Dietary flavanols and platelet reactivity

Epidemiology studies suggest that the consumption of diets rich in flavonoids is associated with reduced risk of cardiovascular disease. Plant-derived foods and beverages, such as red wine, tea, grape and grape juice, cocoa and chocolate, can be rich in 1 particular class of flavonoid, the flavan-3-ols. There is now an increasing body of research that suggests that consuming flavanol-rich foods can positively affect hemostasis, through mechanisms that either directly affect platelet function or increase certain endothelium-derived factors that maintain platelet acquiescence or increase fibrinolysis. In this paper, we will review a series of in vivo studies on the effects of flavanol-rich cocoa and chocolate on platelet activation and platelet-dependent hemostasis. In addition, we will briefly review the body of literature with regard to other flavanol-rich foods and beverages, and possible mechanisms of action.     

Primary pancreatic lymphoma with elevated serum CA19-9 level

We report a case of primary pancreatic lymphoma. The patient was a 71-year-old Japanese male who complained of upper abdominal pain. The findings on imaging examinations including CT scan, angiograph, and ERCP suggested pancreatic head adenocarcinoma. CA 19-9 levels were elevated. The patient underwent choledochojejunostomy and gastrojejunostomy. Histologically, swollen mesenteric lymphnodes biopsied intraoperatively showed lymphoplasmacytic lymphoma findings. Leakage occurred repeatedly postoperatively, and the patient died of sepsis. Retrospectively, relatively clearly defined and homogenous low density mass lesion seen on CT scan were more likely findings for lymphoma than for adenocarcinoma. It is important to consider lymphoma in a patient with suspected adenocarcinoma showing atypical imaging findings no matter how minor they are.     

Toxicity study of a rubber antioxidant, mixture of 2-mercaptomethylbenzimidazoles, by repeated oral administration to rats.

2-Mercaptobenzimidazole (2-MBI), a rubber antioxidant, is known to exhibit potent antithyroid toxicity in rats and is a candidate as an environmental endocrine disrupter. 2-Mercaptomethylbenzimidazoles (a 1:1 mixture of 4-methyl and 5-methyl isomers, MMBIs), are also employed industrially as rubber antioxidants and are suspected to exert antithyroid toxicity such as 2-MBI. In this investigation, acute and subacute oral toxicity studies of MMBIs in Wistar rats were conducted. The clinical signs of acute oral toxicity were observed including decreased spontaneous movement, a paralytic gait, salivation and lacrimation, and adoption of prone and lateral positions. The LD50 was estimated to be 330 mg/kg. In the subacute oral toxicity study, male and female rats were treated with MMBIs by gavage at doses of 0 (corn oil), 4, 20 and 100 mg/kg for 28 consecutive days followed by a 2-week recovery period for the control and highest dose groups. Body weight and food consumption, clinical signs, organ weights, clinical biochemistry and haematological parameters including clotting times and micronuclei induction in bone marrow erythropoeitic cells, and histopathology were examined. Relative organ weights of lung, liver and kidney, and serum cholesterol and phospholipid significantly increased in male rats treated with MMBIs at doses of 20 and 100 mg/kg. Male rats administered 100 mg/kg MMBIs exhibited a 1.8-fold increase in thyroid weight associated with histopathological changes but not altered serum thyroid hormone levels. Female rats administered 100 mg MMBIs/kg exhibited significant increases of liver and kidney but not thyroid weights, and serum cholesterol level. The antithyroid toxicity of MMBIs in rats was estimated to be one-tenth that of 2-MBI. No-observed-effect levels for male and female rats were found to be 4 and 20 mg/kg, respectively, in this subacute oral toxicity study.     

Abnormal development of fourth aortic arch derivatives in the pathogenesis of tetralogy of Fallot

Summary Aortic arch (AoA) anomalies were studied in 233 patients with tetralogy of Fallot (TOF) of whom some had coexisting pulmonary atresia (PA). There was a 23% incidence of a right AoA in patients without PA, 21% in those with both PA and persistent ductus arteriosus (PDA), and 50% in those with PA and major aortopulmonary collateral arteries (MAPCAs). There was a 5% incidence of an aberrant subclavian artery in patients without PA and a 16% incidence in those with PA and MAPCAs. In this cohort an elongated ascending aorta was observed both with and without high aortic arch. These aortic arch anomalies were frequently associated with PA and MAPCAs.     

Fetal cardiovascular cross-sectional morphology of tetralogy of Fallot in rats

In order to clarify cross-sectional morphology of tetralogy of Fallot in the fetus, 202 rat fetuses with tetralogy of Fallot induced by maternal administration of bis-diamine were studied using cesarean section, the whole body freezing method and by photographing cross sections of the fetal heart on a freezing microtome. Some characteristic features such as large subaortic ventricular septal defects, aortic overriding over the ventricular septum, aortomitral fibrous continuity, and narrow infundibulum and pulmonary valve were found. Moreover, three subtypes were noticed. In classic tetralogy of Fallot with stenotic infundibulum, the size of the pulmonary arteries was smaller in proportion to the infundibular stenosis. In the second type with absent infundibular septum and severe valvular pulmonary stenosis, the pulmonary arteries were most hypoplastic. In the third type with absent pulmonary valve, the pulmonary arteries were dilated forming aneurysms. In the last type only, ventricles were dilated and grossly hypertrophic.     

Impaired distensibility of neoaorta after arterial switch procedure

Background. Although the arterial switch operation has become the standard surgical procedure for treatment of complete transposition, postoperative problems have not been fully appreciated. One such problem may be the postoperative function of great arteries that are manipulated radically.

Methods. The diameters at four levels of the aorta were measured in 36 patients who had undergone arterial switch operation and the distensibilities were calculated. The data were compared with that of age-matched controls.

Results. At the level of the Valsalva sinus, aortic diameters after one-staged and two-staged operations were 137.0% ± 21.3%N and 152.4% ± 17.7%N of the normal aorta, respectively. The distensibilities at the Valsalva sinus in patients after one-staged and two-staged operations were 1.2 ± 0.7 and 1.5 ± 0.8 cm² · dyn⁻¹ · 10⁻⁶, and at the supraaortic ridge were 2.5 ± 1.5 and 1.9 ± 1.5 cm² · dyn⁻¹ · 10⁻⁶, respectively.

Conclusions. In patients after arterial switch procedure, the distensibility of the base of aorta is decreased. Long-term follow-up is necessary to clarify the influence of the “stiffness” of the base of aorta.     

Evaluation of the tocolytic effect of a selective cyclooxygenase-2 inhibitor in a mouse model of lipopolysaccharide-induced preterm delivery

The inflammatory process is known to cause preterm delivery. Recently, a cyclooxygenase (COX)-2 inhibitor has been developed as an anti-inflammatory drug with few side-effects. We evaluated the COX-2 inhibitor, Celecoxib, for its tocolytic effects and side-effects on dams and pups using a lipopolysaccharide (LPS)-induced preterm delivery mouse model (preterm delivery rates; 95%). With administration of Celecoxib (50, 10, 1 and 0.3 mg/kg), the preterm labour rate was significantly reduced to 18, 30, 36 and 60% respectively. The prostaglandin F(2alpha)(PGF(2alpha)) and PGE(2) concentrations in murine uterine tissue 4 and 10 h after LPS treatment with Celecoxib (10 and 1 mg/kg) were significantly lower than those in the LPS-treated group without CELECOXIB: With administration of 10 or 100 mg/kg Celecoxib, the fetal ductus arteriosus was constricted significantly in preterm and near-term rats, although constriction rates in preterm rats were significantly lower than those in near-term rats. Reproductive and renal functions in offspring whose mothers were treated with LPS and Celecoxib were normal. These data demonstrate that Celecoxib could be used as a new therapy for preterm labour. However, careful attention to constriction of the fetal ductus arteriosus should be given.     

Effects of 2,5-di(tert-butyl)-1,4-hydroquinone on intracellular free Ca2+ levels and histamine secretion in RBL-2H3 cells

The effects of 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ) on the intracellular free Ca²⁺ level ([Ca²⁺]_i) and histamine secretion of rat basophilic leukemia (RBL-2H3) cells were examined. DTBHQ (0.1–10 µmol/l) alone induced rapid and sustained increases in [Ca²⁺]_i in a concentration-dependent manner. In cells sensitized with anti-dinitrophenyl IgE, DTBHQ (10 µmol/1) further increased the antigen (dinitrophenylated BSA)-induced Ca²⁺ response. In the absence of external Ca²⁺ with addition of 1 mmol/1 EGTA, both DTBHQ (10 µmol/l) and the antigen (10 µg/ml) induced transient increase in [Ca²⁺]_i. In sensitized cells, both DTBHQ (10 µmol/1) and antigen (10 µg/ml) elicited histamine secretion, although the response was far stronger in the latter case. The DTBHQ-induced histamine secretion was markedly enhanced by addition of the protein kinase C activator, phorbol 12-myristate 13-acetate (TPA) (10 ng/ml) whereas TPA alone did not cause any increase. Moreover, DTBHQ enhanced the antigen-induced histamine secretion. The results suggest that DTBHQ increases [Ca²⁺]_i and enhances antigeninduced histamine secretion while DTBHQ alone does not cause as much histamine secretion as antigen, which support the idea that calcium signals are necessary but are not sufficient for maximum histamine secretion in RBL-2H3 cells.     

Increased constriction of the ductus arteriosus by dexamethasone, indomethacin, and rofecoxib in fetal rats.

BACKGROUND: To find a better treatment for patent ductus arteriosus (PDA) in premature infants, the present study investigated the synergism of clinical doses of dexamethasone, indomethacin, and rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on the fetal ductus arteriosus (DA) in rats. METHODS AND RESULTS: Dexamethasone (0.3 mg/kg), indomethacin (0.3 mg/kg), and rofecoxib (0.3 mg/kg), alone or in combination, were administered to preterm (d19) and near-term (d21) fetal rats. The ratio of the inner diameter of the DA to that of the main pulmonary artery (PA) (DA/PA) was studied at 2, 4 and 8 h after drug administration, using a rapid whole-body freezing method. In near-term rats, the combined administration of dexamethasone and indomethacin caused severe constriction, with a DA/PA ratio of 0.52+/-0.08 at 8 h, whereas the DA/PA ratios were 0.83+/-0.03 and 0.90+/-0.02 with dexamethasone and indomethacin, respectively. Combined administration of dexamethasone and rofecoxib also caused severe constriction, with a DA/PA ratio of 0.64+/-0.07 at 8 h, compared with the DA/PA ratio of 0.92+/-0.03 with rofecoxib alone. CONCLUSIONS: Combined therapy may be an option in the medical management of PDA in premature infants before considering surgical treatment.