What — if any — is the role of adrenergic mechanisms in histamine release from mast cells?

The effects of catecholamines on histamine release from rat peritoneal mast cells, was studied in an in vitro system. It was found that norepinephrine (10^–5–10^–3 M) exerts a significant, dose related, repressive effect on compound 48/80-induced histamine release. This effect is greatly potentiated by -antagonists and is noticeable throughout the concentration range 10^–11–10^–3 M norepinephrine. Phentolamine diminishes the repressive effect that norepinephrine shows at 10^–5 M.Norepinephrine (10^–5 M) totally inhibits the progressive histamine release induced by both compound 48/80 and strontium (10 M) in non-Ca²⁺-depleted cells. The release that is dependent on extracellular calcium is inhibited by norepinephrine.The repressive effect of norepinephrine at 10^–3 is counteracted by 5.6 mM d-glucose, 2-deoxyglucose abolishes this effect. The repression of histamine release by 10^–5 M norepinephrine is not influenced byd-glucose.These results suggest that the effects on histamine release, observed within a low concentration range of norepinephrine (<10^–3 M), may be due to -adrenoreceptor mechanisms and an interference in transmembrane calcium transport. Our data further suggest that norepinephrine at 10^–3 M may inhibit oxidative phosphorylation.Isoproterenol and epinephrine (10^–9–10^–5 M) show little effect on 48/80-induced histamine release in a normal medium. However, when calcium is excluded from the medium, histamine release is potentiated. These results seem to indicate that isoproterenol and epinephrine act by displacing intracellular calcium, making it available for the exocytosis process.     

Value appropriation in hepatitis C

The European Journal of Health Economics - In 2015, the Swedish government in an unprecedented move decided to allocate 150 million € to provide funding for new drugs for hepatitis C. This...     

Fibrodysplasia ossificans progressiva: Still turning into wood after 300 years?

Fibrodysplasia ossificans progressiva (FOP), a rare autosomal dominant disorder, is characterized by symmetrical congenital skeletal abnormalities and progressive heterotopic ossification of the connective tissues. At present, more than 300 years after the first report by Patin in 1648 in which he described the woman who turned to wood, its pathogenesis remains largely unknown and its therapy is limited to symptom-modifying trials. However, significant progress has been recently made and new data on the molecular organization and regulation of normal and disordered bone induction are likely to lead to a more specific therapy. FOP is believed to be a genetic disorder characterized by a disturbed expression of the endochondral osteogenesis programme, and the remarkable clues from the fly reported by Kaplan et al. [8] in 1990 suggest a gain-of-function mutation in the genetic regulation of bone morphogenetic proteins.     

Interspecies differences in the kinetic properties of deoxycytidine kinase elucidate the poor utility of a phase I pharmacologically directed dose-escalation concept for 2-chloro-2′-deoxyadenosine

2-Chloro-2-deoxyadenosine (CdA, Cladribine), is a purine antimetabolite currently under investigation in phase II clinical trials for the treatment of lymphoid malignancies. Significant differences in CdA toxicity between mice and humans were observed during phase I clinical evaluation. For the elucidation of interspecies differences in drug toxicity the pharmacokinetics of CdA after subcutaneous injection and the kinetic properties of the CdA-phosphorylating enzyme, deoxycytidine kinase (dCK), were compared in mice and humans. The ratio of the dose lethal to 10% of mice (LD₁₀) to the maximum tolerated dose (MTD) in humans was 50 and the ratio of the area under the curve obtained at approximately one-half the LD₁₀ (AUC_{approx. one-half the LD 10})/AUC_MTD was 49. A significant interspecies difference was observed in the kinetic properties of dCK, the main CdA-activating enzyme. With CdA as a substrate, the Michaelis constant (K _m) of dCK in crude extracts of mouse thymus was 10 times higher than that in human thymus. An approximately 9-fold interspecies difference in maximum velocity (V_max)/K _m indicated a higher efficiency of dCK for CdA in humans than in mice. The peak plasma concentration was 210 times higher and exceeded theK _m in mice. Initial and terminal half-lives were approximately 7 times shorter in mice and trough levels were similar in mice and humans. Thus, the differences in AUCs at equitoxic doses are largely explained by differences in the target enzyme properties and the pharmacokinetic pattern. The observed lower tolerance for CdA in humans as compared with mice confirms the view that antimetabolites may not be good candidates for pharmacokinetically guided dose-escalation schemes unless detailed information on interspecies variability in drug bioactivation is available.     

Diagnostic outcome of repeated mammography screening

Mammographic screening for breast cancer within health service routines was evaluated for the years 1987–1992, with special focus on repeated screening during 1989–1992. The overall attendance rate by women aged 40 to 74 years was 82.8%. During 1989–1992 malignancy was found in 2.6/1000 screened women, giving a 87.4% positive predictive rate at surgery and 95.9% efficiency. Among women aged 45, the positive predictive rate was >94%. Fine-needle aspiration (FNA) biopsy showed invasive cancers in 84% and highly suspected cancer in another 15%; 60% of the lesions were nonpalpable. For first-time (prevalence) screening (1987–1988) the positive predictive rate was 86% and the malignancy yield 6.4/1000. In women aged 40–44 years there were few surgical referrals (1.6%), but the positive predictive rate at surgery was only 48.3%, indicating diagnostic difficulties in young women. The median size of all invasive cancers was 12 mm: 84% were classified as pT1, and 23% had lymph node involvement. Stage II disease was found in 27% of all malignancies. The use of FNA in the diagnostic workup for breast cancer screening is of crucial importance to the maintenance of high positive predictive rates at surgery. Moreover, regular analysis is important even when mammographic screening is incorporated into the routine work of health services.

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Resumen El tamizaje mamográfico para cáncer del seno como parte de las rutinas de los servicios de salud fue evaluado para los años 1987–1992, con especial énfasis en el tamizaje repetido en el período 1989–1992. La tasa de cumplimiento por parte de las pacientes en las edades 40–74 años fue de 82.8%. En 1989–92 se halló neoplasia maligna en 2.6/1000 mujeres tamizadas, lo cual significó un índice de predicción de positividad en la cirugía de 87.4% y de eficiencia de 95.9%. Entre las mujeres con edad 45 años el valor de predicción de positividad fue >94%. La biopsia por aspiración con aguja fina demostró cánceres invasores en 84% y alta sospecha de cáncer en un 15% adicional; 60% de las lesiones fueron no palpables. En el tamizaje de primera vez (prevalencia, 1987–1988) el valor de predicción de positividad fue de 86% y el rendimiento de 6.4/1000. En las mujeres con edades 40–44 años se hicieron menos referencias para cirugía (1.6%) pero el valor de predicción de positividad en la cirugía fue apenas de 48.3%, lo cual indica dificultades diagnósticas en las pacientes más jóvenes. El tamaño promedio de los cánceres invasores fue 12 mm; 84% fueron clasificados como pT1 y 25% presentaban invasión ganglionar; 27% de todos los tumores malignos fueron estado II. La aspiración con aguja fina en la evaluación diagnóstica del tamizaje para cáncer mamario es de importancia crucial para el mantenimiento de un alto valor de predicción de positividad en la cirugía y el análisis regular es importante aun cuando el tamizaje mamográfico quede incorporado en el trabajo rutinario de los servicios de salud.

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Résumé Le dépistage systématique des cancers du sein par mammographie effectuée par les services de santé a été évalué entre 1987–1992, en particulier le dépistage répété pratiqué entre 1989–1992. Le taux de participation des femmes âgées entre 40–74 ans a été de 82.8%. Dans la période 1989–1992, une tumeur maligne a été retrouvée chez 2.6/1000 femmes, la chirurgie permettant de calculer une valeur prédictive positive de 87.4% et une efficacité de 95.9%. Chez les femmes âgées de plus de 45 ans, la valeur prédictive positive a dépassé 94%. La ponction biopsie a fourni la preuve de cancer invasif dans 84% des cas et celle d'une forte suspicion dans 15% des cas, alors que 60% des lésions n'étaient pas palpables. Par comparaison, la valeur prédictive positive pendant la période de dépistage entre 1987–88 a été de 96% pour une prévalence de cancer de 6.4/1000. Chez la femme âgée entre 40–44 ans, très peu de femmes ont été opérées, avec une valeur prédictive positive de 48.3%, ce qui démontre les difficultés de diagnostic chez la femme jeune. La taille médiane de tous les cancers invasifs était de 12 mm: 84% étaient classés comme pT1 et 23% avaient un envahissement lymphatique. On a trouvé un stade II chez 27% des patientes tous cancers confondus. L'utilisation de ponction biopsie est capitale pour le diagnostic de cancer de sein pour maintenir une valeur prédictive positive élevée lors de la chirurgie et une analyse régulière est nécessaire même lorsque le dépistage systématique par mammographie est inclu dans le programme des service de santé.

     

Hepatitis B vaccine and liver problems in U.S. children less than 6 years old, 1993 and 1994

Data to assess the benefits and risks of hepatitis B vaccine for the general population of U.S. children are sparse. This study addressed the problem of external validity found in previous studies of high risk populations by evaluating the benefit of hepatitis B vaccination for the general population of American children. We calculated the risk of liver problems among hepatitis B vaccinated and non-hepatitis B vaccinated children using logistic regression. Hepatitis B vaccinated children had an unadjusted odds ratio of 2.94 and age-adjusted odds ratio of 2.35 for liver problems compared with non-hepatitis B vaccinated children in the 1993 National Health Interview Survey. Hepatitis B vaccinated children had an unadjusted odds ratio of 2.57 and age-adjusted odds ratio of 1.53 for liver problems compared with non-hepatitis B vaccinated children in the 1994 National Health Interview Survey dataset.     

Comparison of observer reliability in assessing alveolar bone changes from color-coded with subtraction radiographs

OBJECTIVES: To assess intra- and interobserver agreement on marginal changes in periodontal bone from color-coded compared with subtraction radiographs. METHODS: Sequential radiographs from patients undergoing periodontal treatment were acquired using direct digital intra-oral radiography. Fifty-one pairs of color-coded and subtraction radiographs were produced and evaluated twice by six dentists for changes in marginal bone. Intra- and interobserver agreement were calculated. RESULTS: Intra-observer agreement was significantly higher for the color-coded radiographs (P < 0.05). Interobserver agreement was significantly higher for color-coded radiographs at the second (P < 0.001) but not the first (P = 0.34) evaluation. CONCLUSIONS: Color coding of radiographic differences by means of image addition may be a feasible alternative to the subtraction technique for evaluating periodontal bone changes.     

MDA in plasma as a biomarker of exposure to pyrolysed MDI-based polyurethane: correlations with estimated cumulative dose and genotype for N-acetylation

The object of this study was to investigate whether exposure of pipe-layers to thermal degradation products of diphenylmethane diisocyanate (MDI) could be assessed by analysing 4,4-methylenedianiline (MDA) in hydrolysed plasma and urine, and whether the genotype for N-acetylation affected these biomarker levels. Blood and urine samples were drawn from 30-pipe-layers who had been welding polyurethane (PUR) insulated pipes during the preceding 3 months. MDA in hydrolysed plasma and urine was determined with a gas chromatography-mass spectrometry technique, and genotype for N-acetylation was analysed with a polymerase chain reaction technique. MDA in plasma was detected in 18 of the 30 pipe-layers. Their plasma concentrations of MDA varied from 0.05 to 8.48 g/1. There was a significant negative correlation between time since last welding of PUR-insulated pipes and P-MDA (r _s = 0.50, P = 0.005). There was also a significant positive correlation between the estimated number of welded PUR-insulated pipes during the preceding 3 months and P-MDA (r _s = 0.68, P = < 0.001). No significant association between genotype of N-acetylation and P-MDA was observed in a multiple regression analysis when adjustment was made for the estimated cumulative exposure to thermal degradation products of MDI. MDA in urine was detected in only four of the 30 pipe-layers. These four subjects had been welding PUR pipes on the same day as the sampling, or on the day before. The present results indicate the spot plasma samples analysed for MDA may give a rather good estimate of exposure to MDI during the preceding months. P-MDA, but not U-MDA, therefore seems to be a useful biomarker of long-term exposure to MDI. The individual N-acetylation capacity did not affect the plasma levels of MDA.     

Biological monitoring of isocyanates and related amines

Summary Five men were exposed to toluene diisocyanate (TDI) atmospheres for 7.5 h. The TDI atmospheres were generated by a gas-phase permeation method, and the exposures were performed in an 8-m3 stainless-steel test chamber. The mean air concentration of TDI was ca. 40 g/m³, which corresponds to the threshold limit value (TLV) of Sweden. The inhaled doses of 2,4- and 2,6-TDI were ca. 120 g. TDI in the test chamber air was determined by an HPLC method using the 9-(N-methyl-aminomethyl)-anthracene reagent and by a continuous-monitoring filter-tape instrument. After hydrolysis of plasma and urine, the related amines, 2,4- and 2,6-toluenediamine 2,4-, and 2,6-TDA), were determined as pentafluoropropionic anhydride (PFPA) derivatives by capillary gas-chromatography using selected ion monitoring (SIM) in the electron-impact mode. The urinary elimination of the TDAs showed a possible biphasic pattern, with rapid first phases for 2,4-TDA (mean t _1/2 for the concentration in urine, 1.9 h) and for 2,6-TDA (mean t _1/2 for the concentration in urine, 1.6 h). The cumulative amount of 2,4-TDA excreted in urine within 28 h ranged from 8% to 14% of the estimated dose of 2,4-TDI, and the cumulative amount of 2,6-TDA in urine ranged from 14% to 18% of the 2,6-TDI dose. The average urinary level of 2,4-TDA was 5 g/l in the 6 to 8-h sample (range 2.8–9.6 g/l), and the corresponding value for 2,6-TDA was 8.6 g/l (range, 5.6–16.6 g/l). Biological monitoring of exposure to 2,4- and 2,6-TDI by analysis of 2,4- and 2,6-TDA in urine is feasible.