Safeness of Simplex-tobramycin bone cement in patients with renal dysfunction undergoing total hip replacement.

PURPOSE: To compare the pharmacokinetic profile of tobramycin in blood, urine, and at the operative site following the use of Simplex-tobramycin bone cement in primary total hip replacement between patients with and without renal dysfunction. METHODS: Six patients with renal dysfunction underwent cemented primary total hip replacement for osteoarthritis. The elution characteristics of Simplex-tobramycin bone cement in the 6 patients with renal dysfunction were compared with 9 patients who had normal renal function. Blood, urine, and drainage fluid specimens were collected for 72 hours postoperatively. RESULTS: Very high concentrations of tobramycin were seen in the drainage fluid of the 2 groups. Mean serum tobramycin levels peaked at postoperative 3 hours, and declined rapidly to negligible levels at 72 hours in both groups. Mean urinary tobramycin concentrations peaked at postoperative 12 hours and declined rapidly until 48 hours in both groups. Urinary tobramycin was excreted significantly more slowly in renal dysfunction group in the first 12 hours, but not thereafter. Although serum creatinine levels of the renal dysfunction group were higher throughout the study period, the difference was not significant. Both groups achieved excellent local delivery of the antibiotic with minimal systemic concentrations. CONCLUSION: Simplex-tobramycin bone cement appears to be an effective and safe means to deliver antibiotic for patients with renal dysfunction who undergo total hip replacement.

Differential antiplatelet efficacy for various GPIIb/IIIa antagonists: role of plasma calcium levels.

OBJECTIVES: The present study was undertaken to determine the effects of free ionized calcium influenced by either the anticoagulant used (citrate vs. heparin) or directly varying the calcium levels after treatment of blood with citrate on the antiplatelet efficacy of two classes of GPIIb/IIIa antagonists. METHODS: The platelet effects of changes in plasma [Ca(++)] with the different GPIIb/IIIa antagonists were determined using light transmittance aggregometry, direct binding kinetics, and (125)I-fibrinogen binding to activated human platelets. RESULTS: A significantly higher IC50s was shown with heparin (free ionized calcium=1.1 mM) as compared to that with citrate (free ionized calcium=0.12 mM) with class II GPIIb/IIIa antagonists (P<0.01) such as Orbofiban, and Integrilin. In contrast, class I GPIIb/IIIa antagonists such as Roxifiban and Abciximab showed no significant changes in their IC50s in either citrate or heparin. Similar data were shown with other non-calcium chelating anticoagulant such as PPACK as compared to that with heparin. Additionally, similar data were shown with regard to the [Ca(++)] sensitivity for GPIIb/IIIa antagonists from Class II but not Class I in the changes in IC50 values required for the inhibition of (125)I-fibrinogen binding to activated human gel filtered platelets. Additionally, examples from Class I GPIIb/IIIa antagonists such as (3)H-active form of Roxifiban showed no significant changes in its platelet binding affinity in response to change in [Ca(++)]. In contrast, GPIIb/IIIa antagonists from class II such as (3)H-active form of Orbofiban demonstrated significant changes (P<0.01) in its platelet binding kinetics and antiplatelet efficacy in response to changes in Ca(++) concentrations. CONCLUSIONS: These data suggest the impact of the method of blood collection or changes in plasma calcium levels on the antiplatelet efficacy for class II but not class I GPIIb/IIIa antagonists depending on their platelet binding kinetics.

Disubstituted indazoles as potent antagonists of the integrin alpha(v)beta(3).

A new series of indazole-containing alpha(v)beta(3) integrin antagonists is described. Starting with lead compound 18a, variations in a number of structural features were explored with respect to inhibition of the binding of beta(3)-transfected 293 cells to fibrinogen and to selectivity for alpha(v)beta(3) over GPIIbIIIa, another RGD-binding integrin. Indazoles attached to a 2-aminopyridine or 2-aminoimidazole by a propylene linker at the indazole 1-position and to a diaminopropionate derivative via a 5-carboxylate amide provided the best potency with moderate selectivity. Several differences in the SAR of the diaminopropionate moiety were observed between this series and a series of isoxazoline-based selective GPIIbIIIa antagonists. Compound 34a (SM256) was a potent antagonist of alpha(v)beta(3) (IC(50) 2.3 nM) with 9-fold selectivity over GPIIbIIIa.

Comparison of phenotype between patients with Prader-Willi syndrome due to deletion 15q and uniparental disomy 15.

Prader-Willi syndrome (PWS) is a complex multiple anomaly syndrome that has been shown to result from deficient expression of paternal chromosome 15(q11-q13). In most cases, it is caused either by deletion of this region in the paternally inherited chromosome 15 or by maternal uniparental disomy (UPD) of chromosome 15. In order to determine whether there are phenotypic differences between patients whose PWS is caused by these two different mechanisms, 54 affected individuals (37 with deletion, 17 with UPD) were personally examined and studied using molecular techniques. The previously recognized increased maternal age in patients with UPD and increased frequency of hypopigmentation in those with deletion were confirmed. Although the frequency and severity of most other manifestations of PWS did not differ significantly between the two groups, those with UPD were less likely to have a "typical" facial appearance. In addition, this group was less likely to show some of the minor manifestations such as skin picking, skill with jigsaw puzzles, and high pain threshold. Females and those with UPD were also older, on average. Possible mechanisms by which these differences could occur and the implications of these differences for diagnosis are described.

Comparison of the effect of different platelet GPIIb/IIa antagonists on the dynamics of platelet/fibrin-mediated clot strength induced using thromboelastography.

The effect of various platelet glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists on the dynamics of platelet-fibrin clot formation and strength induced by various stimuli was measured by thromboelastography (TEG). GPIIb/IIIa antagonists with high affinity for resting and activated platelets and with slow rates of dissociation from GPIIb/IIIa (Class I antagonists) demonstrated potent and comparable inhibition of platelet aggregation and tissue factor (TF), lipopolysaccharide (LPS), Factor Xa, and thrombin-induced clot strength, in contrast to antagonists that dissociate rapidly from GPIIb/IIIa (Class II antagonists). For example, the Class I antagonist XV459 (the free acid form of roxifiban) inhibited TF, endotoxin, Factor Xa, and thrombin-induced maximal clot strength and platelet aggregation with an IC(50)=30-70 nM, whereas the IC(50) of the Class II antagonist YZ211 (the free acid form of sibrafiban) for altering clot formation and strength was 0.3-4.7 microM. Moreover, the IC(50)'s of sibrafiban, and another Class II antagonist, orbofiban, for inhibiting platelet-fibrin clot formation and strength were substantially greater than their clinically achievable concentrations. Further, although aspirin treatment improved the efficacy of all GPIIb/IIIa antagonists, it did not alter the differences between Classes I and II antagonists. Thus, these data indicate that there are differences in the efficacy of various GPIIb/IIIa antagonists in inhibiting platelet-fibrin clot formation and strength. They also suggest that inhibiting platelet aggregation may not be the sole determinant for the in vivo efficacy of various GPIIb/IIIa antagonists.

Dissociation between the anti-aggregatory & anti-secretory effects of platelet integrin alpha IIb beta 3 (GPIIb/IIIa) antagonists, c7E3 and DMP728.

The effects of alpha IIb beta 3 antagonists on the blockade of fibrinogen binding to platelet alpha IIb beta 3 are well documented, however, little is known about their effects on platelet secretion. We compare here the effect of two potent alpha IIb beta 3 antagonists, c7E3 and DMP728, on platelet secretion. Using human platelet-rich plasma, P-selectin expression was measured by flow cytometry and type 1 plasminogen activator inhibitor (PAI-1) secretion as well as beta-thromboglobulin (beta-TG) were determined by ELISA. At various concentrations of the antagonists that inhibited 80-95% of platelet aggregation, neither had any effect on P-selectin expression. In contrast, thrombin-stimulated PAI-1 secretion is only inhibited by c7E3, 49.6% at 3.5 mumol/L (p < 0.05), but not at any other maximally effective anti-aggregatory concentrations of c7E3 or DMP728. Furthermore, a lack of any significant effects on platelet granular secretion of beta-TG induced by either thrombin or ADP was demonstrated with DMP728, c7E3 or LM609. Two protein kinase inhibitors, staurosporine and herbimycin, blocked both ADP and thrombin-induced P-selectin expression at 10 mumol/L, but not PAI-1 secretion. Taken together this suggests that: (1) the mechanism of platelet granular secretion is independent of the integrin alpha IIb beta 3 and (2) the subcellular locations of PAI-1, beta-TG and P-selectin or the signaling mechanisms that regulate their secretion might be different. Although there is no direct effect of platelet alpha IIb beta 3 antagonists on platelet secretion of PAI-1, beta-TG and P-selectin, the present data demonstrates that reduction of platelet number by alpha IIb beta 3 antagonists, via the reduction in thrombus size, might be an alternate mechanism for reduced platelet secretion. In conclusion, a discoupling between the anti-aggregatory and the anti-secretory effects of alpha IIb beta 3 antagonists has been demonstrated.

Platelet GPIIb/IIIa receptor occupancy studies using a novel fluoresceinated cyclic Arg-Gly-Asp peptide.

DMP 728 is a potent and specific platelet GPIIb/IIIa antagonist. Like all GPIIb/IIIa antagonists, DMP 728 has a steep dose-response relationship in inhibiting platelet aggregation. In this study the relationships between receptor occupancy, platelet aggregation and bleeding time was determined in anesthetized dogs after intravenous infusion of DMP 728 (0.01 and 0.1 mg/kg/2h). Receptor occupancy was determined by flow cytometry using XL086, a novel fluorescent cyclic RGD peptide that binds to GPIIb/IIIa with high specificity and affinity (kd approximately 55 nM). Mean number of GPIIb/IIIa as determined by flow cytometric assay was approximately 53,8000 and 79,000 on unactivated and ADP-activated platelets respectively. After DMP 728 intravenous infusion, there was a dose- and time-dependent increase in receptor occupancy, inhibition of platelet aggregation and bleeding time. The two methods of receptor occupancy determination correlate with each other with an r2 = 0.78. The present data suggest that blockade of only 40-60% (approximately 40,000 receptors) of the total platelet GPIIb/IIIa was required to achieve > 90% inhibition of platelet aggregation and > 15 min bleeding time. Our results showed the potential clinical utility of this approach in the study of GPIIb/IIIa dose-response relationship.

Recombinant plasminogen activator inhibitor-1 protects platelets against the inhibitory effects of plasmin.

Plasmin-induced degradation of platelet glycoprotein Ib (GPIb), the von Willebrand factor (vWF) receptor, has been implicated as a mechanism contributing to the development of platelet dysfunction following cardiopulmonary bypass (CPB). The goal of this study was to assess whether biologically active recombinant plasminogen activator inhibitor-1 (rPAI-1), could antagonize the inhibitory effects of plasmin on GPIb. GPIb function, as evaluated by measuring vWF-dependent, ristocetin-induced platelet agglutination in human platelet rich plasma (PRP) was significantly impaired following incubation with plasmin (60 +/- 14% inhibition, p < 0.01). Inclusion of rPAI-1 (10 micrograms/ml) in the PRP antagonized this plasmin effect, restoring agglutination to 92 +/- 8% of the control value (p < 0.01). The effect of rPAI-1 on the enzymatic activity of plasmin was further evaluated in an amidolytic assay with the plasmin substrate S2251 where an apparent second order rate constant of plasmin inhibition by rPAI-1 of 9.4 x 10(4) M-1 S-1 was determined. Our results suggest that rPAI-1, by inhibiting both tissue plasminogen activator-induced plasmin generation and plasmin activity directly, may have clinical value for improving platelet function during and after CPB.

Role of platelet GpIIb/IIIa receptors in the modulation of platelet plasminogen activator inhibitors type-1 (PAI-1) release.

This study was undertaken to determine the role of platelet glycoprotein (GP) IIb/IIIa receptors in the modulation of plasminogen activator type-1 (PAI-1) release from human platelets as compared to other platelet functions. To address this issue, the effect of various agonists on human platelet aggregation, [125I]fibrinogen binding and the release of PAI-1 was examined in normal and Glanzmann's thrombasthenic (GT) platelets. In control subjects, maximum platelet aggregation and PAI-1 secretion were observed within 5 min in response to the different agonists including thrombin, collagen, adenosine diphosphate (ADP), and arachidonic acid. Agonist-induced platelet GpIIb/IIIa receptor activation was confirmed by [125I]fibrinogen binding analysis. In contrast, platelets from GT subjects demonstrated a lack of fibrinogen binding and a lack of an aggregatory response to all agonists tested except to the GPIb- mediated aggregation induced by ristocetin. However, GT platelets demonstrated normal responsiveness in secreting PAI-1 in response to the various agonists. Similarly, when platelet GpIIb/IIIa receptors were blocked in normal platelets by the tripeptide Arg-Gly-Asp (RGD) or the tetrapeptide Arg-Gly-Asp-Ser (RGDS) at 10(-3) M, agonist-induced platelet aggregation and fibrinogen binding were blocked, but platelet PAI-1 release was not blocked. Furthermore, flow cytometric analysis using dual fluorescence markers for the platelet GPIIb/IIIa membrane receptors (FITC-labeled cyclic RGD analog, XL086) and for the alpha granule (PE-monoclonal antibody for P-selectin) demonstrated a dissociation between the platelet GPIIb/IIIa receptors and granular secretion. These results suggest a lack of a role for platelet GpIIb/IIIa receptors in the modulation of platelet PAI-1 release.

Human platelet alphaIIbeta3 integrin binding affinity and specificity of SJ874: antiplatelet efficacy versus aspirin.

OBJECTIVE: To define the affinity and specificity of SJ874, a nonpeptide antiplatelet agent for platelet glycoprotein Ilb/IIIa integrin, and to determine the antiplatelet efficacy of SJ874 relative to those of glycoprotein IIbIIIa antagonists and aspirin. METHODS: Binding affinity and specificity of SJ874 for platelet glycoprotein IIb/IIIa integrin were determined using integrin-mediated binding and adhesion assays with human cells. Additionally, the antiplatelet efficacy of SJ874 was determined and compared with those of other glycoprotein IIb/IIIa antagonists and aspirin using light-transmittance and laser-scattering aggregometry. RESULTS: SJ874 inhibited aggregation of human platelets induced by 10 micromol/l adenosine diphosphate (ADP) with a concentration for half-maximal effect of 0.046 +/- 0.005 micromol/l using light-transmittance aggregometry. Using laser-scattering aggregometry, SJ874 was found to totally inhibit formation both of micro-aggregates and of macro-aggregates induced either by ADP or by epinephrine. In contrast, administration of 325 mg aspirin to normal healthy volunteers attenuated formation of macro-aggregates but not micro-aggregates. SJ874 inhibited binding of [125I]-fibrinogen to activated (by ADP, epinephrine, and arachidonic acid at concentrations of 100 micromol/l each) gel-filtered human platelets with a concentration for half-maximal effect of 0.0012 +/- 0.0005 micromol/l. SJ874 was demonstrated to associate more tightly with resting human platelets than did DMP754 [1] and slightly less tightly than did DMP802 [2]. SJ874 was demonstrated to exhibit a high degree of specificity for platelet glycoprotein IIb/IIIa (alphaIIb/beta3) integrin compared with other known integrins, including alphavbeta3, alphavbeta5, and alpha5beta1 (concentration for half-maximal effect > 100 micromol/l). CONCLUSION: SJ874 is a potent and specific platelet glycoprotein IIb/IIIa antagonist with high affinity for and tight association with human platelets. These data suggest that SJ874 might have good antiplatelet utility for inhibiting formation both of platelet micro-aggregates and of macro-aggregates of platelets and a long duration of action in humans due to its slow dissociation from human platelets.

Thrombolytic and antithrombotic efficacy of the platelet GPIIb-IIIa antagonist DMP728.

OBJECTIVE: This study was undertaken to determine the antithrombotic and thrombolytic efficacy of DMP728 alone and in conjunction with thrombolytic agents. BACKGROUND: Coronary artery reocclusion continues to be a significant clinical problem after thrombolytic therapy or balloon angioplasty, with incidence rates of 5-20% regardless of thrombolytic intervention. To date, no adjunctive therapy has been shown to eliminate the incidence of rethrombosis after thrombolysis. DMP728, a novel small-molecular-weight platelet GPIIb-IIIa receptor antagonist, has been shown to prevent rethrombosis after thrombolysis in various arterial thrombosis models in dogs. It might therefore have potential utility in optimizing the clinical outcome of currently available thrombolytic agents. The present investigation was designed to examine the thrombolytic potential of DMP728 alone and in conjunction with different thrombolytic agents. METHODS: The deaggregatory effect of DMP728 in reversing human platelet aggregation after initiation of platelet aggregation by 10 mumol/l adenosine 5'-diphosphate was determined using light-transmittance aggregometry. The in-vitro efficacy of DMP728, alone and in combination with thrombolytic drugs, in dispersing a preformed platelet-rich clot was determined using a clot-dispersion assay. In addition, the in-vivo thrombolytic effects of DMP728, alone and in conjunction with streptokinase, were examined in an electrolytically induced femoral artery thrombosis model in dogs. RESULTS: DMP728 had concentration-dependent deaggregatory and thrombolytic effects in reversing aggregates and in dispersing a preformed platelet-rich thrombus in vitro. Furthermore, it exhibited significant potentiation (P < 0.01) when combined with different thrombolytic drugs such as streptokinase, tissue-type plasminogen activator (t-PA) and urokinase in lysing platelet-rich thrombus. DMP728 had significant in-vivo thrombolytic effects along with synergy in fully restoring arterial flow upon its concomitant use with subeffective to ineffective doses of streptokinase in an electrolytically induced femoral artery thrombosis model in dogs. It also reduced the time to reperfusion and prevented the incidence of rethrombosis after streptokinase. CONCLUSIONS: These findings suggest the potential utility and benefits of DMP728, not only in preventing arterial thrombosis but also in optimizing the efficacy of thrombolytic drugs.

Novel nonpeptide antiplatelet glycoprotein IIb/IIIa receptor antagonist, DMP754: receptor binding affinity and specificity.

OBJECTIVE: To define the antiplatelet efficacy and specificity of the glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist prodrug DMP754 and its free acid form, XV459. METHODS AND MATERIALS: DMP754 has an IC50 > 1 mumol/l, and, upon its conversion with esterases to its free acid form, demonstrated high potency (IC50 20-45 nmol/l) in inhibiting human platelet aggregation induced by 10 mumol/l adenosine diphosphate, 20 micrograms/ml collagen, 1 mmol/l epinephrine, 10 mumol/l platelet activating factor or 0.5 IU/ml thrombin. The in-vitro rate of hydrolysis of DMP754 or XV459 is much faster with human or canine liver esterases (t 1/2 = 2.4-23 min) than with plasma esterases (t 1/2 = 5.5-7.6 h). Platelet GpIIb/IIIa integrin binding affinity and specificity for XV459 were determined using cell binding/adhesion assays. RESULTS: The range of IC50 values of XV459 in inhibiting platelet aggregation in platelet-rich plasma obtained from 12 subjects was 0.035-0.069 mumol/l with a mean IC50 of 0.050 +/- 0.003 mumol/l. Additionally, XV459 inhibited platelets obtained from mongrel dogs, baboons, sheep, guinea pigs, and mice with IC50 in the range 0.024-0.06 mumol/l, and IC50 in the range 0.16-5.8 mumol/l in pigs, rabbits, and rats. XV459 inhibited [125I]-fibrinogen binding to activated human platelets with an IC50 of 0.011 +/- 0.003 mumol/l. XV459 demonstrated a high degree of selectivity in specifically inhibiting fibrinogen binding to the platelet integrin, GPIIb/IIIa (IC50 = 0.00025 +/- 0.00005 mumol/l) compared with inhibiting other integrins (alpha v beta 3, IC50 > 10 mumol/l; or alpha v beta 5, alpha 5 beta 1, or alpha 4 beta 1, for which the IC50 exceeded 100 mumol/l). CONCLUSION: DMP754 is a potent antiplatelet agent in inhibiting platelet aggregation, and has a high specificity and affinity for human platelet GPIIb/IIIa receptors.

Mental health and stress in the workplace: the case of general practice in the UK.

This study adopted a 'workforce' perspective in a study of job strain in primary care (general practice) in the UK. It explored the level of stress amongst workers in general practice and between practices and examined the relationship between level of stress and work characteristics. Postal questionnaires were sent to a random sample of general practices (n = 81) in southern England. The study showed that 23% of all responders could be classified, according to the GHQ-12, as suffering from mental distress with practice managers having the highest level of stress and clerical and administrative staff the lowest. Work characteristics as measured by Karasek's Job Content Instrument were shown to be significant predictors of job stress as were marital status and health status. The implications of these findings are discussed, particularly focusing on the value of the job strain model for explaining job stress in general practice.

Effect of thrombin inhibitors on platelet functions: comparative analysis of DuP 714 and hirudin.

Since thrombin plays an important role in platelet-mediated arterial thrombosis, we have examined the antiplatelet activity of a synthetic thrombin inhibitor, DuP 714 (Ac-(D)Phe-Pro-boroArg), in comparison with that of the naturally occurring inhibitor hirudin. Hirudin was slightly more potent than DuP 714 in inhibiting thrombin-induced aggregation in washed human platelets (IC50s of 72 nM and 150 nM, respectively) and in inhibiting the secretion of plasminogen activator inhibitor-I from human platelets (IC50s of 300 nM and 900 nM, respectively). In contrast, DuP 714 was more potent than hirudin in inhibiting thrombin-induced [125I]fibrinogen binding to gel purified platelets, and in inhibiting thrombin-induced intracellular calcium mobilization in washed platelets. These results indicate that the tripeptide DuP 714 has comparable antiplatelet activity to the 65 amino acid hirudin. We conclude that DuP 714 may have clinical utility in the prevention of platelet-dependent, arterial thrombotic processes.

New concepts in the diagnosis and treatment of infections of the cervical spine.

Of the three major areas of the spinal column, the cervical spine is least commonly infected; approximately 3 to 5 per cent of all spinal infections involve the cervical spine. Tuberculous, pyogenic, fungal, and parasitic infections may involve the cervical spine and occur in this order of decreasing frequency. Difficulty in differential diagnosis most commonly involves tumor. Fungal and parasitic infections of the cervical spine are extremely rare, but fungal infections have been increasing over the past three decades. Clinical suspicion, radiologic examination, and definitive diagnosis via tissue biopsy are necessary so that definitive procedures can be instituted. Specific antibiotic coverage, surgery to facilitate the body's defenses and antibiotic penetration, and stabilization of the spine are the most important therapeutic measures to be instituted.

Professional nurse information day: a recruitment strategy for registered nurses.

The shortage of and demand for professional registered nurses is growing at an ever-increasing rate. Military facilities must consider alternative strategies for recruiting these professionals into their staffs even in the midst of worsening budget and personnel constraints. One idea is reported here that proved successful for a medical center overseas with no money expenditure. Recommendations for repetitions of a similar program are included.

Doctors as patients: postal survey examining consultants and general practitioners adherence to guidelines.

OBJECTIVES: To examine the adherence by senior NHS medical staff to the BMA guidelines on the ethical responsibilities of doctors towards themselves and their families. DESIGN: Postal semistructured questionnaire. SETTING: Four randomly selected NHS trusts and three local medical committees in South Thames region. SUBJECTS: Consultants and principals in general practice. MAIN OUTCOME MEASURES: Personal use of health services. RESULTS: The response rate was 64% (724) for general practitioners and 72% (427) for consultants after three mailings. Most (1106, 96%) respondents were registered with a general practitioner, although little use was made of their services. 159 (26%) general practitioners were registered with a general practitioner in their own practice and 80 (11%) admitted to looking after members of their family. 73 (24%) consultants would never see their general practitioner before obtaining consultant advice. Most consultants and general practitioners admitted to prescribing for themselves and their family. Responses to vignettes for different health problems indicated a general reluctance to take time off, but there were differences between consultants and general practitioners and by sex. Views on improvements needed included the possibility of a "doctor's doctor," access to out of area secondary care, an occupational health service for general practitioners, and regular health check ups. CONCLUSION: The guidelines are largely not being followed, perhaps because of the difficulties of obtaining access to general practitioners outside working hours. The occupational health service should be expanded and a general practitioner service for NHS staff piloted.

The Health Security Act: implications for reimbursement.

The current health care reform environment, with its myriad of legislative proposals, provides exciting possibilities for advanced practice nurses to finally secure direct reimbursement rights. Although other plans are being considered, the Clinton administration's Health Security Act remains the central focus of the debate over health care reform. In this article, specific aspects of the Clinton proposal are examined, and arguments are delineated that support nursing's ability to lower costs, improve access, and provide quality patient care. Recommendations for pursuing passage of legislation are also developed.

General practice. All stressed up and nowhere to go?

A survey of 1,545 staff in general practices in South East region found that GPs and practice managers were the most stressed. GPs believed that dealing with difficult patients was particularly stressful. The relationships between the senior partner and practice manager and the GP-nurse relationship were seen as crucial. The relationship between GPs and nurses is characterised by ambivalence and uncertainty. The division of labour between GPs and practice managers needs clarification if the government's proposals for improving general practice are to succeed.