Mode of action of cholecystokinin octapeptide on smooth muscles of stomach, ileum and gall bladder

Mechanical activity of preparations isolated from canine and guinea-pig stomach, ileum and gall bladder was recorded. At least 2 strips were cut out from each organ and investigated simultaneously in thermostatically controlled organ baths. Responses to acetylcholine (ACH) were used for comparison. Octapeptide of cholecystokinin (CCK-OP) at concentrations of 5 X 10(-11) M to 10(-8) M produced dose-dependent tonic concentrations in all muscle strips and showed a higher affinity but lower efficacy as compared to ACH. Atropine (10(-7) M 10(-5) M) had no effect on the CCK-OP responses in stomach and gall bladder muscle strips but it significantly decreased the CCK-OP responses in ileum muscle strips. Dibutyryl cyclic GMP (dbc GMP) at concentrations of 10(-5) M-5 X 10(-4) M did not change the ACH dose-response curves but shifted to the right in parallel to the control the dose-response curves for CCK-OP in all muscle preparations with pA2 values 5, 5.3, 7.2, and 6 for canine stomach and guinea-pig stomach, ileum and gall bladder, respectively. Michaelis-Menten's analysis suggested a competitive type of interaction of dbc GMP on CCK-OP contractile responses of guinea-pig ileum and gall bladder; at a higher concentration (5 X 10(-4) M) the antagonistic effect of dbc GMP in canine and guinea-pig stomach appeared to be a mixed or uncompetitive type. The data suggest that the contractile effects of CCK-OP in the iliac smooth muscle are caused by cholinergic and direct mechanisms whereas on the gall bladder and gastric smooth muscles by direct myogenic mechanisms only.     

Importance of the breathing manoeuvre in detecting mild air flow obstructions in a lung function screening.

Maximal expiratory flow-volume curves (MEFVC) were recorded in 610 workers using two different breathing manoeuvres. Inspiration in one was forced and maximal, while in the other, it was slow and maximal. In both manoeuvres, the ventilatory function was defined according to the diagnostic classification proposed by I. Kirin. Two groups of workers with mild obstructive changes were found. In one group, we diagnosed a condition defined as transitional state to obstructive ventilatory disorder (Tr.OVD) using both manoeuvres. In the second group, we detected normal lung functions using one of the breathing manoeuvres while the other manoeuvre disclosed Tr.OVD. In the second group, the relative share of workers scoring below the lower limits on the test of Tiffeneau was significantly lower than in the first group. Instantaneous flows also were significantly lower in the second group. Also, the FEV1, FEV1/FVC and MEF25-75% were significantly higher in the second group. The results showed that obstructions were milder in the second group than in the first. A new approach is suggested to detect obstructions milder than Tr.OVD. This approach would be practical for use in mass epidemiological screening studies because its performance does not require complicated equipment.     

Angiogenesis is an early event in the development of chemically induced skin tumors

In this study we have analyzed the vascular response induced in the two- stage carcinogenesis model in SENCAR mice. The role of angiogenesis has not been explored in this model, which is the paradigm of multistage carcinogenesis and a model for neoplastic lesions derived from exophytic premalignant lesions (e.g. colon carcinoma, bladder papilloma). We investigated if angiogenesis is involved in the formation of papillomas and in the progression from papilloma to carcinoma. To this end we analyzed the vasculature of normal and hyperplastic skin, focal epidermal hyperplasias that are precursors of papillomas, papillomas at different stages and squamous cell carcinomas. We also analyzed the vascularization of papillomas induced in two strains of mice that differ in their susceptibility to malignant progression. We show here that angiogenesis is turned on in the earliest stages of papilloma formation. In late stages, regardless of state of progression, the predominant response is an increase in the size of blood vessels. Thus, in the SENCAR mouse model, representative of exophytic tumors, the angiogenesis switch is a very early event, probably mechanistically related to the development of the primarily exophytic lesions. Therefore, the density of blood vessels cannot be used as a predictor of malignant progression in this model.      

Prognostic significance of urokinase plasminogen activator receptor and its cleaved forms in blood from patients with non‐small cell lung cancer

Urokinase plasminogen activator (uPA) cleaves its three‐domain cell surface receptor, uPAR, liberating domain I [uPAR(I)] and leaving the cleaved uPAR(II‐III) on the cell surface. Both intact and cleaved uPAR can be shed from the cell surface. uPAR(I) was previously shown to be a prognostic factor in lung tumour extracts. Here we analyse uPAR forms in blood from patients with non‐small cell lung cancer (NSCLC). Preoperatively sampled plasma/serum from 32 patients with NSCLC was analysed. Three time‐resolved fluoroimmunoassays (TR‐FIAs) measuring intact uPAR(I‐III) (TR‐FIA 1), uPAR(I‐III) + uPAR(II‐III) (TR‐FIA 2) and uPAR(I) (TR‐FIA 3) were applied. The Spearman rank correlations between plasma and serum levels of uPAR(I‐III), uPAR(I‐III) + uPAR(II‐III), and uPAR(I) were 0.89, 0.94 and 0.68 respectively. Survival analysis demonstrated that high levels of all uPAR forms were associated with shorter survival. Adjusted for histological subtype high plasma uPAR(I‐III) and uPAR(I) levels as well as serum uPAR(I) levels were significantly associated with shorter OS (hazards ratios = 4.3, 2.8 and 3.8 respectively). High blood levels of intact uPAR and its cleaved forms are associated with poor prognosis in NSCLC.     

Quantitative structure-activity relationship (QSAR) and three-dimensional QSAR analysis of a series of xanthates as inhibitors and inactivators of cytochrome P450 2B1

1. Various xanthates (R-OCS2) were found to be mechanism-based inactivators of cytochrome P450 2B1 (CYP2B1) and CYP2B6 via formation of reactive metabolites. 2. In the present study, quantitative structure-activity relationships (QSARs) were derived with inhibitory and inactivation potencies of 15 xanthates (R = two to 20 methylene groups, allyl, cyclohexyl or O-tricyclo[5.2.1.0(2,6)]dec-9-yl (D609)) against purified, reconstituted rat liver CYP2B1. Factor, regression and comparative molecular field analyses (CoMFA) were used. 3. The compounds formed two groups whose activities depended on different structural features: the first group consisted of compounds with ethyl, propyl, allyl, cyclohexyl and D609 substituents; the second involved compounds with eight to 20 methylene groups. 4. High correlation between the molecular volume and inhibitory potency of the xanthates of the second group was found. The inactivation potency in the first group correlated with the charge of the first carbon atom of R, identifying this atom as a potential target for metabolic attack. A decrease in the inactivation potency with an increase in the size of R was observed in the second group. This finding could be explained by a decreased rate of metabolism of the long alkyl chain compounds and/or by difficulty in binding of the resulting metabolite(s) to the enzyme molecule.     

A clinical and epidemiologic study morsicatio buccarum/labiorum

abstract – A study of habitual self mutilation of the buccal and/or labial mucosa by biting was conducted on 8,589 persons attending the Royal Dental College, Copenhagen. Forty-two cases were found. The youngest patient was 5 years old and the oldest was 47. The condition occurred most frequently (1.77%) among persons aged 15–19 years. There was no difference in prevalence between males and females. Combined mutilation of cheek(s) and lip(s) was more frequent (62%) than isolated mutilation of the cheek(s) (24%) or isolated mutilation of the lip(s) (14%). Bilateral biting of the cheeks was more frequent than unilateral biting, and biting of the lower lip was more frequent than biting of the upper lip. Ninety-three per cent of the patients were aware of their habit, and most of them stated that they had been biting for years. Twenty patients were re-examined; in all but one patients the biting persisted but in 7 patients the location of the lesions had changed. In several cases a link could be traced to personal problems and mental stress. It was further noticed that many patients were students and white-collar workers, suggesting that "intellectual" work may predispose for the habit.