The renin-angiotensin system: it's all in your head

Components of the renin-angiotensin system (RAS) are expressed in a number of areas in the brain involved in cardiovascular control. However, it has been difficult to link RAS actions in circumscribed brain regions to specific physiological functions. In a study appearing in this issue of the JCI, Sakai and associates use a combination of sophisticated transgenic techniques and stereotaxic microinjection of recombinant viral vectors to demonstrate a pivotal role in the regulation of thirst and salt appetite of angiotensin II generated in the subfornical organ in the brain (see the related article beginning on page 1088).     

Illness understanding in children and adolescents with heart disease

AIMS—To evaluate illness knowledge and understanding in children and adolescents with congenital and acquired heart disease, and whether the degree of understanding is related to age, sex, or complexity of the heart disease.
DESIGN—Prospective cohort study.
SETTING—Tertiary paediatric cardiac centre.
METHODS—Patients' understanding of their congenital heart disease was assessed in a representative sample of volunteers aged between 7-18 years using semistructured interviews based upon Leventhal's illness representation model.
RESULTS—63 of 69 interviews were suitable for analysis. There were similar numbers of boys and girls and a wide distribution of heart defects. Only 30% of patients had a good understanding of their illness; 77% did not know the medical name of their condition, and 33% had a wrong or poor understanding of their illness. Understanding was unrelated to age, sex, or the nature of the heart disease. Understanding of illness duration was significantly related to age, but not to sex or to the nature of the disease.
CONCLUSIONS—Illness understanding is poor in children and adolescents with heart disease, and many have an entirely wrong concept of their disease. Intensified efforts to ensure better patient and parental understanding are needed.


Keywords: understanding illness; children; heart disease     

Drug levels in fatal cases where death was not directly attributable to drug toxicity

Forensic Toxicology -     

Calcium Influx,But Not Intracellular Calcium Release,Supports PACAP-Mediated ERK Activation in HEK PAC1 Receptor Cells

In HEK cells expressing GFP-tagged PAC1Hop1 receptors, PACAP augments ERK phosphorylation through two parallel pathways: one through PACAP/PAC1 receptor internalization/endosome MEK/ERK signaling and the other through PLC/DAG/PKC activation. We examined whether elevation of intracellular calcium ([Ca²⁺]_i) was required for either of the PACAP/PAC1 receptor-mediated ERK activation mechanisms. The PACAP (25 nM)-induced elevation of [Ca²⁺]_i was greater with cells maintained in Ca²⁺-containing than in Ca²⁺-deficient solution, suggesting that both calcium release from internal stores and calcium influx contributed to the rise in [Ca²⁺]_i. A thapsigargin-induced increase in [Ca²⁺]_i also was greater with calcium in the external solution. OAG, the cell permeable analogue of DAG, increased [Ca²⁺]_i, but only in Ca²⁺-containing solution. Decreasing external calcium or depleting internal calcium stores did not block PACAP-induced PAC1 receptor internalization. Omission of calcium from the external solution, but not thapsigargin pretreatment, significantly blunted PACAP-stimulated ERK phosphorylation. The PKC inhibitor BimI decreased PACAP-mediated ERK activation in both Ca²⁺-containing or Ca²⁺-deficient solutions. In contrast, following Pitstop 2 pretreatment to block endocytic mechanisms, PACAP activated ERK only when calcium was present in the external solution. We conclude that the endosome signaling pathway is largely calcium-independent whereas calcium influx appears necessary for the PLC/DAG/PKC component of PACAP-induced ERK activation.     

Bladder perforation during sling procedures: diagnosis and management of injury

Introduction and hypothesis

Midurethral slings are an effective and minimally invasive treatment for stress urinary incontinence. One of the most common intraoperative complications is bladder perforation, complicating between 2 and 10 % of all operations, and on average 4.7 %. It is usually corrected during surgery, with repositioning of the trocars. The purpose of this video is to demonstrate a method of replacing the trocars under direct vision.

Methods

This video exhibits a bladder perforation during insertion of a retropubic midurethral sling (Advantage Fit?; Boston Scientific) and gives a step-by step guide to the removal and repositioning of the sling under direct visualisation.

Conclusion

Repositioning of the trocars under direct vision in cases of bladder perforation may have numerous advantages. It may prevent damage to the urethra, possibly reduce the risk of postoperative infection and may be beneficial for trainees.     

Activation of Fyn tyrosine kinase upon secretagogue stimulation of bovine chromaffin cells

Adrenal medullary chromaffin cells derive from the neural crest during embryogenesis and differentiate into dedicated secretory cells that release catecholamines in response to acetylcholine in vivo or nicotinic agonists in vitro. Previous studies have indicated that tyrosine kinases participate in early secretagogue-induced events in these cells and are required for exocytosis. Abundant levels of the cytoplasmic tyrosine kinases, c-Src and c-Yes, have been detected in chromaffin cells, thereby implicating them as kinases relevant to these events. However, c-Src has been found to undergo a decrease in activity following secretagogue-stimulation, and c-Yes appears to exist in a constitutively low activity state, suggesting that other tyrosine kinases are involved. Furthermore, other members of the Src family of tyrosine kinases have been implicated as playing roles in secretion in a variety of cell types. Therefore, we sought to determine if other Src family members were present in chromaffin cells, and if so, to examine them for subcellular localization and changes in activity following treatment with nicotinic agonists. To this end, antibodies for Fyn, Lck, Lyn, and Fgr were assembled and used in immunoprecipitation, in vitro autokinase, and Western immunoblotting assays. Of these four kinases, only Fyn was found to be expressed at detectable levels. Differential centrifugation studies revealed that Fyn resides predominantly (>95%) in the crude plasma membrane fraction and undergoes nicotinic- and carbachol-induced activation. This activation is reduced by the nicotinic antagonist, mecamylamine, is not elicited by muscarine, and is dependent upon the presence of extracellular Ca²⁺. These results suggest that Fyn is involved in signalling through the nicotinic receptor and may be one of the relevant kinases responsible for at least some of the tyrosine phosphorylations detected after stimulation. © 1996 Wiley-Liss, Inc.