[A case of asymptomatic Sjögren's syndrome who developed interstitial pneumonia during monoclonal antibody therapy of Crohn's disease].

A 67-year-old woman was diagnosed with ileocolic Crohn's disease at 61 years of age. Remission had been induced by the monoclonal antibody adalimumab, and maintenance therapy had continued since her diagnosis. However, she developed respiratory symptoms, including a dry cough. A chest CT scan revealed interstitial shadows in the lower pulmonary lobes. Although no sicca symptoms were noted, she was serologically positive for both anti-Sjögren's syndrome-related antigen A and B antibodies, and salivary gland biopsy showed lymphocytic infiltration. Consequently, she was diagnosed as having asymptomatic Sjögren's syndrome. Infection or drug-induced pulmonary disease was considered unlikely, and the interstitial pneumonia was considered an extra-glandular presentation of Sjögren's syndrome. Thus, interstitial shadows, which appear during immunotherapy for Crohn's disease, could indicate asymptomatic Sjögren's syndrome; clinicians should consider this rare clinical picture when assessing such a patient.

Contribution of CYP3A isoforms to dealkylation of PDE5 inhibitors: a comparison between sildenafil N-demethylation and tadalafil demethylenation.

The aim of this study was to characterize the kinetics of metabolite formation of the phosphodiesterase type-5 (PDE5) inhibitors sildenafil and tadalafil by CYP3A4, CYP3A5, and CYP3A7 isoforms. The formations of N-desmethyl sildenafil and desmethylene tadalafil were examined using CYP3A supersomes co-expressing human P450 oxidoreductase and cytochrome b5. Both sildenafil N-demethylation and tadalafil demethylenation were catalyzed by CYP3A4, CYP3A5, and to a lesser extent by CYP3A7. The kinetics of desalkyl metabolite formation of the two drugs were well fitted to the Hill equation; however, the Hill coefficients (n) suggested CYP3A-mediated negative cooperativity. Next, we analyzed the kinetics with a two binding sites model assuming two reaction steps: reaction 1 with high-affinity and low-capacity metabolism and reaction 2 with low-affinity and high-capacity metabolism. The kinetics of desalkyl metabolite formation were also fitted to the two binding sites model. The intrinsic clearance (CLint) values of reactions 1 and 2 for sildenafil N-demethylation were 0.733 and 0.033 µL/min/pmol P450 for CYP3A4, 0.788 and 0.019 µL/min/pmol P450 for CYP3A5, and 0.079 and 0.004 µL/min/pmol P450 for CYP3A7, respectively. The CLint values of reactions 1 and 2 for tadalafil demethylenation were 0.187 and 0.014 µL/min/pmol P450 for CYP3A4, 0.050 and <0.001 µL/min/pmol P450 for CYP3A5, and 0.004 and <0.001 µL/min/pmol P450 for CYP3A7, respectively. These results may provide the basis not only for understanding the metabolic properties of the two PDE5 inhibitors, but also for one possible explanation of the mechanisms of CYP3A-mediated negative cooperativity.

Plasma concentrations of tadalafil in children with pulmonary arterial hypertension.

BACKGROUND: There is no report documenting the plasma concentrations of tadalafil in children. This study was performed to evaluate the variability in the pharmacokinetics of tadalafil in children with pulmonary arterial hypertension (PAH) treated routinely with the drug. METHODS: Plasma samples were taken twice (post- and predose) after repetitive oral administration, and the pharmacokinetic parameters (CL/F and V/F) in individual patients were estimated by the Bayesian method using the nonlinear mixed effects model. We also determined the unbound concentration of tadalafil using ultrafiltration. RESULTS: Tadalafil was administered to 23 children aged between 0.25 and 17.4 years, with a mean age of 3.58 years. The mean (±SD) daily dose of tadalafil was 0.97 ± 0.41 mg/kg. Sixteen of the 23 children received bosentan concomitantly. The mean CL/F and V/F values of tadalafil were 0.149 L·h-1·kg-1 and 1.87 L/kg, respectively, which were higher than those reported in adults. No effects of age, bosentan, or the estimated glomerular filtration rate were observed on the CL/F value, indicating that other residual factors might account for the interindividual variability among children with PAH. The unbound tadalafil concentrations of the postdose samples ranged from 5.9 to 146 (46.9 ± 37.1) nmol/L, higher than the reported IC50 value of this phosphodiesterase-5 drug for humans (2-4 nmol/L, corresponding to 0.8-1.6 ng/mL). CONCLUSIONS: We demonstrated variability in the total and unbound plasma concentrations of tadalafil in children. However, all children received the empirical doses of the drug; a mean dose of 0.97 mg·kg-1·d-1 showed sufficient unbound concentrations needed for half-maximal inhibition of human phosphodiesterase-5 in vitro. These observations may provide information for the proper use of tadalafil to treat children with PAH.

[The correlation between the intraoperative flow of coronary artery bypass grafts and the patency of grafts at midterm follow-up].

We evaluated the correlation between the intraoperative flow of coronary artery bypass grafting (CABG) and the patency of grafts at midterm follow-up. When internal mammary arteries were used as grafts, there was no correlation between graft flow rate and graft patency rate. On the other hand, when saphenous vein was used, the greater graft flow was associated with better graft patency. Receiver operator characteristic( ROC) analysis identified the optimum threshold for the intraoperative flow rate to predict the patency at midterm follow-up as 23 ml/min (sensitivity 78%, specificity 71%). The difference in the correlation( of flow rate with patency rate) between the 2 graft types was attributed to the difference of physiological reaction of each type of grafts.

[Evaluation of preoperative intraaortic balloon pumping for high risk off-pump coronary artery bypass grafting].

We evaluated the effect of preoperative intraaortic balloon pumping (IABP) support in high risk patients undergoing off-pump coronary artery bypass grafting (OPCAB). Between November 1999 and December 2010, 65 high-risk patients underwent OPCAB with the support of IABP inserted preoperatively. High risks were considered as (1) left main coronary artery stem stenosis > or = 75%, (2) unstable angina requiring intravenous nitrates and heparin, (3) preoperative left ventricular ejection fraction < or = 30%, (4) bilateral carotid artery stenosis > or = 75%. There were no hospital deaths or cerebrovascular complications. During operations, hemodynamics was stable with the support of low dose catecholamines, and no patient needed conversion to on-pump coronary artery bypass grafting. All patients were able to be weaned from IABP within 3 days (mean 5.7 hours) after the operation and were extubated within 4 days (mean 11.5 hours) after the operation. One patient had a peripheral embolism which might be related to insertion of IABP (1.5%). Preoperative IABP in high-risk patients undergoing OPCAB was considered to be useful and safe.

Effects of ß-adrenoceptor antagonists on anaphylactic hypotension in conscious rats.

Anaphylactic shock is sometimes fatal or resistant to therapy in patients treated with propranolol, a nonselective ß-adrenoceptor antagonist, against cardiovascular diseases. However, it remains unknown which subtype of ß-adrenoceptors, ß(1)- or ß(2)-adrenoceptor, is primarily responsible for the detrimental effects of propranolol on anaphylactic hypotension. Effects of ß(1)- and ß(2)-adrenoceptor antagonists were therefore determined on the survival rate and systemic hypotension in conscious Sprague-Dawley rats that suffered from anaphylactic shock. Mean arterial pressure and portal venous pressure were simultaneously measured. The control rats showed a decrease in mean arterial pressure and an increase in portal venous pressure, but did not die within 48h after an injection of ovalbumin antigen. The survival rate of the rats pretreated with propranolol (1mg/kg; n=7), the selective ß(2)-adrenoceptor antagonist ICI 118,551 (0.5mg/kg; n=7), or adrenalectomy (n=7) was significantly smaller than that with the selective ß(1)-adrenoceptor antagonist atenolol (2mg/kg; n=7). However, the changes in mean arterial pressure and portal venous pressure were similar for 10min after antigen among any groups, although propranolol and atenolol attenuated the antigen-induced increase in heart rate. Furthermore, bolus injections of epinephrine (3µg/kg) at 3 and 5min after antigen prevented the death of the atenolol-pretreated rats, but only marginally prolonged the survival rates for the ICI 118,551- or propranolol-pretreated and adrenalectomized rats. In conclusion, in rat anaphylactic shock, inhibition of ß(2)-adrenoceptor causes more detrimental effects than that of the ß(1)-adrenoceptor. These ß-adrenoceptor antagonists may exert detrimental effects on rat systemic anaphylaxis via inhibiting beneficial actions of catecholamines endogenously released from the adrenal gland.

Aqueous and ethanolic extract fractions from the Brazilian propolis suppress azoxymethane-induced aberrant crypt foci in rats.

We investigated the effects of the two fractions, aqueous (AEP) and ethanolic extracts of propolis (EEP) of the Brazilian propolis on azoxymethane (AOM)-induced aberrant crypt foci (ACF). Male Wistar Hannover (GALAS) rats were administered two weekly subcutaneous injections of AOM (20 mg/kg bw) and fed with diets mixed with AEP (100, 500 and 1,000 ppm) or EEP (500 and 1,000 ppm) for 4 weeks, starting one week before the first dosing of AOM. The modifying effects of the test extracts on ACF formation were assessed by counting the incidence and multiplicity of ACF at week 4. Proliferation cell nuclear antigen (PCNA)-labeling nuclei and apoptotic index were also immunohistochemically determined. Dietary supplementation with AEP and EEP significantly reduced the multiplicity of ACF with the effect of EEP being more potent than AEP. In the ACF and their surrounding non-lesional crypts, significantly lowered cell proliferation was observed in the rats, administered with AOM, and the extracts, while neither fraction affected the apoptotic index. Our findings suggest that AEP and EEP possess a chemopreventive ability in the early phase of colon carcinogenesis through the modulation of cell proliferation.

Differences between right- and left-sided colon cancer in patient characteristics, cancer morphology and histology.

BACKGROUND AND AIM: Recently, the clinical and biological differences between right- and left-sided colon cancers have been widely debated. However, close analyses of these clinical differences, based on large-scale studies, have been scarcely reported. METHODS: A total of 3552 consecutive Japanese colorectal cancer cases were examined and the clinical differences between right- and left-sided colon cancer cases were investigated. RESULTS: The proportion of right-sided colon cancer was relatively high in patients aged less than 40 years (33%) and more than 80 years (43%). The proportion of right-sided colon cancer in patients aged 40-59 years was relatively low (male 22% and female 29%). In male patients the proportion increased in the 70-79 years age group (30%), while in female patients the proportion increased in the 60-69 years age group (39%). Right-sided colon cancer was more likely to be detected at an advanced stage (T1 stage; left 22%, right 15%) (P < 0.01) with severe symptoms. Polypoid-type early cancer was dominant in the left colon (left 59%; right 40%) (P < 0.01), while the proportion of flat-type early cancer in the right colon was significantly higher than that in the left colon (left 25%; right 44%) (P < 0.01). CONCLUSIONS: Specific age distribution of right-sided colon cancer was observed and the difference between male and female patients was highlighted. Other clinical features also differed between right- and left-sided colon cancer, suggesting that different mechanisms may be at work during right and left colon carcinogenesis.

9trans,11trans conjugated linoleic acid inhibits the development of azoxymethane-induced colonic aberrant crypt foci in rats.

We investigated the effects of 9trans,11trans (9t,11t)-conjugated linoleic acid (CLA) isomer on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in rats. Male F344 rats were given 2 weekly subcutaneous injections of AOM (20 mg/kg bw) to induce colonic ACF. They also were fed a diet containing either 0.01%, 0.1%, or 1% 9t,11t-CLA for 4 wk starting 1 wk before the first dosing of AOM. The group that received a diet supplemented with 9t,11t-CLA had a significantly lower number of ACF/colon in comparison to the AOM alone group in a dose-dependent manner up to 0.1%. Furthermore, treatment with 9t,11t-CLA induced apoptosis and suppressed cell proliferation activity in the non-lesional crypts. The downregulation of cyclooxygenase-2 and cyclin D1 and the activation of peroxisome proliferators activated receptor gamma were observed in the colonic mucosa of rats fed a diet supplemented with 9t,11t-CLA. Our findings thus provide some novel insight into the chemopreventive effect of 9t,11t-CLA against preinitiation as well as postinitiation stages of colorectal carcinogenesis.

A lipophilic statin, pitavastatin, suppresses inflammation-associated mouse colon carcinogenesis.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are known to modulate carcinogenesis. In this study, we investigated whether a lipophilic HMG-CoA reductase inhibitor pitavastatin suppresses inflammation-related mouse colon carcinogenesis. Male CD-1 (ICR) mice were initiated with a single intraperitoneal injection of azoxymethane (AOM, 10 mg/kg body weight) and promoted by 2% (w/v) dextran sodium sulfate (DSS) in drinking water for 7 days. The experimental diets containing pitavastatin at 2 dose levels (1 and 10 ppm) were fed to male CD-1 (ICR) mice for 17 weeks, staring 1 week after the cessation of DSS exposure. The effects of dietary pitavastatin on colonic tumor development were assessed at Weeks 5, 10 and 20. Feeding with pitavastatin at both doses significantly inhibited the multiplicity of colonic adenocarcinoma at Week 20. Furthermore, the treatment significantly lowered the positive rates of proliferating cell nuclear antigen and increased the apoptotic index in the colonic epithelial malignancies. The treatment also reduced nitrotyrosine-positivity in the colonic mucosa. Our findings thus show that pitavastatin is effective in inhibiting colitis-related colon carcinogenesis through modulation of mucosal inflammation, oxidative/nitrosative stress, and cell proliferation.

Tumor-initiating potency of a novel heterocyclic amine, aminophenylnorharman in mouse colonic carcinogenesis model.

A novel heterocyclic amine, 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), which is formed from nonmutagenic 9H-pyrido[3,4-b]indole (norharman) and aniline, is mutagenic to bacteria and mammalian cells and potently carcinogenic in rats. APNH is detected in human urine samples, suggesting that humans are continuously exposed to APNH. In the present study, (32)P-postlabelin analysis revealed that the levels of APNH-DNA adduct 24 hr after the treatment with APNH (1, 5 and 20 mg/kg body weight) in male ICR mice were increased in a dose-dependent manner in the colon and liver. Based on these findings, we determined the tumor-initiating potency of APNH in an inflammation-related and two-stage mouse colon carcinogenesis model. Male Crj: CD-1 (ICR) mice were given a single intragastric administration (1, 2, 5 or 10 mg/kg body weight) of APNH and subsequent 1-week oral exposure to dextran sodium sulfate (DSS, 2% in drinking water). Treatment with APNH and DSS resulted in numerous colon tumor development: the incidence and multiplicity of the tumors were the highest in the mice received 10 mg/kg body weight of APNH and followed by DSS. Development of colon tumors was dose-dependent of APNH. Seven of 9 (77.8%) colonic adenocarcinomas developed in mice treated with APNH (10 mg/kg body weight) and DSS had beta-catenin gene mutations at codons 32 and 37, being predominantly transversion. These findings indicate that APNH has an initiating activity in inflamed mouse colon and the APNH-DNA adduct formation correlates with its tumorigenic potential.

Citrus auraptene suppresses azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db mice.

The current study was designed to investigate whether dietary citrus auraptene (AUR) suppresses the development of azoxymethane (AOM)-induced colorectal preneoplastic lesions in C57BL/KsJ-db/db (db/db) mice with obese and diabetic phenotypes. Female db/db and wild (+/+) mice were divided into the AOM + AUR, AOM alone, AUR alone, and the untreated groups in each phenotype. AOM was given 3 weekly intraperitoneal injections (10 mg/kg bw). AUR (250 ppm) was given in diet during the study (for 10 wk). Dietary AUR significantly reduced the number of aberrant crypt foci (ACF) and Beta -catenin-accumulated crypt (BCAC) in both phenotypes. The treatment also lowered cell proliferation activity and increased apoptotic cells in both lesions. Our findings indicate that dietary AUR is able to suppress the early phase of colon carcinogenesis in both phenotypes, suggesting possible application of AUR as a chemopreventive agent in both the high-risk and general populations for colorectal cancer.

Ursodeoxycholic acid versus sulfasalazine in colitis-related colon carcinogenesis in mice.

PURPOSE: Inflammation influences carcinogenesis. In the current study, we investigated whether ursodeoxycholic acid (UDCA) can inhibit colitis-related mouse colon carcinogenesis and compared it with the effects of sulfasalazine. EXPERIMENTAL DESIGN: Male CD-1 mice were given a single i.p. injection of azoxymethane followed by 1-week oral exposure of 1% dextran sodium sulfate in drinking water. They are then maintained on a basal diet mixed with UDCA (0.016%, 0.08%, or 0.4%) or sulfasalazine (0.05%) for 17 weeks. At week 20, the tumor-inhibitory effects of both chemicals were assessed by counting the incidence and multiplicity of colonic neoplasms. The immunohistochemical expression of the proliferating cell nuclear antigen labeling index in colonic epithelial malignancies was also assessed. Finally, at week 5, the mRNA expressions for cyclooxygenase-2, inducible nitric oxide synthase, peroxisome proliferator-activated receptor-gamma, and tumor necrosis factor-alpha were measured in nontumorous mucosa. RESULTS: Feeding the mice with UDCA at all doses significantly inhibited the multiplicity of colonic adenocarcinoma. The treatment also significantly lowered the proliferating cell nuclear antigen labeling index in the colonic malignancies. UDCA feeding reduced the expression of inducible nitric oxide synthase and tumor necrosis factor-alpha mRNA in the colonic mucosa, while not significantly affecting the expression of cyclooxygenase-2 mRNA and peroxisome proliferator-activated receptor-gamma mRNA. Sulfasalazine caused a nonsignificant reduction in the incidence and multiplicity of colonic neoplasia and did not affect these mRNA expression. CONCLUSIONS: Our findings suggest that UDCA rather than sulfasalazine could serve as an effective suppressing agent in colitis-related colon cancer development in mice.

A specific inducible nitric oxide synthase inhibitor, ONO-1714 attenuates inflammation-related large bowel carcinogenesis in male Apc(Min/+) mice.

It is generally assumed that inflammation influences carcinogenesis. We previously reported that dextran sodium sulfate (DSS) strongly enhances colon carcinogenesis in the Apc(Min/+) mice and the over-expression of inducible nitric oxide synthase (iNOS) contributes to this enhancement. In the current study, we investigated the effect of a selective iNOS inhibitor, ONO-1714 on colitis-related colon carcinogenesis in the Apc(Min/+) mouse treated with DSS. Male C57BL/6J Apc(Min/+) and Apc(+/+) mice were exposed to 1% DSS in their drinking water for 7 days. ONO-1714 was given to the mice at a dose level of 50 or 100 ppm in diet for 5 weeks (during the administration of DSS). The tumor inhibitory effects by ONO-1714 were assessed at week 5 by counting the incidence and multiplicity of colonic neoplasms. Additionally, we assessed serum lipid levels and colonic mRNA expression for cyclooxygenase (COX)-2, iNOS, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. Feeding with ONO-1714 significantly inhibited the occurrence of colonic adenocarcinoma in a dose-dependent manner in the Apc(Min/+) mice. In addition, the treatment with ONO-1714 significantly lowered the serum triglyceride levels and mRNA expression levels of COX-2, TNFalpha and IL-1beta of colonic mucosa in the DSS-treated Apc(Min/+) mice. Neither ONO-1714 nor DSS affected the colonic pathology in the Apc(+/+) mice. Our findings may suggest that ONO-1714 could therefore serve as an effective agent for suppression of colitis-related colon cancer development in the Apc(Min/+) mice.

Dietary beta-cryptoxanthin inhibits N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice.

Recent epidemiological studies have indicated that high dietary consumption of fruit and vegetables results in lower risk of bladder cancer. To confirm these findings, we investigated in the current study the effects of dietary administration with beta-cryptoxanthin extracted from Citras unshiu oranges on N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder carcinogenesis in mice. Male ICR mice were divided into 6 experimental and control groups. Groups 1 through 4 were given OH-BBN (500 ppm) in drinking water for 6 weeks to induced urinary bladder neoplasms. Mice in groups 2, 3 and 4 were fed the diets mixed with 1, 5 and 25 ppm of beta-cryptoxanthin, respectively, starting 1 week after the cessation of OH-BBN exposure, and kept on these diets for 24 weeks until the termination of the study. Group 5 was treated with the diet containing the test compound (25 ppm) alone, and group 6 served as an untreated control. All animals were sacrificed at week 32 for histopathology and immunohistochemistry (cyclin D1). Feeding with beta-cryptoxanthin decreased the incidence and multiplicity of preneoplastic and neoplastic lesions of urinary bladder. Notably, the highest dose (25 ppm) of the test chemical significantly lowered the occurrence of bladder carcinoma, in conjunction with reducing the cyclin D1-positive cell ratio. These findings suggest that beta-cryptoxanthin is able to prevent OH-BBN-induced bladder carcinogenesis in mice.

Diet supplemented with citrus unshiu segment membrane suppresses chemically induced colonic preneoplastic lesions and fatty liver in male db/db mice.

The modulatory effects of dietary citrus unshiu segment membrane (CUSM) on the occurrence of aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCACs) were determined in male C57BL/KsJ-db/db (db/db) mice initiated with azoxymethane (AOM). Male db/db, db/+ and +/+ mice were given 5 weekly subcutaneous injections of AOM (15 mg/kg body weight), and then they were fed the diet containing 0.02%, 0.1% or 0.5% CUSM for 7 weeks. At Week 12, a significant increase in the numbers of ACF and BCAC was noted in the db/db mice in comparison with the db/+ and +/+ mice. Feeding with CUSM caused reduction in the frequency of ACF in all genotypes of mice and the potency was high in order of the db/db mice, db/+ mice and +/+ mice. The number of BCACs was also reduced by feeding with CUSM, thus resulting in a 28-61% reduction in the db/db mice, possibly due to suppression of cell proliferation activity in the lesions by feeding with CUSM-containing diet. Clinical chemistry revealed a low serum level of triglyceride in mice fed CUSM. In addition, CUSM feeding inhibited fatty metamorphosis and fibrosis in the liver of db/db mice. Our findings show that CUSM in the diet has a chemopreventive ability against the early phase of AOM-induced colon carcinogenesis in the db/db as well as db/+ and +/+ mice, indicating potential use of CUSM in cancer chemoprevention in obese people.

Catalpa seed oil rich in 9t,11t,13c-conjugated linolenic acid suppresses the development of colonic aberrant crypt foci induced by azoxymethane in rats.

Catalpa (Catalpa ovata) seed oil (CPO) is a unique oil that contains a high amount of 9trans,11trans,13cis-conjugated linolenic acid. In the present study, we investigated whether dietary administration with CPO affects the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats to elucidate its possible cancer chemopreventive efficiency. Also, the effect of CPO on the fatty acid composition of liver tissue and colonic mucosa, the serum levels of total cholesterol and triglyceride, and the mRNA expression of cyclooxygenase (COX)-2 in the colonic mucosa were measured. In addition, the cell proliferation activity and apoptotic index in the colonic mucosa were estimated immunohistochemically. Animals were given two weekly subcutaneous injections of AOM (20 mg/kg body weight). They also received the experimental diet containing 0.01%, 0.1% or 1% CPO for 4 weeks, starting one week before the first dosing of AOM. AOM exposure produced a substantial number of ACF (99+/-28) at the end of the study (week 4). Dietary administration of CPO reduced the number of ACF (AOM + 0.01% CPO, 32+/-11, P<0.001; AOM + 0.1% CPO, 35+/-18, P<0.001; AOM + 1% CPO, 18+/-10, P<0.001). 9t,11t-conjugated linoleic acid was detected in the liver tissue and colonic mucosa of rats fed the CPO-containing diet. Additionally, dietary administration with CPO decreased the serum triglyceride level and the expression of COX-2 mRNA in the colonic mucosa. The indices of cell proliferation and apoptosis in the colonic mucosa of rats treated with AOM and 1% CPO have significant differences when compared with the AOM alone group. These findings suggest the possible chemopreventive activity of CPO in the early phase of colon carcinogenesis.

Growth inhibition and apoptosis induction by all-trans-conjugated linolenic acids on human colon cancer cells.

Conjugated linolenic acids (CLN) are geometric and positional isomers of linolenic acid. Growth inhibition and apoptosis induction by alpha-eleostearic acid (c9,t11,t13-CLN), beta-eleostearic acid (t9,t11,t13-CLN), alpha-calendic acid (t8,t10,c12-CLN) and beta-calendic acid (t8,t10,t12-CLN) were compared. beta-Eleostearic acid and beta-calendic acid, which have all-trans-conjugated double bonds, exerted stronger growth inhibition and more DNA fragmentation, an indicator of apoptosis induction, in the human colon cancer cells Caco-2 than alpha-eleostearic acid and alpha-calendic acid with the cis configuration. Down-regulation of bcl-2 and up-regulation of bax mRNA by beta-eleostearic acid were also greater than by alpha-eleostearic acid. Interestingly, the cytotoxic effects of beta-eleostearic acid and beta-calendic acid were not counteracted completely by alpha-tocopherol, whereas the cytotoxic effects of alpha-eleostearic and alpha-calendic acids were lost in the presence of alpha-tocopherol. These results suggest that beta-eleostearic and beta-calendic acids have signaling pathways different from those of alpha-eleostearic and alpha-calendic acids and exhibit high potency for reducing the cell viability of Caco-2.

Preventive effects of chrysin on the development of azoxymethane-induced colonic aberrant crypt foci in rats.

The modifying effects of dietary feeding with chrysin (5,7-dihydroxyflavone) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effect of chrysin on mitosis and apoptosis in 'normal appearing' crypts. To induce ACF, rats were given two weekly subcutaneous injections of AOM (20 mg/kg body weight). They also received an experimental diet containing chrysin (0.001 or 0.01%) for 4 weeks, starting 1 week before the first dose of AOM. AOM exposure produced a substantial number of ACF (73+/-13/rat) at the end of the study (week 4). Dietary administration of chrysin caused significant reduction in the frequency of ACF: 0.001% chrysin, 37+/-17/rat (49% reduction, P<0.001); and 0.01% chrysin, 40+/-10/rat (45% reduction, P<0.001). In addition, chrysin administration significantly reduced the mitotic index and significantly increased the apoptotic index in 'normal appearing' crypts. These findings might suggest a possible chemopreventive activity of chrysin in the early step of colon tumorigenesis through modulation of cryptal cell proliferation activity and apoptosis.

A case of lymphangioleiomyomatosis affecting the supraclavicular lymph nodes.

The case of a 46-year-old woman with lymphangioleiomyomatosis (LAM) involving the supraclavicular, mediastinal, and pelvic lymph nodes in addition to the lungs is reported. Computed tomography incidentally revealed multiple thin-walled pulmonary cysts and low-attenuating masses in the supraclavicular, mediastinal, and retroperitoneal lymph nodes. A biopsy of the supraclavicular mass was performed and diagnosed as LAM histopathologically. The common sites of extrapulmonary LAM include retroperitoneal and mediastinal lymph nodes; however, supraclavicular lymph node involvement is extremely rare.