Cruciate Retaining compared with Posterior Stabilised Nexgen total knee arthroplasty: results at 10 years in a matched cohort.

INTRODUCTION Debate has persisted for many years about whether to sacrifice or replace the posterior cruciate ligament when performing total knee arthroplasty. A paucity of long-term follow-up studies comparing outcomes between cruciate-retaining and posterior-stabilised knees exist. We aimed to compare results at ten-year follow-up. METHODS A matched paired study comparing a cohort of 107 Zimmer Nexgen® Cruciate Retaining (CR) patients with a cohort of 107 Nexgen Posterior-Stabilised (PS) knees matched for age, sex, body mass index and preoperative American Knee Society score was undertaken. All patients underwent independent clinical assessment and knee society scoring preoperatively and at 1, 3, 5, 7 and 10 years postoperatively. RESULTS Fifty-three patients (49.5%) in the CR group and 44 patients (41.1%) in the PS group were alive at 10-year follow-up. There were no significant differences between the CR and PS groups with regards to functional assessment (P = 0.95), overall range of movement (P = 0.46) or patient satisfaction (P = 1.0) at 10 years. However, there was a significantly better score improvement in range of movement in PS knees compared with CR knees (P = 0.027). There were six revisions (5.6%) in the PS group and 1 (0.93%) in the CR group (P = 0.12). Both CR and PS knees showed excellent survivorship with no significant difference at 10 years (P = 0.068). CONCLUSIONS There were no significant differences in functional score, overall range of motion or patient satisfaction between the Nexgen cruciate retaining and posterior stabilised total knee arthroplasty at 10-year follow-up. However, PS knees had a greater score improvement in range of motion compared with CR knees.

Prasugrel inhibits platelet-enhanced pro-inflammatory CD4+ T cell responses in humans.

While platelets have well characterized effects on monocytes, the effect of platelet activation on CD4+ T-cell differentiation and cytokine production is not clear. To examine the effects of platelet T-cell interactions on T-cell phenotype, and whether these interactions were altered by prasugrel, we conducted a randomized, double-blind, placebo-controlled crossover study in healthy subjects. At baseline the addition of platelets to CD4+ T-cells resulted in an increase in the release of pro-inflammatory cytokine IFN-γ (192% increase in IFN-γ levels, p = 0.01) and pro-inflammatory CD4+ phenotypes, (38% and 58% increase in Th1 and Th17 phenotypic markers respectively, p = 0.01) but no change in Tregs. Prasugrel abolished the effects of platelets on CD4+ T-cells with similar levels of pro-inflammatory cytokines and cell numbers to T-cells stimulated. Antiplatelet therapy may provide therapeutic benefit both from direct platelet inhibition and also through indirect effects on immune response development.

Prevalence and significance of CYP2C19*2 and CYP2C19*17 alleles in a New Zealand acute coronary syndrome population.

BACKGROUND: High on-treatment platelet reactivity has been associated with poor outcomes following acute coronary syndromes (ACS). Both the loss of function CYP2C19*2 allele and the gain of function CYP2C19*17 allele along with a range of clinical characteristics have been associated with variation in the response to clopidogrel. AIM: The study aims to examine the frequency of CYP2C19 variants and understand the factors associated with on-treatment platelet reactivity in a New Zealand ACS population. METHODS: We prospectively enrolled 312 ACS patients. We collected clinical characteristics and measured on-treatment platelet reactivity using two validated point-of-care assays, VerifyNow and Multiplate. DNA was extracted and CYP2C19*2 and *17 alleles were identified using real-time polymerase chain reaction. RESULTS: CYP2C19*2 or CYP2C19*17 alleles were observed in 101 (32%) and 106 (34%) of patients, respectively, with significant differences in distribution by ethnicity. In Maori and Pacific Island patients, 47% (confidence interval (CI) 31-63%) had CYP2C19*2 and 11% (CI 4-19%) CYP2C19*17 compared with 26% (CI 19-32%) and 41% (CI 32-49%) in white people. Carriage of CYP2C19*2 alleles was associated with higher levels of platelet reactivity measured by either assay, but we observed no relationship between platelet reactivity and CYP2C19*17. In multivariate analysis diabetes, clopidogrel dose and CYP2C19*2 status were all significant independent predictors of platelet reactivity. CONCLUSIONS: Both CYP2C19*2 and *17 were common in a New Zealand ACS population, with CYP2C19*2 observed in almost half the Maori and Pacific Island patients. CYP2C19*2, diabetes and clopidogrel dose were independent contributors to on-treatment platelet reactivity.

Suboptimal response to clopidogrel and the effect of prasugrel in acute coronary syndromes.

BACKGROUND: High on clopidogrel platelet reactivity (HPR) has been associated with adverse outcomes following acute coronary syndromes (ACS). This study investigated the rate of HPR in a New Zealand ACS population and examined the effectiveness of prasugrel in reducing platelet reactivity in those with HPR. METHODS: In this prospective cohort study, 250 patients with ACS were pretreated with aspirin and clopidogrel and residual platelet reactivity was measured using whole blood multiple electrode platelet aggregometry. Twenty-seven of the patients with HPR were treated with prasugrel at the discretion of their physician, and platelet reactivity retested. RESULTS: Ninety-five patients (38%) had HPR. Maori and Pacific Island patients had a higher rate of HPR compared to Europeans (57% versus 35.9%, p=0.013). Additionally, patients with diabetes were also found to have higher rate of HPR compared to non-diabetics (50% versus 34.8%, p=0.045). Patients treated with a low dose clopidogrel regimen had significantly higher rates of HPR (45.4%) compared to those treated with intermediate (25.4%) or high dose regimens (26.8%, p=0.009). All of the 27 patients with HPR who were subsequently treated with prasugrel (60 mg) had a significant decrease in platelet reactivity (660 AU min (565-770) before versus 230 AU min (110-345) after, p<0.001), and was reduced to below the HPR cutoff in 24 (88.9%) of the patients. CONCLUSIONS: Ethnicity, diabetes and clopidogrel dose contributed to HPR. The use of prasugrel in those with HPR resulted in a consistent and marked reduction in platelet reactivity.

Self-expanding stents for malignant dysphagia.

Self-expanding metallic stents have been employed successfully for vascular, urethral, and biliary strictures. In a prospective study we examined the efficacy of the 16 mm Wallstent for palliation of malignant dysphagia. Eight patients with severe dysphagia due to advanced primary (four) or secondary (four) oesophageal malignant disease were recruited and nine Wallstents were inserted (one patient required two). Dysphagia was reduced in all but one patient, who died after oesophageal perforation; a second patient had a self-limiting bout of haematemesis. Two patients required subsequent treatment for tumour ingrowth but five had no further palliative therapy from stent insertion to time of death. With careful patient selection and skillful application, a 16 mm self-expanding metal endoprosthesis affords effective palliation in malignant oesophageal obstruction.

Investigations on the percutaneous absorption of the antidepressant rolipram in vitro and in vivo.

In vitro experiments using full-thickness human skin showed that it was feasible to deliver therapeutic amounts of the new antidepressant drug rolipram. Simple transdermal devices were constructed, and the presence of isopropyl myristate (IPM) in a silicone adhesive (Dow Corning X7-2920) enhanced the flux across excised human skin. The steady-state fluxes from adhesive mixtures containing 0, 5, and 10% IPM were 3, 5.2, and 6 micrograms/cm2/hr, respectively. The in vitro experiments were confirmed in a clinical study involving six healthy male volunteers. The formulations tested were an alcoholic solution and adhesive patches containing 5 and 10% IPM. The dose of drug administered was 0.5 mg/cm2 and the device size 25 cm2. Blood samples were withdrawn over a 24-hr period and analyzed using radioimmunoassay. The topical applications were well tolerated, with only mild or no side effects. A lag time of approximately 2 hr was found for the detection of rolipram in the plasma (detection limit, 50 pg/ml). Interindividual variations both for the peak drug levels and throughout the delivery were quite high but this magnitude of variation has been observed in many other transdermal studies. Plasma levels between 1 and 2 ng/ml were found for all formulations and the AUC0-30 hr was significantly higher for the patch containing 5% IPM.

The effects of ions and hypothalamic factors on the in vitro activity of rainbow trout prolactin cells.

The influence of various ions and of dopamine and somatostatin on the in vitro activity of rainbow trout prolactin (PRL) cells was investigated. There was a positive correlation between medium Ca2+ concentration and both PRL synthesis and release up to 1.8 mM Ca2+, above which no further increase occurred. Even with no Ca2+ in the medium, there was still PRL secretion during the incubation. Replacement of Ca2+ with Ba2+ in the medium did not elevate either total PRL levels or PRL release above that in Ca2 +)-free medium. Neither elevated Mg2+ nor increased medium K+ had any effect on PRL synthesis or release. Dopamine inhibited PRL release but not synthesis, as did the D2 receptor agonist, apomorphine. However, the D2 receptor antagonist, (+)-butaclamol was unable to prevent the action of dopamine on PRL release. Somatostatin inhibited both PRL synthesis and release in normal Ca2+ medium, but release only in reduced Ca2+ medium. Thus, Ca2+, dopamine, and somatostatin may all have roles in regulating prolactin secretion in this fish. In addition, oPRL reduced trout PRL release, indicating a possible negative feedback mechanism for trout PRL secretion.

The intracellular regulation of prolactin cell function in the rainbow trout, Salmo gairdneri.

The mechanisms for regulation of prolactin (PRL) secretion in the rainbow trout were investigated. The inhibitory action of dopamine on PRL release in vitro was enhanced by GTP and dopamine also reduced pituitary cAMP content. Forskolin increased both PRL release and cAMP content in vitro, but this effect was prevented by dopamine and did not occur in Ca2+-free medium. The cAMP analogue, dbcAMP increased PRL synthesis in low Ca2+ medium, though release was not significantly affected. The calcium ionophore, A23187, increased PRL release, but this effect was not seen with flunarizine, a voltage-dependent Ca2+-channel blocker. The calmodulin blocker, pimozide, increased PRL synthesis and pituitary PRL content in vivo and a second calmodulin blocker, trifluoperazine, also increased PRL synthesis, though not percentage release, in vitro. Both drugs elevated pituitary cAMP levels. These results indicate an involvement of agonist-dependent Gi proteins, Ca2+, calmodulin, and cAMP in the control of PRL cells in this teleost.