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.

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.

Chronic occupational repetitive strain injury.

OBJECTIVE: To review common repetitive strain injuries (RSIs) that occur in the workplace, emphasizing diagnosis, treatment, and etiology of these conditions. QUALITY OF EVIDENCE: A MEDLINE search from January 1966 to June 1999 focused on articles published since 1990 because RSIs are relatively new diagnoses. MeSH headings that were explored using the thesaurus included "cumulative trauma disorder," "overuse injury," and "repetitive strain injury." The search was limited to English articles only, and preference was given to randomized controlled trials. MAIN MESSAGE: Repetitive strain injuries result from repeated stress to the body's soft tissue structures including muscles, tendons, and nerves. They often occur in patients who perform repetitive movements either in their jobs or in extracurricular activities. Common RSIs include tendon-related disorders, such as rotator cuff tendonitis, and peripheral nerve entrapment disorders, such as carpal tunnel syndrome. A careful history and physical examination often lead to the diagnosis, but newer imaging techniques, such as magnetic resonance imaging and ultrasound, can help in refractory cases. Conservative management with medication, physiotherapy, or bracing is the mainstay of treatment. Surgery is reserved for cases that do not respond to treatment. CONCLUSION: Repetitive strain injury is common; primary care physicians must establish a diagnosis and, more importantly, its relationship to occupation. Treatment can be offered by family physicians who refer to specialists for cases refractory to conservative management.

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.

Unicondylar knee arthroplasty: a cementless perspective.

OBJECTIVE: To compare the results of cementless unicondylar knee arthroplasty (UKA) with those already reported in a similar study on cemented UKA. DESIGN: A case-series cross-sectional study. SETTING: The Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax. PATIENTS: Fifty-one patients who underwent a total of 57 UKAs between May 1989 and May 1997. Inclusion criteria were osteoarthritis involving the predominantly the medial compartment of the knee, relative sparing of the other compartments, less than 15 degrees of varus, minimal knee instability, and attendance at the postoperative clinical visit. INTERVENTION: Cementless UKA. MAIN OUTCOME MEASURES: Clinical parameters that included pain, range of motion and the Knee Society Clinical Knee Score. Roentgenographic parameters that included alpha, beta, gamma and sigma angles and the presence of periprosthetic radiolucency or loose beads. RESULTS: Age, weight, gender and follow-up interval did not significantly affect the clinical results in terms of pain, range of motion or knee score. Knees with more than 1 mm of radiolucency had significantly lower knee scores than those with no radiolucency. Knees that radiologically had loose beads also had significantly lower knee scores. The clinical outcomes of cementless UKA were comparable to those already reported on cemented UKA. Cementless femurs had less radiolucency than the cemented femurs, whereas cementless tibias had more radiolucency than their cemented counterparts. CONCLUSIONS: Cementless UKA seems to be as efficacious as cemented UKA. However, there is some concern about the amount of radiolucency in the cementless tibial components. A randomized clinical trial comparing both cementless and cemented tibial components with a cementless femur (hybrid knee) is needed to further assess this controversial issue in UKA.

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.

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.

Comparative in vitro efficacy of different platelet glycoprotein IIb/IIIa antagonists on platelet-mediated clot strength induced by tissue factor with use of thromboelastography: differentiation among glycoprotein IIb/IIIa antagonists.

In the present study, the in vitro efficacy of different platelet glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists on platelet-fibrin-mediated clot strength under shear was compared with the antiaggregatory efficacy by using tissue factor (TF) thromboelastography (TEG). The ability of platelets to augment the elastic properties of blood clots under shear conditions was measured by computerized TEG under conditions of maximal platelet activation accelerated by recombinant TF. Under these conditions, platelets significantly enhance clot strength 8-fold (relative to platelet-free fibrin clots). This effect was inhibited to a different extent by various platelet GPIIb/IIIa receptor antagonists; this inhibition appears to be dependent on the transmission of platelet contractile force to fibrin via the GPIIb/IIIa receptors. The GPIIb/IIIa antagonists with high binding affinity for resting and activated platelets and slow platelet dissociation rates (class I) but not those with fast platelet dissociation rates (class II) demonstrated potent and comparable inhibition of platelet aggregation and TF-TEG clot strength. Platelet GPIIb/IIIa antagonists of class I, such as XV459 (free-acid form of roxifiban), DMP802, XV454, and c7E3, demonstrated comparable inhibitory dose responses of TF-TEG clot strength and platelet aggregation, with an IC(50) of 50 to 70 nmol/L. In contrast, platelet GPIIb/IIIa antagonists from class II, with comparable antiaggregatory efficacy, such as DMP728, YZ202 (free-acid form of orbofiban), YZ211 (free-acid form of sibrafiban), YZ751, and other antagonists, have a much lower efficacy in altering the strength of TF-mediated clot formation (IC(50) >1.0 micromol/L). These data suggest differential efficacy among different GPIIb/IIIa antagonists in inhibiting platelet-fibrin clot retraction despite of equivalent antiaggregatory potency.

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.

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.

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.

XV454, a novel nonpeptide small-molecule platelet GIIb/IIIa antagonist with comparable platelet alpha(IIb)beta3-binding kinetics to c7E3.

XV454 demonstrated high potency (IC50 = 14-25 nM) in inhibiting human platelet aggregation induced by adenosine diphosphate (ADP, 10 microM), thrombin receptor agonist peptide (TRAP) (10 microM), or collagen (20 microg/ml). XV454 exhibited a high degree of selectivity for platelet alpha(IIb)beta3 in comparison with c7E3, which is a nonspecific antagonist for both alpha(IIb)beta3 and alpha(v)beta3. Both XV454 and c7E3 bind with high affinity to either activated (A) or unactivated (U) human, baboon, or canine platelets. XV454 binds with a relatively higher affinity [Kd = 0.5 nM (A), 0.6 nM (U)] as compared with c7E3 [Kd = 9.1 nM (A), 9.2 (U) nM]. XV454 demonstrated a tight association with human, baboon, and, to a lesser extent, with canine platelets (t(1/2) of dissociation = 110 +/- 6, 80 +/- 10, and 23 +/- 2 min, respectively). Both c7E3 and XV454 associate tightly with a slower dissociation rate with unactivated human platelets: t(1/2) of 42 and 116 min, respectively. In non-human primates, oral (0.1 mg/kg, p.o.) and intravenous (0.05 mg/kg, i.v. bolus administration of XV454 methyl ester pro-drug resulted a long-lasting maximal antiplatelet efficacy for < or = 72 h with significant but reversible prolongation of bleeding time and without effects on platelet count, clinical chemistry, or hemodynamic profile. In conclusion, XV454 represents a potent antiplatelet agent in inhibiting platelet aggregation along with a high affinity and relatively slow dissociation rate from human platelet GPIIb/IIIa receptors that allow a long-lasting antiplatelet efficacy after single i.v. or oral administration.

Antiplatelet efficacy of XV459, a novel nonpeptide platelet GPIIb/IIIa antagonist: comparative platelet binding profiles with c7E3.

Recent advances in the development of i.v. platelet glycoprotein alphaIIb/beta3 integrin (GPIIb/IIIa) antagonists led to the development of either a class of small-molecular-weight antagonists with a short to ultra-short duration of antiplatelet effects (Integrelin, Tirofiban, DMP728) or a very long-acting antagonist (ReoPro). Thus the present study was undertaken to characterize the antiplatelet efficacy of a small-molecule GPIIb/IIIa antagonist, DMP754/XV459, and to determine its platelet GPIIb/IIIa receptor binding profiles. DMP754, upon its conversion with esterases to its free acid form XV459, and XV459 itself, demonstrated high potency (IC50 = 0.030-0.060 microM) in inhibiting human platelet aggregation induced by ADP (100 microM), thrombin receptor agonist peptide (10 microM) or collagen (20 microgram/ml) in citrate or heparin. Maximal platelet aggregation inhibition was achieved at 50 to >/=80% receptor occupancy, depending on the agonist used. Both XV459 and c7E3 bind with high affinity to either activated human platelets (Kd = 0.0008 and 0.0091 microM, respectively) or unactivated human platelets (Kd = 0.0025 and 0.0092 microM, respectively). XV459 demonstrated tight association with human, baboon and (to a lesser extent) canine platelets (t1/2 of dissociation = 7 +/- 0, 8 +/- 1 and 1.4 +/- 0.1 minutes, respectively). Both c7E3 and XV459 associate tightly with slower dissociation rates to unactivated human platelets. XV459 represents a potent antiplatelet agent in inhibiting platelet aggregation along with offering high affinity and a relatively slow dissociation rate from human platelet GPIIb/IIIa receptors that might allow for once-a-day p.o. dosage.

Oral antiplatelet efficacy and specificity of a novel nonpeptide platelet GPIIb/IIIa receptor antagonist, DMP 802.

This study was undertaken to define the platelet glycoprotein alphaIIb beta3 integrin (GPII/IIIa) affinity, specificity, and oral antiplatelet efficacy of DMP 802, a small-molecule nonpeptide antiplatelet agent. Platelet GPIIb/IIIa integrin binding affinity and specificity for DMP 802 were determined by using binding and adhesion assays with cells from various species, including human. DMP 802 demonstrated a potent antiplatelet efficacy [median inhibitory concentration (IC50), 0.029 +/- 0.0042 microM] in inhibiting human platelet aggregation induced by 10 microM adenosine diphosphate (ADP), as assessed by light-transmittance aggregometry. DMP 802 inhibited 125I-fibrinogen binding to activated (ADP, epinephrine, and arachidonic acid at 100 microM each) gel purified human platelets with an IC50 of 0.012 +/- 0.003 microM. DMP 802 demonstrated tight association with unactivated human, baboon, or canine platelets (t(1/2) of dissociation, 32 +/- 2, 32 +/- 13, and 11 +/- 1 min, respectively). DMP 802 binds with high affinity to both unactivated and activated human platelets (Kd = 0.61 +/- 0.17, 0.57 +/- 0.21 nM, respectively). DMP 802 demonstrated species specificity in inhibiting platelet aggregation with IC50 values ranging from 0.025 to 0.092 microM (human, guinea pig, dog, swine, hamster) and 0.88-1.0 microM (rabbit and rat) in platelets obtained from these various species. DMP 802 demonstrated a high degree of specificity for platelet GPIIb/IIIa (alphaIIb/beta3) as compared with other integrins including alpha(v)beta3 (IC50, >10 microM), alpha(v)beta5 (IC50, >100 microM), alpha4beta1 (IC50, >100 microM), and alpha5beta1 (IC50, >10 microM). Oral antiplatelet efficacy of DMP 802 was examined after single oral (0.05-0.20 mg/kg) and after repeated oral dosing at 0.05 mg/kg daily for 5 days in mongrel dogs. Dose-dependent antiplatelet efficacy with an extended duration of antiplatelet efficacy was demonstrated based on ex vivo inhibition of platelet aggregation induced by 100 microM ADP. DMP 802 has an oral bioavailability of 14.9% in dogs. In conclusion, the alpha sulfonamide isoxazoline analog, DMP 802, is a novel oral antiplatelet agent with high affinity, relatively slow dissociation rate and specificity for human platelet GPIIb/IIIa receptors.

Intravenous and oral antiplatelet/antithrombotic efficacy and specificity of XR300, a novel nonpeptide platelet GPIIb/IIIa antagonist.

Currently used antiplatelet drugs including aspirin, ticlopidine, and others are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. Thus our study was undertaken to define the antiplatelet efficacy, specificity, and the intravenous and oral antiplatelet/antithrombotic effects of a nonpeptide glycoprotein alphaIIb beta3 integrin (GPIIb/IIIa) antagonist XR300, an ethyl ester prodrug of XR299. XR300, on its conversion to the active form XR299, inhibited human platelet aggregation induced by 100 microM adenosine diphosphate (ADP) with a median inhibitory concentration (IC50) of 0.09 microM. Similarly, XR299 inhibited 125I-fibrinogen binding to human gel-purified platelets (IC50, 0.01 microM) regardless of the agonist used. In purified human GPIIb/IIIa, XR299 demonstrated a competitive high-affinity binding with an IC50 of 1.2 nM. XR299 demonstrated a high degree of specificity for platelet GPIIb/IIIa (alphaIIb beta3) as compared with other integrins including alpha(v)beta3, alpha(v)beta5, and alpha4beta1, where IC50 values were >10 microM. XR300 administered to mongrel dogs either intravenously (0.5-1.0 mg/kg, i.v.) or orally at 1.0-2.0 mg/kg, demonstrated maximal antiplatelet effects with rapid onset and extended duration. XR300 demonstrated maximal antithrombotic efficacy in preventing the incidence of occlusive thrombosis or cyclic flow reduction (CFR) in the carotid or femoral artery thrombosis models induced either electrolytically or by mechanical injury along with stenosis. In conclusion, XR300 is a novel intravenous and oral antiplatelet/antithrombotic agent with high affinity and specificity for platelet GPIIb/IIIa receptors.

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.

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.

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.

Advanced life support in the wilderness: 5-year experience of the Reach and Treat team.

Increasing recreation in the wilderness raises questions about the value of providing advanced life support (ALS) care in the backcountry. Since 1989 the Reach and Treat (RAT) team has provided ALS care in the wilderness area that surrounds Mount Hood, Oregon. The purpose of our study was to describe patient demographics, terrain, injuries, and ALS treatment in the wilderness environment. We utilized a retrospective, observational analysis of RAT missions from 1989 to 1994 based on data sheets maintained by the RAT team, prehospital run sheets, and hospital charts. Of the 114 missions analyzed, the median time of missions was 3 h, 9 min (range, 44 min-76 h) and 20% required technical climbing skills. Of the 74 patients treated, 55 (90%) received ALS care: 8 were intubated, 52 had intravenous lines established, and 24 received morphine for pain. Twenty patients were entered into the local trauma system. The most common injuries were extremity injuries (58), head injuries (18), and hypothermia (15). Mean time from arrival to return to staging area was 95 min. No injuries to RAT team members occurred during these missions, although two minor injuries occurred during training and testing. We found that wilderness-trained paramedics safely provided ALS care in a backcountry environment. This care may improve patient comfort during long extrication and speeds the arrival of potentially life-saving interventions such as advanced airway management.