Stromal expression of thrombospondin-1 is correlated with growth and metastasis of human gallbladder carcinoma.

Thrombospondin-1 (TSP1) is one of the extracellular matrix glycoproteins that affect cell adhesion, motility and growth. Based on its effects on tumors, TSP1 is thought to be a potential regulator of tumor growth and metastasis. In this study, we examined TSP1 expression in human gallbladder adenocarcinoma and its clinicopathological significance. TSP1 immunoreactivity was detected mainly in the cancer stroma and was observed infrequently in cancer cells. According to the TNM classification, 74.5% (29/39) of the T2 and T3 gallbladder cancers were TSP1-positive, while none (0/14) of the T1 cancers showed TSP1 expression (p<0.001). Lymph node metastasis and venous involvement were frequently found in the TSP1-positive cases (90.0% and 87.1%, respectively) of gallbladder adenocarcinoma (p<0.001). These observations suggested that TSP1 expression plays an important role in cancer cell growth and metastasis of human gallbladder adenocarcinomas, and that stromal TSP1 immunoreactivity is a good predictor of vascular involvement and lymph node metastasis.     

Quantitative prediction of catalepsy induced by amoxapine, cinnarizine and cyclophosphamide in mice

Parkinsonism can be a side effect of antipsychotic drugs, and has recently been reported with peripherally acting drugs such as calcium channel blockers, antiarrhythmic agents and so on. In this study, we examined the quantitative prediction of drug-induced catalepsy by amoxapine, cinnarizine and cyclophosphamide, which have been reported to induce parkinsonism. Dose-dependent catalepsy was induced by these drugs in mice. In vivo dopamine D(1), D(2) and muscarinic acetylcholine (mACh) receptor occupancies by these drugs in the striatum were also examined. The in vitro binding affinities (K(i) values) of amoxapine and cinnarizine to dopamine D(1), D(2) and mACh receptors in rat striatal synaptic membrane were 200 and 2900 nM, 58.4 and 76.4 nM and 379 and 290 nM, respectively. Cyclophosphamide did not bind to these receptors at concentrations up to 100 microM. Twenty drugs, including those mentioned above, showed a significant correlation between the observed intensity of catalepsy and the values predicted with a pharmacodynamic model (Haraguchi K, Ito K, Kotaki H, Sawada Y, Iga T. Prediction of drug-induced catalepsy based on dopamine D(1), D(2), and muscarinic acetylcholine receptor occupancies. Drug Metab Disp 1997; 25: 675-684) based on in vivo occupancy of dopamine D(1), D(2) and mACh receptors. We conclude that occupancy of dopamine D(1) and D(2) receptors contributes to catalepsy induction by amoxapine and cinnarizine.     

An outbreak of enterocolitis due to Clostridium perfringens in a hospital for the severely disabled

We had an outbreak of 14 cases of enterocolitis due to Clostridium perfringens (Cl. perfringens) in a hospital for the severe multiply-disabled, where the 100 disabled were admitted, in summer in 1985. The signs and symptoms shown by this enterocolitis were primarily diarrhea without fever and loss of appetite. The feces of 10 cases were examined bacteriologically. The test showed 10(3) to 10(6) cells of Cl. perfringens per one gram of their feces and all the strains isolated were untypable by the classification of Hobbs. Nine out of 10 cases were randomly selected and all of the 9 cases were proved to have enterotoxin producing strains. All the strains were highly sensitive to many kinds of antibiotics except kanamycin and gentamicin. Eleven out of the 14 cases were admitted in the same ward and the 7 out of the 11 cases were in the same room of this ward. Considering the spreading route of this infection, it is unlikely that this outbreak occurred due to food supplied from kitchen in this hospital, because all of the disabled, admitted in this hospital, had little chance by which some of the disabled only in a specific ward or room were supplied with bacteriologically contaminated meals from the point of view of cooking and supplying system of this hospital. Adding to this fact, if this outbreak was due to food-born infection, the symptoms of most patients should occur within 1-2 days, because the incubation period of this disease is within a day, however, the patients increased day by day for more than a week.(ABSTRACT TRUNCATED AT 250 WORDS)     

A case of Bartonella henselae infection from a dog

A 50-year-old male with left cervical lymphadenopathy visited our hospital. Infectious and lymphomatous diseases were suspected in the patient. Since the patient owned a dog, which often licked the patient's face, Bartonella infection was also suspected. Histopathological examination in the lymph node biopsy revealed the epithelioid granuloma, but B. henselae was not detected from the culture of the lymphnode. B. henselae DNA also was not detected from the lymph node. Since the antibody titer (lgG) to B. henselae showed 1:128 by immunofluorescent antibody technique (IFA), he was serdogicalg diagnosed as cat-scratch disease. 'Cat-scratch disease' is named after cat scratch, however we propose 'B. henselae infection' which is more appropriate since other animals could serve as a cause of infection.     

Progression of phosphorylated α‐synuclein in Macaca fuscata

Prion‐like spreading of abnormal proteins is proposed to occur in neurodegenerative diseases, and the progression of α‐synuclein (α‐syn) deposits has been reported in the brains of animal models injected with synthetic α‐syn fibrils or pathological α‐syn prepared from patients with Parkinson''s disease (PD) and dementia with Lewy bodies (DLB). However, α‐syn transmission in nonhuman primates, which are more similar to humans, has not been fully clarified. Here, we injected synthetic human α‐syn fibrils into the left striatum of a macaque monkey (Macaca fuscata). At 3 months after the injection, we examined neurodegeneration and α‐syn pathology in the brain using α‐syn epitope‐specific antibodies, antiphosphorylated α‐syn antibodies (pSyn#64 and pSer129), anti‐ubiquitin antibodies, and anti‐p62 antibodies. Immunohistochemical examination with pSyn#64, pSer129, and α‐syn epitope‐specific antibodies revealed Lewy bodies, massive α‐syn‐positive neuronal intracytoplasmic inclusions (NCIs), and neurites in the left putamen. These inclusions were also positive for ubiquitin and p62. LB509, a human‐specific α‐syn antibody targeting amino acid residues 115–122, showed limited immunoreactivity around the injection site. The left substantia nigra (SN) and the bilateral frontal cortex also contained some NCIs and neurites. The left hemisphere, including parietal/temporal cortex presented sparse α‐syn pathology, and no immunoreactivity was seen in olfactory nerves, amygdala, hippocampus, or right parietal/temporal cortex. Neuronal loss and gliosis in regions with α‐syn pathology were mild, except for the left striatum and SN. Our results indicate that abnormal α‐syn fibrils propagate throughout the brain of M. fuscata via projection, association, and commissural fibers, though the progression of α‐syn pathology is limited.     

Relation between neutrophil counts on admission, microvascular injury, and left ventricular functional recovery in patients with an anterior wall first acute myocardial infarction treated with primary coronary angioplasty

Increased neutrophil counts have been associated with an increased risk of adverse clinical events after acute myocardial infarction (AMI). We examined the association of neutrophil counts on admission with degree of microvascular injury and left ventricular functional recovery after primary coronary angioplasty in AMI. We studied 116 patients with a first anterior wall AMI who underwent primary coronary angioplasty within 12 hours of onset. Patients were categorized into 3 groups based on initial neutrophil count: low (<5,000/mm(3)), intermediate (5,000 to 10,000/mm(3)), and high (>10,000/mm(3)). Coronary flow velocity parameters were assessed immediately after reperfusion using a Doppler guidewire. We defined severe microvascular injury as the presence of systolic flow reversal and a diastolic deceleration time <600 ms. Echocardiographic wall motion was analyzed before revascularization and 4 weeks after revascularization. In patients with a high neutrophil count, systolic flow reversal was more frequently observed, diastolic deceleration time was shorter, and coronary flow reserve was lower. By regression analysis, neutrophil count significantly correlated with diastolic deceleration time (r = -0.38, p <0.0001), coronary flow reserve (r = -0.33, p = 0.0004), and score for change in wall motion (r = -0.36, p = 0.0004). Multivariate analysis showed that neutrophil count on admission was an independent predictor of severe microvascular injury (odds ratio 2.94, p = 0.02). In conclusion, neutrophilia on admission is associated with impaired microvascular reperfusion and poor functional recovery after primary coronary angioplasty.     

Subchronic exposure to ethyl tertiary butyl ether resulting in genetic damage in Aldh2 knockout mice

Ethyl tertiary butyl ether (ETBE) is biofuel additive recently used in Japan and some other countries. Limited evidence shows that ETBE has low toxicity. Acetaldehyde (AA), however, as one primary metabolite of ETBE, is clearly genotoxic and has been considered to be a potential carcinogen. The aim of this study was to evaluate the effects of ALDH2 gene on ETBE-induced genotoxicity and metabolism of its metabolites after inhalation exposure to ETBE. A group of wild-type (WT) and Aldh2 knockout (KO) C57BL/6 mice were exposed to 500 ppm ETBE for 1–6 h, and the blood concentrations of ETBE metabolites, including AA, tert-butyl alcohol and 2-methyl-1,2-propanediol, were measured. Another group of mice of WT and KO were exposed to 0, 500, 1750, or 5000 ppm ETBE for 6 h/day with 5 days per weeks for 13 weeks. Genotoxic effects of ETBE in these mice were measured by the alkaline comet assay, 8-hydroxyguanine DNA-glycosylase modified comet assay and micronucleus test. With short-term exposure to ETBE, the blood concentrations of all the three metabolites in KO mice were significantly higher than the corresponding concentrations of those in WT mice of both sexes. After subchronic exposure to ETBE, there was significant increase in DNA damage in a dose-dependent manner in KO male mice, while only 5000 ppm exposure significantly increased DNA damage in male WT mice. Overall, there was a significant sex difference in genetic damage in both genetic types of mice. These results showed that ALDH2 is involved in the detoxification of ETBE and lack of enzyme activity may greatly increase the sensitivity to the genotoxic effects of ETBE, and male mice were more sensitive than females.     

Norepinephrine‐induced diastolic dysfunction with aortic valve opening under calcium‐loading in rats

Heart failure associated with a high plasma level of norepinephrine (NE) has an extremely poor prognosis with NE being the most powerful predictor of all‐cause mortality. An increase in the diastolic intracellular calcium level (Ca²⁺) occurs in left ventricular dysfunction; however, the cause‐and‐effect relationships among Ca²⁺loading, high plasma NE, and an increase in diastolic ventricular pressure is unclear. Here, we examined the relationship between diastolic dysfunction and NE with and without Ca²⁺loading in rats. Animals were studied in four groups: Ca²⁺loading for 45 min (Ca²⁺group), NE alone for 25 min (30 µg/kg/min NE for 25 min; NE group), Ca²⁺loading and NE for 25 min after Ca²⁺loading (Ca²⁺‐NE group), and a vehicle group. Hemodynamics were examined using a micromanometer‐tipped pressure catheter, and diastolic function was studied using Doppler echocardiography. Significantly increased left ventricular end‐diastolic pressure (LVEDP) and decreased E and Ea waves and deceleration time (DCT) were found in the Ca²⁺‐NE group, compared with the Ca²⁺and NE groups. There were no changes in left ventricular pressure (LVP) and LV ejection fraction (EF) among the four groups. NE‐induced diastolic contracture (NEIDC) with aortic valve opening occurred in the diastole when LVP overshot the aortic pressure after co‐administration of NE and Ca²⁺after Ca²⁺loading, and pulmonary hemorrhage was observed in all animals of the Ca²⁺‐NE group. The results support the suggestion that NE may be an important factor in the development of diastolic dysfunction in ischemic heart disease. Drug Dev. Res. 67:511–518, 2006. © 2006 Wiley‐Liss, Inc.     

Interactions between clarithromycin and digoxin in patients with end-stage renal disease

OBJECTIVE: To report a significant increase in the serum levels of digoxin associated with the use of clarithromycin in six patients undergoing renal replacement therapy. CASE SUMMARY: All six patients were males with end-stage renal disease and in need of renal replacement therapy. Four patients were anuric. The mean age was 78.8 +/- 5.8 (66-83) years. All patients except one, who was treated by hemofiltration, were treated by hemodialysis. All patients except one, who had been treated with metildigoxin (0.35 mg/week), were also taking digoxin (0.375 mg/week). Clarithromycin was administered at a dose of 200-400 mg/day for the treatment of bronchitis in all patients. The concomitant administration of clarithromycin increased serum digoxin levels from 1.8-4.0-fold in all cases. In two of six cases, a high probability of digoxin intoxication and suspicion of digoxin intoxication was evident. In three of six cases, serum digoxin levels increased within 12 days after the co-administration of clarithromycin, while in the other three cases, serum digoxin levels were increased 53-190 days after the administration of clarithromycin. CONCLUSION: The simultaneous administration of clarithromycin caused an increase in digoxin levels in six patients undergoing renal replacement therapy. The increase in the serum digoxin can be attributed to the inhibition of P-glycoprotein in the intestine and/or bile capillary rather than the kidney by clarithromycin since renal function was dramatically impaired, and four of the patients were anuric. The issue of why serum digoxin levels were increased so late in three patients undergoing renal replacement is unclear. However, this interaction seemed to be clinically significant even in ESRD patients, whose renal function was highly impaired. The simultaneous use of digoxin and clarithromycin should be avoided even in patients undergoing renal replacement therapy whose renal function is impaired, since digoxin levels may increase unexpectedly.