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Introduction: The number of adolescents referred to specialized gender identity clinics for gender dysphoria appears to be increasing and there also appears to be a corresponding shift in the sex ratio, from one favoring natal males to one favoring natal females., Aim: We conducted two quantitative studies to ascertain whether there has been a recent inversion of the sex ratio of adolescents referred for gender dysphoria., Methods: The sex ratio of adolescents from two specialized gender identity clinics was examined as a function of two cohort periods (2006-2013 vs. prior years). Study 1 was conducted on patients from a clinic in Toronto, and Study 2 was conducted on patients from a clinic in Amsterdam., Results: Across both clinics, the total sample size was 748. In both clinics, there was a significant change in the sex ratio of referred adolescents between the two cohort periods: between 2006 and 2013, the sex ratio favored natal females, but in the prior years, the sex ratio favored natal males. In Study 1 from Toronto, there was no corresponding change in the sex ratio of 6,592 adolescents referred for other clinical problems., Conclusions: Sociological and sociocultural explanations are offered to account for this recent inversion in the sex ratio of adolescents with gender dysphoria., (© 2015 International Society for Sexual Medicine.)

Cross-institutional data sharing for cohort discovery is critical to enabling future research. While particularly useful in rare diseases, the ability to target enrollment and to determine if an institution has a sufficient number of patients is valuable in all research, particularly in the initiation of projects and collaborations. An optimal technology solution would work with any source database with minimal resource investment for deployment and would meet all necessary security and confidentiality requirements of participating organizations. We describe a platform-neutral reference implementation to meet these requirements: the Federated Aggregate Cohort Estimator (FACE). FACE was developed and implemented through a collaboration of The University of Alabama at Birmingham (UAB), The Ohio State University (OSU), the University of Massachusetts Medical School (UMMS), and the Denver Health and Hospital Authority (DHHA) a clinical affiliate of the Colorado Clinical and Translational Sciences Institute. The reference implementation of FACE federated diverse SQL data sources and an i2b2 instance to estimate combined research subject availability from three institutions. It used easily-deployed virtual machines and addressed privacy and security concerns for data sharing., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Reducing energy density (ED) of the diet is an important strategy for controlling obesity. This 1-year, randomized clinical trial examined the effect of substituting mushrooms for red meat ('mushroom diet'), compared to a standard diet ('meat diet'), on weight loss and maintenance among 73 obese adults (64 women, 9 men). The subjects completed anthropometric measurements and 7-day food records four times during a standardized weight loss and maintenance regimen. At the end of the 1-year trial, compared to participants on the standard diet, participants on the mushroom diet (n=36) reported lower intakes of energy (mean ± [SE]=-123 ± 113 kcals) and fat (-4.25 ± 6.88 g), lost more pounds and percentage body weight (-7.03 ± 3.34 lbs, 3.6%), achieved lower body mass index (-1.53 ± 0.36), waist circumference (-2.6 ± 3.5 in.) and percent total body fat (-0.85 ± 0.53), and had lower systolic and diastolic pressure (-7.9 and -2.5 mmHg); their lipid profile and inflammatory markers also improved. After initial weight loss, subjects following the mushroom diet maintained that loss well. Those who completed the full 12-month trial still weighed a mean of 7 lbs less than baseline. Thus, encouraging adults to substitute mushrooms for red meat was a useful strategy for enhancing weight loss, weight maintenance, and health parameters., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Myocardial disease in the Boxer dog is characterized by 1 of 2 clinical presentations, dilated cardiomyopathy (DCM) characterized by ventricular systolic dysfunction, dilatation and tachyarrhythmias, and arrhythmogenic right ventricular cardiomyopathy (ARVC) characterized by ventricular tachyarrhythmias, syncope, and sudden death. Boxer ARVC has been associated with a deletion in the striatin gene in some families., Hypothesis/objectives: We hypothesized that both presentations represent a single disease, and the development of DCM in the Boxer is associated with the striatin deletion., Animals: Thirty-three adult Boxer dogs with DCM, 29 adult Boxer dogs with the striatin deletion and ARVC, and 16 Boxers without cardiac disease., Methods: DNA samples were evaluated for the striatin deletion. Association of the deletion with the DCM phenotype was tested by a Fisher's exact test. T-tests were used to evaluate potential differences between the positive heterozygous and positive homozygous groups with DCM with regard to age, LVIDD, LVIDS, and FS%., Results: Thirty of 33 dogs with DCM were positive for the striatin deletion. The striatin mutation and the homozygous genotype were strongly associated with the DCM phenotype (P < .001 and P = .005). There was no statistical difference between the heterozygous and homozygous groups with regard to age and echocardiographic measurements., Conclusions and Clinical Importance: This study demonstrates an association between DCM in the Boxer dog and the striatin mutation, particularly with the homozygous genotype. The observation that 3/33 dogs developed DCM and lacked the striatin mutation suggests that there is at least 1 other cause of DCM in the Boxer dog., (Copyright © 2013 by the American College of Veterinary Internal Medicine.)

Previous studies based on DNA restriction-site and sequence variation have shown that the Hawaiian lobeliads are monophyletic and that the two largest genera, Cyanea and Clermontia, diverged from each other ca. 9.7 Mya. Sequence divergence among species of Clermontia is quite limited, however, and extensive hybridization is suspected, which has interfered with production of a well-resolved molecular phylogeny for the genus. Clermontia is of considerable interest because several species posses petal-like sepals, raising the question of whether such a homeotic mutation has arisen once or several times. In addition, morphological and molecular studies have implied different patterns of inter-island dispersal within the genus. Here we use nuclear ISSRs (inter-simple sequence repeat polymorphisms) and five plastid non-coding sequences to derive biparental and maternal phylogenies for Clermontia. Our findings imply that (1) Clermontia is not monophyletic, with Cl. pyrularia nested within Cyanea and apparently an intergeneric hybrid; (2) the earliest divergent clades within Clermontia are native to Kauài, then Òahu, then Maui, supporting the progression rule of dispersal down the chain toward progressively younger islands, although that rule is violated in later-evolving taxa in the ISSR tree; (3) almost no sequence divergence among several Clermontia species in 4.5 kb of rapidly evolving plastid DNA; (4) several apparent cases of hybridization/introgression or incomplete lineage sorting (i.e., Cl. oblongifolia, peleana, persicifolia, pyrularia, samuelii, tuberculata), based on extensive conflict between the ISSR and plastid phylogenies; and (5) two origins and two losses of petaloid sepals, or--perhaps more plausibly--a single origin and two losses of this homeotic mutation, with its introgression into Cl. persicifolia. Our phylogenies are better resolved and geographically more informative than others based on ITS and 5S-NTS sequences and nuclear SNPs, but agree with them in supporting Clermontia's origin on Kauài or some older island and dispersal down the chain subsequently.

The exponential increase in the number of women parolees and probationers in the last decade has made women the most rapidly growing group of offenders in the United States. The purpose of this descriptive, qualitative study is to understand the unique gendered experiences of homeless female ex-offenders, in the context of healthcare needs, types of health services sought, and gaps in order to help them achieve a smooth transition post prison release. Focus group qualitative methodology was utilized to engage 14 female ex-offenders enrolled in a residential drug treatment program in Southern California. The findings suggested that for homeless female ex-offenders, there are a myriad of healthcare challenges, knowledge deficits, and barriers to moving forward in life, which necessitates strategies to prevent relapse. These findings support the development of gender-sensitive programs for preventing or reducing drug and alcohol use, recidivism, and sexually transmitted infections among this hard-to-reach population.

Chronic hypertension in pregnancy is one of the most common medical diseases affecting pregnancy. It is associated with serious maternal and fetal complications, including superimposed pre-eclampsia, fetal growth restriction, premature delivery, placental abruption, and stillbirth. Baseline evaluation as early as possible is important to differentiate women with essential hypertension from those with severe hypertension, coexisting end-organ damage, and secondary causes of hypertension, as their risks of poor outcomes are increased. An optimal plan for maternal treatment and fetal surveillance can then be formulated. Coordination of care after delivery is important for long-term maternal health and future pregnancies.

Drug induced liver injury during drug development is evidenced by a higher incidence of serum alanine aminotransferase (ALT) elevations in treated versus placebo populations and termed an "ALT signal". We sought to quantify whether an ALT signal in pre-marketing clinical trials predicted post-marketing hepatotoxicity. Incidence of ALT elevations (ALT ≥ 3 times upper limits normal [× ULN]) for drug and placebo of new chemical entities and approved drugs associated with hepatotoxicity was calculated using the Food and Drug Administration (FDA) website. Post-marketing liver safety events were identified using the FDA Adverse Event Reporting System (AERS). The association of FDA AERS signal score (EB05 ≥ 2) and excess risk of pre-marketing ALT elevation (difference in incidence of ALT ≥ 3× ULN in treated versus placebo) was examined. An ALT signal of ≥ 1.2% was significantly associated with a post-marketing liver safety signal (p ≤ 0.013) and a 71.4% positive predictive value. An absent ALT signal was associated with a high likelihood of post-marketing liver safety; negative predictive value of 89.7%. Daily drug dose information improved the prediction of post-marketing liver safety. A cut-off of 1.2% increase in ALT ≥ 3× ULN in treated versus placebo groups provides an easily calculated method for predicting post-marketing liver safety., (Published by Elsevier Inc.)

Cement kilns are known to emit polychlorinated dibenzo(p)dioxins and furans (PCDD/Fs; "dioxins"), but estimates of the amounts and patterns of these emissions vary widely. These variations may stem from a combination of factors, including the design and operating conditions of the kiln, and the fuels and raw materials fed into the kiln. The goal of this study was to examine the patterns of dioxin emissions in a large set of stack-tests at two Portland cement kilns in Portugal that use a variety of fuels. A total of 152 stack-tests provided data on PCDD/F congener concentrations during which the kilns combusted a varied mix of fuels, including petroleum coke, coal, various "special" supplemental fuels, and refinery distillation ends, which are classified as hazardous wastes. The use of coal to fuel the kilns was found to generate significantly different emission-profiles relative to the use of petroleum coke, but the addition of hazardous wastes as a supplemental fuel did not significantly alter profiles. All of the kiln emission profiles were found to differ markedly from profiles in ambient air. However, the small absolute dioxin emission rates from the kilns suggested that kiln impacts would not be detectable via ambient air monitoring, even in rural settings., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To determine the effect of shipping blood in Streck blood collection tubes (BCT) prior to processing on cell-free DNA (cf-DNA) levels., Methods: Blood was collected in ethylenediaminetetraacetic acid (EDTA) and BCT tubes from 10 pregnant women carrying male fetuses. One set of each tube for each subject was processed to plasma immediately (standard cf-DNA protocol), whereas the other set was shipped by air courier and then processed. DNA was extracted and total and fetal DNA concentrations were measured by TaqMan multiplexed quantitative real-time PCR., Results: No significant difference was observed in total cf-DNA in plasma between immediately processed EDTA (control) and immediately processed BCT samples. Moreover, no significant change in total cf-DNA was detected in plasma of BCT samples shipped at room temperature. Significant differences in total cf-DNA leading to a significantly decreased fetal fraction were found in shipped EDTA samples and BCT samples shipped at 4°C., Discussion: BCT tubes are suitable for shipping whole blood prior to processing with respect to cf-DNA levels. However, care should be taken to ensure that samples are not exposed to extreme temperatures during shipment. This finding will benefit the development and clinical application of noninvasive methods of fetal diagnosis that utilize cf-DNA., (Copyright © 2012 S. Karger AG, Basel.)

Emissions from Portland cement manufacturing facilities may increase health risks in nearby populations and are thus subject to stringent regulations. Direct testing of pollutant concentrations in exhaust gases provides the best basis for assessing the extent of these risks. However, these tests (i) are often conducted under stressed, rather than typical, operating conditions, (ii) may be limited in number and duration, and (iii) may be influenced by specific fuel-types and attributes of individual kilns. We report here on the results of more than 150 emissions-tests conducted of two kilns at a Portland cement manufacturing plant in Portugal. The tests measured various regulated metals and polychlorinated dibenzo(p)dioxins and furans (PCDD/Fs). Stack-gas concentrations of pollutants were found to be highly variable, with standard deviations on the order of mean values. Emission rates of many pollutants were higher when coal was used as the main kiln fuel (instead of petroleum coke). Use of various supplemental fuels, however, had little effect on stack emissions, and few statistically significant differences were observed when hazardous waste was included in the fuel mix. Significant differences in emissions for some pollutants were observed between the two kilns despite their similar designs and uses of similar fuels. All measured values were found to be within applicable regulatory limits., (Published by Elsevier B.V.)

A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker γH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m²/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic., (©2011 AACR.)

Background: Screening tests for Trisomy 21 (T21), also known as Down syndrome, are routinely performed for the majority of pregnant women. However, current tests rely on either evaluating non-specific markers, which lead to false negative and false positive results, or on invasive tests, which while highly accurate, are expensive and carry a risk of fetal loss. We outline a novel, rapid, highly sensitive, and targeted approach to non-invasively detect fetal T21 using maternal plasma DNA., Methods and Findings: Highly heterozygous tandem Single Nucleotide Polymorphism (SNP) sequences on chromosome 21 were analyzed using High-Fidelity PCR and Cycling Temperature Capillary Electrophoresis (CTCE). This approach was used to blindly analyze plasma DNA obtained from peripheral blood from 40 high risk pregnant women, in adherence to a Medical College of Wisconsin Institutional Review Board approved protocol. Tandem SNP sequences were informative when the mother was heterozygous and a third paternal haplotype was present, permitting a quantitative comparison between the maternally inherited haplotype and the paternally inherited haplotype to infer fetal chromosomal dosage by calculating a Haplotype Ratio (HR). 27 subjects were assessable; 13 subjects were not informative due to either low DNA yield or were not informative at the tandem SNP sequences examined. All results were confirmed by a procedure (amniocentesis/CVS) or at postnatal follow-up. Twenty subjects were identified as carrying a disomy 21 fetus (with two copies of chromosome 21) and seven subjects were identified as carrying a T21 fetus. The sensitivity and the specificity of the assay was 100% when HR values lying between 3/5 and 5/3 were used as a threshold for normal subjects., Conclusions: In summary, a targeted approach, based on calculation of Haplotype Ratios from tandem SNP sequences combined with a sensitive and quantitative DNA measurement technology can be used to accurately detect fetal T21 in maternal plasma when sufficient fetal DNA is present in maternal plasma.

Two cytidine analogues, gemcitabine (dFdC) and 1-beta-d-arabinofuranosylcytosine (AraC), show significant therapeutic effect in a variety of cancers. However, response to these drugs varies widely. Evidence from tumor biopsy samples shows that expression levels for genes involved in the cytidine transport, metabolism, and bioactivation pathway contribute to this variation in response. In the present study, we set out to test the hypothesis that variation in gene expression both within and outside of this "pathway" might influence sensitivity to gemcitabine and AraC. Specifically, Affymetrix U133 Plus 2.0 GeneChip and cytotoxicity assays were performed to obtain basal mRNA expression and IC(50) values for both drugs in 197 ethnically defined Human Variation Panel lymphoblastoid cell lines. Genes with a high degree of association with IC(50) values were involved mainly in cell death, cancer, cell cycle, and nucleic acid metabolism pathways. We validated selected significant genes by performing real-time quantitative reverse transcription-PCR and selected two representative candidates, NT5C3 (within the pathway) and FKBP5 (outside of the pathway), for functional validation. Those studies showed that down-regulation of NT5C3 and FKBP5 altered tumor cell sensitivity to both drugs. Our results suggest that cell-based model system studies, when combined with complementary functional characterization, may help to identify biomarkers for response to chemotherapy with these cytidine analogues.

Landrace potato cultivars are native to two areas in South America: the high Andes from eastern Venezuela to northern Argentina and the lowlands of south-central Chile. Potato first appeared outside of South America in Europe in 1567 and rapidly diffused worldwide. Two competing hypotheses suggested the origin of the "European" potato from the Andes or from lowland Chile, but the Andean origin has been widely accepted over the last 60 years. All modern potato cultivars predominantly have Chilean germplasm, explained as originating from breeding with Chilean landraces subsequent to the late blight epidemics beginning in 1845 in the UK. The Andean origin has been questioned recently through examination of landraces in India and the Canary Islands, but this evidence is inferential. Through a plastid DNA deletion marker from historical herbarium specimens, we report that the Andean potato predominated in the 1700s, but the Chilean potato was introduced into Europe as early as 1811 and became predominant long before the late blight epidemics in the UK. Our results provide the first direct evidence of these events and change the history of introduction of the European potato. They shed new light on the value of past breeding efforts to recreate the European potato from Andean forms and highlight the value of herbarium specimens in investigating origins of crop plants.

Context: There is limited information that accounts for comorbidity on the impact of role disability associated with a wide range of mental and physical disorders in population-based samples., Objective: To estimate the comparative effects of common mental and physical conditions on role disability in the general population using a novel method that accounts for comorbidity., Design: Direct interviews about physical and mental conditions during the past year., Setting: The National Comorbidity Survey Replication, a nationally representative series of face-to-face interviews., Patients: A nationally representative sample of adults living in households (N = 5962 respondents, 18 years and older)., Main Outcome Measure: Disability in major life roles was assessed with the World Health Organization Disability Assessment Schedule. Simulations that allow for complex interactions among conditions were used to estimate the conditions' effects on disability days, when respondents were completely unable to carry out their usual daily activities because of problems with mental or physical health, in the past 12 months., Results: An estimated 53.4% of US adults have 1 or more of the mental or physical conditions assessed in the survey. These respondents report an average 32.1 more role-disability days in the past year than demographically matched controls, equivalent to nearly 3.6 billion days of role disability in the population. Musculoskeletal disorders and major depression had the greatest effects on disability days. Mental conditions accounted for more than half as many disability days as all physical conditions at the population level. Associations of specific conditions with disability decreased substantially after controlling for comorbidity, suggesting that prior studies, which generally did not control for comorbidity, overestimated disease-specific effects., Conclusion: The staggering amount of health-related disability associated with mental and physical conditions should be considered in establishing priorities for the allocation of health care and research resources.

Venous thromboembolism (VTE) is known as a common complication in surgical and non-surgical patients. We hypothesized that according to the underlying risk factors and the acute illness, the prevalence ofVTE in non-surgical patients admitted to hospital is widely underestimated. For three months each patient admitted to the department of internal medicine with an acute illness, but without known deep venous thrombosis (DVT) was investigated by ultrasound compression sonography. Patients' history, risk factors and extent of immobilisation were documented. In patients with newly detected DVT D-dimer and fibrinogen were measured as well as computer tomography scans performed. Follow-up investigations of the DVT population were performed at four weeks and three months. Six hundred seventeen patients (49.3% men) were included. In 16 patients (men = 7) a previously unknown thrombosis (2.6%) was detected, mainly in patients with acute cardio-pulmonary disease (56%) and the elderly (mean age 75.6 years). Eight patients had femoro-popliteal (50.0%), four a femoral (25.0%), and four a popliteal vein thrombosis (25.0%). Five had pulmonary embolism (31.3%). In patients with DVT D-dimer was 875 +/- 1,228 mg/l, fibrinogen 568 +/- 215 mg/dl and C-reactive-protein 58.54 +/- 73.65 mg/dl. One patient died from sepsis during hospitalisation, one died from sudden cardiac death at home. None of the other 14 surviving patients relapsed. The study shows a 2.6% risk for DVT in outpatients with acute illness admitted to the department of internal medicine. These data demonstrate the high risk of DVT is in non-surgical patients. Early prophylaxis has to be considered in internal medicine patients especially in the elderly.

Purpose: Pemetrexed, an antifolate involved in purine and pyrimidine formation, is a potential alternative to fluoropyrimidines in the treatment of colorectal cancer. A phase I trial was performed to establish the maximum tolerated dose (MTD) of pemetrexed and oxaliplatin when B(12) and folate supplementation is used., Patients and Methods: Patients with metastatic colorectal cancer received folate (> 350 microg) daily and vitamin B(12) (1000 microg) every 9 weeks starting 7 days before chemotherapy. Pemetrexed over 10 minutes and oxaliplatin over 2 hours were given every 3 weeks in escalating dose cohorts., Results: Twenty-two patients were entered on 6 dose levels. The MTD was established at the highest dose level, pemetrexed 900 mg/m(2) and oxaliplatin 130 mg/m(2). Toxicities related to treatment at the MTD included grade 3 neutropenia and thrombocytopenia. For all dose levels combined, grade 3/4 toxicities included hematologic, neurologic, and gastrointestinal. Nine of 21 evaluable patients responded overall (response rate, 43%). The time to tumor progression was 11.9 months., Conclusion: The MTD was determined to be pemetrexed 900 mg/m(2) and oxaliplatin 130 mg/m(2) every 21 days when folate and B (12) supplementation are used. Because of the observed tolerability and activity of this regimen, further evaluation is warranted.

Objective: To describe the pain relief, satisfaction, and health-related quality of life results of moderate or severe migraines treated with a sumatriptan/naproxen sodium combination tablet., Methods: Sumatriptan and naproxen sodium as a single-dose formulation tablet was used to treat moderate to severe migraines over a 12-month period in a phase 3, open-label, multicenter study (n = 565) in patients with at least 6 months' history of migraine headaches., Results: Seventy percent of all attacks were treated with 1 dose of sumatriptan/naproxen sodium. Overall subjects treated 24,485 attacks; of these, 81% attacks achieved pain relief and 60% pain-free by 2 hours. At 3 months, the percentage of patients satisfied or very satisfied increased from baseline on all 8 Patient Perception of Migraine Questionnaire (PPMQ) items and remained high throughout the study. Mean Migraine-Specific Quality of Life Questionnaire (MSQ) domain scores also increased by 13-15 points from baseline during this time and remained high., Conclusions: Sumatriptan/naproxen sodium provides consistent relief of migraine attacks over 12 months, resulting in improved patient satisfaction and migraine specific quality of life.

Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG)., Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m(2)/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy., Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in alpha-fetoprotein and stable disease over three cycles. At 270 mg/m(2)/dose, the C(max) and areas under the plasma concentration-time curves of 17-AAG were 5,303 +/- 1,591 ng/mL and 13,656 +/- 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 +/- 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m(2) dose level., Conclusions: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m(2)/d. Non-DMSO-containing formulations may improve acceptance of this drug by children and their families.

Background: Many patients and physicians interpret episodic headache in the presence or absence of nasal symptoms as "sinus' headache, while ignoring the possible diagnosis of migraine., Objective: The purpose of this study was to assess the efficacy and tolerability of sumatriptan succinate 50-mg tablets in patients with migraine presenting with "sinus" headache., Methods: A randomized, double-blind, placebo-controlled, multicenter study was conducted in adult (aged 18-65 years) migraine patients presenting with self-described or physician-diagnosed "sinus" headache. From November 2001 to March 2002, patients meeting International Headache Society criteria for migraine (with > or =2 of the following: unilateral location, pulsating quality, moderate or severe intensity, aggravation by moderate physical activity; and > or =1 of: phonophobia and phonophobia, nausea and/or vomiting) and with no evidence of bacterial rhinosinusitis were enrolled and randomized in a 1:1 ratio via computer-generated randomization schedule to receive either 1 sumatriptan 50-mg tablet or matching placebo tablet. The primary efficacy end point was headache response (moderate or severe headache pain reduced to mild or no headache pain) at 2 hours after administration. The presence or absence of migraine-associated symptoms and sinus and nasal symptoms was also measured. Tolerability was assessed through patient-reported adverse events (AEs)., Results: Two hundred sixteen patients with self-described or physician-diagnosed "sinus" headache received a migraine diagnosis and treated 1 migraine attack with sumatriptan 50 mg. The efficacy (intent-to-treat) analysis included 215 patients treated with sumatriptan 50 mg (n = 108; mean [SD] age, 39.6 [12.3] years; mean [SD] weight, 77.7 [17.7] kg; sex, 71% female; race, 69% white) or placebo (n = 107; mean [SD] age, 41.0 [11.3] years; mean [SD] weight 80.7 [20.9] kg; sex, 69% female; race, 64% white). Significantly more patients treated with sumatriptan 50 mg achieved a positive headache response at 2 and 4 hours after administration compared with those treated with placebo (69% vs 43% at 2 hours and 76% vs 49% at 4 hours, respectively; both, P < 0.001). Significantly more sumatriptan-treated patients were free from sinus pain compared with placebo recipients at 2 hours (63% vs 49% placebo, P = 0.049) and 4 hours (77% vs 55%, P = 0.001). All treatments were generally well tolerated. The most common drug-related AEs reported in the sumatriptan and placebo groups, respectively, were dizziness (5% vs < 1%), nausea (3% vs 2%), other pressure/tightness (defined as sense of heaviness; heaviness of upper body, upper extremities; jaw tension; neck tension) (4% vs 0%), and temperature sensations (defined as warm feeling of back of neck, or flushing) (2% vs 0%). No patients experienced any serious AEs., Conclusions: Sumatriptan 50-mg tablets were effective and generally well tolerated in the treatment of these patients presenting with migraine headaches that were self-described or physician-diagnosed as sinus headaches.

Objective: The aim of this study was to assess the efficacy and tolerability of sumatriptan injection in the treatment of morning migraine., Methods: In 2 multicenter (20 sites for study 1 and 25 sites for study 2), randomized, double-blind, controlled, parallel-group studies, male and female patients aged 18 to 65 years with migraine meeting International Headache Society criteria received SC sumatriptan succinate injection 6 mg or inactive vehicle (control) for the outpatient treatment of a single morning migraine, defined as migraine with moderate or severe pain on awakening. The primary end point was the percentage of patients who achieved pain-free relief (moderate or severe pain reduced to no pain) at 2 hours after treatment. Tolerability was assessed using spontaneous reporting or noted by a clinician during the studies, assessed at the return visit., Results: The efficacy analysis included, in the succinate group, 145 patients in study 1, 148 in study 2; control, 152 in study 1, 139 in study 2. The mean (SD) ages in the sumatriptan group were 40.2 (9.7) and 38.8 (10.1) years in studies 1 and 2, respectively; control, 41.4 (10.4) and 39.3 (9.7) years. The majority of patients in the 2 studies were female (sumatriptan, 84% and 93% in studies 1 and 2, respectively; control, 82% and 81%) and white (sumatriptan, 83% and 81%; control, 78% and 89%). Two hours after treatment, 48% and 57% of patients treated with sumatriptan injection compared with 18% and 19% of control patients reported pain-free relief in studies 1 and 2, respectively (both, P < 0.001). Two hours after treatment, 72% and 77% of patients treated with sumatriptan injection reported headache relief (moderate or severe pain reduced to mild or no pain) compared with 32% and 41% of control patients (both, P < 0.001). Onset of efficacy versus control (the first time point with statistical significance of pain relief) was observed beginning 10 minutes postdose (P < 0.05 sumatriptan injection vs placebo across pooled studies). Mean time to efficacy in the sumatriptan group was 10 minutes (P < 0.05 vs controls). The most commonly reported adverse events were nausea (sumatriptan, 6% and 4%; control, 2% and 2%) and injection-site reaction (ie, burning or stinging at the injection site) (sumatriptan, 5 % and 5%; control, 2% and 1%). Injection-site reaction was also the only adverse event considered treatment related and reported in > or =5 % of all patients., Conclusion: The results of these 2 randomized, double-blind, controlled studies suggest that sumatriptan injection was effective and well tolerated in the acute treatment of morning migraine in these adults.

Background: Ankle-brachial pressure index (ABI) is a simple, inexpensive, and useful tool in the detection of peripheral arterial occlusive disease (PAD). The current guidelines published by the American Heart Association define ABI as the quotient of the higher of the systolic blood pressures (SBPs) of the two ankle arteries of that limb (either the anterior tibial artery or the posterior tibial artery) and the higher of the two brachial SBPs of the upper limbs. We hypothesized that considering the lower of the two ankle arterial SBPs of a side as the numerator and the higher of the brachial SBPs as the denominator would increase its diagnostic yield., Methods: The former method of eliciting ABI was termed as high ankle pressure (HAP) and the latter low ankle pressure (LAP). ABI was assessed in 216 subjects and calculated according to the HAP and the LAP method. ABI findings were confirmed by arterial duplex ultrasonography. A significant arterial stenosis was assumed if ABI was <0.9., Results: LAP had a sensitivity of 0.89 and a specificity of 0.93. The HAP method had a sensitivity of 0.68 and a specificity of 0.99. McNemar's test to compare the results of both methods demonstrated a two-tailed P < .0001, indicating a highly significant difference between both measurement methods., Conclusions: LAP is the superior method of calculating ABI to identify PAD. This result is of great interest for epidemiologic studies applying ABI measurements to detect PAD and assessing patients' cardiovascular risk.

Objective: Research on the workplace costs of mood disorders has focused largely on major depressive episodes. Bipolar disorder has been overlooked both because of the failure to distinguish between major depressive disorder and bipolar disorder and by the failure to evaluate the workplace costs of mania/hypomania., Method: The National Comorbidity Survey Replication assessed major depressive disorder and bipolar disorder with the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) and work impairment with the WHO Health and Work Performance Questionnaire. A regression analysis of major depressive disorder and bipolar disorder predicting Health and Work Performance Questionnaire scores among 3,378 workers was used to estimate the workplace costs of mood disorders., Results: A total of 1.1% of the workers met CIDI criteria for 12-month bipolar disorder (I or II), and 6.4% meet criteria for 12-month major depressive disorder. Bipolar disorder was associated with 65.5 and major depressive disorder with 27.2 lost workdays per ill worker per year. Subgroup analysis showed that the higher work loss associated with bipolar disorder than with major depressive disorder was due to more severe and persistent depressive episodes in those with bipolar disorder than in those with major depressive disorder rather than to stronger effects of mania/hypomania than depression., Conclusions: Employer interest in workplace costs of mood disorders should be broadened beyond major depressive disorder to include bipolar disorder. Effectiveness trials are needed to study the return on employer investment of coordinated programs for workplace screening and treatment of bipolar disorder and major depressive disorder.

Objective: To compare the efficacy and tolerability of sumatriptan nasal spray (NS) (5, 20 mg) versus placebo in the acute treatment of migraine in adolescent subjects., Background: Currently, no triptan is approved in the United States for the treatment of migraine in adolescent subjects (12 to 17 years). In a previous randomized, placebo-controlled study of 510 adolescent subjects, sumatriptan NS at 5, 10, and 20 mg doses was well tolerated. However, the primary efficacy analysis for headache relief with 20 mg at 2 hours did not demonstrate statistical significance (P = .059). A second study was initiated to evaluate the efficacy of sumatriptan NS in this population., Methods: This was a randomized (1:1:1), placebo-controlled, double-blind, parallel-group study. Overall, 738 adolescent subjects (mean age: 14 years) with > or = 6-month history of migraine (with or without aura) self-treated a single attack of moderate or severe migraine. The primary endpoints were headache relief at 1 hour and sustained relief from 1 to 24 hours. Pain-free rates, presence/absence of associated symptoms, headache recurrence, and use of rescue medications were also assessed. Tolerability was based on adverse events (AEs) and vital signs., Results: Sumatriptan NS 20 mg provided greater headache relief than placebo at 30 minutes (42% vs. 33%, respectively; P = .046) and 2 hours (68% vs. 58%; P = .025) postdose, but did not reach statistical significance at 1 hour (61% vs. 52%; P = .087) or for sustained headache relief from 1 to 24 hours (P = .061). Significant differences (P < .05) in favor of sumatriptan NS 20 mg over placebo were observed for several secondary efficacy endpoints including sustained relief from 2 to 24 hours. In general, sumatriptan NS 5 mg percentages were slightly higher than placebo but the differences did not reach statistical significance. Both doses of sumatriptan NS were well tolerated. No AEs were serious or led to study withdrawal. The most common event was taste disturbance (2%, placebo; 19%, sumatriptan NS 5 mg; 25%, sumatriptan NS 20 mg)., Conclusions: This study suggests that sumatriptan may be beneficial to some adolescents and is generally well tolerated in the acute treatment of migraine in this population.

Purpose: Vinorelbine (Navelbine) is an orally absorbable Vinca with broad antitumor activity. It differs from other Vinca in that it is structurally modified on the catharanthine nucleus and has differential actions on tubulin that render it less neurotoxic than other compounds in this class. We conducted a phase I study of vinorelbine given the activity of Vinca alkaloids in many pediatric tumors., Experimental Design: We evaluated the safety and pharmacokinetics of oral and i.v. vinorelbine administered weekly x 6 in children (age, 2-17 years) with different tumors. Patients with disease involvement in the bone marrow were eligible but were stratified and dose-escalated separately. Oral vinorelbine (week 1) was administered as liquid-filled gelatin capsules at thrice the i.v. dose. Intravenous vinorelbine doses of 24 to 37.5 mg/m(2) were administered on weeks 2 to 6., Results: The dose-limiting toxicity in patients without marrow involvement was reversible neutropenia. Common nonhematologic toxicities included < or = grade 2 nausea/vomiting and increased hepatic transaminases. A higher mean i.v. Cl(TB) was observed (1.75 +/- 1.0 L/h/kg) compared with adult reports, with a mean t(1/2B) of 16.5 +/- 9.7 hours. Mean oral bioavailability was 28.5 +/- 22.5%. The apparent oral clearance (12.1 +/- 13.0 L/h/kg) and volume of distribution (69.4 +/- 30.6 L/kg) were substantially higher than in adults given similar oral doses., Conclusions: The maximum tolerated dose in children without bone marrow involvement was 30 mg/m(2), similar to that reported in adults, with myelosuppression being the dose-limiting toxicity. Higher plasma clearance resulted in lower area under the plasma concentration-time curves at a given dose compared with that reported in adults.

Objective: The prevalence and workplace consequences of adult attention deficit/hyperactivity disorder (ADHD) are unknown., Methods: An ADHD screen was included in a national household survey (n = 3198, ages 18-44). Clinical re-interviews calibrated the screen to diagnoses of Diagnostic and Statistical Manual of Mental Disorders, 4th edition ADHD. Diagnoses among workers were compared with responses to the WHO Health and Work Performance Questionnaire (HPQ)., Results: A total of 4.2% of workers had ADHD. ADHD was associated with 35.0 days of annual lost work performance, with higher associations among blue collar (55.8 days) than professional (12.2 days), technical (19.8 days), or service (32.6 days) workers. These associations represent 120 million days of annual lost work in the U.S. labor force, equivalent to dollar 19.5 billion lost human capital., Conclusions: ADHD is a common and costly workplace condition. Effectiveness trials are needed to estimate the region of interest of workplace ADHD screening and treatment programs.

Purpose: We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity., Patients and Methods: An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity., Results: Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m(2) were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t(1/2)) of 17-AAG were 11.6 L/h/m(2) and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t(1/2) of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance., Conclusion: The MTD of weekly 17-AAG is 308 mg/m(2). 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.

Background: Symptoms referable to the sinus area are frequently reported during migraine attacks, but are not recognized in diagnostic criteria. Underrecognition of migraine may be partly attributed to a variable clinical presentation, and migraines with "sinus" symptoms contribute to this problem. This study was conducted to determine the prevalence of migraine-type headache (International Headache Society [IHS]-defined migraine without aura [IHS 1.1], migraine with aura [IHS 1.2], or migrainous disorder [IHS 1.7]) in patients with a history of self-described or physician-diagnosed "sinus" headache., Methods: During a clinic visit, patients with a history of "sinus" headache, no previous diagnosis of migraine, and no evidence of infection were assigned an IHS headache diagnosis on the basis of headache histories and reported symptoms., Results: A total of 2991 patients were screened. The majority (88%) of these patients with a history of self-described or physician-diagnosed "sinus" headache were diagnosed at the screening visit as fulfilling IHS migraine criteria (80% of patients) or migrainous criteria (8% of patients). The most common symptoms referable to the sinus area reported by patients at screening were sinus pressure (84%), sinus pain (82%), and nasal congestion (63%)., Conclusions: In this study, 88% of patients with a history of "sinus" headache were determined to have migraine-type headache. In patients with recurrent headaches without fever or purulent discharge, the presence of sinus-area symptoms may be part of the migraine process. Migraine should be included in the differential diagnosis of these patients.

Objective: To estimate the efficacy of sumatriptan 50-mg and 100-mg tablets in menstrually associated migraine when treatment is administered during the mild pain phase., Methods: A randomized, double-blind, placebo-controlled, single-attack study was conducted. Menstrually associated migraine was defined as any migraine beginning on or between day -2 and day 4, with day 1 = first day of flow. Patients had at least a 1-year history of migraine as defined by International Headache Society criteria and reported regularly occurring menstrually associated migraines typically having a mild pain phase. Patients treated attacks within 1 hour of the onset of pain but only if the pain was mild at onset and while the pain was still mild., Results: In the 349 women with menstrually associated migraine, sumatriptan was significantly more effective than placebo: 61% and 51% of patients who used sumatriptan 100 mg and 50 mg, respectively, were pain-free 2 hours after treatment compared with 29% of patients who used placebo (P <.001 for both comparisons). At 2 hours, 51% and 45% of patients who used sumatriptan 100 mg and 50 mg were free of pain and associated symptoms (photophobia, phonophobia, nausea, vomiting) compared with 25% of placebo patients (P <.001 for both comparisons). Adverse events were low for sumatriptan 100 and 50 mg, and both doses were generally well tolerated., Conclusion: Sumatriptan 50-mg and 100-mg tablets are generally well tolerated and effective in providing pain-free relief and relief of the associated symptoms of menstrually associated migraine when administered in the mild pain phase.

Background: Heat shock protein 90 (Hsp90) is responsible for chaperoning proteins involved in cell signaling, proliferation and survival. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is an anticancer agent currently in phase I trials in the USA and UK. It represents a class of drugs, the benzoquinone ansamycin antibiotics, capable of binding and disrupting the function of Hsp90, leading to the depletion of multiple oncogenic client proteins., Materials and Methods: Studies were identified through a PubMed search, review of bibliographies of relevant articles and review of abstracts from national meetings., Results: Preclinical studies have demonstrated that disruption of many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. Following an overview of the mechanism of action of ansamycin antibiotics and the pathways they disrupt, we review the current clinical status of 17-AAG, and discuss future directions for combinations of traditional antineoplastics with 17-AAG., Conclusions: 17-AAG represents a class of drugs capable of affecting multiple targets in the signal transduction pathway involved in tumor cell proliferation and survival. Early results from phase I studies indicate that 17-AAG administration results in an acceptable toxicity profile while achieving in vivo disruption of client proteins.

Other than nitrosoureas (carmustine and lomustine) and temozolomide, no agents have consistently demonstrated clinically meaningful benefits for patients with gliomas. The active metabolite of irinotecan, 7-ethyl-10-hydroxy camptothecin (SN-38), exhibited promising antitumor effects in preclinical glioma models. Clinical trials using weekly or every 3 weeks dosing of irinotecan have been completed. Toxicity consisted primarily of mild to moderate neutropenia and diarrhea with both schedules, with occasional severe toxicity including one death from neutropenia and infection. Preliminary analyses have suggested imaging responses in 10-15% of patients. Preclinical models and our understanding of the mechanism of action suggest that irinotecan may sensitize glioma cells to the cytotoxic actions of radiation therapy and alkylating agents; clinical trials designed to assess the therapeutic benefit of combination therapy currently are in progress. There is substantial clinical evidence that the concurrent administration of irinotecan with certain anticonvulsants produces reduced exposure to SN-38. In the absence of anticonvulsants, there is also substantial interpatient variability in drug exposure, perhaps reflecting inherited differences in drug metabolism. Finally several mechanisms of tumor cell resistance to irinotecan have been hypothesized, but the clinical significance of these observations has not been confirmed. Correlative studies to address these pharmacokinetic, pharmacogenetic, and drug resistance questions are ongoing., (Copyright 2003 American Cancer SocietyDOI 10.1002/cncr.11304)

To determine the maximum tolerated dose (MTD) and assess the toxicity profile and pharmacokinetics of weekly gemcitabine infusions in pediatric patients with refractory hematologic malignancies. Fourteen patients under 21 years old were given infusions of gemcitabine for escalating durations at 10 mg/m2/min weekly for three consecutive weeks. Two males and two females were studied at each dose level. Pharmacokinetics of the drug's metabolism were measured by high pressure-liquid chromatography (HPLC) for 24 h after the first dose. Intracellular difluorodeoxycytidine triphosphate formation in leukemic blasts was measured in selected patients. The MTD of gemcitabine in these patients was 3600 mg/m2/week for three consecutive weeks (10 mg/m2/min for 360 min). Hepatotoxicity was the dose limiting toxicity. Thirty to fifty percent of patients exhibited fever, rash, or myalgia. Rare instances of hypotension and pulmonary toxicity were observed. Two of six patients [one acute lymphoblastic leukemia (ALL) and one acute myelogenous leukemia (AML)] treated at the MTD had at least M2 marrows, although peripheral blood counts did not recover sufficiently for the patients to be considered in complete response. Pharmacokinetics of gemcitabine fit a two-compartment open model with terminal half-life and plasma clearance value of 62 min and 2.2 l/min/m2, respectively. No gender differences were observed. In conclusion, the MTD of gemcitabine was 10 mg/m2/min for 360 min every week for 3 weeks. This is the recommended phase II dose schedule for children with leukemia. The activity of the drug at this schedule in heavily pretreated, refractory patients warrants a phase II trial in hematologic malignancies.

Objective: To compare the effect of treatment decisions guided by phenotypic resistance testing (PRT) or standard of care (SOC) on short-term virological response., Design: A prospective, randomized, controlled clinical trial conducted in 25 university and private practice centers in the United States., Participants: A total of 272 subjects who failed to achieve or maintain virological suppression (HIV-1-RNA plasma level > 2000 copies/ml) with previous exposure to two or more nucleoside reverse transcriptase inhibitors and one protease inhibitor., Interventions: Randomization was to antiretroviral therapy guided by PRT or SOC., Main Outcome Measures: The percentage of subjects with HIV-1-RNA plasma levels less than 400 copies/ml at week 16 (primary); change from baseline in HIV-1-RNA plasma levels and number of "active" (less than fourfold resistance) antiretroviral agents used (secondary)., Results: At week 16, using intent-to-treat (ITT) analysis, a greater proportion of subjects had HIV-1-RNA levels less than 400 copies/ml in the PRT than in the SOC arm (P = 0.036, ITT observed; P = 0.079, ITT missing equals failure). An ITT observed analysis showed that subjects in the PRT arm had a significantly greater median reduction in HIV-1-RNA levels from baseline than the SOC arm (P = 0.005 for 400 copies/ml; P = 0.049 for 50 copies/ml assay detection limit). Significantly more subjects in the PRT arm were treated with two or more "active" antiretroviral agents than in the SOC arm (P = 0.003)., Conclusion: Antiretroviral treatment guided prospectively by PRT led to the increased use of "active" antiretroviral agents and was associated with a significantly better virological response.

Twelve patients undergoing cementless hip joint arthroplasty were retransfused with unwashed drainage blood collected postoperatively. Global coagulation parameters, coagulation factors (factor V:C, factor VIII:C, activated factor XII, and factor XIII) and markers of thrombin generation (F1+2 Fibrin split products, thrombin-antithrombin complexes), fibrin generation (fibrinogen and fibrin degradation products), and fibrinolysis (D-dimers, thrombin degradation products, plasminogen) were determined. High levels of factor XIIa, thrombin and fibrin generation markers, and markers of fibrinolysis were present in the shed blood. After retransfusion (mean, 433 mL), increased levels of these markers together with decreased values for factor XIII and plasminogen were indicative of renewed clot formation and fibrinolysis in the circulation. These changes were highly significant compared with preretransfusion values. The unwashed drainage blood contained high levels of procoagulation material and induced an activation of the plasma coagulation pathway with renewed clot formation and fibrinolysis in the patients.

Sodium fluoride (NaF) has been used to fluoridate drinking water in the United States since the mid 1940s. Because of the lack of reliable studies on the multigeneration effects of the compound, NaF (0, 25, 100, 175 or 250 ppm in drinking water) was given to rats continuously during three generations. Parental (F0) generation rats were treated for 10 weeks and mated within groups. At gestation day 20, caesarean sections were performed and eight F0 females per group and their litters (F1) were observed for implant status, fetal weight and length, sex and morphological development. The remaining F0 females (29-32 per group) were allowed to litter. F1 offspring (36 of each sex per group) were mated within groups, and caesarean sections were performed at gestation day 20. The F1 females and their litters (F2) were observed for implant status, fetal weight and length, sex and morphological development. In addition, F2 fetuses were evaluated for internal (soft-tissue) and skeletal development. Decreased fluid consumption for F0 and F1 dams at 175 and 250 ppm was attributed to decreased palatability of the solution. No dose-related effects in feed consumption or mean body weight gain were observed in either F0 or F1 females. Numbers of corpora lutea, implants, viable fetuses and fetal morphological development were similar in all groups. No dose-related anomalies in internal organs were observed in F2 fetuses. Ossification of the hyoid bone of F2 fetuses was significantly decreased at 250 ppm. Because of the decreased ossification of the hyoid bone, 250 ppm is considered the effect level.

Since the mid 1940s, fluoride has been added to tap water in American communities in an effort to reduce the incidence of dental caries in the population. When the levels of fluoride in drinking water were tested and set, water was the only measurable source of fluoride for most communities. Now, adults and children ingest fluoride with foods and beverages prepared with fluoridated water, and they are exposed to fluoride-containing dental products. As a result, exposure to fluoride is greater than had been anticipated. In the early 1990s, the existing reproductive studies were reviewed in several reports and were considered to be inadequate to determine potential reproductive or developmental hazards. The effects of sodium fluoride ingestion at 0, 25, 100, 175 or 250 ppm in drinking water measured in rats throughout three generations are reported here. Feed and fluid consumption, body weights and clinical signs were recorded at regular intervals. Decreased fluid consumption observed at 175 and 250 ppm was attributed to decreased palatability and did not affect reproduction. No cumulative effects were observed in the three generations. Mating, fertility and survival indices were not affected. Organ-to-body-weight ratios and organ-to-brain weight ratios were not affected. Sodium fluoride up to 250 ppm did not affect reproduction in rats.

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase with clinical activity in colorectal cancer. The combination of raltitrexed and 5-iodo-2'-deoxyuridine (IdUrd, a cytotoxic pyrimidine analog) resulted in increased IdUrd incorporation into DNA and exhibited in vitro synergism against colon and bladder human carcinoma cell lines. We designed a phase I trial to determine the MTD, pharmacokinetics, and biologic effects of escalating doses of the combination of IdUrd given as a 24-hour infusion after a raltitrexed 15-minute infusion every three weeks. Thirty-four patients received 95 courses of raltitrexed and IdUrd at doses ranging from raltitrexed 1 mg/m2 and IdUrd 750 mg/m2 to raltitrexed 2.5 mg/m2 and IdUrd 10,400 mg/m2. The median number of cycles administered was 2 (range 1-10). Dose limiting hematologic toxicity occurred at doses of raltitrexed 2.5 mg/m2 and IdUrd 10,400 mg/m2. In addition, we determined the mean plasma concentrations C(SS) of IdUrd, the iodouracil level at 22 hours and the IdUrd clearance. Raltitrexed did not appear to affect the pharmacokinetics of IdUrd in the dose range tested. The recommended phase II dose is raltitrexed 2 mg/m2 and IdUrd 10,400 mg/m2 repeated every three weeks. Evidence of potential antitumor activity was observed: 1 patient (with colon cancer) had a partial response while 15 others had stable disease.

Dacarbazine (DTIC) is a prodrug that is clinically effective in the treatment of Hodgkin's disease, melanoma and soft tissue sarcoma. To better characterize the clinical pharmacology of parent drug and reactive metabolites, a reversed-phase HPLC method with UV detection was developed for simultaneous determination of dacarbazine and the metabolites 5-(3-hydroxymethyl-3-methyl-1-triazeno)imidazole-4-carboxamide (HMMTIC) and 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC). Chromatographic separation was achieved with a Zorbax SB-CN column and with a mobile phase of 80% 50 mM ammonium phosphate, pH 6.5, 20% methanol and 0.1% triethylamine. HMMTIC, MTIC and DTIC were extracted from plasma with methanol precipitation of the proteins. Recovery of DTIC and the metabolites from whole blood was greater than 92%. Rapid processing of whole blood, methanol extraction and storage at -70 degrees C substantially increased the stability of HMMTIC and MTIC from less than 15 min to 3 days. Precision for HMMTIC, MTIC and DTIC ranged from 3.7 to 16.3% relative standard deviation. The accuracy ranged from 101 to 114% for all three analytes. The validated assay was used to determine the pharmacokinetic data for dacarbazine and its active metabolites for human patients with recurrent glioma receiving DTIC intravenously.

A Phase I trial was conducted to determine the safety, biological activity, and hematopoietic recovery by the combination of interleukin 6 (IL-6) and granulocyte-colony stimulating factor (G-CSF) after myelosuppressive chemotherapy in children. Patients <22 years of age at diagnosis with either recurrent or refractory solid tumors received ifosfamide 1,800 mg/m2/day x 5 days, carboplatin 400 mg/m2/ day x 2 days, and etoposide 100 mg/m2/day x 5 days, followed by daily s.c. G-CSF (5 microg/kg/day) and IL-6 (2.5, 3.75, or 5.0 microg/kg/day). Pharmacokinetic, proinflammatory mediator levels, hematopoietic colony assays, and cytokine receptor expression studies were performed during course one. Nineteen patients were evaluable for toxicity and received IL-6 at doses of 2.5 (n = 8), 3.75 (n = 5), or 5.0 (n = 6) microg/kg/day. Dose-limiting constitutional toxicity occurred in two of six patients at 5.0 microg/kg/day, two of five patients at 3.75 microg/kg/day, and two of eight patients at 2.5 microg/kg/day. The maximum tolerated dose (MTD) exceeded the lowest dose tested. Because of lack of drug availability, an MTD was not established. The maximum concentration of IL-6 (2.5 microg/kg/day) was 0.799 +/- 1.055 ng/ml (mean +/- SD). During the first course, the median time to absolute neutrophil count > or = 1,000/mm3 and platelets > or = 100,000 mm3 was estimated at 19 and 23 days, respectively. Peripheral blood progenitor cells expressing receptors to IL-3, IL-6, and G-CSF increased significantly over baseline (P < 0.05). After the first dose of IL-6, IFN-gamma levels were abnormal in 13 patients, and IL-1beta levels were abnormal in 10 patients. IL-6 has a high incidence of constitutional toxicity and a lower MTD in children compared with adults. In vivo use of IL-6 in children after chemotherapy remains limited. However, IL-6 may be more optimally investigated in children under ex vivo conditions.

The carcinoid tumor is an uncommon neuroendocrine neoplasm the hallmark of which is excessive serotonin production. In studying kinetics of tryptophan hydroxylase and aromatic-L-amino acid decarboxylase (AAAD) in human carcinoid hepatic metastases and adjacent normal liver (J. A. Gilbert et al, Biochem. Pharmacol., 50: 845-850, 1995), we identified one significant difference: the Vmax of carcinoid AAAD was 50-fold higher than that in normal liver. Here, we report Western and Northern analyses detecting large quantities of AAAD polypeptide and mRNA in human carcinoid primary as well as metastatic tumors compared with normal surrounding tissues. To assess the feasibility of targeting these high AAAD levels for chemotherapy, AAAD inhibitors carbidopa (alpha-methyl-dopahydrazine), alpha-monofluoromethyldopa (MFMD), and 3-hydroxybenzylhydrazine (NSD-1015) were incubated (72 h) with NCI-H727 human lung carcinoid cells. Carbidopa and MFMD were lethal (IC50 = 29 +/- 2 microM and 56 +/- 6 microM, respectively); NSD-1015 had no effect on proliferation. On exposure to other human tumor lines, carbidopa was lethal only to NCI-H146 and NCI-H209 small cell lung carcinoma (SCLC) lines (IC50 = 12 +/- 1 microM and 22 +/- 5 microM, respectively). Carbidopa (100 microM) decreased growth of (but did not kill) SK-N-SH neuroblastoma and A204 rhabdomyosarcoma cells and did not affect proliferation of DU 145 prostate, MCF7 breast, or NCI-H460 large cell lung carcinoma lines. The rank order of lines by AAAD activity was NCI-H146 > NCI-H209 > SK-N-SH > NCI-H727, whereas A204, DU 145, MCF7, and NCI-H460 had no measurable activity. For lung tumor lines (carcinoid, two SCLC, and one large cell lung carcinoma), AAAD activity was correlated with the potency of carbidopa-induced cytotoxicity. However, carcinoid cell death was not solely attributable to complete inhibition of either AAAD activity or the serotonin synthetic pathway. In further evaluating potential applications of these findings with carbidopa, we determined that sublethal doses of carbidopa produced additive cytotoxic effects in carcinoid cells in combination with etoposide and cytotoxic synergy in SCLC cells when coincubated with topotecan.

We conducted a randomized phase II study to determine the efficacy of dacarbazine (DTIC) in recurrent gliomas. Patients were randomly assigned to receive either DTIC 750 mg/m2 IV day 1 every 28 days (Arm A) or DTIC 200 mg/m2 IV days 1-5 every 28 days (Arm B). Pharmacokinetics were studied in 6 patients on each arm using HPLC analysis. Thirty-nine patients (30 male, 9 female), ages 27-67 years (median 53) were entered on the study (20 on Arm A, 19 on Arm B). No objective responses were seen. Median time to progression was 3 months. Median survival was 8 months. Treatment was generally well tolerated. Major toxicities were grade 1-2 nausea (33%). lethargy (28%), diarrhea (15%), alopecia (15%), and grade 3 neutropenia (8%). Four patients on Arm A had mild self-limited episodes of intravascular hemolysis occurring immediately after drug infusion, the mechanism of which is unknown. Mean AUC for DTIC, HMMTIC (5-[3-hydroxymethyl-3-methyl-1-triazeno] imidazole-4-carboxamide), and MTIC (5-[3-methyl-1-triazenol imidazole-4-carboxamide), in Arm A were 14.8, 0.17, and 1.15 mM min, respectively. Corresponding values for Arm B (on day 1 of 5) were 1.7, 0.06, and 0.29 mM min, respectively. The predicted HMMTIC and MTIC exposure over 5 days for Arm B, based on the day 1 data, is higher than with Arm A. We conclude that DTIC is well tolerated but does not have activity in patients with recurrent gliomas. The 5-day schedule appears less toxic, and pharmacokinetic studies show that it provides greater exposure to MTIC and HMMTIC compared to the one-day schedule.

Reactive oxygen species (ROS) act as signaling molecules in the cardiovascular system, regulating cellular proliferation and migration. However, an excess of ROS can damage cells and alter endothelial cell function. We hypothesized that endogenous mechanisms protect the vasculature from excess levels of ROS. We now show that superoxide can inhibit endothelin-converting enzyme activity (ECE) and decrease endothelin-1 synthesis. Superoxide inhibits ECE but hydrogen peroxide and nitric oxide do not. Superoxide inhibits ECE by ejecting zinc from the enzyme, and the addition of exogenous zinc restores enzymatic activity. Superoxide may inhibit other zinc metalloproteinases by a similar mechanism and may thus play an important role in regulating the biology of blood vessels.

Fine atmospheric particulate material was collected at five sites in upstate New York and analyzed for its trace element composition by instrumental neutron activation analysis. Of the 3700 daily samples collected over a 2-yr period, 1459 were analyzed for 39 elements, providing a large and detailed data set. Factor analysis (FA) was used to identify potential pollution sources or source regions and to construct inorganic source profiles for each. Following FA, the method of absolute factor scores-multiple linear regression was used to estimate the absolute elemental contribution of each of the identified sources. Factor analysis identified nine sources impacting the sampling region. Seven of these were found to be present in varying degrees among of the sampling sites. The other two sources had more localized impacts and were observed at only one of the sites each. Regional sources (such as the midwestern United States and eastern Canada) and crustal/soil material accounted for the greatest amount of the trace elements measured in the collected material.

The present study was undertaken to examine the mechanistic basis for the recent observation that the pyridine nucleotide derivative 6-aminonicotinamide (6AN, NSC 21206) enhances the accumulation and resulting cytotoxicity of cisplatin in a variety of tumor cell lines. When A549 lung cancer cells or K562 leukemia cells were treated with 62.5 microM 6AN for 21 h and then pulse-labeled with [(35)S]methionine for 1 h, increased labeling of five polypeptides, one of which corresponded to a M(r) approximately 78,000 glucose-regulated protein (GRP78), was observed. Two subsequent observations, however, suggested that up-regulation of these polypeptides was unlikely to explain the interaction between 6AN and cisplatin: 1) the concentration of 6AN required to induce GRP78 was 4-fold higher than the dose required to sensitize cells to cisplatin; and 2) simultaneous treatment of cells with 6AN and cycloheximide prevented the increase in GRP78 but not the sensitizing effect of 6AN. On the contrary, treatment with the protein synthesis inhibitors cycloheximide, anisomycin, or puromycin as well as prolonged exposure to the RNA synthesis inhibitor actinomycin D mimicked the biochemical modulating effects of 6AN on cisplatin action. Conversely, 6AN inhibited protein synthesis, whereas 18 6AN analogs that failed to enhance Pt-DNA adducts and cisplatin cytotoxicity failed to inhibit protein synthesis. These observations are consistent with a model in which 6AN and other inhibitors of protein synthesis act as modulating agents by increasing cisplatin accumulation, thereby enhancing the formation of Pt-DNA adducts and subsequent cisplatin-induced cell death.

The purpose of this study was to determine the toxicity, maximum tolerated dose, and pharmacokinetics of a 21-day continuous infusion of topotecan in children with relapsed solid tumors. Fifteen patients received 40 courses of continuous ambulatory infusions of topotecan every 28 days or when there was resolution of hematological toxicity and any grade 2 or greater nonhematological toxicity. The starting dose was 0.4 mg/m2/day. Total topotecan levels were measured on days 1, 7, 14, and 21. Three of four patients who received a starting dose of 0.4 mg/m2/day experienced dose-limiting myelosuppression. At the reduced dose of 0.3 mg/ m2/day, only two of the seven patients experienced dose-limiting myelosuppression. Subsequently, four patients with more limited prior therapy were treated with 0.4 mg/m2/ day; three had dose-limiting myelosuppression. Two patients with a dose-limiting toxicity at 0.4 mg/m2/day tolerated additional courses at 0.3 mg/m2/day. An equal number of patients had grade 4 neutropenia or thrombocytopenia. Other adverse events were rare. Two patients with ependymoma, one with rhabdomyosarcoma, and one with retinoblastoma metastatic to the brain had objective responses. The steady state plasma concentration and clearance of topotecan (Css) was achieved by day 1. Css in six patients with complete data were 1.44 +/- 0.50 and 2.13 +/- 0.83 ng/ml at 0.3 and 0.4 mg/m2/day, respectively. Thus, a 21-day topotecan infusion was well-tolerated at 0.3 mg/m2/day. Myelo-suppression was the dose-limiting toxicity at 0.4 mg/m2/day. The steady state and clearance of topotecan in this study are similar to those reported in adult patients.

Vascular damage due to arthroscopy is a rare complication. Postoperative occurrence of an arteriovenous fistula after using an electric hook for arthroscopic partial medial meniscectomy is described. Due to uncharacteristic symptoms of the arteriovenous fistula as a vascular complication after arthroscopy, the correct diagnosis may take a long time. In order to avoid damage to the popliteal vessels, the removal of the posterior horn of the medial meniscus should be performed under best visibility conditions with mild flexion and only mild external rotation of the calf. Considering the severe consequences, popliteal vascular damage is worth mentioning during preoperative information, even if it is an extremely rare complication.

The pyridine nucleotide 6-aminonicotinamide (6AN) was shown recently to sensitize a number of human tumor cell lines to cisplatin in vitro. The present studies were undertaken to compare the drug concentrations and length of exposure required for this sensitization in vitro with the drug exposure that could be achieved in mice in vivo. Human K562 leukemia cells and A549 lung cancer cells were incubated with 6AN for various lengths of time, exposed to cisplatin for 1-2 hr, and assayed for Pt-DNA adducts as well as the ability to form colonies. K562 cells displayed progressive increases in Pt-DNA adducts and cisplatin sensitivity during the first 10 hr of 6AN exposure. An 18-hr 6AN exposure was likewise more effective than a 6-hr 6AN exposure in sensitizing A549 cells to cisplatin. HPLC analysis of 6AN and its metabolite, 6-amino-NAD+, permitted assessment of exposures achieved in vivo after i.v. administration of 10 mg/kg of 6AN to CD2F1 mice. 6AN reached peak serum concentrations of 80-90 microM and was cleared rapidly, with T1/2alpha and T1/2beta values of 7.4 and 31.3 min, respectively. Bioavailability was 80-100% with identical plasma pharmacokinetics after i.p. administration. At least 25% of the 6AN was excreted unchanged in the urine. The metabolite 6-amino-NAD+ was detected in perchloric acid extracts of brain, liver, kidney, and spleen, but not in serum. Efforts to prolong systemic 6AN exposure by administering multiple i.p. doses or using osmotic pumps resulted in lethal toxicity. These results demonstrated that 6AN exposures required to sensitize tumor cells to cisplatin in vitro are difficult to achieve in vivo.