may occur in Japan under any environmental conditions, and that some genetic factor may take part in the onset of this disease.

Aspects of the preparation of 18F-2-deoxy-2-fluoro-D-glucose (18FDG) for medical use.

Fluorine-18-2-deoxy-2-fluoro-D-glucose (18FDG) for medical use had been prepared with the attention regarding radiochemical yield and purity, specific activity and quality control. More than four 18F-by-products in 18F-adducts from the reaction of triacetyl glucal with 18F2 were detected by the autoradiography of thin layer plates in which two by-products could not be perfectly removed by a column chromatography, and selective collection of the eluate gave 18FDG with the purity of 96.7% as an average in 12 runs. At end of synthesis (EOS) 259-925 MB (7-25 mCi) of a sterilized, isotonic solution of 18FDG was obtained with the specific activity of 629-851 MBq (17-23 mCi)/mg at end of bombardment (EOB) after preparation time of 3-3.5 hr, in which bacteria and pyrogen were not detected.