Sudden unexpected death as a result of anomalous origin of the right coronary artery from the left sinus of Valsalva.

The association of sudden unexpected death with coronary artery anomalies has been limited to cases of anomalous origin of the left main coronary artery, either from the right sinus of Valsalva or from the main pulmonary artery. In contrast, anomalies involving the origin of the right coronary artery have been considered to be benign. Postmortem examination in a patient who died suddenly at 23 years of age disclosed that the right coronary artery originated anomalously from the left sinus of Valsalva. The findings in this patient: (1) constitute the first necropsy documentation of premature sudden unexpected death in a patient whose sole pathologic abnormality was anomalous origin of the right coronary artery; (2) have important implications regarding previously proposed mechanisms of sudden death due to anomalous origin of the left main coronary artery; and (3) support recent suggestions that markedly acute angulation of either coronary artery, even when located in the appropriate sinus of Valsalva, may predispose to sudden unexpected death.

Substituted thiopyrano[2,3,4-c,d]indoles as potent, selective, and orally active inhibitors of 5-lipoxygenase. Synthesis and biological evaluation of L-691,816.

Thiopyrano[2,3,4-c,d]indoles are a new class of 5-lipoxygenase (5-LO) inhibitors. SAR studies have demonstrated that the thiopyran ring, the 5-phenylpyridine substituent, and an acidic functional group on a four-carbon C-2 side chain are all required for optimal inhibitor potency. In contrast, the indolic nitrogen may be substituted with a variety of lipophilic groups. As a result of the SAR investigation, 44 (L-691,816; 5-[3-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy ]- 4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpro pyl]-1H- tetrazole) has been identified as a potent inhibitor of the 5-LO reaction both in vitro and in a range of in vivo models. Compound 44 inhibits 5-HPETE production by both rat and human 5-LO and LTB4 synthesis in human PMN leukocytes (IC50s 16, 75, and 10 nM, respectively). The mechanism of inhibition of 5-LO activity by compound 44 appears to involve the formation of a reversible deadend complex with the enzyme and does not involve reduction of the nonheme iron of 5-LO. Compound 44 is highly selective for 5-LO when compared to the inhibition of human FLAP, porcine 12-LO, and also ram seminal vesicle cyclooxygenase. In addition, 44 is orally active in a rat pleurisy model (inhibition of LTB4, ED50 = 1.9 mg/kg; 8 h pretreatment) as well as in the hyperreactive rat model of antigen-induced dyspnea (ED50 = 0.1 mg/kg; 2-h pretreatment). Excellent functional activity was also observed in both the conscious allergic monkey and sheep models of asthma. In the latter case, the functional activity observed correlated with the inhibition of urinary LTE4 excretion.

Dioxabicyclooctanyl naphthalenenitriles as nonredox 5-lipoxygenase inhibitors: structure-activity relationship study directed toward the improvement of metabolic stability.

Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites: the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure-activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhibits the oxidation of arachidonic acid to 5-hydroperoxy-eicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile 9ac is accompanied by an improved resistance to oxidative metabolism. In addition, 9ac is orally active in the functional model of antigen-induced bronchoconstriction in allergic squirrel monkeys (95% inhibition at 0.1 mg/kg).

Frequency in nonangioplasty patients of morphologic findings reported in coronary arteries treated with transluminal angioplasty.

The coronary arteries from 70 consecutive patients in whom percutaneous transluminal angioplasty (PTA) had not been performed during life were examined at necropsy for findings that have been previously described in patients or animals treated with PTA. In 33 (49%) of the 70 patients, 1 or more findings identical to those observed in necropsy studies of PTA-treated arteries were observed: "plaque fractures" in 31 (44%), "dissection clefts" in 26 (33%), and extensive medial thinning in 40 (57%). Observations in these 70 patients indicate that findings previously described in PTA-treated patients cannot necessarily be assumed to represent the results of PTA. The fact that improved vessel patency may be seen in the absence as well as the presence of such lesions precludes firm assurance that such lesions are the sole basis for successful angioplasty.

Pharmacology of L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpro pan oic acid); a potent, selective thromboxane/prostaglandin endoperoxide antagonist.

L-655,240 (3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]2,2-dimethylpropa noic acid) has been studied in vitro on the guinea-pig tracheal chain, pulmonary artery and thoracic aorta ring and shown to be a potent, competitive antagonist of contractions induced by the prostaglandin endoperoxide analogue, U-44069 (pA2 values 8.0, 8.4 and 8.0 respectively). Selectivity on the guinea-pig trachea was indicated by non-competitive antagonism of contractions induced by prostaglandin D2 and minimal activity against contractions induced by leukotriene D4, prostaglandin F2 alpha, serotonin, histamine and acetylcholine. L-655,240 was a potent inhibitor of the aggregation of washed human platelets induced by U-44069 (IC50 value 7 X 10(-9) M) and inhibited aggregation of human platelet rich plasma induced by U-44069, U-46619, thromboxane A2 and collagen but not ADP or platelet activating factor. In vivo i.v. L-655,240 administered to guinea-pigs inhibited bronchoconstriction induced by i.v. U-44069 and arachidonic acid (ED50 values 0.09 and 0.23 mg kg-1) but not histamine, acetylcholine or serotonin. When administered to rhesus monkeys (3 and 10 mg/kg p.o.), L-655,240 inhibited ex vivo platelet aggregation induced by U-44069 but not ADP. It is concluded that L-655,240 is a potent, selective, orally active thromboxane/prostaglandin endoperoxide antagonist.

Sensitivity to "atypical" mycobacteria in high school children in two community health departments.

To evaluate the prevalence of atypical mycobacteria infections in our population, a study was done among students of secondary fifth grade (15-19 years of age) in the community health departments of Maisonneuve-Rosemont in Montreal and of Sherbrooke. The tuberculin used was the RT-23 2 T.U. with Tween 80 and the sensitins prepared by the Statens Serum Institute of Copenhagen from Mycobacterium intracellulare (Battey) and from Mycobacterium kansasii. Each student had a tuberculin test on one arm and a sensitin test on the other. The sensitins were randomly allocated. Depending on how the prevalence is calculated, the Mycobacterium intracellulare infection varies from 3 to 20% in Montreal and from 0 to 9.6% in Sherbrooke. The Mycobacterium kansasii infection is much less important in both regions. All reactions to those atypical mycobacteria are in the range of tuberculin reactions of 0 to 9 mm. In our population which is weakly infected with atypical mycobacteria, the level of positivity of tuberculin reactions to 2 T.U. RT-23 or 5 T.U. P.P.D. would give a more realistic evaluation of M. tuberculosis infection if it was fixed at 5 mm than at 10 mm as it is now.

Condylomatous lesions of the cervix and vagina. I. Cytologic patterns.

Condylomatous lesions, although readily diagnosed on the vulva, are often missed in the vagina and on the cervix by clinical examination alone. The lesions are, however, quite common and may be misdiagnosed as mild dysplasia by cytology, colposcopy and even tissue examination. Condylomatous lesions are presently diagnosed on cytologic evidence in nearly two per cent of asymptomatic patients screened in our program and followed-up by colposcopy and tissue examination, when indicated. The cytologic presentation of these lesions is quite characteristic. The main features are seen in squamous cells: enlargement, bi- or multinucleation, hyperchromasia, peri-nuclear clearing, amphophilia and dyskeratotic changes. Our present experience indicates that a large number of lesions previously classed as mild dysplasias actually represent various stages of condylomatous lesions. When these stages of viral changes are removed from the group of dysplasias, the remaining cases become of much greater significance as the early stages of evolution of carcinomata of the cervix.

Behavioral influences of rectal diazepam in solution on dental patients with mentally and physically handicapping conditions.

The hypothesis of this study was to determine whether the use of rectal diazepam in solution would effectively modify the uncooperative behavior of patients with mentally and physically handicapping conditions during dental treatment. The sample consisted of 42 patients with mild to severe mentally handicapping conditions, 4 to 31 years old, who live in a homecare center. Supragingival and subgingival scaling and prophylaxis were attempted during a 5-minute period and the patient's behavior was assessed. Conscious sedation using a rectal solution of diazepam (Stesolid) was used for those patients with voluntary or involuntary uncooperative behavior that prevented treatment. Twenty-two subjects (52.4%) were treated without diazepam. The rectal solution of diazepam proved to be a significantly (P less than .01) effective agent for behavior modification permitting the successful treatment of 16 (80%) of the 20 remaining subjects. The following behaviors were significantly modified: places hand(s) or arm(s) in front of mouth (P less than .01); does not open mouth, lips held firmly together (P less than .05); turns head to one side or side to side (P less than .05); attempts to grab instruments (P less than .05). No relationship was found between the results and the variables of medical history, gender, age, weight, quantity of diazepam administered, routine medication, pulse rate, blood pressure, and respiration.

Aerial measurement of radioxenon concentration off the west coast of Vancouver Island following the Fukushima reactor accident.

In response to the Fukushima nuclear reactor accident, on March 20th, 2011, Natural Resources Canada conducted aerial radiation surveys over water just off the west coast of Vancouver Island. Dose-rate levels were found to be consistent with background radiation, however a clear signal due to (133)Xe was observed. Methods to extract (133)Xe count rates from the measured spectra, and to determine the corresponding (133)Xe activity concentration, were developed. The measurements indicate that (133)Xe concentrations on average lie in the range of 30-70 Bq/m(3).

The allosteric regulation of pyruvate kinase.

Pyruvate kinase (PK) is critical for the regulation of the glycolytic pathway. The regulatory properties of Escherichia coli were investigated by mutating six charged residues involved in interdomain salt bridges (Arg(271), Arg(292), Asp(297), and Lys(413)) and in the binding of the allosteric activator (Lys(382) and Arg(431)). Arg(271) and Lys(413) are located at the interface between A and C domains within one subunit. The R271L and K413Q mutant enzymes exhibit altered kinetic properties. In K413Q, there is partial enzyme activation, whereas R271L is characterized by a bias toward the T-state in the allosteric equilibrium. In the T-state, Arg(292) and Asp(297) form an intersubunit salt bridge. The mutants R292D and D297R are totally inactive. The crystal structure of R292D reveals that the mutant enzyme retains the T-state quaternary structure. However, the mutation induces a reorganization of the interface with the creation of a network of interactions similar to that observed in the crystal structures of R-state yeast and M1 PK proteins. Furthermore, in the R292D structure, two loops that are part of the active site are disordered. The K382Q and R431E mutations were designed to probe the binding site for fructose 1, 6-bisphosphate, the allosteric activator. R431E exhibits only slight changes in the regulatory properties. Conversely, K382Q displays a highly altered responsiveness to the activator, suggesting that Lys(382) is involved in both activator binding and allosteric transition mechanism. Taken together, these results support the notion that domain interfaces are critical for the allosteric transition. They couple changes in the tertiary and quaternary structures to alterations in the geometry of the fructose 1, 6-bisphosphate and substrate binding sites. These site-directed mutagenesis data are discussed in the light of the molecular basis for the hereditary nonspherocytic hemolytic anemia, which is caused by mutations in human erythrocyte PK gene.

5-Lipoxygenase-activating protein is the target of a quinoline class of leukotriene synthesis inhibitors.

An indole class of leukotriene synthesis inhibitors, exemplified by MK-886, which does not directly inhibit 5-lipoxygenase, has been shown to bind to an 18-kDa leukocyte membrane protein and to inhibit 5-lipoxygenase membrane translocation. It was demonstrated that the 18-kDa protein is necessary for the cellular activation of leukotriene synthesis and was named 5-lipoxygenase-activating protein (FLAP). We describe here a class of leukotriene synthesis inhibitors based on a quinoline structure, which is structurally distinct from MK-886. However, similar to MK-886, several quinolines are potent inhibitors of cellular leukotriene synthesis but are poor inhibitors of soluble 5-lipoxygenase. To determine whether FLAP is the protein target of leukotriene synthesis inhibitors of the quinoline class, we investigated the ability of these compounds to inhibit photoaffinity labeling of FLAP and to elute FLAP from indole affinity gels. The abilities of the quinoline inhibitors to interact with FLAP correlated well with their abilities to inhibit leukotriene synthesis in human polymorphonuclear leukocytes. L-674,573, a potent quinoline leukotriene synthesis inhibitor, inhibited indole photoaffinity labeling of FLAP in a concentration-dependent manner. In addition, L-674,573 selectively eluted FLAP from indole affinity gels, in contrast to L-671,480, a quinoline that was inactive as an inhibitor of leukotriene synthesis. When human leukocyte membranes were labeled with the indole photoaffinity probe [125I]L-669,083 and immunoprecipitated with a FLAP antibody, the labeling of FLAP was inhibited by L-674,573 but not by L-671,480. These results suggest a direct binding site for the quinoline leukotriene synthesis inhibitors on FLAP and provide further evidence for the essential role of FLAP in cellular leukotriene synthesis.

Microsomal metabolism of the 5-lipoxygenase inhibitors L-746,530 and L-739,010 to reactive intermediates that covalently bind to protein: the role of the 6,8-dioxabicyclo[3.2.1]octanyl moiety.

Hepatic microsomes from different species were used to study the oxidative metabolism of L-746,530 and L-739,010, two potent and specific 5-lipoxygenase inhibitors. HPLC analysis of the incubates obtained from the microsomal incubations of L-739,010 and L-746,530 showed only traces of metabolites. However, recovery of the starting material in the supernatant was less than quantitative in all of the species studied (approximately 90% in rat, approximately 70% in the dexamethasone-induced rat, approximately 70-90% in humans, and approximately 60% in the rhesus monkey for both compounds). The recovery of the starting material was found to be time- and NADPH-dependent, suggesting that metabolite(s) were formed and reacting with the microsomal proteins. Evidence that the cytochrome P4503A (CYP3A) contributed to the formation of the reactive metabolite(s) was shown by the low recovery of material that was observed upon incubation with microsomes obtained from dexamethasone-treated rats (a CYP3A inducer), compared with microsomes obtained from untreated rats. Also, the recovery of material was improved when troleandomycin, a CYP3A inhibitor, was added to rhesus monkey microsomal incubations (25% more parent compound detected in the supernatant with 100 microM of troleandomycin). Using radiolabeled L-746,530 and gel electrophoresis analysis, it was confirmed that radiolabeled material was covalently bound to the microsomal protein. Incubations of L-739,010 and L-746,530 in the presence of semicarbazide resulted, in both cases, in the formation of two adducts. Using a combination of NMR, liquid secondary-ion MS, and UV techniques, these adducts were identified as isomers of an oxidized metabolite that had been trapped by semicarbazide. The site of oxidation was determined to be on the dioxabicyclo moiety. The importance of this moiety in the formation of reactive metabolite(s) was verified by incubating analogs of the 5-lipoxygenase inhibitors that contained blocking methyl groups at the proposed site of oxidation on the bicyclo moiety. Incubations of these gemdimethyl analogs of L-746,530 and L-739,010 with microsomes from different species resulted in significantly improved recovery of the starting material (approximately 94% in the rat, 85% in the dexamethasone-induced rat, 95% in humans, and 85% in the rhesus monkey for both compounds) and significantly less radioactive binding to the microsomal protein.