Opioid agonist affinity in the guinea-pig ileum and mouse vas deferens

The affinity of morphine, normorphine, methadone, Tyr-D-Ala-Gly-MePhe-NH(CH2)2(N-O)(CH3)2 (RX 783030), [D-Ala2,D-Leu5]enkephalin (DADLE), ketazocine and ethylketocyclazocine (EKC) were determined for their pharmacological receptors in two bioassay tissues, the guinea-pig ileum and the mouse vas deferens (MVD). The method involved the use of the irreversible antagonist, beta-chlornaltrexamine (beta-CNA), and the method of partial receptor blockade. The agonist concentration-effect curves were displaced to the right with decreasing maximum effect, a pattern typical of partial, irreversible blockade of receptors. The concentrations of beta-CNA required to produce a rightward displacement in the concentration-effect curves for different agonists, ranged between 2 and 3000 nM. No similarity was found between the IC50 and the dissociation constant (KA), values predicted to be equivalent only if a linear relationship exists between receptor occupation and observed effect; the dissociation constant for the agonists were between 3 and 218 times larger than the IC50 values. When methadone was used as the agonist in the guinea-pig ileum, beta-CNA produced parallel displacement of the concentration-effect curve, regardless of the blocking concentration chosen, preventing the determination of KA for this agonist, in this tissue; this problem was not encountered in the mouse vas deferens. The KA of morphine, RX 783030 and ketazocine were found not to differ in the guinea-pig ileum and mouse vas deferens. As expected, DADLE had significantly different affinity in the two tissues, showing 117-fold lower affinity in the guinea-pig ileum. Surprisingly, the normorphine affinity was found to be 7-fold higher in the guinea-pig ileum. While the difference in affinity of DADLE may be due to the suggested lack of functional delta receptors in the guinea-pig ileum, the difference in affinity seen with normorphine, but not morphine, in the two tissues is difficult to explain. Taken together with the insensitivity of methadone to beta-CNA blockade in the guinea-pig ileum, but not mouse vas deferens, the difference in the affinity of normorphine in these tissues may suggest the possibility of differences in local milieu of mu receptors or of mu receptor subtypes in the two tissues. The results provide fundamental information regarding opioid agonist affinity in two standard bioassays in vitro, and support the view of (1) a difference in receptors activated by DADLE in the guinea-pig ileum (mu) and mouse vas deferens (delta), as well as (2) possible differences in mu-receptors in these tissues.     

Implementation of a Patient Charting System: Challenges Encountered and Tactics Adopted in a Burn Center

The rapid movement of information technologies into health care organizations has raised managerial concern regarding the capability of today's institutions to satisfactorily manage their introduction. Indeed, several health care institutions have consumed huge amounts of money and frustrated countless people in wasted information systems implementation efforts. Unfortunately, there are no easy answers as to why so many health informatics projects are not more successful. In this light, the aim of this study is to provide a deeper understanding of how clinical information systems are being implemented by emphasizing research efforts on the dynamic nature of the process, that is, the “how” and “why” of what happened. Using a case study methodology, we examined the implementation of a patient charting system in the Burn Center of a large, not-for-profit, teaching hospital. Based on an in-depth examination of this implementation, several insights are offered to those who have responsibility for managing complex and risky clinical information system implementation projects.     

The views of medical students and junior doctors on pre-graduate clinical teaching.

A total of 277 third and fourth year medical students and 304 house officers and senior house officers were asked to prioritise the content and methods of clinical teaching. Response rates were poor, but similar to that in market surveys. Bedside teaching and medical clerking were considered the most valuable methods of teaching and training in practical procedures such as venepunctures and urinary catheterisation was seen as valuable. The design of new curricula in medical education will need to accommodate the views of its clients.     

Development of cranial flexure and Rathke's pouch in the chick embryo

Experiments were done to investigate the cause of the cranial (mesencephalic) flexure of the chick brain during stages 10 to 14. Measurements of the length and thickness of the roof and floor of the mesencephalon gave values similar to the values obtained previously by others. The labeling index was determined in the roof and floor of the prosencephalon, mesencephalon, and rhombencephalon as a preliminary measure of cell division. The labeling index was about the same in all regions, and was high enough to suggest that most of the cells were dividing. The labeling indices did not suggest that differential growth was caused by differential rates of cell division in the roof and floor of the mesencephalon. It was found through time lapse photography that the foregut and heart remained stationary along the rostrocaudal axis, whereas the prosencephalon moved rostrally and the mesencephalon underwent flexure. Measurements suggested that the neural tube cranial to the otic primordium grew in volume exponentially at a rate consistent with the labeling index. The rostral tip of the neural tube was observed to be linked to the rostral tip of the foregut by the ectoderm that formed Rathke's pouch at the neural tube and the pharyngeal membrane (prospective stomodeum) at the foregut. As the neural tube grew in length, the link between the neural tube and the foregut did not. We suggest that because of this link, the growing neural tube had to bend around the foregut, forming the cranial flexure, and the ectoderm folded where it attached to the prosencephalon, forming Rathke's pouch. © 1994 Wiley-Liss, Inc.     

Acquired cystic disease in chronically rejected renal transplants.

Acquired cystic disease has been documented to complicate most forms of chronic renal damage; it has only infrequently been described in transplanted kidneys. Five patients with noncystic ESRD and chronically rejected transplants in which acquired cystic disease arose are reported. The diagnosis of acquired cystic disease was established in examination of transplant nephrectomies from four patients and a core biopsy from the fifth. The allografts were in place from 44 to 80 months; three patients were treated with hemodialysis before the diagnosis of acquired cystic disease, whereas two received peritoneal dialysis. Three of the four patients evaluated had cysts in the native kidneys. Although papillary hyperplasia of lining epithelium was evident in four specimens, only one kidney was the site of neoplasms in the form of multiple small tubular adenomas. No malignant neoplasms were noted in this study or in the few similar previous ones; however, it is possible that chronically rejected transplanted kidneys may harbor neoplasms with the same malignant potential as those in acquired cystic disease in native kidneys.     

Ventilatory effects of dexmedetomidine, atipamezole, and isoflurane in dogs.

Dexmedetomidine (DMED) is a novel alpha 2 adrenergic agonist that has been shown to have potent analgesic and anesthetic sparing effects. This study was designed to investigate the effects of DMED, both alone and combined with isoflurane, on resting ventilation, the hypercapnic response, and the hypoxic response in dogs. When given alone, 1 microgram/kg decreased resting ventilation by 22% but at larger doses (10, 20, and 100 micrograms/kg) resting ventilation increased, doubling at 100 micrograms/kg. Doses of 10 micrograms/kg and greater caused a maximum depression of 60% in the slope of the hypercapnic response, but no dose had a significant effect on the hypoxic ventilatory response. A dose of 3 micrograms/kg of DMED reduced isoflurane MAC from 1.3% to 0.37%, and the ventilatory effects of this 1 MAC combination were intermediate between the awake values and those of isoflurane-anesthetized (1.3%) dogs. Atipamezole is a specific centrally acting alpha 2 receptor antagonist and when given with DMED in isoflurane-anesthetized dogs prevented the ventilatory depression. However, atipamezole alone also ventilatory stimulating effects, which may indicate tonic alpha 2 adrenergic activity. The ventilatory depression caused by DMED, either alone or combined with isoflurane, at doses that significantly reduce anesthetic requirements are relatively mild.     

K-ras activation and ras p21 expression in latent prostatic carcinoma in Japanese men.

Twenty-three clinically silent prostatic carcinomas discovered in Japanese men at autopsy were surveyed for ras proto-oncogene mutations by mutation-specific oligonucleotide probe hybridization after polymerase chain reaction (PCR) amplification from a section of formalin-fixed, paraffin-embedded tissue. Six of the 22 that were satisfactory amplified contained activating point mutations in codon 12 of K-ras, a significantly higher frequency than has been reported in patients with clinically advanced disease in the United States. Of the six cases with activating point mutations in codon 12 of K-ras, one had a GGT----GAT transition, four had GGT----GTT transversions, and one had both GGT----GAT and GGT----GTT mutations. Sections from the same tissues were immunohistochemically stained with an anti-ras p21 antibody. Carcinoma cells stained for ras p21 to some degree in 13 cases. Immunohistochemically detectable expression of p21 was always focal and was not necessarily associated with K-ras mutation. K-ras oncogene activation in prostatic carcinoma appears to merit additional study as a significant event in the pathogenesis of this neoplasm.