An incidental finding of persistent trophoblastic tissue.
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Abortion, Incomplete↗
Biomedical subjects
S Holden
Publications and source records attributed to S Holden.
A phase I and pharmacokinetic study of BAY59: a novel taxane.
PURPOSE: To determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLT) and the pharmacokinetics of BAY59, a novel taxane given as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: Initially, 15 patients with previously treated (median of 4 prior chemotherapy regimens) refractory cancers, but with normal marrow, hepatic and renal function were treated with BAY59 at doses of 15, 30, 50, 75 and 100 mg/m2 using a standard dose escalation design. Subsequently, 11 patients were treated, 5 at 90 mg/m2 and 6 who had had prior oxaliplatin at 75 mg/m2. RESULTS: At 75 mg/m2, grade 4 neutropenia was noted in 2/6 patients, of whom 1 had grade 4 neutropenia lasting more than 5 days (DLT). At 100 mg/m2, 2/2 patients had febrile neutropenia, with 1 fatality. At 90 mg/m2, 2/5 patients had DLTs, including grade 3 neuropathy, severe lower extremity pain, dehydration and grade 4 neutropenia. The MTD was determined to be 75 mg/m2. A cohort of 6 patients, previously exposed to oxaliplatin, were enrolled at the MTD to evaluate the incidence of neurotoxicity. While DLTs (grade 3 arthralgia, grade 4 neutropenia) were noted in 3/6 patients, there was no increase in the incidence of neurotoxicity. There were no responses. Pharmacokinetics of BAY59 was linear over the doses studied, with a median terminal half-life of 21 h. CONCLUSIONS: The recommended phase II dose for BAY59 is 75 mg/m2.
Adult↗
The effectiveness of community-based animal health workers, for the poor, for communities and for public safety.
The development of community animal health (CAH) is an invaluable tool for addressing a series of challenges, particularly for the policy-maker, whose prime concern is public welfare. This paper examines three of the major challenges which confront governments, particularly the governments of less-developed countries, namely, the collapse of government services, the crucial issue of poverty reduction and the misuse of animal drugs. Although CAH is a potentially powerful tool for approaching all of these problems, the authors argue that CAH can only be fully exploited on a macroscopic level by developing strong institutions to support and regulate such community initiatives. In some countries, developing such institutions depends upon accepting the more fundamental and controversial principle of legalising non-professional animal health service providers who work within the private sector. In Section 1, the authors outline the three principal challenges which face governments, particularly in developing countries, and to which CAH offers a potential solution. Sections 2 to 4 investigate the evidence relating to each of these challenges in turn. Section 5 briefly draws on the lessons that have been generated by field experiences over the years, to propose how governments may develop CAH systems to their best advantage.
Animal Welfare↗
Tissue Doppler echocardiography in patients with thalassaemia detects early myocardial dysfunction related to myocardial iron overload.
AIMS: To compare an echocardiographic method for detecting abnormal cardiac function before development of overt cardiomyopathy with a recently validated technique of quantifying myocardial iron load. METHODS AND RESULTS: We examined thalassaemia patients whose myocardial iron load had been evaluated with magnetic resonance imaging (MRI). By tissue Doppler echocardiography, myocardial velocities were sampled continuously from base to apex in the RV and LV free wall, and the septum in 52 patients aged 29.2 (14.2-43.1) years and 52 age-matched controls. Ninety-six percent of patients had normal LV ejection fraction by MRI. Thirty-eight (73%) had abnormal iron loading of the myocardium, and 33 of those had regional wall motion abnormalities detected in the septum (n=29), LV (n=2), RV (n=1), and septum plus LV (n=1). The incidence of wall motion abnormalities was significantly higher (P<0.04) in patients with myocardial iron overload (87%) than in the 14 without (35%). Furthermore, myocardial iron overload was suggested by a low T2(*)(15.1+/-15.8 ms) in patients with wall motion abnormalities vs those with normal wall motion (T2(*): 30+/-19 ms) (P<0.007). CONCLUSIONS: Wall motion abnormalities may represent an early sign of cardiac disease despite preserved global function. The regional abnormalities are related to iron overload and easily detectable with tissue Doppler echocardiography.
Adolescent↗
Drug design by machine learning: support vector machines for pharmaceutical data analysis.
We show that the support vector machine (SVM) classification algorithm, a recent development from the machine learning community, proves its potential for structure-activity relationship analysis. In a benchmark test, the SVM is compared to several machine learning techniques currently used in the field. The classification task involves predicting the inhibition of dihydrofolate reductase by pyrimidines, using data obtained from the UCI machine learning repository. Three artificial neural networks, a radial basis function network, and a C5.0 decision tree are all outperformed by the SVM. The SVM is significantly better than all of these, bar a manually capacity-controlled neural network, which takes considerably longer to train.
Algorithms↗
Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload.
AIMS: To develop and validate a non-invasive method for measuring myocardial iron in order to allow diagnosis and treatment before overt cardiomyopathy and failure develops. METHODS AND RESULTS: We have developed a new magnetic resonance T2-star (T2*) technique for the measurement of tissue iron, with validation to chemical estimation of iron in patients undergoing liver biopsy. To assess the clinical value of this technique, we subsequently correlated myocardial iron measured by this T2* technique with ventricular function in 106 patients with thalassaemia major. There was a significant, curvilinear, inverse correlation between iron concentration by biopsy and liver T2* (r=0.93, P<0.0001). Inter-study cardiac reproducibility was 5.0%. As myocardial iron increased, there was a progressive decline in ejection fraction (r=0.61, P<0.001). All patients with ventricular dysfunction had a myocardial T2* of <20 ms. There was no significant correlation between myocardial T2* and the conventional parameters of iron status, serum ferritin and liver iron. Multivariate analysis of clinical parameters to predict the requirement for cardiac medication identified myocardial T2* as the most significant variable (odds ratio 0.79, P<0.002). CONCLUSIONS: Myocardial iron deposition can be reproducibly quantified using myocardial T2* and this is the most significant variable for predicting the need for ventricular dysfunction treatment. Myocardial iron content cannot be predicted from serum ferritin or liver iron, and conventional assessments of cardiac function can only detect those with advanced disease. Early intensification of iron chelation therapy, guided by this technique, should reduce mortality from this reversible cardiomyopathy.
Adolescent↗
401(k) plan asset allocation, account balances, and loan activity in 1999.
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Adult↗
Contribution behavior of 401(k) plan participants.
This Issue Brief examines the 1999 contribution behavior of 1.7 million 401(k) plan participants drawn from the EBRI/ICI Participant-Directed Retirement Plan Data Collection Project. The findings in this paper build on previous academic research examining the contribution activity of 401(k) participants, by using a large sample of participants in a wide range of plan sizes and by examining in detail the factors that influence contribution activity. Eighty-five percent of participants in the sample only made before-tax contributions to their plans, and 97 percent of all dollars contributed by employees were contributed on a before-tax basis. On average, participants contributed 6.8 percent of their salaries on a before-tax basis. Before-tax contribution activity varied among participants. About 61 percent of participants contributed more than 5 percent of their salaries on a before-tax basis and about 21 percent set aside more than 10 percent of their salaries on a before-tax basis. Eleven percent of participants analyzed in this study earning more than $40,000 a year contributed at the $10,000 before-tax IRC limit in 1999. Thirteen percent of participants with salaries between $70,000 and $80,000 contributed at the cap, and 18 percent of those with salaries between $80,000 and $90,000 were at the limit. However, it appears that among participants not contributing at the IRC limit, 52 percent could not have done so because of formal plan-imposed contribution limits below the IRC limit. Older participants tended to contribute a higher percentage of their salaries to plans than did younger participants, even after factoring out differences in salary and job tenure. Participants tended to increase the share of their salary (and amounts) contributed to their 401(k) plan as their salaries rose until salaries reached $80,000. For individuals with salaries above $80,000, before-tax contribution rates (though not the amounts contributed) tended to fall as salaries rose because IRC, and possibly plan sponsor, contribution limits became binding for some participants. Giving employees the option of borrowing from their 401(k) accounts increased participant contribution rates. On average, a participant in a plan offering loans appeared to contribute 0.6 percentage point more of his or her salary to the plan than a participant in a plan with no loan provision. Total contributions--the sum of employee and employer contributions--were higher for participants who received an employer contribution as part of their 401(k) plan than for those who did not. The average total contribution rate was 10 percent of salary for employees in plans offering an employer contribution, compared with 7.4 percent for those in plans not offering an employer contribution.
Adult↗
401(k) plan asset allocation, account balances, and loan activity in 2000.
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Adult↗
Down-Regulation of prostate-specific antigen expression by ligands for peroxisome proliferator-activated receptor gamma in human prostate cancer.
The peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily. Recent studies found that ligand-activated PPARgamma regulated differentiation and clonal growth of several types of cancer cells, including prostate cancer, suggesting that PPARgamma could be a tumor suppressor. Troglitazone was a widely used antidiabetic drug that activates PPARgamma. Recently, we reported that this agent had antiprostate cancer effects in vitro and in vivo. In this study, we administered troglitazone for over 1.5 years to an individual with occult recurrent prostate cancer. Using the prostate-specific antigen (PSA) levels as a surrogate marker of the disease, the oral administration of troglitazone (600-800 mg/day) reduced the increase velocity of PSA levels, suggesting clinical efficacy of troglitazone in prostate cancer. PSA promoter/ enhancer reporter assays showed that the PPARgamma ligands troglitazone (10(-5) M), pioglitazone (10(-5) M), or 15-deoxy-delta12,14-prostaglandin J2 (10(-5) M) down-regulated androgen-stimulated reporter gene activity in LNCaP cells, a prostate cancer cell line. The PSA promoter contains androgen receptor response elements (AREs). Reporter gene studies showed that troglitazone inhibited androgen activation of the AREs in the PSA regulatory region. Consistent with inhibition of gene expression, 2 days of incubation of LNCaP with troglitazone dramatically suppressed PSA protein expression without suppressing AR expression, suggesting that troglitazone inhibited ARE activation by a mechanism other than down-regulation of expression of the AR. Taken together, ligands of PPARgamma may be a useful therapeutic approach for the treatment of prostate cancer and may be acting, in part, by inhibiting transactivation of androgen-responsive genes.
Adenocarcinoma↗
PC-SPES: a unique inhibitor of proliferation of prostate cancer cells in vitro and in vivo .
BACKGROUND: Management of prostate cancer that has spread beyond the capsule is a difficult problem. Innovative and nontoxic approaches to the disease are urgently required. Recently, a commercially available herbal mixture called PC-SPES showed potent antitumor activities on a variety of malignant cells in vitro. METHODS: PC-SPES was evaluated for its ability to inhibit clonal growth, and to induce cell cycle arrest of three human prostate cancer cell lines (LNCaP, PC-3, and DU 145). Western blot analysis examined the effect of PC-SPES on levels of p21(waf1), p27(kip1), Bcl-2, and E-cadherin in the three cell lines; and telomerase activity was examined by telomeric repeat amplification protocol (TRAP) assay. Furthermore, the effect of oral PC-SPES (250 mg/kg/day) on growth of PC-3 and DU 145 tumors present in male BNX nu/nu triple immunodeficient mice was studied. LNCaP cells were not analyzed in mice because they grow only with difficulty in these immunodeficient mice. RESULTS: PC-SPES markedly inhibited clonal growth of LNCaP, PC-3, and DU 145 prostate cancer cells, with a 50% inhibition (ED50) at approximately 2 microl/ml. Pulse-exposure studies showed that a 5-day pulse-exposure to PC-SPES (2 microl/ml) in liquid culture achieved a 50% inhibition of PC-3 clonal growth in soft agar, suggesting that the growth inhibition mediated by the extracts remained after removal of PC-SPES. Cell cycle analysis using the prostate cancer cell lines found that PC-SPES induced a significant increase in the number of cells in G0-G1 and G2/M, with a concomitant decrease in the number of cells in S phase. PC-SPES (2 microl/ml, 4 days) increased slightly the levels of p21(waf1) in the three cell lines, decreased by 40% the levels of Bcl-2 in PC-3, and the levels of p27(kip1) and E-cadherin and telomerase were unchanged in each of the lines. In vivo treatment with oral PC-SPES of male BNX mice having DU 145 tumors produced significant inhibition of their growth (P < 0.001), with no objective side effects including blood chemistries, weights, or autopsy analysis. The PC-SPES showed no statistical effect on the in vivo growth of PC-3 cells. CONCLUSIONS: PC-SPES inhibits clonal proliferation of human prostate cancer cells both in vitro and in vivo, using a murine model.
Androgens↗
Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major.
Clinical complications of transfusional iron overload are still common in patients with thalassaemia major (TM) and it is not clear how best to monitor body iron stores during long-term follow-up to anticipate tissue damage. In this study, we have reviewed a group of 32 patients who underwent liver biopsy between 1984 and 1986. We developed a method of assessing the trend in serum ferritin (TSF) during long-term monitoring and compared this with mean serum ferritin (MSF) and initial liver iron (LI) concentration to determine whether, individually or in combination, they were accurate in predicting clinical outcome. LI levels were low (< 7 mg/g), medium (7-15 mg/g) and high (> 15 mg/g dry weight) in 15, 7 and 10 patients respectively. MSF was low (< 1500 microg/l), medium (1500-2500 microg/l) and high (> 2500 microg/l) in 10, 14 and 8 patients. TSF was low, medium and high risk in 9, 9 and 11 out of 29 evaluable patients. During a median follow-up of 13.6 years (range 2.3-14.8 years) after biopsy, nine patients died and an additional three patients developed heart failure. Hypothyroidism developed in five, hypoparathyroidism in four, and diabetes mellitus in seven patients. Cirrhosis developed in four of 10 evaluable patients. The clinical end-point of death or cardiac failure was significantly associated with increasing iron load using all three means of assessment. Although numbers were insufficient for statistical analysis, MSF or TSF were more closely associated with complications of iron overload than LI. There was no clear additional value in combining LI with MSF or TSF. The data show that quantitation of liver iron from a single liver biopsy has little value in long-term monitoring of iron stores. Most complications can be avoided if ferritin levels can be brought down to <1500 microg/l.
Adolescent↗
The April 8, 1998 tornado: assessment of the trauma system response and the resulting injuries.
BACKGROUND: On April 8, 1998, an F5 tornado touched down in two counties of Alabama producing a wide path of destruction. The presence of a regional trauma system in this area presents an opportunity to evaluate the effectiveness of the system in responding to the victims of this natural disaster. METHODS: Emergency room logs and the regional trauma system database were searched for all patients treated for injuries sustained from the tornado, and medical records were reviewed for demographic information, mode of transportation to hospital, injuries, treatment, and outcome. Fatalities were identified by means of the coroner's office. RESULTS: A total of 224 patients were evaluated at nine area hospitals, of whom 63 (28%) required admission. There were 32 deaths: 30 persons were dead at the scene, and 2 patients subsequently died at Level I trauma centers. Among patients with nonfatal injuries, 39% were managed at Level I facilities, 46% at Level III facilities, and 15% at nontrauma facilities. Forty patients (55%) seen at Level I facilities required admission compared with 15 patients (17%) at Level III facilities and 8 patients (29%) at nontrauma facilities; Level I facilities also had the highest Injury Severity Score. Of patients requiring admission, 83% were transported by emergency medical services; these patients also had the highest Injury Severity Score. CONCLUSION: The regional trauma system facilitated appropriate and efficient triage to system hospitals, routing the most severely injured patients to the Level I centers without overwhelming them with the more numerous, less severely injured patients.
Adult↗
401(k) plan asset allocation, account balances, and loan activity in 1998.
The Employee Benefit Research Institute (EBRI) and the Investment Company Institute (ICI) have been collaborating for the past three years to collect data on participants in 401(k) plans. This effort, known as the EBRI/ICI Participant-Directed Retirement Plan Data Collection Project, has obtained data for 401(k) plan participants from certain of EBRI and ICI members serving as plan record keepers and administrators. The report includes 1998 information on 7.9 million active participants in 30,102 plans holding nearly $372 billion in assets. The data include demographic information, annual contributions, plan balances, asset allocation, and loans, and are broadly representative of the universe of 401(k) plans. The database also includes three years of longitudinal information on approximately 3.3 million participants. Key findings include: For all 401(k) participants in the 1998 EBRI/ICI database, almost three-quarters of plan balances are invested directly or indirectly in equity securities. Specifically, 49.8 percent of total plan balances are invested in equity funds, 17.7 percent in company stock, 11.4 percent in guaranteed investment contracts (GICs), 8.4 percent in balanced funds, 6.1 percent in bond funds, 4.7 percent in money funds, and 0.3 percent in other stable value funds. Participant asset allocation varies considerably with age. Younger participants tend to favor equity funds, while older participants are more disposed to invest in GICs and bond funds. On average, participants in their 20s have 62.1 percent of their account balances invested in equity funds, in contrast to 39.8 percent for those in their 60s. Participants in their 20s invest 4.7 percent of their assets in GICs, while those in their 60s invest 20.6 percent. Bond funds, which represent 4.7 percent of the assets of participants in their 20s, amount to 9.0 percent of the assets of participants in their 60s. Investment options offered by 401(k) plans appear to influence asset allocation. For example, the addition of company stock substantially reduces the allocation to equity funds and the addition of GICs lowers allocations to bond and money funds. The average account balance (net of plan loans) for all participants was $47,004 at year-end 1998, which is 26 percent higher than the average account balance at year-end 1996. The median account balance was $13,038 at year-end 1998. The balances, however, represent only amounts with current employers and do not include amounts remaining in the plans of prior employers. The average balances of older workers with long tenure indicate that a mature 401(k) plan program will produce substantial account balances. For example, individuals in their 60s with at least 30 years of tenure have average account balances in excess of $185,000. The ratio of account balance to 1998 salary varies with salary, increasing slightly as earnings rise from $20,001 to $80,000, and falling a bit for salaries greater than $80,000. The increase in ratio likely reflects a greater propensity of higher-income participants to save, whereas the decline after $80,000 results from contribution and nondiscrimination rule constraints.
Adult↗
The economics of the delivery of veterinary services.
Low livestock productivity in many developing countries is commonly considered to reflect, among other factors, the inadequate supply of services to control disease. Veterinary services have traditionally been provided by the state, but public finance constraints have limited the availability and effectiveness of public services. The author explains how economic theory can be used to identify alternative delivery systems (beyond the state) for providing animal health care and proposes new roles for the state and private sector in service delivery. The author highlights a number of barriers that currently limit the potential contribution of the private sector to service delivery, and describes a variety of approaches that have been used by the state to create an enabling environment for the private sector.
Animals↗
Nursing home residents: demands on GPs.
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Drug Costs↗
Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo.
Troglitazone, a thiazolidinedione derivative, is a widely used antidiabetic drug that binds and activates peroxisome proliferator-activated receptor gamma (PPARgamma) and enhances insulin sensitivity. It induces differentiation of adipocytes, which highly express PPARgamma. We report that human prostate cancer cells expressed PPARgamma at prominent levels and normal prostate tissues had very low expression. Dose-response clonogenic assays of the PC-3 prostate cancer cell line with troglitazone showed an antiproliferative effect (ED50, 3 x 10(-7) M) and other PPARgamma ligands (BRL49653: ED50, 8 x 10(-8) M; 15-deoxy-delta12,14-prostaglandin J2: ED50, 2 x 10(-6) M; ciglitizone: ED50, not reached; indomethacin: ED50, not reached) showed similar effects. Combinations of troglitazone and a ligand specific for either retinoid X receptor or retinoic acid receptor did not show a synergistic effect. Pulse-exposure to troglitazone (10(-5) M) for different durations showed that 4 days of pulse-exposure to the agent irreversibly inhibited 50% clonal growth of PC-3 cells. Interestingly, PC-3 cells cultured with troglitazone (10(-5) M) showed dramatic morphological changes both by light and electron microscopy, suggesting that the cells became less malignant. Nevertheless, troglitazone did not affect either the cell cycle or several markers of differentiation. LNCaP cells constitutively produced prostate-specific antigen, and levels were markedly enhanced by all-trans-retinoic acid. Troglitazone (10(-5) M, 4 days) decreased by 50% the levels of prostate-specific antigen produced by these cells. In vivo treatment of PC-3 tumors growing in male BNX triple immunodeficient mice with oral troglitazone (500 mg/kg/day) produced significant inhibition of tumor growth (P = 0.01). The only objective side effect of troglitazone in mice was the elevation of serum transaminases. Short-term culture of four surgically obtained human prostate cancer tumors with troglitazone (10(-5) M, 4 days) produced marked and selective necrosis of the cancer cells (about 60%) but not the adjacent normal prostate cells. Taken together, these results suggest that troglitazone may be a useful therapeutic agent for the treatment of prostate cancer, especially in the setting of low disease burden.
Animals↗
Antibody-IL-12 fusion proteins are effective in SCID mouse models of prostate and colon carcinoma metastases.
IL-12 is a complex cytokine in both its structure and its range of biologic activities. Fusions of this heterodimeric molecule with an intact antitumor Ab were made to test the feasibility and efficacy of targeting IL-12 to tumors to elicit a local immune response. Fusion proteins composed of the human p35 and p40 subunits had IL-12 bioactivities that were nearly as potent on human immune cells as the rIL-12 standard, but were inactive on mouse cells. Hybrid IL-12 fusion proteins composed of mouse p35 and human p40, fused to Ab, were capable of inducing IFN-gamma, but were much less active on mouse spleen cells than a mouse IL-12 standard. Despite this relatively low activity, the hybrid fusion protein was as effective in a SCID mouse model as a fully active Ab-IL-2 fusion protein in eliminating established pulmonary metastases of CT26 colon carcinoma. Specific targeting of a human IL-12 fusion protein to metastatic prostate carcinoma xenografts was also shown to be effective in SCID mice transplanted with human lymphocyte-activated killer cells. These results demonstrate the importance of directing this potent cytokine to the tumor microenvironment and suggest an important alternative to systemic IL-12 administration or gene therapy for increasing its therapeutic index.
Animals↗