Vitamin E reversal of the effect of extracellular calcium on chemically induced toxicity in hepatocytes.

Isolated rat hepatocytes were incubated in the presence or absence of extracellular calcium and alpha-tocopherol succinate with three different toxic chemicals; namely, adriamycin in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea, ethyl methanesulfonate, and the calcium ionophore A23187. In the absence of extracellular calcium these three compounds were far more toxic to the cells than in its presence. The addition of vitamin E to calcium-free medium, however, protected hepatocytes against toxic injury, whereas cells incubated in medium containing calcium were not protected. Hepatocyte viability during each toxic insult correlated well with the cellular alpha-tocopherol content but not with the presence or absence of extracellular calcium. These results suggest that cellular alpha-tocopherol maintains the viability of the cell during a toxic insult and that the presence or absence of vitamin E in the incubation medium probably explains the conflicting reports on the role of extracellular calcium in toxic cell death.

Recombinant factor VIIa to prevent surgical bleeding in factor XI deficiency.

Factor XI (FXI) deficiency is associated with bleeding after invasive procedures. Risks of human plasma-derived FXI replacement products include transfusion transmitted infection, thrombosis and fluid overload. This study was designed to test the hypothesis that recombinant factor VIIa (rFVIIa) is an effective haemostatic agent in patients with FXI deficiency undergoing surgery. Fourteen FXI deficient patients [five severely deficient (FXI:C <20 U dL(-1)) and nine partially deficient (FXI:C 20-70 U dL(-1)] received rFVIIa to prevent surgical bleeding during five major, four minor and six dental procedures. Minor surgical and dental procedures were covered with two doses of rFVIIa (90 microg kg(-1) i.v.), the first pre-operatively and the second 4 h postoperatively. Major surgery was covered with 90 microg kg(-1) i.v. two hourly for the first 24 h and four hourly for the second 24 h. Oral tranexamic acid was given for 7 days postoperatively. Effective haemostasis was observed in all cases and no alternative haemostatic agents or blood transfusions were required. Three adverse events were recorded; an acute cerebrovascular accident in a patient with a history of cardiovascular disease, an allergic reaction and local phlebitis. In this study, rFVIIa was an effective alternative to plasma-derived FXI replacement for the prevention of surgical bleeding in FXI deficient patients but rFVIIa may not be suitable for patients with pre-existing risk factors for thrombosis.

Cell calcium, vitamin E, and the thiol redox system in cytotoxicity.

The controversial role of extracellular Ca2+ in toxicity to in vitro hepatocyte systems is reviewed. Recent reports demonstrate that extracellular Ca2+-related cytotoxicity is dependent on Ca2+-influenced vitamin E (alpha-tocopherol) content of isolated hepatocytes. Based on a Ca2+-omission model of in vitro oxidative stress, the role of vitamin E in cytotoxicity is further explored. This model demonstrates the interdependence of the GSH redox system and vitamin E as protective agents during oxidative stress. Following chemical oxidant-induced depletion of intracellular GSH, cell morphology and viability are maintained by the continuous presence of cellular alpha-tocopherol above a threshold level of 0.6-1.0 nmol/10(6) cells. alpha-Tocopherol threshold-dependent cell viability is directly correlated with the prevention of the loss of cellular protein thiols in the absence of intracellular GSH. Potential mechanisms for this phenomenon are explored and include a direct reductive action of alpha-tocopherol on protein thiyl radicals, and the prevention of oxidation of protein thiols by scavenging of lipid peroxyl radicals by alpha-tocopherol. It is suggested that in light of the threshold phenomenon of vitamin E prevention of potentially severe oxidative stress-induced cytotoxicity, its use as a protective agent against an oxidative challenge in vivo should be reassessed.

Structural and functional assembly of rat intestinal cytochrome P-450 isozymes. Effects of dietary iron and selenium.

We have reported previously that both dietary iron and selenium regulate intestinal cytochrome P-450 content by modulating the synthesis of its prosthetic heme moiety. Whether these elements are required for synthesis and/or viability of its apocytochrome moiety is unknown. We have examined the effects of intraluminal deprivation of these elements on the apocytochrome moieties of the constitutive (P-450) and the beta-naphthoflavone inducible (P-448) intestinal isozymes. The relative content of intestinal apocytochrome P-450 moieties generated by dietary deprivation of iron and/or selenium was assessed indirectly by complexing with exogenous heme in vitro, to reassemble the holocytochromes which could be monitored spectrally and catalytically. We now report that, whereas both intraluminal iron and selenium are required for maintenance of the prosthetic apocytochrome moiety of the constitutive intestinal isozyme, only intraluminal selenium is required for the viability of apocytochrome P-448. The latter apparently survives in the absence of intraluminal iron and can be assembled to the holocytochrome, with exogenously added heme. The mechanistic basis of the critical requirement of intestinal apocytochromes for intraluminal selenium is unclear. It is intriguing, however, that the deleterious effects of selenium deprivation are principally exerted in cell systems actively synthesizing protein and inexorably dependent on their extracellular milieu for their nutriment.

Regulation of intestinal cytochrome P-450 and heme by dietary nutrients. Critical role of selenium.

The intestinal cytochrome P-450 (I-P-450)-dependent mixed function oxidase (MFO) system is regulated to a remarkable extent by various ingested xenobiotics, including drugs and carcinogens, as well as dietary nutrients. Accordingly, acute dietary iron deprivation is found to result in a marked decrease in I-P-450 content and activity. This decrease is most pronounced in the villous tip cells, the very cells committed to absorption of ingested materials. We investigated the mechanistic basis for such acute reduction and report that iron was not only required as a co-substrate for I-P-450 heme formation, but also as a regulator of two key heme-synthetic enzymes, delta-aminolevulinic acid synthetase and ferrochelatase. In addition, our studies revealed that dietary deprivation of selenium for a single day dramatically reduced I-P-450-dependent MFO activity. This prompt reduction apparently reflects impaired I-P-450 formation resulting from lowered ferrochelatase activity and consequently decreased intestinal heme availability, and was not a consequence of intracellular peroxidation presumably enhanced by concomitant lowering of the seleno-dependent glutathione peroxidase. Thus, we report the novel observation that dietary selenium also appears to be a critical modulator of intestinal cytochrome P-450-dependent metabolism of ingested drugs, carcinogens, and toxins that are absorbed by the intestinal mucosa.

Extracellular calcium effects on cell viability and thiol homeostasis.

Studies of chemically induced cell injury and death, which have used as model systems freshly isolated rat hepatocytes and hepatocytes in culture, are discussed. An important model uses the omission of Ca2+ from the medium during rat hepatocyte incubations. Ca2+ omission induces an intense oxidative stress within hepatocytes incubated in a 95% O2 + 5% CO2 atmosphere. The relationship of calcium homeostasis to the parameters of oxidative stress is important to understanding the progression from reversible to irreversible injury. In the Ca2+ omission model, the vitamin E (Vit. E) content of hepatocytes is important for the prevention of cell injury. Recent studies with rat hepatocytes show that ruthenium red (RR) and La3+, which block Ca2+ translocation through the mitochondrial uniport, can prevent malondialdehyde (MDA) formation, reduced glutathione (GSH), and protein-SH loss, Vit. E loss, and LDH leakage induced by Ca2+ omission from the incubation medium. Ca2+ omission promoted a marked loss of mitochondrial transmembrane potential (delta phi) that was prevented by RR, EGTA, Vit. E, and desferrioxamine. The absence of extracellular Ca2+ may cause mitochondrial Ca2+ cycling that contributes to the observed oxidative stress, resultant loss of cell viability, and protein thiol homeostasis. Chemical agents including a glutathione-depleting agent, ethacrynic acid, and a redox cycling agent, adriamycin, increase the loss of cell viability caused by a Ca2(+)-free medium, but they have some additional effects on cellular processes. The demise of cell viability by the agent is also preventable by Vit. E supplementation. Ca2+ has a role in cell injury that appears to uniquely involve mitochondrial homeostasis.

Identification of S-(2,5-dihydroxyphenyl)-cysteine and S-(2,5-dihydroxyphenyl)-N-acetyl-cysteine as urinary metabolites of acetaminophen in the mouse. Evidence for p-benzoquinone as a reactive intermediate in acetaminophen metabolism.

S-(2,5-Dihydroxyphenyl)-cysteine and S-(2,5-dihydroxyphenyl)-N-acetyl-cysteine [the cysteine- and N-acetyl-cysteine adducts, respectively, of hydroquinone (HQ)] were identified and quantified in the urine of mice administered [ring-U-14C]acetaminophen [14C]APAP, 200 mg kg-1, i.p.). Urine was collected for 24 h and fractionated by HPLC to isolate the above adducts. These conjugates were then converted to a common derivative, viz. O,O',S-tris-acetyl-3-thio-hydroquinone, which was characterized by GC/MS. Neither of the HQ adducts was detected in the urine of control mice which had not received APAP. Quantification of urinary HQ-cysteine and HQ-N-acetyl-cysteine was performed by HPLC techniques, which indicated that these conjugates accounted for approx. 1.5% of the administered dose of APAP after 24 h, a figure which is equivalent to 6.3% of the corresponding APAP-thiol conjugates in the urine. These findings provide strong indirect evidence that p-benzoquinone is formed as a reactive, but apparently non-hepatotoxic, metabolite of APAP in vivo.

Covalent binding of acetaminophen to mouse hemoglobin. Identification of major and minor adducts formed in vivo and implications for the nature of the arylating metabolites.

When hepatotoxic doses of [ring-U-14C]acetaminophen ([ring-U-14C]APAP) were administered to mice, radioactivity became bound irreversibly to hemoglobin as well as to proteins in the liver and kidney. The covalent binding to hemoglobin was dose-dependent, and in phenobarbital-pretreated mice occurred to the extent of approximately 8% of the corresponding binding to liver proteins. Degradation of the modified globin by acid hydrolysis yielded 3-cystein-S-yl-4-hydroxyacetanilide as the major radioactive product, accounting for approximately 70% of protein-bound drug residues. This finding is consistent with the view that the majority of covalent binding of APAP to proteins is mediated by N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite which preferentially arylates cysteinyl thiol residues. However, after administration of [acetyl-3H]APAP to mice, it was found that approximately 20% of the drug bound to hemoglobin had lost the N-acetyl side-chain, indicating the existence of a second type of APAP-protein adduct. One minor component of the globin hydrolysate was identified as S-(2,5-dihydroxyphenyl)-cysteine, which most likely arises from binding to hemoglobin of p-benzoquinone, a hydrolysis product of NAPQI. The two adducts reported represent the first identified examples of arylating drugs binding to hemoglobin. Experiments on the influence of different cytochrome P-450 inducing agents on the ratio of drug bound to hemoglobin versus hepatic proteins suggested that the reactive metabolites of APAP are formed in the liver and migrate to the erythrocyte, rather than being produced by hemoglobin-catalyzed oxidation of APAP. These findings imply that the reactive metabolites of APAP escape from hepatocytes in some latent forms, which then participate in the arylation of protein thiols in red blood cells and, possibly, at other remote sites.

The Andover Working Group--accelerating the implementation of standards.

The Andover Working Group was formed with the objective to accelerate and broadly deliver standards-based solutions for healthcare which feature plug and play interoperability across the continuum of care. In this paper, organization and processes used by the Andover Working Group are discussed. A description of how multilateral message profiles, combined with object-oriented component middleware supporting application developments, systems integration and systems operation remove many of the barriers to deployment of systems of standards based applications is also given.

Patient satisfaction in primary health care: a literature review and analysis.

This paper reviews the literature on patient satisfaction in primary health care settings. Definitions and models of satisfaction are considered first. Attention is given to the conceptualization of satisfaction by investigators concerned about consumers in general as well as by researchers focusing on consumers of medical services. Research findings are discussed and used to develop a model of patient satisfaction. The measurement of patient satisfaction and the findings of empirical studies are then reviewed, including summaries of effect sizes. It is concluded that patient satisfaction information can provide a dependent measure of service quality and serves as a predictor of health-related behavior. Issues deserving further investigation and recommendations regarding research strategies are presented.

The evaluation ranking scale: a new methodology for assessing satisfaction.

Most patient satisfaction scales produce high, undifferentiated levels of reported satisfaction that fail to detect program areas that consumers do not like. Methodological problems apparently contribute to these results. An alternative procedure, the Evaluation Ranking Scale (ERS), was formulated and tested. A 2 X 3 design was employed with 246 public health center patients randomly assigned to one of two measurement techniques (ERS vs. a global measure) and one of three informational sets. A secondary group of subjects was a convenience sample of 26 staff members, which allowed comparisons of staff evaluations of the health center to patients' evaluations of the health center. Compared to the global measure, the ERS provided more specific information about particular program components, was more discriminating, and resulted in mean satisfaction scores that were significantly lower. This new approach may be a more effective technique for assessing the psychosocial effectiveness of human service programs.

Comparison of indirect and direct approaches to measuring patient satisfaction.

One indirect (PSQ) and two direct (CSQ-18B and ERS) measures of patient satisfaction were compared across a series of psychometric, acceptability, and concurrent validity criteria. None of the three measures was significantly related to health status or demographic characteristics. Each measure performed as expected from prior research on their psychometric properties. The scales contrasted, however, in regard to acceptability, with the PSQ being much less acceptable to patients than the other two. The PSQ also produced more missing data. The results on the PSQ reflected patient inconsistency on cross-check items and patients tended to be uncertain in their responses to many items. In multivariate analyses the three measures were used as predictors of patient-rated indices of global service satisfaction. The CSQ-18B and the ERS were significant predictors of patient-rated indices of global service satisfaction, whereas the PSQ was unrelated to these indices. It was concluded that the direct and indirect approaches measure different satisfaction domains. The PSQ likely assesses more generalized attitudes about health services while the CSQ-18B and the ERS efficiently reflect opinions about the specific setting in which they are administered.

Relationship of service satisfaction to life satisfaction and perceived well-being.

Two procedures for gaining patients' evaluations of health services were compared: (a) the Client Satisfaction Questionnaire (CSQ-18B), a direct approach assessing the setting and services actually encountered, and (b) the Patient Satisfaction Questionnaire (PSQ), an approach that indirectly assesses satisfaction with service by inquiring about general health care attitudes. Results from 148 public health patients indicated that the PSQ produced the most acceptability problems and was tapping aspects of life satisfaction other than service satisfaction. However, the PSQ produced significantly lower reports of satisfaction. Additional comparison and interpretation of typical responses generated from the two approaches suggested, on the whole, that the CSQ-18B data provided clearer, more efficient, and more useful information for program planning and evaluation. In this study, service satisfaction measured by the CSQ-18B did not have any significant relationship to global or multidimensional (LDQ-30) measures of life satisfaction and well-being. In contrast, over a third of the variance in PSQ scores was accounted for by measures of life satisfaction. It appears that the PSQ elicits attitudes toward the more generalized health care delivery system as well as aspects of life satisfaction rather than reactions to specific services actually received.

The evaluation ranking scale: clarification of methodological and procedural issues.

Compared with CSQ-8, a typical questionnaire approach to assessing global patient satisfaction, the Evaluation Ranking Scale (ERS) had equally good patient acceptability, yielded more normally distributed satisfaction scores, and results allowed comparative information about patients' evaluation of specific service dimensions. The study also addressed key questions that have emerged about the ERS procedure. Patients apparently do not distinguish conceptually between "importance" of dimensions and "satisfaction" with dimensions in the first phase (ranking) of the ERS. Results did confirm that the ERS sequence of ranking and then rating the dimensions is essential to achieving optimal utility of results. The ranking task seems to have an organizing effect on patients' approach to the rating task. This effect does not work to dictate results in the rating phase but rather seems to familiarize patients with the dimensions to be rated thereby yielding greater potential discriminative capacity for the ERS. Finally, results indicate that the ERS can be administered in a flexible fashion that yields additional information about the absolute importance of the six dimensions without loss of desired operating characteristics for the measure.

Transfix: a new range of all-silicone male incontinence sheaths.

Urinary incontinence can have a significant detrimental effect on a person's body image and self-esteem because it undermine society's norms relating to control of the body. This can be further complicated by the use of devices to control urinary incontinence. Sheath drainage systems are the most common method of managing urinary incontinence in men. A discreet, reliable sheath drainage system can have both physical and psychological benefits. A full continence assessment is paramount for a successful outcome as there are several potential problems associated with this method of management. There are many products available, so the health professional needs a comprehensive knowledge of both products and application techniques. The Sims Portex Transfix range of all-silicone self-adhesive sheathes have many benefits and offer a reliable form of sheath management for male urinary incontinence.

Evaluation of two coated catheters in intermittent self-catheterization.

Intermittent self-catheterization (ISC) has addressed the problems of mechanical or functional urological voiding since the 1970s. Patient quality of life is enhanced by the increased independence and security offered by ISC (Lapides et al, 1972). A randomized, comparative crossover study was undertaken in two centres to evaluate the performance of SpeediCath (Coloplast) and Lofric (Astra Tech) catheters. A total of 27 subjects were recruited, all of whom had been performing ISC more than twice a day for longer than 3 months with a coated catheter. Each catheter was used for 1 week to assess catheter performance and acceptability. There were no significant differences recorded for the performance of each catheter. However, SpeediCath demonstrated favourable statistical significance in relation to ease of use, speed of use, and the concept of water as an integral part of the packaging of the catheter.

Hospital discharges. Creating bed room.

A review of hospital discharge arrangements in one health authority has reduced the number of lost bed days by two-thirds. Previously, some patients were waiting in acute beds for six months, and 10 per cent of all beds in the acute hospitals were occupied by patients ready for discharge. The number of patients waiting for discharge has fallen from 280 last summer to 60. The HA has used winter pressures money to top up social services funding for residential home places and has bought intermediate care places in homes.