Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents

This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.     

Calcium compartmentation in cardiac tissue culture: the effects of extracellular sodium depletion

The effect of extracellular sodium depletion upon cellular calcium distribution in myocardial tissue culture is studied with the use of sucrose or lithium chloride as substitutes for sodium. With sucrose substitution more than 50% of the increase in calcium at the cellular surface secondary to [Na]0 depletion is probably localized to a screening layer with the remainder bound to the sarcolemma of the cell. Calcium distribution (sucrose substituted) is studied under three different perfusion conditions: (1) In HEPES-buffered perfusate (pH = 7.1-7.35) the 113% gain in Ca at the cellular surface upon 33 mM [Na]0 perfusion is rapidly exchangeable, completely lanthanum (La) displaceable and more than 90% reversible. 5 X 10(-5) verapamil does not affect the response. (2) In 10 mM Pi (phosphate) solution at pH = 7.15, in which a slowly exchangeable mitochondrial Ca compartment is added, the gain in Ca after low [Na]0 is again rapidly exchangeable and 85% reversible that is, similar to the response in HEPES-buffered solution. (3) In 10 mM Pi solution at pH = 7.35 in which slow phase calcium uptake in 133 mM [Na]0 is increased, the initial rapid Ca response to low [Na]0 is similar to that in (1) and (2) but the slow phase uptake rate is further increased by 3.75 times. The major portion of this uptake is not reversible upon return to 133 mM [Na]0. The results distinguish two markedly different effects of [Na]0 depletion in tissue culture dependent upon the pre Na-depletion state of Ca compartmentation: (1) Addition of almost all the calcium to rapidly exchangeable sites at the cellular surface when exchange is limited to these sites and to mitochondria. (2) Further addition of calcium to more slowly exchangeable cellular site(s) when slow phase uptake is increased, by elevation of Pi at pH = 7.35, prior to low [Na]0 perfusion.     

Pegylated asparaginase in combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in first remission: a pilot study

The German Multicentre acute lymphoblastic leukaemia (ALL) study group (GMALL) performed a pilot study using pegylated asparaginase (PEG-ASP) in combination with high-dose methotrexate as consolidation therapy in the 05/93 protocol. The aim of the study was an intra-individual comparison of two different doses of PEG-ASP in 26 patients, with regard to the depletion of asparagine in serum and toxicity. 'Pharmacokinetic' monitoring was performed to evaluate the effect of an intra-individual dose escalation of PEG-ASP from 500 to 1000 U/m2 intravenously in successive doses. Serum asparaginase activity was targeted at > or =100 U/l for 1 week and > or =50 U/l for 10 d. The second course of PEG-ASP was administered to 23 patients. Due to hypersensitivity reactions in five patients, only 18 patients were evaluable for pharmacokinetic monitoring. With respect to the PEG-ASP activity, an effective depletion of asparagine could be postulated in the majority of patients during 10 d after the first administration. The effect of an intraindividual dose escalation form 500 to 1000 U/m2 was evaluable in 17 of 22 patients. An increment in peak PEG-ASP activity >70% was observed in 65% of the patients. PEG-ASP was well tolerated. Despite the long half-life of PEG-ASP, neither pancreatic nor central nervous toxicities occurred among the 26 adult patients treated in this pilot study.     

A qualitative study of patient choices in using emergency health care for long-term conditions: The importance of candidacy and recursivity

Objective

We aimed to explore how patients with long-term conditions choose between available healthcare options during a health crisis.

Methods

Patients in North-West England with one or more of four long-term conditions were invited to take part in a questionnaire cohort study of healthcare use. Semi-structured interviews were conducted with a sub-sample of fifty consenting patients. Data were analysed qualitatively, using a framework approach.

Results

Patients described using emergency care only in response to perceived urgent need. Their judgements about urgency of need, and their choices about what services to use were guided by previous experiences of care, particularly how accessible services were and the perceived expertise of practitioners.

Conclusion

Recursivity and candidacy provide a framework for understanding patient decision-making around emergency care use. Patients were knowledgeable and discriminating users of services, drawing on experiential knowledge of healthcare to choose between services. Their sense of ‘candidacy’ for specific emergency care services, was recursively shaped by previous experiences.

Practice implications

Strategies that emphasise the need to educate patients about healthcare services use alone are unlikely to change care-seeking behaviour. Practitioners need to modify care experiences that recursively shape patients’ judgements of candidacy and their perceptions of accessible expertise in alternative services.     

3D skull modelling and description of a new baurusuchid (Crocodyliformes,Mesoeucrocodylia) from the Late Cretaceous (Bauru Basin) of Brazil

Baurusuchidae is one of the most diverse groups of South American notosuchians, unambiguously recorded in Late Cretaceous deposits of Brazil and Argentina. The group is characterized by a reduced tooth formula, a lateromedially compressed rostrum, and a verticalized quadrate, representing one of the top predators of their faunas. Historically, skull morphology is the most employed tool to investigate the relationships of baurusuchids, as most of the species have been primarily based on cranial remains. The present study describes a new baurusuchid species from the Bauru Basin of Brazil, based on the first tridimensional digital reconstruction of individualized skull bones for Notosuchia, and discusses its phylogenetic position within the group. The new species differs from all the other known baurusuchids by a depression on the posterior portion of the nasal bearing a crest, an infraorbital crest of the jugal that extends until the anterior margin of the lacrimal, the dorsal surface of the frontal lacking a longitudinal crest or depression, and the lateral convexity of the squamosal prongs participating in the occipital wall. The new taxon is consistently positioned as sister to the remaining baurusuchines, with Aplestosuchus sordidus and Stratiotosuchus maxhechti, as successive sister-taxa to a monophyletic Baurusuchus (Ba. albertoi, Ba. Salgadoensis, and Ba. pachecoi). Our updated phylogenetic analysis helps to differentiate the two major Baurusuchidae lineages, Baurusuchinae and Pissarrachampsinae. Yet, the new species shares morphological features with both groups, suggesting the occurrence of “Zones of Variability” in the radiation of Baurusuchidae.     

Enzymatic modification of plasma low density lipoproteins in rabbits: a potential treatment for hypercholesterolemia.

Phospholipase A2 (EC 3.1.1.4) hydrolyzes certain phospholipids of low density lipoprotein (LDL). Plasma clearance of phospholipase A2-modified human LDL is up to 17 times faster than that of native human LDL in hypercholesterolemic rabbits. Modification of blood lipoproteins of hypercholesterolemic rabbits was performed by using an extracorporeal circuit containing immobilized phospholipase A2. After 90-min treatments, nearly 30% decreases in plasma cholesterol concentrations were observed. Erythrocyte, leukocyte, and platelet counts showed no net change after treatment. This technique does not require any fluid replacement or sorbent regeneration and offers a potential approach for lowering serum cholesterol and LDL levels.     

Frequent methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene in pancreatic endocrine tumors

Molecular mechanisms contributing to the tumorigenesis of pancreatic endocrine tumors (PETs) are still not well understood. Allelic deletions at chromosome 22q12.3 were detected in about 30-60% of PETs, suggesting that inactivation of one or more tumor suppressor genes on this chromosomal arm is important for their pathogenesis. Because the putative tumor suppressor gene tissue inhibitor of metalloproteinase-3 (TIMP-3) has been located at 22q12.3, we undertook a genetic analysis of TIMP-3 to determine its role in the tumorigenesis of PETs. Single-strand conformational polymorphism analysis, methylation-specific PCR, RNA expression analysis, and immunohistochemistry of TIMP-3 were performed in 21 sporadic PETs. Thirteen of 21 PETs (62%) revealed TIMP-3 alterations, including promoter hypermethylation and homozygous deletion. The predominant TIMP-3 alteration was promoter hypermethylation, identified in 8 of 18 (44%) PETs. It was tumor-specific and corresponded to loss or strong reduction of TIMP-3 protein expression. Notably, 11 of 14 (79%) PETs with metastases had TIMP-3 alterations, compared with only 1 of 7 (14%) PETs without metastases (P < 0.02). These data suggest a possibly important role of TIMP-3 in the tumorigenesis of human PETs, especially in the development of metastases, which has to be further evaluated in large-scale studies.     

Frequency and clinicopathological features of fibroelastotic changes in the gastrointestinal tract

Fibroelastotic changes (FEC) and especially elastotic polyps of the gastrointestinal (GI) tract are considered rare benign lesions. They consist of accumulations of elastic fibers within the mucosal, submucosal, or muscular layer, occurring in all parts of the GI tract and often appearing as polyps, but also as diffuse non-polyp-forming deposits. They have been the subject of only a few studies. To explore the clinical and histopathological features of FEC in the GI tract, a series of 162 elastotic lesions was collected within a 2-year period. The clinical data and endoscopic findings were correlated. FEC appeared as polyp-forming lesions of the large intestine in 23 samples (14 %), all other samples concerning histological findings without an identifiable gross mass. Frequently related findings were postinterventional status (9 %), previous irradiation (7 %), and history of GI lymphoma (4 %). Eight samples (5 %) presented endoscopically with lesions justifying surgical intervention. We identified three different histological patterns of FEC, which we have called fibroelastosis, angioelastosis, and elastofibroma. Consistent with previous studies, CD34 immunohistochemical staining (performed on 38 polypoid FEC specimens) showed an increase of CD34-positive mesenchymal cells in 95 % of immunostained samples, suggesting a potential role for CD34-positive mesenchymal cells in the accumulation of elastic fibers. In conclusion, FEC are more common in the GI tract than previously recognized. They often present as a benign polyp. Many accompany other diseases like ulcers and atrophic gastritis or represent a residual finding after an intervention.