Lifetime and 10-year risks of cardiovascular mortality in relation to risk factors in middle and old age: 50-year follow-up of the Whitehall study of London Civil Servants.

BACKGROUND: Cardiovascular disease (CVD)-related mortality has declined substantially in the United Kingdom (UK) in recent decades, but the continued relevance of conventional risk factors for prediction of CVD mortality throughout the life-course is uncertain. We compared the 10-year risks and lifetime risks of CVD mortality associated with conventional risk factors recorded in middle and old age. METHODS: The Whitehall study was a prospective study of 19,019 male London civil servants (mean age 52 years) when enrolled in 1967-1970 and followed-up for 50 years for cause-specific mortality. In 1997, 7044 (83%) survivors (mean age 77 years) were re-surveyed. The 10-year and lifetime risks of CVD mortality were estimated by levels of CVD risk factors recorded in middle-age and old-age, respectively. RESULTS: By July 2020, 97% had died (22%, 51% and 80% before age 70, 80 and 90 years, respectively) and 7944 of 17,673 deaths (45%) were from CVD. The 10-year and lifetime risks of CVD death increased linearly with higher levels of CVD risk factors recorded in middle-age and in old-age. Individuals in the top versus bottom 5% of CVD risk scores in middle age had a 10.3% (95% CI:7.2-13.4) vs 0.6% (0.1-1.2) 10-year risk of CVD mortality, a 61.4% (59.4-65.3) vs 31.3% (24.1-34.5) lifetime risk of CVD mortality and a 12-year difference in life expectancy from age 50 years. The corresponding differences using a CVD risk score in old-age were 11.0% (4.4-17.5) vs 0.8% (0.0-2.2) for 10-year risk and 42.1% (28.2-50.0) vs 30.3% (6.0-38.0) for lifetime risk of CVD mortality and a 6-year difference in life expectancy from age 70 years. CONCLUSIONS: Conventional risk factors remained highly predictive of CVD mortality and life expectancy through the life-course. The findings highlight the relevance of estimation of both lifetime risks of CVD and 10-year risks of CVD for primary prevention of CVD.

National pholcodine consumption and prevalence of IgE-sensitization: a multicentre study.

BACKGROUND: The aim of this study was to test, on a multinational level, the pholcodine (PHO) hypothesis, i.e. that the consumption of PHO-containing cough mixtures could cause higher prevalence of IgE antibodies to PHO, morphine (MOR) and suxamethonium (SUX). As a consequence the risk of anaphylaxis to neuromuscular blocking agents (NMBA) will be increased. METHODS: National PHO consumptions were derived from the United Nations International Narcotics Control Board (INCB) database. IgE and IgE antibodies to PHO, MOR, SUX and P-aminophenyl-phosphoryl choline (PAPPC) were measured in sera from atopic individuals, defined by a positive Phadiatop test (>0.35 kU(A)/l), collected in nine countries representing high and low PHO-consuming nations. RESULTS: There was a significant positive association between PHO consumption and prevalences of IgE-sensitization to PHO and MOR, but not to SUX and PAPPC, as calculated both by exposure group comparisons and linear regression analysis. The Netherlands and the USA, did not have PHO-containing drugs on the markets, although the former had a considerable PHO consumption. Both countries had high figures of IgE-sensitization. CONCLUSION: This international prevalence study lends additional support to the PHO hypothesis and, consequently, that continued use of drugs containing this substance should be seriously questioned. The results also indicate that other, yet unknown, substances may lead to IgE-sensitization towards NMBAs.

A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance.

PURPOSE: The aim of this study was to determine (i) the maximum tolerated dose (MTD) of liposomal doxorubicin (L-DOX) and paclitaxel (DP), (ii) the MTD of DP plus valspodar (DPV) and (iii) pharmacokinetic (PK) interactions of valspodar with L-DOX and paclitaxel. METHODS: Twenty-three patients with metastatic cancers received DP, followed 4 weeks later by DPV. Dose levels of DP were (mg/m2 for L-DOX/paclitaxel): 30/135 (n = 7), 30/150 (n = 4), 35/150 (n = 8) and 40/150 (n = 4). Dose levels of DPV were 15/70 (n = 10) and 15/60 (n = 10). Serial, paired PK studies were performed. RESULTS: The MTD of DP was 40/150. For DPV at 15/70, five of 10 patients experienced grade 4 neutropenia. In the next cohort, a reduced dose of 15/60 was well tolerated. Valspodar produced reversible grade 3 ataxia in seven patients, requiring dose reduction from 5 to 4 mg/kg. Paired PK studies indicated no interaction between L-DOX and valspodar, and a 49% increase in the median half-life of paclitaxel. Two partial and one minor remissions were noted. CONCLUSIONS: The use of valspodar necessitated dose reductions of DP, with neutropenia being dose limiting. Valspodar PK interactions were observed with paclitaxel but not L-DOX.

Can peripheral DXA measurements be used to predict fractures in elderly women living in the community?

While axial dual energy X-ray absorptiometry (DXA) is the accepted "gold standard" method both for diagnosing osteoporosis and predicting fractures, appropriate equipment is not universally available. Peripheral bone mass measurements may have the potential to identify patients at risk of fracture and to be used to target appropriate treatment. We assessed the effectiveness of peripheral DXA (PIXI, GELunar) in the assessment of risk and targeting treatment to prevent future fracture in 7,604 women aged 60-80 from five centres across Britain. At enrolment women completed a lifestyle and risk factor questionnaire and had a PIXI DXA scan of the heel. Women were categorised by PIXI DXA bone mineral density (BMD) into high, medium or low risk of future osteoporotic fracture. Treatment was recommended to those at highest risk. Follow-up was by simple questionnaire 18-24 months after baseline assessment. Seventy-four percent returned the follow-up questionnaire. The area under the receiver operator characteristic (ROC) curves for any fracture and osteoporotic fracture were comparable to those published using other sites and technologies. A 1-SD decrease in PIXI BMD was associated with an 86% increase in risk of osteoporotic fracture. Of the women identified as high risk, 74% had started treatment following their heel scan and 84.7% continued to take treatment at follow-up. No significant difference was noted in fracture rates in those who started treatment after assessment compared to those who did not. While peripheral DXA is highly effective for predicting older women who are at increased risk of future fracture, it has yet to be established as an effective method for targeting bisphosphonate or other therapy.

Determinants of PGA tour success: an examination of relationships among performance, scoring, and earnings.

Professional Golf Association (PGA) statistics for the 2002 season were analyzed to estimate the relationships between performance variables, scoring, and earnings. Two newly considered variables, Scrambling and Bounce Back percentages, showed meaningful correlation to Simple Scoring Average (rs = -.69 and -.40, respectively), and each made a significant contribution to a regression model. While the full model of performance variables explained most of the variance in Simple Scoring Average (R2 = .94), an adjusted scoring figure, accounting for the performance of the full field of players in each round, better correlated with Earnings over a PGA Tour season (r = .77).

Immunologic compensation in a patient with a large IgH constant region deletion.

BACKGROUND: Deficiencies of serum Ig of the IgG isotype typically predispose individuals to recurrent infections in some but not all cases. Patients with large deletions of the Ig heavy chain genes are free of recurrent and severe infections. OBJECTIVE: We sought to determine a mechanism of immunologic compensation that would possibly explain the reason for this patient's paucity of infection despite lacking several classes of serum Ig. METHODS: The patient is a 50-year-old white man. Serum Ig levels and specific antibody titers were measured by using various methods, including nephelometry, enzyme immunoassay, and radial immunodiffusion. The status of the Ig heavy chain genes was examined by means of Southern blotting of genomic DNA isolated from EBV-transformed B cells. RESULTS: The patient's serum lacked detectable IgG1, IgG2, IgG4, and IgA1 levels. Southern blot analysis demonstrated a large heavy chain constant (C) region gene deletion that included Cgamma1, Calpha1, psiCgamma, Cgamma2, and Cgamma4. Antibody responses to capsular pneumococcal and hemophilus polysaccharide antigens were essentially absent. However, IgG3 antibodies against the protein antigen tetanus toxoid were present. Relatively high antibody titers were found against pneumococcal surface proteins as well. CONCLUSION: We conclude that our patient's relative freedom from serious infection may be as a result of production of IgG3 antibodies to pneumococcal capsular proteins.

DICE 2: a further investigation of the effects of chance in life, death and subgroup analyses.

In an investigation into how chance might influence the distribution of deaths in a randomised trial and the time of those deaths, and to highlight the possible dangers of subgroup analyses, 100 randomised controlled trials were simulated and 50 subgroup pairs were simulated for some of these trials. Each of 580 control patients from a colorectal cancer trial was randomly coded to simulate allocation to treatment or control, the main outcome measure being time to death. Not surprisingly, most of the 100 trials gave non-significant results. Four were conventionally significant with logrank 2p-values of less than 0.05. The most extreme result was associated with a logrank 2p-value of 0.003, showing an absolute reduction in four-year mortality of 40% (SD 15) for patients allocated to treatment. One of the simulated prognostic factors for this trial (subgroup 13) showed that mortality for one type of patient was non-significantly slightly increased by treatment, whereas treatment reduced four-year mortality by 64% (SD 16) among the other patients in the trial (2p = 0.00006). Similar, extreme results were found for a trial of borderline statistical significance overall. Chance can influence the overall results of any randomised controlled trial, regardless of how well it is conducted, and can play an even more powerful role in the results of subgroup analyses. This should be borne in mind both by trialists when reporting their results and by readers and reviewers of those reports.

A phase I trial of doxorubicin, paclitaxel, and valspodar (PSC 833), a modulator of multidrug resistance.

PURPOSE: P-glycoprotein is an efflux pump for many drugs including doxorubicin and paclitaxel. This study evaluated the coadministration of these drugs with the P-glycoprotein inhibitor valspodar (PSC 833) with the aim of determining: (a) maximum tolerated doses (MTDs) of doxorubicin followed by paclitaxel (DP); (b) the MTD of DP combined with PSC 833 (DPV), without and with filgrastim (G-CSF); and (c) the pharmacokinetic interactions of PSC 833 with doxorubicin and paclitaxel. EXPERIMENTAL DESIGN: For the first cycle, patients received doxorubicin as a 15-min infusion followed by paclitaxel as a 1-h infusion. For the second cycle, patients received reduced doses of DP with PSC 833 at 5 mg/kg p.o., four times a day for 12 doses. RESULTS: Thirty-three patients with various refractory malignancies were enrolled and assessable. The MTD of DP without PSC 833 was 35 mg/m(2) doxorubicin and 150 mg/m(2) paclitaxel. The MTD of DPV without G-CSF was 12.5 mg/m(2) doxorubicin and 70 mg/m(2) paclitaxel. The dose-limiting toxicity for both DP and DPV was neutropenia without thrombocytopenia. With G-CSF, the MTD for DPV was 20 mg/m(2) doxorubicin and 90 mg/m(2) paclitaxel. No grade 4 nonhematological toxicities were observed. Five partial and two minor tumor remissions were observed. Paired pharmacokinetics with and without PSC 833 revealed substantial drug interactions with both doxorubicin and paclitaxel. CONCLUSIONS: PSC 833 can be administered safely with doxorubicin and paclitaxel. The pharmacokinetic profiles of these drugs are significantly affected by PSC 833, requiring approximately 60% dose reductions for equivalent degrees of myelosuppression.

Effects of timing of coil embolization after aneurysmal subarachnoid hemorrhage on procedural morbidity and outcomes.

OBJECTIVE: To elucidate the effect of treatment timing on procedural clinical outcomes after aneurysmal subarachnoid hemorrhage (SAH) for patients treated by endosaccular coil embolization. METHODS: A group of 327 patients who were consecutively treated, during a 46-month period, for ruptured intracranial aneurysms by coil embolization within 30 days after SAH were evaluated. Outcomes were assessed by comparing immediate pretreatment World Federation of Neurological Surgeons (WFNS) grades, 72-hour posttreatment WFNS grades, and modified Glasgow Outcome Scale scores at 6 months for patients treated within 48 hours (Group 1), 3 to 10 days (Group 2), or 11 to 30 days (Group 3) after SAH. RESULTS: The three interval-to-treatment groups included 33, 38, and 29% of the patients, respectively. Before treatment, 70% of the patients in Group 1, 78% of those in Group 2, and 83% of those in Group 3 were in good clinical grades (i.e., WFNS Grade 1 or 2). After coil embolization, the WFNS grades were either unchanged or improved for 93.5% of the patients in Group 1, 89.5% of those in Group 2, and 91.5% of those in Group 3. After 6 months, 81.3% of the patients in Group 1 experienced good outcomes (modified Glasgow Outcome Scale scores of 1 or 2), as did 84% of those in Group 2 and 80% of those in Group 3. No statistical difference was demonstrated between the three groups when they were compared for these two variables. CONCLUSION: The interval between endovascular treatment and SAH did not affect periprocedural morbidity rates or 6-month outcomes. Coil embolization should therefore be performed as early as possible after aneurysmal SAH, to prevent aneurysmal rerupture.

Corticosteroids do not alter the threshold for vertebral fracture.

Corticosteroid use is one of the most important secondary causes of osteoporosis. Generally, it has been believed that in addition to its effect on bone mineral density (BMD), it also causes an alteration in bone quality that means that fractures occur at a lower BMD than might be expected. To establish if this is the case, we have compared the relationship between BMD and vertebral fracture in patients receiving corticosteroids with that in patients who had never received such therapy. Information was gathered on those patients who had been referred to the participating centers and had both BMD measurements and lateral thoracolumbar radiographs. In all, 452 patients (391 female) were identified; of these 82 (63 female) were receiving corticosteroids. There was no significant difference in BMD between the patients on corticosteroids and those with other suspected causes of osteoporosis. Vertebral fractures were present in 53% of patients on steroids compared with 35% of those who had no such treatment (p = 0.0035). The fractures were more likely to be multiple in patients on corticosteroids (p = 0.0042). However, if the relationship between bone density and fracture is investigated by plotting the cumulative prevalence of fracture against the bone density, measured by T score, the median BMD for fractures actually was marginally lower in patients on steroids, -2.74 (95% confidence interval [CI], -2.77 to -2.70) compared with -2.65 (95% CI, -2.66 to -2.65) in those who had not received steroids. Our results fail to support the notion that the fracture threshold is altered in patients on long-term steroids and suggest that the same diagnostic criteria should be used for osteoporosis in patients whether or not they are taking corticosteroid therapy.

Direct access testing in the clinical laboratory: should laboratories offer testing services directly to the consumer?

This article outlines the author's views on the many issues to consider if a laboratory plans to initiate a program to offer clinical laboratory testing directly to the public. Direct access testing and why is it important are discussed in detail. The regulatory issues are outlined with some alternatives for laboratories in states with restrictive regulations. To illustrate many of the operational issues to consider, the author describes the Personal Diagnostic Center (PDC) in Kansas City. Finally, some of the key business issues are mentioned, including several approaches to promote this type of testing program.

Phase I study of an antisense oligonucleotide to protein kinase C-alpha (ISIS 3521/CGP 64128A) in patients with cancer.

Protein kinase C (PKC) is an attractive target in cancer therapy. It is overexpressed in a variety of cancers, and nonspecific inhibitors of PKC have demonstrated antitumor activity. Antisense oligonucleotides targeted against PKC-alpha, which have high specificity, can inhibit mRNA and protein expression as well as the growth of tumors in vitro and in vivo. This Phase I study sought to characterize the safety profile and to determine the maximum tolerated dose of antisense to PKC-alpha when administered by continuous infusion in patients. Patients with incurable malignancies received ISIS 3521, a 20-length phosphorothioate oligodeoxynucleotide specific for PKC-alpha. Treatment was delivered over a period of 21 days by continuous i.v. infusion followed by a 7-day rest period. Doses were increased from 0.5 to 3.0 mg/kg/day. Patients continued on the study until evidence of disease progression or unacceptable toxicity was detected. Between August 1996 and September 1997, 21 patients were treated in five patient cohorts. The maximum tolerated dose was 2.0 mg/kg/day. The dose-limiting toxicities were thrombocytopenia and fatigue at a dose of 3.0 mg/kg/day. Pharmacokinetic measurements showed rapid plasma clearance and dose-dependent steady-state concentrations of ISIS 3521. Evidence of tumor response lasting up to 11 months was observed in three of four patients with ovarian cancer. The recommended dose of ISIS 3521 for Phase II studies is 2.0 mg/kg/day when given over a period of 21 days. Side effects are modest and consist of thrombocytopenia and fatigue. Evidence of antitumor activity provides the rationale for Phase II studies in ovarian cancer and other malignancies.

Overcoming multidrug resistance: valspodar as a paradigm for nursing care.

PURPOSE/OBJECTIVES: To review the mechanisms of multidrug resistance (MDR) in human cancer and the clinical use of MDR modulators to overcome or reverse P-glycoprotein (P-gp)-mediated MDR. DATA SOURCES: Current literature, ongoing clinical trials, and clinical experience. DATA SYNTHESIS: Agents, such as valspodar, that block the activity of P-gp can reverse or overcome MDR caused by overexpression of P-gp. The MDR modulator valspodar (PSC 833; Novartis Pharmaceuticals Corporation, East Hanover, NJ) is examined as a model for establishing nursing guidelines for this new class of therapeutic agents. CONCLUSIONS: The dose of some chemotherapy agents must be modified with concurrent valspodar administration. Studies examining the safety and efficacy of valspodar as a prototype of MDR modulators provide the basis for establishing nursing care guidelines. IMPLICATIONS FOR NURSING PRACTICE: Nursing care for the administration of valspodar includes understanding patient selection, criteria, dosing, and administration; side-effect management; patient monitoring and follow-up; and patient education.