Comprehensive Evaluation of (+)-Usnic Acid-induced Cardiotoxicity in Rats by Sequential Cross-omics Analysis.

Two-week administration of (+)-usnic acid (UA) induces mitochondrial swelling of cardiomyocytes, and toxicogenomic analysis of the heart revealed upregulation of oxidative stress, amino acid limitation, and endoplasmic reticulum stress-related genes in rats. To analyze the pathogenesis, UA was orally administrated to rats for 1, 4, 7, and 14 days, and sequential histopathological, genomic, and metabolomic analyses were performed on the heart, liver, and plasma. As a result, mitochondrial swelling of cardiomyocytes was observed on day 15 preceded by genomic upregulation on days 5 and 8. Of the focused gene groups, amino acid limitation-related genes represented by Mthfd2 showed numerically higher values or upregulation from day 5, which was sustained through the experimental period. On the contrary, oxidative stress-related genes were upregulated temporally on day 5. In metabolomic analysis, amino acids such as taurocholate and their metabolites fluctuated in concert with the upregulation of amino acid limitation-related genes in the heart, liver, and plasma. Moreover, accumulations of bile acids were manifested in all the tested tissues, while no histopathological change was seen in the liver. Increased bile acids might have an indirect effect on the myocardium; however, more detailed analysis is required. In conclusion, amino acid limitation was suggested as the pivotal toxic trigger of UA-induced cardiotoxicity.

Low-grade myofibroblastic sarcoma of the maxillary region in a dog.

A subcutaneous tumour was identified in the maxillary region of a 14-year-old mixed breed dog. This tumour had grown rapidly over 2 weeks. Microscopically, the tumour had ill-defined borders and was composed of bundles and whorls of atypical spindle cells accompanied by abundant collagen fibres. Immunohistochemically, neoplastic cells were immunoreactive for vimentin, α-smooth muscle actin and calponin and negative for S100 protein, von Willebrand factor, desmin and smoothelin. These results suggested that the neoplastic cells were derived from myofibroblasts and that the tumour was a low-grade myofibroblastic sarcoma.

Mixed germ cell tumor with embryonal carcinoma, choriocarcinoma, and epithelioid trophoblastic tumor in the ovary of a cynomolgus monkey.

A seven-year-old female cynomolgus monkey had a mass in the left ovary with metastasis to the lung and the right ovary. The mass of these organs showed three different characteristics, and its immunohistochemical profiles were consistent with embryonal carcinoma (EC), choriocarcinoma (CC), and epithelioid trophoblastic tumor (ETT). The EC was characterized with sheets and glandlike structures with large pleomorphic, single-nucleated epithelial cells that were immunohistochemically positive for α-fetoprotein, octamer-4, and CD30, and with multinucleated giant cells resembling syncytiotrophoblasts. The CC also represented biphasic proliferation of the cytotrophoblast positive for cytokeratin 7 (CK7), which showed negative immunoreactivity for all three of the above antibodies, and it was syncytiotrophoblast positive for human chorionic gonadotropin. The ETT showed numerous floating cells in an abundant eosinophilic extracellular matrix with vacuolated or eosinophilic cytoplasm and was immunohistochemically positive for CK7, p63, and α-inhibin, which features nodule or cordlike structures. Collectively, this neoplasm was identified as a mixed germ cell tumor with EC, CC, and ETT. To our knowledge, this is the first report of EC in nonhuman primates as a component of mixed germ cell tumor.

Spermatocytic seminoma with neuroectodermal differentiation and sertoli cell tumor in a dog.

Two distinct nodules developed in a cryptorchid testis of an 8-year-old male West Highland White Terrier. One nodule was a Sertoli cell tumor. The other was a spermatocytic seminoma with focal primitive neuroectodermal differentiation: formation of Homer-Wright rosettes and perivascular pseudorosettes, with immunoreactivity for S-100 protein, neuron-specific enolase, synaptophysin, neurofilament-68 kDa, microtubule-associated protein 2, and vimentin. The dog was alive and healthy 2 years after castration.

A case of submandibular malignant rhabdoid tumor transformed from papillary thyroid carcinoma.

Malignant rhabdoid tumor (MRT) in the neck region is very rare. We report a case of MRT in a 60-year-old woman who had a history of papillary carcinoma of the thyroid gland 7 years previously. One year before admission, in 1995, thyroid carcinoma recurred, and the tumor contained a small undifferentiated region with rhabdoid features. The tumor in 1996 consisted of round to oval rhabdoid cells with abundant cytoplasm, and the growth pattern was diffuse and infiltrative, with no papillary structures. We therefore concluded that the lesion was MRT, transformed from papillary thyroid carcinoma.

[Effect of FUT-187, oral serine protease inhibitor, on inflammation in the gastric remnant].

Excessive enterogastric reflux following partial gastrectomy is believed to be responsible for the cause of inflammation in the gastric remnant. We examined the effect of FUT-187, a synthetic serine protease inhibitor, on symptoms and endoscopic findings in 33 patients who were diagnosed endoscopically as postgastrectomy gastritis. Patients took 50 mg FUT-187 orally after each meal and at bedtime for 8 weeks. Before treatment, 30 patients (91%) suffered from several symptoms including regurgitation and/or bitter taste in the mouth (49%), epigastric pain (42%) and nausea (36%). From endoscopic observation, erythema was detected in 32 patients, edema in 23 patients and erosion and/or ulcer in 9 patients. After treatment the global improvement rating for subjective symptoms was 76.7% (23/30) and the improvement of endoscopic findings was 63.6% (21/33). Diarrhea was observed in one patient but could be easily controlled by discontinuation of the drug. Our results suggest that FUT-187 can be a useful drug for the treatment of postgastrectomy gastritis with its efficacy and safety.

[A case of sarcoidosis with middle lobe atelectasis].

We report a case of sarcoidosis complicated by middle lobe atelectasis. A chest radiograph and a chest CT film on admission revealed middle lobe atelectasis and mediastinal lymphadenopathy. Bronchofiberscopic findings showed slit-like stenosis and reddish, edematous mucosal change of the middle lobe orifice. On admission, the serum angiotensin-converting enzyme (ACE) level was within the normal range. However, the ACE level had increased beyond the normal range by 2 months later, histological examination of a specimen from a transbronchial lung biopsy (TBLB) of the middle lobe revealed noncaseating epithelioid cell granulomas. We diagnosed sarcoidosis because of the histological findings from the TBLB and serum ACE elevation. Treatment with predonisolone resulted in remarkable alleviation of middle lobe atelectasis and mediastinal lymphadenopathy. Cases of sarcoidosis with middle lobe atelectasis are rare in Japan.

[A multi-institutional study for prevalence, diagnosis and treatment of deep fungal infection in gastrointestinal surgery].

A multi-institutional study was conducted for prevalence, diagnosis and treatment of deep fungal infection in gastrointestinal surgery. Forty five cases including thirty six complete cases were entered basing on the diagnostic criteria and the mortality of complete cases was 17%. By the administration of miconazole (MCZ), clinical response rate was obtained in 87%, mycological radiation rate in 82% and valuable rate in 71%, with occurrence of side effects in 20%. Fungal endophthalmitis was found in 41% (12/29 cases). beta-glucan [the toxinometer method (T), the Seikagaku-Kogyo method (S)] and candida antigen [the C and-Tec method (C)] were monitored as sero-diagnostic methods, the positive rates for all cases, fungemia, and mycosis of which were 63, 83, 62% (T), 88, 100, 92% (S) and 52, 83, 50% (C), respectively. After mycological re-classification, the positive rates of the T method and endophthalmitis, and the mortality rates were 86, 60, 38% in fungemia, 63, 43, 23% in urinary tract infection, 64, 80, 7% in TPN infection, and 33, 17, 33% in drain infection, respectively. High association of endophthalmitis was found in TPN infection. The beta-glucan assay and a prospective ophthalmoscopic examination are useful for the early diagnosis of deep fungal infection and it is reasonable to treat patients in gastrointestinal surgery by MCZ when mycosis is confirmed or suspected.

[A case report of miliary tuberculosis with tubercular meningitis diagnosed and followed by polymerase chain reaction method].

We report here a case of miliary tuberculosis with tubercular meningitis in which the polymerase chain reaction (PCR) amplification method was useful for its rapid diagnosis and follow up. A 70 year old male was hospitalized for further examination and treatment of diffuse small nodular shadows on the chest X-ray. After receiving antimicrobial therapy shadows still remained and he gradually lost visual acuity. He had no meningeal signs, and no remarkable finding on cranial CT. Cerebrospinal fluid examination showed increased cell number with predominantly lymphocytes. Cranial MRI (Gd DTPA) showed lateral ventricular ependymitis. Pulmonary tuberculosis and secondary tubercular meningitis were suspected, but we failed to detect microorganisms from the cerebrospinal fluid, gastric juice, sputum, and urine by the conventional method. However, by the polymerase chain reaction amplification method specific DNA fragments of Mycobacterium tuberculosis complex was detected from the cerebrospinal fluid, gastric juice, bronchoalveolar lavage fluid and serum. The final diagnosis of miliary tuberculosis with tubercular meningitis was established. We administered antitubercular drugs and observed the clinical course. He recovered and the polymerase chain reaction showed negative consequences in all samples. The judgement of PCR and the clinical course were compatible and parallel with the clinical course.

Calcium metabolism in elderly hypertensive patients: possible participation of exaggerated sodium, calcium and phosphate excretion.

1. Renal handling of electrolytes, including calcium (Ca), in response to physiological saline infusion (20 mL/kg, i.v., for 2 h) as well as basal circulating levels of Ca-regulating hormones were compared in 27 hypertensive elderly females (mean age 80 +/- 9 years), in 44 normotensive elderly females (79 +/- 9 years) and in 19 young normotensive females (23 +/- 4 years). 2. The hypertensive elderly females showed excessive increase in urine volume and urinary excretions of sodium (Na), Ca and inorganic phosphate (P) in response to saline infusion, associated with slight but significant decrease in circulating levels of Na and ionized Ca compared with those in the other groups. These hypertensive elderly patients also showed characteristic features both in circulating blood pressure and Ca regulating factors; they showed significantly low levels of plasma renin activity and aldosterone concentration, significantly high plasma levels of atrial natriuretic peptide and noradrenalin, compared with those in young controls and normotensive elderly females. 3. Moreover they showed significant increase in basal serum levels of parathyroid hormone and 1,25-dihydroxyvitamin D, and significant decrease in basal serum levels of calcitonin, 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D, compared with those in the other groups. 4. These results suggest that the exaggerated natriuresis associated with excessive loss of Ca and P in urine may participate in the abnormality of Ca metabolism in low-renin hypertensive elderly patients.

Exaggerated natri-calci-uresis and increased circulating levels of parathyroid hormone and 1,25-dihydroxyvitamin D in patients with senile hypertension.

Renal handling of Na and Ca in response to physiological saline infusion (20 ml/kg i.v. for 2 h) was compared between 27 hypertensive (mean +/- SD age 79.8 +/- 9.2 years) and 44 normotensive (79.1 +/- 4.1 years) senile females. Compared to the normotensive group, the hypertensive group showed statistically significant decreases in the basal values of serum Ca and PRA, and significant increases in basal circulating levels of parathyroid hormone and 1,25(OH)2D and in urinary excretions of Na, Ca and Pi in the 2-hour urine specimens during the saline infusion. These results suggest that the excessive excretions of Ca and Pi associated with exaggerated natriuresis may participate in aberration of Ca metabolism in low-renin hypertensive seniles.

Absence of nocturnal fall in blood pressure in elderly persons with Alzheimer-type dementia.

Circadian changes of the blood pressure and heart rate in elderly normotensive bedridden patients with severe dementia of the Alzheimer type (group D) were compared with those in elderly normotensive bedridden patients without dementia (group R), normotensive subjects with normal daily activity (group N), and hypertensive patients with normal daily activity (group H). In groups R, N, and H, the blood pressure increased in the afternoon and decreased at midnight; in group D, however, although it increased in the afternoon, it did not decrease at night. The circadian changes of the heart rate were similar in all four groups, showing maxima in the afternoon and minima at midnight. Thus, a specific alteration was found in the circadian rhythm of the blood pressure in patients with Alzheimer-type dementia.

Dietary salt, blood pressure and circulating levels of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine in patients with essential hypertension.

The effects of dietary salt on circulating levels of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16 PAF) in patients with essential hypertension were studied by gas chromatography/mass spectrometry with negative ion chemical ionization. Circulating levels of C16 PAF in patients with essential hypertension (18.1 +/- 5.3 pg/ml, n = 16) were not changed compared with those in normotensive subjects (17.2 +/- 7.2 pg/ml, n = 14). Although changes in circulating levels of C16 PAF were small with changes in dietary salt, net changes in circulating C16 PAF levels significantly and positively correlated with net changes in mean arterial blood pressure (r = 0.47, P less than 0.05). Changes in C16 PAF levels also correlated with changes in creatinine clearance (r = 0.55, P less than 0.05). However, changes in C16 PAF levels did not correlate with changes in plasma sodium concentration, plasma chloride concentration and plasma volume. These results indicate that C16 PAF plays an antihypertensive role and this may be reflected as small changes in circulating levels of C16 PAF.

[Laboratory studies on doxycycline intravenous (author's transl)].

The results of laboratory studies on doxycycline intravenous are summarized as follows: 1. The standard curves of doxycycline in five dilution systems were compared. Zones of growth inhibition were largest in the phosphate buffer solution at pH 7.2 and smallest in human serum. Lung system was close to the buffer system, liver system close to the serum system, and kidney system intermediate. 2. The doxycycline concentrations in blood of healthy male adults were compared by cross-over method. The concentration following intravenous injection of 200 mg, dissolved in 40 ml of 20% glucose and injected in 5 minutes, was high than that after oral administration of 200 mg immediately after the injection, but was same after 3 hours and thenafter. 3. No tendency of accumulation was observed in six volunteers injected intravenously with 100 approximately to 200 mg of doxycycline daily for three days. 4. In a patient with chronic broncho-bronchitis injected intravenously with 200 mg, the blood level reached a peak of 4.8 mcg/ml after 30 minutes, while the sputum level reached a peak of 1.8mcg/ml after 90 minutes. The sputum level was 30 to approximately 40% that of serum. 5. The urinary excretion of doxycycline was 94 mg/day (47.0%) after a single intravenous injection of 200 mg. and 53 mg/day (26.5%) after a single oral administration of 200 mg.