An international, open-label, randomised trial comparing a two-step approach versus the standard three-step approach of the WHO analgesic ladder in patients with cancer.

BACKGROUND: Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. PATIENTS AND METHODS: We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. RESULTS: One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P = 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P = 0.009) and costs were less. CONCLUSION: This trial provides some evidence that the two-step approach is an alternative option for cancer pain management.

Screening for viral hepatitis prior to rituximab chemotherapy.

In 2008, the CDC published guidelines recommending screening of all persons undergoing treatment with rituximab to identify persons at risk of hepatitis B virus (HBV) reactivation. We evaluated implementation of this recommendation in veterans, who are at increased risk of HBV, and determined characteristics of those screened. We also evaluated a control setting, rates of hepatitis C virus (HCV) screening among the same rituximab-treated patients. There are no guidelines that recommend HCV screening prior to initiation of rituximab. Medical records of patients receiving rituximab between January 2006 and December 2012 were reviewed according to two time periods: 2006-2008 (period 1, pre-guidelines) and 2009-2012 (period 2, post-guidelines). Patient demographics, concomitant chemotherapy regimen (protocol, dose, duration), treatment indication, risk factors for hepatitis infection (substance abuse, homelessness, human immunodeficiency virus (HIV)), and HBV/HCV screening status were documented. During the study period, 102 patients were treated with rituximab (49 in period 1 and 53 in period 2). During periods 1 and 2, 22 and 32 % of rituximab-treated patients were screened for HBV, respectively (p = 0.375). Treatment during 2009 was the only significant predictor of HBV screening in the adjusted model (p = 0.01). For HCV during periods 1 and 2, 22 and 21 % of patients were screened, respectively (p = 1.00). There were no significant predictors of HCV screening. Rates of screening for HBV among rituximab-treated patients were low, both before and after dissemination of guidelines recommending universal HBV screening of rituximab-treated patients.

Extended thromboprophylaxis post gynaecological cancer surgery; the effect of weight adjusted and fixed dose LMWH (Tinzaparin).

OBJECTIVE: Gynaecological cancer surgery is associated with high rates of venous thromboembolism (VTE) despite recommended prophylaxis. We sought to investigate the impact of extended prophylaxis with fixed dose and weight based LMWH in patients undergoing gynaecological cancer surgery. METHODS: VTE rates were recorded in patients who received LMWH prophylaxis (4500 IU Tinzaparin once daily) for the duration of hospital stay (2006-2012) (n = 610) and were compared with VTE rates in patients who underwent surgery after the introduction of extended prophylaxis (3500/4500 IU Tinzaparin for patients with BMI < 40kg/m2 and 75 IU/kg for BMI > 40 kg/m2) (2012-2017) (n = 651). Peak (4 h) anti-Xa levels in a subset of patients were also evaluated. RESULTS: 73 (5.7%) cases of VTE were recorded during 1 year of follow-up. 20 cases occurred during hospital stay. There was no significant difference in the rate of VTE between the extended prophylaxis cohort and the standard prophylaxis cohort. 23/24 patients who developed VTE in the extended prophylaxis cohort received a fixed (4500 units) dose of Tinzaparin. 63% of patients who received a fixed LMWH dose had peak anti-Xa levels below the target range (0.2-0.4 IU/ml). Peak anti-Xa was lower in patients who subsequently developed VTE compared with those who received either fixed dose (P = 0.041) and weight adjusted Tinzaparin (P = 0.0006). CONCLUSIONS: Extended prophylaxis with Tinzaparin does not significantly reduce VTE rates in gynaecological cancer patients post surgery. Peak anti-Xa levels may be suboptimal in many patients receiving a fixed LMWH dose. Further studies are required to determine whether weight adjusted doses of Tinzaparin may provide more effective prophylaxis following gynaecological cancer surgery.

Application of optimal band-limited control protocols to quantum noise sensing.

Essential to the functionality of qubit-based sensors are control protocols, which shape their response in frequency space. However, in common control routines out-of-band spectral leakage complicates interpretation of the sensor's signal. In this work, we leverage discrete prolate spheroidal sequences (a.k.a. Slepian sequences) to synthesize provably optimal narrowband controls ideally suited to spectral estimation of a qubit's noisy environment. Experiments with trapped ions demonstrate how spectral leakage may be reduced by orders of magnitude over conventional controls when a near resonant driving field is modulated by Slepians, and how the desired narrowband sensitivity may be tuned using concepts from RF engineering. We demonstrate that classical multitaper techniques for spectral analysis can be ported to the quantum domain and combined with Bayesian estimation tools to experimentally reconstruct complex noise spectra. We then deploy these techniques to identify previously immeasurable frequency-resolved amplitude noise in our qubit's microwave synthesis chain.

OC-12 - Peri operative venous thromboembolism prophylaxis in gynaecological cancer patients. A survey of current practice.

INTRODUCTION: Gynaecological cancer is associated with some of the highest rates of venous thromboembolism (VTE) with some subtypes of ovarian cancer associated with rates as high as 20%. VTE prophylaxis is an important part of post-operative management in gynaecological cancer patient care. Despite the evidence base and guidelines recommending extended VTE prophylaxis for patients undergoing major cancer surgery, adherence to best practice guidelines has been found to be low. AIM: The aim of this study is to assess gynaecological oncologist's awareness of the guidelines surrounding VTE prophylaxis for post-operative gynaecological cancer patients and to determine the type and duration of VTE prophylaxis implemented by gynaecological oncologists. MATERIALS AND METHODS: The study used the European Society Gynaecology Oncology (ESGO) membership as the population studied. ESGO is a multidisciplinary, non-profit association, founded in 1983. ESGO consisit of more than 1800 professional of different specialities dealing with gynaecological oncology. The e mail address of 650 member were avilable on the ESGO website. We send a Survey Monkey link to the questionnaire by email to a total of 650 ESGO member whose email addresses were obtained from the ESGO directory. 205 e mails returned back as the email used was invalied, only 445 e mail successfully delivered. The survey remained open for 44 days. Results were analysed on Survey Monkey. RESULTS: A 59.3% of respondents said that they decided upon appropriate VTE prophylaxis for a patient according to national/international best practice guidelines. A further 39.4% respondents said that they made their choice based upon clinical judgement. 59.8% of respondents said that they begin VTE prophylaxis pre-operatively for the high risk patients. 6.1% said that they begin prophylaxis in the operating theatre, 18.9% begin prophylaxis 6 hours post-operatively and 9.1% begin prophylaxis 12 hours post-operatively. The remaining respondents said that they begin VTE more than 24 hours post operatively 44.7% said that they prescribe VTE prophylaxis for 4 weeks. A further 15.9% said that they prescribe VTE prophylaxis for 6 weeks and 4.75% for longer than 6 weeks. CONCLUSIONS: In conclusion, the adherence to current guidelines for VTE prophylaxis in the peri-operative period for gynaecological oncology patients is still poor. Awareness needs to be raised in order to decrease the morbidity/mortality of VTE in this high risk group of patients. The adoption of multidiscplinary approach to manage gynaecological cancer patients, which includes the involvment of thrombosis specialist, may reduce post operative VTE rates and improve cancer care.

PO-24 - Determinants of thrombin generation in gynaecological malignancies.

INTRODUCTION: Increased thrombin production is associated with malignancy and is a marker for venous thromboembolism (VTE). Our group has shown that thrombin generation is increased in gynaecological malignancies. Although tumour derived Tissue Factor (TF) has been implicated, the precise mechanism by which thrombin production is increased is not fully understood. Our group has shown that gynaecological cancers can alter tumour expression of cogulation proteases. These changes may be implicated in the increased thrombin generation observed. Previous studies in normal control patients by other groups have shown that multiple coagulation factors are implicated in thrombin generation and that the effects depend on assay conditions however free Tissue Factor Pathway Inhibitor (TFPI), Factors V, VIIIc and protein S, were significant determinants of thrombin generation. AIM: The aim of this study was to determine the effect of factor V factor, VIIIc, TFPI and free protein S on the thrombin generation in patients with endometrial and ovarian cancer compared with benign controls. MATERIALS AND METHODS: Patients with a gynaecological malignancy (n=43) (ovarian or endometrial) were matched with patients with a benign tumour (n=43) gave full and informed consent. Venous blood samples were obtained prior to surgery and chemotherapy. Thrombin generation was was measured using a fluorogenic assay. Lag time, peak thrombin and area under the thrombin generation curve (ETP) was determined and reported for each sample. Free protein S, free TFPI and factor V were determined using ELISA. Factor VIIIc was determined using a hromogenic assay. RESULTS: Factor V and factor VIIIc were significantly increased in the malignant group compared with the benign group (P<0.03; P<0.006). Increased free TFPI levels were also observed in the malignant group but this did not reach significance (P<0.06). There was no difference in free Protein S levels between the groups. Highest levels of peak thrombin generation were observed in the high grade serous and clear cell ovarian cancer patients. Changes were less marked in the endometrial patients. Free TFPI, factor V and factor VIIIc were important determinants of thrombin generation in the malignant group. CONCLUSIONS: Coagulation factors V and VIIIc and free TFPI are altered in patients with gynaecological malignancies and contribute to the increased thrombin generation found in these cancer patients. We have previously found increased expression of factor V in tumours from patients with ovarian cancer in addition to increased TF expression. These changes may explain the high rate of venous thromboembolism found in these patients.

Procoagulant activity in gynaecological cancer patients; the effect of surgery and chemotherapy.

BACKGROUND: Gynaecological cancers are associated with high rates of venous thromboembolism (VTE). Studies on ambulatory cancer patients do not support thromboprophylaxis during chemotherapy. Approximately 6-7% of gynaecological cancer patients suffer a postoperative VTE despite Low Molecular Weight Heparin prophylaxis (LMWH). Large cancer studies have shown that Calibrated Automated Thrombogram (CAT) and Microparticles (MP) assays may be useful in predicting VTE but data on gynaecological cancer patients is scarce. OBJECTIVE: Our objective was to identify whether the CAT assay and MP functional assays have potential as biomarkers predictive of VTE in gynaecological cancer patients. PATIENTS AND METHODS: Gynaecological cancer patients were investigated before surgery (n=146) and at 5, 14 and 42days post-surgery (n=78). Fourteen additional patients were investigated before chemotherapy and after 3 and 6 cycles of therapy. Thrombin generation was measured before and after addition of thrombomodulin. RESULTS: Patients with clear cell cancer (CCC) of the ovary and patients with endometrial cancer had higher ETP and peak thrombin compared with patients with benign disease. Patients who developed VTE (n=8) following surgery had enhanced thrombin generation prior to surgery which persisted during the post-operative period despite LMWH prophylaxis. Both neoadjuvant and adjuvant chemotherapy showed increased thrombin generation following addition of thrombomodulin. There were no differences in MP levels during the study. CONCLUSIONS: CAT assay shows potential as a promising biomarker for the prediction of VTE in gynaecological cancer patients. The identification of high risk patients combined with individualised LMWH prophylaxis might reduce VTE in this high risk group.

PO-14 - Tumour expression of coagulation proteases of the aPC pathway - a role in the pathogenesis of gynaecological cancers?

INTRODUCTION: The close relationship between coagulation, thrombosis and cancer has long been established. Gynaecological cancers, in particular ovarian cancers, carry a high risk of thrombosis but coagulation activation is also thought to play a role in tumorigenesis and metastasis. In experimental animal models of metastasis, mice with a genetic procoagulant phenotype are prone to develop metastasis and anticoagulant therapy dramatically reduces pulmonary metastasis in these models. The aPC pathway is a key natural anticoagulant pathway, in addition to its role in venous thrombosis, dysregulation of this pathway is also thought to play a role in the pathogenesis of some cancers. No data exists in ovarian and endometrial cancers. AIM: The aim of this study is to determine the expression of key proteins of the activated protein C pathway in endometrial and ovarian malignant tumours compared to benign tumours and to assess their role in patient survival. MATERIALS AND METHODS: RNA was extracted from 78 (54 malignant and 24 benign) fresh frozen ovarian and endometrial tumours samples. Tumour biopsies were mRNA expression of endothelial protein C receptor (EPCR), protein S (PS), protein C (PC), thrombomodulin (TM), Factor V (FV) and VIII (FVIII) and PAR-1 and PAR-2 was measured using TaqMan Low Density Arrays. mRNA fold change relative to benign expression was determined using the 2 -delta delta Ct method with 18s as internal standard. All patients gave full and informed consent and the study had the approval of the hospital ethics committee. Total cell protein was extracted from ovarian tumour tissue. Enzyme-linked immunosorbent assay (ELISA) was used to measure protein plasma expression RESULTS: EPCR (P<0.001), protein S (P<0.0001) and Factor VIII (P<0.003) mRNA expression was significantly downregulated in malignant tumours compared with benign. Factor V and PAR-2 were significantly upregulated (P<0.001; P<0.004). Protein C was not consistently expressed. Reduced EPCR and TM protein expression was also observed in malignant tumours with increased plasma levels of Factor V. Reduced protein S and increased FV were associated with decreased survival. Plasma levels of Factor V were related to grade in the endometrial cancer group. PAR-2 mRNA expression was increased in ovarian tumours (P<0.001) however PAR-1 expression remained unchanged. CONCLUSIONS: Our results show reduced expression of key proteins associated with activation of protein C combined with increased expression in FV in gynaecological malignancies. These changes may contribute to local thrombin production and tumour progression and metastasis. Further work is required to determine the precise mechanisms involved.

Role of anticardiolipin antibodies in young persons with migraine and transient focal neurologic events: a prospective study.

Anticardiolipin antibodies (aCL) are a risk factor for cerebral ischemia. In migraine, the association is controversial, with widely varying results in different small series. The controversy in part may be due to the inherent difficulty in distinguishing the transient focal neurologic events (TFNE) of migraine from TIA. To assess the frequency of aCL in migraine, we prospectively evaluated consecutive adults under 60 years of age with migraine without aura and with recent TFNE (<24-hour duration) clinically suggestive of either migraine with aura or TIA. We concomitantly enrolled persons with no CNS disease. Each person was interviewed and had blood drawn for solid-phase ELISA with IgG and IgM aCL isotyping. Neuroradiologic studies were reviewed. Patients with TFNE were followed every 6 months for the duration of the 3-year study. The frequency of aCL positivity (IgG >20, IgG >40, IgM >7.5) for the 645 patients with TFNE (8.8, 3.1, 4.2%), the 518 persons in the TFNE subgroup with migraine with aura (8.9, 3.3, 4.1%), the 497 persons with migraine without aura (7.0, 2.0, 3.6%), and the 366 control subjects (9.3, 3.6, 3.9%) did not differ significantly between groups. In TFNE patients with elevated aCL titer, the association was positive with diabetes mellitus, TFNE duration <15 minutes, and diplopia and was negative with hemiparesis, tinnitus, and family history of stroke. Findings on imaging consistent with cerebral ischemia were more frequent in aCL-positive persons. The short-term risk of stroke was uniformly low. In young persons, aCL is not associated with migraine or with TFNE, although diabetes mellitus, negative family history of stroke, and brief duration of symptoms (including diplopia) may predict immunoreactivity. Imaging studies suggest an ischemic etiology of TFNE in this cohort.

The shrinking renal replacement therapy "break-even" point.

BACKGROUND: This study examines the current cost of live donor (LD) transplantation at our institution, and compares it with that of dialysis. METHODS: The study population consisted of 184 consecutive adult recipients of laparoscopically procured LD kidney transplants. Cost-containment measures instituted during this series included elimination of routine postoperative antilymphocyte induction and an accelerated discharge clinical pathway with planned discharge of the recipient on postoperative day (POD) 2. Costs of the transplants to Medicare were estimated from hospital charges, readmission rates, and immunosuppressant usage. These were compared with published costs of dialysis to Medicare in terms of a fiscal transplant-dialysis break-even point. RESULTS: Kaplan-Meier patient and graft survival rates at 1 year were 97 and 93%, respectively. Among patients followed for at least 90 days and treated with no induction and either cyclosporine-mycophenolate mofetil or tacrolimus-mycophenolate mofetil, acute rejection rates were low (27.6 and 13.9%, respectively). In the last 124 patients, 32.3% were discharged by POD 3 and 71.8% by POD 6, with corresponding mean transplant hospital charges (excluding organ acquisition) of $11,873 and $17,350, respectively. The 30-day readmission rate for patients discharged on the accelerated pathway by POD 3 was only 16%. The least expensive subgroup in the present study (30% of patients) was that of patients discharged by POD 6 and not readmitted during the first year; the break-even point with dialysis costs was calculated as 1.7 years after the transplant. CONCLUSIONS: The cost of LD transplants can be safely reduced by elimination of routine postoperative anti-lymphocyte immune induction and by an early discharge clinical pathway. Uncomplicated LD kidney transplants, meaning those with a short length of stay in the hospital after transplantation and no need for readmission within the first year, accrue savings over dialysis within 2 years.

Effect of oestrogen dose on whole blood platelet activation in women taking new low dose oral contraceptives.

Oral contraceptive use is known to cause changes in the haemostatic system. These changes are thought to be related to oestrogen dose and to provide a possible link between the increased risk of thromboembolic disease known to occur in women taking oestrogen containing oral contraceptives. This study measured whole blood platelet activation, serially, in women taking oral contraceptives containing 20 micrograms and 30 micrograms ethinyloestradiol combined with desogestrel. Increased levels of ADP and arachidonic acid induced aggregation were observed in women taking the 30 micrograms ethinyloestradiol combination. Platelet release of beta-thromboglobulin (beta TG) was also significantly increased. Increased collagen induced aggregation was observed but this failed to reach statistical significance for the individual treatment groups. In women taking the 20 micrograms ethinyloestradiol combination, a significant increase was only observed when platelets were stimulated with arachidonic acid. Platelet factor 4 (PF4) levels were unchanged in both groups. Significantly higher levels of beta TG were observed in women taking the 30 micrograms ethinyloestradiol combination compared with women taking the 20 micrograms ethinyloestradiol combination. These results show that oral contraceptive use is associated with platelet activation. Women taking the 20 micrograms ethinyloestradiol combination show less changes in platelet activation than women taking the 30 micrograms ethinyloestradiol combination. This lower dose pill may therefore be particularly suitable for high risk women wishing to use oral contraception.

PIP: To evaluate the effects of low-dose oral contraceptives (OCs) on platelet function, hematologic measures were compared in 45 Irish women taking OCs containing 20 or 30 mcg of ethinyl estradiol as well as 150 mcg of desogestrel. Serum samples were collected before treatment and at 6, 14, and 22 weeks after OC use commenced. ADP induced whole blood platelet aggregation was significantly increased in users of OCs containing 30 mcg of ethinyl estradiol, reaching a maximum at 22 weeks, but not in users of the low-dose OC. A significant increase in collagen induced aggregation was observed when both groups of OC users were combined, but not when either was tabulated separately. Both groups showed significant increases in arachidonic acid induced aggregation. Platelet count, hematocrit, and platelet factor 4 levels were unaffected. Increased levels of beta-thromboglobulin were observed at 6, 14, and 22 weeks in the 30 mcg group; there was no significant change in the 20 mcg group. Since the low-dose 20 mcg ethinyl estradiol OC produced fewer changes in platelet activation, its use is recommended for women with risk factors for thromboembolic disease.

Nitric oxide in the uteroplacental, fetoplacental, and peripheral circulations in preeclampsia.

OBJECTIVE: Altered production of nitric oxide by the vascular endothelium may influence the pathogenesis of preeclampsia. The aim of this study was to measure circulating levels of nitric oxide metabolites (nitrites) in the uteroplacental, fetoplacental, and peripheral circulation of preeclamptic pregnancies compared with normotensive controls. METHODS: Fifteen women with preeclampsia were compared with 16 women with normotensive pregnancies. At cesarean, blood samples were taken from the uterine vein draining the placental site, the umbilical vein, and the antecubital vein after delivery of the baby but before delivery of the placenta. Plasma nitrites were measured using the Greiss reaction after conversion of plasma nitrates to nitrites using nitrate reductase. RESULTS: Nitric oxide metabolites were higher in the uteroplacental (P < .01), fetoplacental (P < .001), and peripheral (P < .02) circulations in samples from preeclamptic pregnancies compared with control pregnancies. In samples from the fetoplacental circulation only, nitric oxide metabolite levels were negatively correlated with gestational age (r = -.489, P < .01) and birth weight (r = -.544, P < .004). Nitric oxide metabolite levels were not significantly correlated with blood pressure, placental weight, or maternal age. CONCLUSION: In established preeclampsia, production of nitric oxide was higher in the uteroplacental, fetoplacental, and peripheral circulation than in normotensive pregnancies. This increase may be part of a compensatory mechanism to offset the pathologic effects of preeclampsia.

The in vitro effect of aspirin on increased whole blood platelet aggregation in oral contraceptive users.

PIP: The effects of triphasic oral contraceptives on whole blood platelet aggregation in 36 Italian women are reported here. Aspirin's effects on platelet aggregation were also studied. 18 women took a triphasic oral contraceptive; 10 women took Trinordiol, while 8 took Trinovum for at least 90 days. The remaining 18 women took nothing and served as controls. The study was aligned with each woman's birth control pill cycle. Blood was taken daily on days 15-21 of their cycle. Either saline solution or acetylsalicylic acid was added to the blood samples and compared. All data was statistically analyzed using unpaired student's t-test. Effects of 3 aggregating agents, ADP, PAF, and EDTA, on platelet aggregation were studied. Arachidonic acid and adrenalin bitartrate were also studied in this manner. An increase in platelet aggregation was observed in women taking oral contraceptives. No difference was found between patients taking Trinordiol and those taking Trinovum. The results of this study indicate an increase in whole blood platelet sensitivity to collagen, adrenalin, and arachidonic acid when using oral contraceptives. Aspirin, at low doses, may have a role in preventing early thrombus formation in women taking oral contraceptives.^ieng

The role of thromboxane A2 in increased whole blood platelet aggregation in oral contraceptive users.

Epidemiological studies have shown that oral contraceptives increase the risk of thromboembolic disease in susceptible women however the mechanisms involved are unclear. We investigated whole blood platelet aggregation in 44 women randomly allocated to 6 cycles of treatment with either gestodene (75ug) or desogestrel (150ug) combined with 30ug ethinyloestradiol (EE). The in vitro effects of aspirin and a thromboxane synthetase inhibitor, dazmegrel (UK38485) were also investigated. Oral contraceptive treatment caused a significant increase in collagen, arachidonic acid (AA) and ADP induced whole blood platelet aggregation. PAF induced aggregation was unchanged. There were no significant differences in the levels of platelet aggregation between the desogestrel/30ugEE and gestodene/30ugEE groups. In vitro incubation of platelets with aspirin and dazmegrel prevented the oral contraceptive induced increase in platelet aggregation. Dazmegrel caused an on treatment decrease in PAF induced aggregation in the desogestrel/30ugEE but not the gestodene/30ugEE group. The results of this study indicate that the use of oral contraceptives is associated with an increase in platelet aggregation that is mediated by changes in thromboxane/prostacyclin ratio(TXA2/PGI2). Although no significant differences were found between the two different progestogen combinations, the effects of dazmegrel on PAF induced aggregation suggest a possible difference in the progestogen modifying effects of desogestrel and gestodene which is unmasked when thromboxane synthetase is inhibited.

PIP: In Ireland, researchers randomly assigned 44 healthy women, 18-34 years old, to either the group using the oral contraceptive (OC) containing 30 mcg ethinyl estradiol (EE) and 150 mcg desogestrel (Marviol) or the group using the OC containing 30 mcg EE and 75 mcg gestodene (Femodene) to determine the progestogen's modifying effect on whole blood platelet aggregation. In vitro, they incubated the platelets with aspirin and a thromboxane synthetase inhibitor (dazmegrel) to examine the role of thromboxane (TXA2) in any increased aggregation. The women were recruited from the postnatal clinic of the Coombe Women's Hospital in Dublin. OC use caused a significant increase in collagen-, arachidonic acid- (AA), and ADP-induced whole blood platelet aggregation (p 0.03, 0.001, and 0.01, respectively). It had no effect on PAF-induced aggregation, however. No significant differences in platelet aggregation levels existed between gestodene and desogestrel. Both aspirin and dazmegrel had a significant inhibitory effect on OC-induced increase in platelet aggregation in terms of collagen, AA, and ADP. This suggests that OCs act synergistically with ADP to cause a TXA2 mediated increase in platelet aggregation. Dazmegrel, but not aspirin, caused a decrease in PAF-induced platelet aggregation in the desogestrel/30 mcg EE group only, suggesting a possible difference in the modifying effects of the 2 progestogens, which is revealed when thromboxane synthetase is inhibited. Dazmegrel's inhibitory effect suggests that increased thromboxane synthetase activity plays a role in the OC-induced platelet hyperactivity. Changes in the TXA2/prostacyclin ratio appear to mediate OCs' effect on platelet aggregation.

Rotational modes of Ca2+-liganded calmodulin, as determined by time-domain fluorescence.

The time decay of fluorescence anisotropy was monitored as a function of pH and temperature for complexes of 2,6-toluidinylnaphthalenesulfonate with calmodulin, with its proteolytic fragments, and with the 1:1 complex of calmodulin and melittin. For all the conditions examined the anisotropy decay of native calmodulin involved at least two rotational modes. These corresponded to a short correlation time of 2-3 ns, reflecting a localized motion in the vicinity of the binding site and a longer correlation time which arises from the rotation of a major portion of the molecule. The relative amplitudes of the two rotational modes were dependent upon temperature in the range 11-40 degrees C, the contribution of the more rapid mode increasing with temperature. The maximum immobilization of the probe occurred at pH 5.0 and 12 degrees C. While these results indicate the presence of internal rotations in Ca2+-liganded calmodulin, the magnitude of the longer correlation time is consistent with the crystallographic structure.

Effects of oral contraceptives containing different progestogens on sodium-lithium countertransport in normal females.

In view of the lack of unanimity on the effect of long-term intake of combined oral contraceptives (OC) on external sodium-dependent lithium efflux, otherwise known as sodium-lithium countertransport (SLC), we undertook a double-blind study to investigate the possible interaction between SLC and OC in healthy women with regular menstrual cycles. In a group of 17 volunteers, aged 27.0 +/- 1.1 years (mean +/- s.e.m.) and weighing 61.4 +/- 2.0 kg, ingestion of 30 microg ethinyloestradiol + 150 microg desogestrel for 3 months caused an increase in SLC activity from a baseline value of 0.254 +/- 0.017 mmol/lcell x h to 0.274 +/- 0.017 mmol/lcell x h (P = 0.05). The activity of the transport system after 6 months treatment remained higher than at baseline (0.280 +/- 0.016 mmol/lcell x h, P < 0.025) but was comparable to that at 3 months. Blood pressure and weight remained unaltered during the study period. In a comparable group of 16 volunteers of age 26.1 +/- 1.3 years and weight 63.5 +/- 2.1 kg, control SLC activity (0.218 +/- 0.012 mmol/lcell x h) was comparable to that after 3 months (0.215 +/- 0.011 mmol/lcell x h) and 6 months (0.216 +/- 0.011 mmol/lcell x h) intake of 35 microg ethinyloestradiol + 2 mg cyproterone acetate. Body weight and blood pressure remained similarly unchanged. These results not only confirm that long-term intake of OC may cause increased SLC activity, but also suggest that the type of the progesterone in the medication used could be an important determinant of such interaction.

PIP: This double-blind study investigates the possible interaction between sodium-lithium countertransport (SLC) and oral contraceptives (OCs) in healthy women with regular menstrual cycles. 33 healthy females with regular menstrual cycles aged 18-35 years and weighing 43.5-73.0 kg were recruited. Each volunteer was randomly given either a 30 mcg ethinyl estradiol/150 mcg desogestrel combination or a 35 mcg ethinyl estradiol/2 mg cyproterone acetate combination. For each volunteer, blood was taken in the morning of days 15-18 of their menstrual cycle for biochemistry and SLC assay before treatment, and at the same stage of the cycle after 3 and 6 months. The study showed different effects of two different OC preparations in two groups of otherwise comparable volunteers. Administration of ethinyl estradiol/cyproterone acetate combinations for 6 months was not associated with alteration in any of the parameters measured. However, SLC activity increased after 3 and 6 months of ethinyl estradiol/desogestrel medication. These results not only confirm that long-term intake of OCs may cause increased SLC activity, but also suggest that the type of progesterone in the medication used could be an important determinant of such alteration in the activity of the transport system.

Everyday problem solving across the adult life span: influence of domain specificity and cognitive appraisal.

Differences in problem-solving strategies for situations varying in three domains, consumer, home management, and conflict with friends, were examined among younger, middle-aged, and older adults. In addition, this study examined the influence of perceived ability to resolve the problem, controllability, and causal attributions on strategy selection. In the 2 instrumental domains, older adults were more problem focused in their approach than adolescents and younger adults, whereas adolescents and younger adults selected more passive-dependent strategies. In the more interpersonal domain, conflict with friends, older adults tended to select avoidant-denial strategies more so than younger adults. Finally, across domains, the greater the perceived ability to resolve a problem the less the avoidant-denial strategy was selected. The importance of distinguishing between social and instrumental problem solving and of examining the cognitive appraisal of a problem situation are discussed.

Haemostatic risk factors in healthy postmenopausal women taking hormone replacement therapy.

OBJECTIVE: To compare changes in haemostatic parameters in healthy postmenopausal women taking either tibolone or 17beta-oestradiol/norethisterone acetate. METHODS: Factor VIIc, antithrombin, fibrinogen, thrombin-antithrombin complex (TAT), FDP (D-Dimer), tissue plasminogen activator (tPA) and plasminogen activator inhibitor I (PAI-1) were measured in 80 healthy postmenopausal women after 3, 6 and 12 months therapy with either 17beta-oestradiol/norethisterone acetate or tibolone. RESULTS: Both treatments significantly reduced fibrinogen, factor VIIc, antithrombin, tPA and PAI-1 antigen. Significantly lower levels of factor VIIc activity were observed on treatment with tibolone compared with 17beta-oestradiol/norethisterone acetate. TAT was unchanged with both treatments as was tPA activity. FDP (D-dimer) was increased on treatment with both preparations. CONCLUSIONS: The enhanced fibrin turnover and reduced antithrombin activity may play a role in the increased risk of venous thromboembolism in some susceptible women taking hormone replacement therapy (HRT) and could explain the lack of benefit of HRT in the secondary prevention of cardiovascular disease. The decreased levels of fibrinogen and factor VIIc found during treatment with 17beta-oestradiol/norethisterone acetate or tibolone may offer some degree of cardioprotection in healthy woman without pre-existing disease.