Antihypertensive mechanism of action of ketanserin and some ketanserin analogues in the spontaneously hypertensive rat

Summary Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)₂ receptors and at higher concentrations also to ₁-adrenoceptors. The present study was designed to evaluate the relative functional importance of the antagonism of ₁-adrenoreceptors and 5-HT₂-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration. In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker -adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat. The agents tested reduced the blood pressure only in a dose range where they blocked ₁-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses. 5-HT₂-receptor blockade alone did not influence basal blood pressure. However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced.It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an ₁-adrenoceptor blockade but that the 5-HT₂-receptor blockade contributes.Abbreviations 5-HT 5-hydroxytryptamine - SHR spontaneously hypertensive rat - SNS sympathetic nervous stimulation     

Placental transfer and fetal distribution of cadmium and mercury after treatment with dithiocarbamates

The distribution in pregnant C57BL mice (day 18 of gestation) of intravenously administered cadmium (Cd) chloride and mercury (Hg) chloride (0.75 mol/kg b.w.) was studied, with or without previous dithiocarbamate pretreatment. Diethyldithiocarbamate (DEDTC), disulfiram, or thiram (2×1 mmol/kg b.w.) or vehicle (gelatine) alone, were given by gavage 2 h before and immediately after injection of the metals. The mice were sacrificed 4 and 24 h later and subjected to autoradiography or impulse counting of excised organs.All the dithiocarbamates increased the concentration of both Cd and Hg in brain and most other maternal organs. While DEDTC and thiram, in that order, strongly increased Cd concentrations in whole fetuses (around 17-fold at 4 h) and all fetal organs measured, disulfiram caused a decrease in fetal Cd concentrations. For Hg, all the dithiocarbamates substantially decreased fetal levels. Disulfiram, for example, decreased Hg levels by a factor of 5. The 24 h values confirmed those at 4 h both elements, although the differences between control and treatment groups were less pronounced.Although the results suggest the formation of lipid-soluble metal-dithiocarbamate complexes in vivo (e.g., increased concentration in brain), this does not necessarily lead to increased fetal levels of the metals. The increased levels of Cd after thiram and DEDTC pretreatment, however, indicate a risk for higher Cd fetotoxicity. It is likely that Cd is released in fetal cells following metabolism of the dithiocarbamate moiety of the complex.     

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...     

Autologous regulatory T cells in clinical intraportal allogenic pancreatic islet transplantation

Allogeneic islet transplantation in type 1 diabetes requires lifelong immunosuppression to prevent graft rejection. This medication can cause adverse effects and increases the susceptibility for infections and malignancies. Adoptive therapies with regulatory T cells (Tregs) have shown promise in reducing the need for immunosuppression in human transplantation settings but have previously not been evaluated in islet transplantation. In this study, five patients with type 1 diabetes undergoing intraportal allogeneic islet transplantation were co-infused with polyclonal autologous Tregs under a standard immunosuppressive regimen. Patients underwent leaukapheresis from which Tregs were purified by magnetic-activated cell sorting (MACS) and cryopreserved until transplantation. Dose ranges of 0.14–1.27 × 10⁶ T cells per kilo bodyweight were transplanted. No negative effects were seen related to the Treg infusion, regardless of cell dose. Only minor complications related to the immunosuppressive drugs were reported. This first-in-man study of autologous Treg infusion in allogenic pancreatic islet transplantation shows that the treatment is safe and feasible. Based on these results, future efficacy studies will be developed under the label of advanced therapeutic medical products (ATMP), using modified or expanded Tregs with the aim of minimizing the need for chronic immunosuppressive medication in islet transplantation.     

Complications Following Swedish Adjustable Gastric Banding: A Long-Term Follow-up

Background: The Swedish adjustable gastric band (SAGB) has been in use since 1985. The aim of this study was to analyze short and long-term complications linked to the SAGB. Materials and Methods: Between August 1990 and December 1996, we operated on a series of 326 patients (78 men and 248 women) at the Huddinge University Hospital and the Norra ?lvsborg County Hospital. The mean age of patients at surgery was 40 years (range 19-62). The mean preoperative weight was 125 kg (range 81-181). The mean excess weight was 80%. Results: The mean time of follow-up was 28 months (range 6-76). Complications requiring reoperation included two (0.6%) band dislocations, six (1.8%) band leakages, and 16 (4.6%) band migrations-erosions. The most common reason for abdominal reoperation, band migration, was attributed to overfilling of the band system. In the patients in whom migration occurred, the bands had been filled with a mean volume of 12.6 ml fluid. In the remaining patients, the mean volume was 8.7 ml. The most common complication not requiring reoperation was reflux disease (4.7%). In cases with a small pouch, this complication did not seem to be a serious problem. The mean excess weight loss in the 296 patients without complications was 68%. Conclusion: The overall long-term complication rate following SAGB is reasonable. With improved operating technique and closer follow-up, it should be possible to reduce the complication rate further. Reoperation because of band migration appears to be related to overfilling of the system and should therefore be avoidable in most cases.     

Early diagnosis of Alzheimer dementia based on clinical and biological factors

Alzheimer’s disease (AD) is common in elderly individuals; it causes distress for the patients and their relatives as well as large costs for the society. With the advent of symptomatic treatment at present and probable etiology-based cures in the future, it will be possible to relieve and put an end to these negative effects. Therefore, it is necessary to diagnose the disease as early as possible. In this review, we briefly summarize the state-of-the-art concerning various available clinical and biochemical methods for identifying AD. Increasing age, heritage, and presence of ApoE e4 allele have been confirmed as risk factors for AD as well as some putative factors (e.g., low education, hypertension, hypotension) based on epidemiological recent research. Selective impairment of episodic memory has been found to be a preclinical marker for future development of AD based on convergent data from asymptomatic AD-related mutation carriers, longitudinal studies of patients with mild cognitive impairment (MCI), and epidemiological studies of incident AD cases. Neurophysiological methods are inexpensive and useful for the identification of changes in brain dysfunction in AD and new promising methods are under development. Using magnetic resonance imaging (MRT), structural measurements of brain atrophy and specific brain structures such as the hippocampus have been reported to detect dementia development early in the course of disease. Similarly, functional measurements of brain activity (e.g., blood flow) have revealed that hypometabolism in bilateral parietotemporal brain areas early in the disease course. Finally, biochemical studies have demonstrated that certain proteins (e.g., tau the Aβ_1-42/43 metabolite of the amyloid precursor protein) may be associated with the disease process in AD, although the specificity of these markers remains to be established. It is concluded that still no single marker of AD exists, which makes it necessary to rely on data from multiple sources in order to arrive at the best possible diagnosis of AD.     

Titration of human brain monoamine oxidase-A and-B by clorgyline andl-deprenil

Summary The interaction of clorgyline andl-deprenil with the-A and-B forms of human brain monoamine oxidase (MAO) has been studied. Both compounds inhibit cerebrocortical MAO in a manner consistent with a suicide inactivation of the enzyme. The interaction of clorgyline with the-A form of the enzyme appears to take place almost entirely at specific binding sites, and the conditions required for this inhibitor to titrate the concentrations of MAO-A have been elucidated.l-Deprenil has also been used to titrate the concentration of the-B form of MAO in cerebrocortical homogenates, but there is a considerable degree of non-specific binding of this compound. The two inhibitors have been used to titrate the concentrations of the two enzyme forms in frontal cortex homogenates from different age groups. There was a significantly higher MAO-B activity for the age range 73–95 years than for the age range 2–63 years. No significant differences between the two age groups were found for MAO-A. The activity of MAO-A in the samples correlated very well with the concentration of this enzyme form. Titration of the B-form of the enzyme withl-deprenil indicated an increased enzyme concentration with age, although other factors, such as the non-specific binding of this compound, could contribute to this effect.     

Quality of life: A model for evaluating Health for all. Conceptual considerations and policy implications

Summary The potential of the quality of life (QoL) concept lies in its basically positive meaning and interdisciplinary acceptance. This can be used when the Public Health sector tries to develop health into a resource concept, as is the intention of the WHO Health For All Strategy. Out of different scientific views on QoL this paper synthetises a theoretical framework of QoL and describes how this concept can be used in practice when evaluating the health resources of a population.

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Zusammenfassung Das Potential des Begriffs Lebensqualität liegt in der grundliegenden positiven Bedeutung und querwissenschaftlichen Anerkennung. Dieses kann von Nutzen sein, wenn das öffentliche Gesundheitswesen versucht, Gesundheit als einen Hilfsmittelbegriff zu entwickeln, welches das Ziel der Strategien von Gesundheit für Alle der WHO ist. Diese Abhandlung schafft einen theoretischen Rahmen aus verschiedenen wissenschaftlichen Anschauungen und beschreibt wie dieser Begriff praktisch in der Auswertung der Gesundheit der Bevölkerung angewendet werden kann.

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Résumé Le concept de qualité de vie a l'avantage de présenter à la base un sens positif et aussi une acceptation interdisciplinaire. Cela peut se révéler utile à un moment où la science de la santé publique essaie de développer la santé selon un concept de moyens et cela constitue un but parmi les directives de Santé pour Tous énoncés par l'OMS (Organisation Mondiale de la Santé). Cette présentation résume un cadre théorique concernant le concept de la qualité de vie, émanant de différentes interprétations scientifiques et montre aussi comment le concept peut être applicable à l'évaluation des ressources de santé dans une population.

     

Pre-operative and post-operative radiotherapy and rectal cancer

The appropriate role for additional radiotherapy in patients with resectable rectal cancer is not yet settled. Irradiation has been considered by surgeons and radiotherapists as superfluous since no effect on survival has been shown. However, numerous trials have demonstrated that perioperative radiotherapy decreases an often high local recurrence rate while others believe it has a definite place in routine management. Several surgeons have, on the contrary, claimed that a skilled surgeon compared to a less skilled surgeon, will get the same acceptably low local recurrence rates. Since we will probably never have a randomized trial comparing good and bad surgeons, this argument cannot be settled. A further obstacle arises in the difficulty of persuading surgeons to organize their routine work so that it is performed in an optimal way by those specializing in this field. The question also arises whether radiotherapy should be delivered pre-operatively, postoperatively or as a sandwich technique, i.e., both pre-operatively and postoperatively. According to radio-biological considerations and results from reported trials, the best effect on local tumor control has been achieved using pre-operative radiotherapy.

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Resumen Aún no se ha defindo la indicación apropriada para radioterapia adicional en pacientes con cáncer rectal. La irradiación ha sido considerada como superflua por cirujanos y radioterapeutas, puesto que no se ha demostrado efecto sobre la sobrevida. Sin embargo, numerosos ensayos clínicos han demostrado que la radioterapia perioperatoria disminuye la que con frecuencia es una elevada tasa de recurrencía local, mientras ostros creen que tiene un lugar definido en el manejo rutinario. Por el contrario, varios cirujanos han planteado que un cirujano hábil comparado con uno menos hábil, logra las mismas aceptables tasas de recurrencia, alg que jamás se ha decidido, puesto que nunca habremos de realizar ensayos comparando buenos cirujanos con malos cirujanos. Un obstáculo adicional surge de la dificultad en cuanto a persuadir a los cirujanos de organizar su trabajo rutinario de tal manera que sea realizado en forma óptima por aquellos que se especializan en este campo. También ha surgido el interrogante sobre si la radioterapia debe ser administrada preoperatoriamente, postoperatoriamente o como técnica de sandwich, o sea tanto pre como postoperatoriamente. Según consideraciones radio-biológicas y los resultados de los ensayos clínicos, el mejor efecto sobre el control local del tumor ha sido logrado mediante el uso de radioterapia preoperatoria.

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Résumé La place de la radiothérapie adjuvante chez les patients ayant un cancer du rectum reste discutée. La radiothérapie est estimée superflue par certains chirurgiens et radiothérapeutes car aucun bénéfice n'a eté clairement démontré en ce qui concerne la survie. De nombreux essais cliniques ont indiqué, cependant, que la radiothérapie périopératoire diminuait le taux habituellement élevé des récldives locales, et certains estiment que la radiothérapie a toujours une place dans le schéma thérapeutique. D'autres, au contraire, croient que la quialité et l'expérience de l'opérateur influencent directement le taux de récidives, et équivalent l'efficacité de la radiothérapie. Puisqu'il est peu probable qu'on réalise une étude randomisée entre les bons et les mauvais chirurgiens, on ne peut régler cette querelle. Un autre obstacle incontournable semble être de persuader les chirurgiens d'organiser leur travail de façon à ce que cette chirurgie soit faite par des spécialistes. Le meilleur moment pour réaliser la radiothérapie (préopératoire, postopératoire, ou les deux) reste à déterminer. Selon les données radiobiologiques et les résultats des essais contrôlés, il semble que le meilleur contôle sur les récidives locales soit obtenu par la radiothérapie préopératoire.

     

Embryotoxicity of chromium: Distribution in pregnant mice and effects on embryonic cells in vitro

The embryonic and fetal uptake of Na₂ ⁵¹Cr₂O₇(Cr VI) was about 10 times higher than that of ⁵¹CrCl₃(Cr III) when these two were given in the same doses i. v. to pregnant C57BL mice. On day 13 of gestation, embryonic concentrations were 12% (Cr VI) and 0.4% (Cr III) of the maternal serum concentration 1 h after injection to the mother. After injection of Cr(III) radioactivity was not detectable in embryonic structures in early gestation, when autoradiographic techniques were used. In late gestation, administration of both forms of Cr resulted in an accumulation in the calcified areas of the fetal skeleton. The radioactivity after administration of Cr(VI) may represent Cr(III) after reduction in the tissues. When added to chick limb bud mesenchymal cells in vitro, Cr(VI) inhibited chondrogenesis at a concentration of about 0.1 g/ml medium, which is around 1/10 of the embryonic concentration achieved after giving teratogenic doses to pregnant mice. Cr(III) on the other hand did not show any overt cytotoxicity even at 15 g/ml ( 500 times higher than the in vivo embryonic concentrations after teratogenic doses). Especially Cr(III) accumulated strongly in the visceral yolk sac, probably after binding to and transport by maternal serum proteins. The possibilities that Cr(III) excerts its teratogenic action by inhibiting embryotrophic nutrition is discussed.