NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial.

BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the most lethal malignancies, with few treatment options. NAPOLI 3 aimed to compare the efficacy and safety of NALIRIFOX versus nab-paclitaxel and gemcitabine as first-line therapy for metastatic pancreatic ductal adenocarcinoma (mPDAC). METHODS: NAPOLI 3 was a randomised, open-label, phase 3 study conducted at 187 community and academic sites in 18 countries worldwide across Europe, North America, South America, Asia, and Australia. Patients with mPDAC and Eastern Cooperative Oncology Group performance status score 0 or 1 were randomly assigned (1:1) to receive NALIRIFOX (liposomal irinotecan 50 mg/m2, oxaliplatin 60 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2, administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2, administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Balanced block randomisation was stratified by geographical region, performance status, and liver metastases, managed through an interactive web response system. The primary endpoint was overall survival in the intention-to-treat population, evaluated when at least 543 events were observed across the two treatment groups. Safety was evaluated in all patients who received at least one dose of study treatment. This completed trial is registered with ClinicalTrials.gov, NCT04083235. FINDINGS: Between Feb 19, 2020 and Aug 17, 2021, 770 patients were randomly assigned (NALIRIFOX, 383; nab-paclitaxel-gemcitabine, 387; median follow-up 16·1 months [IQR 13·4-19·1]). Median overall survival was 11·1 months (95% CI 10·0-12·1) with NALIRIFOX versus 9·2 months (8·3-10·6) with nab-paclitaxel-gemcitabine (hazard ratio 0·83; 95% CI 0·70-0·99; p=0·036). Grade 3 or higher treatment-emergent adverse events occurred in 322 (87%) of 370 patients receiving NALIRIFOX and 326 (86%) of 379 patients receiving nab-paclitaxel-gemcitabine; treatment-related deaths occurred in six (2%) patients in the NALIRIFOX group and eight (2%) patients in the nab-paclitaxel-gemcitabine group. INTERPRETATION: Our findings support use of the NALIRIFOX regimen as a possible reference regimen for first-line treatment of mPDAC. FUNDING: Ipsen. TRANSLATION: For the plain language summary see Supplementary Materials section.

Ramucirumab for the treatment of patients with gastric or gastroesophageal junction cancer in community oncology practices.

BACKGROUND: Limited real-world research has investigated ramucirumab for the treatment of patients with gastric or gastroesophageal junction (GEJ) cancer. This study was designed to describe ramucirumab monotherapy or combination therapy use in a community oncology practice setting. METHODS: This was a retrospective observational cohort study to describe the treatment of adult patients with gastric or GEJ cancer who initiated ramucirumab treatment between 4/21/14 and 6/30/16 within the US Oncology Network. Kaplan-Meier method and Cox proportional hazards regression analyses were used to assess clinical outcomes. Multivariable logistic regression models were used to assess patient-level predictors of ramucirumab monotherapy or combination therapy. RESULTS: A total of 505 patients (mean age 64.4 years; 75.1% male) were included in the analysis; subgroups included: monotherapy (22.8%; n = 115), combination therapy (77.2%; n = 390). Monotherapy patients were significantly older (67.7 vs. 63.4 years; P = 0.0006), received ramucirumab approximately 3 months later after diagnosis (16.9 vs. 14.1 months; P = 0.0318) and more frequently initiated ramucirumab in the third or later lines of treatment (38.3 vs. 8.2%; P<0.0001) than patients receiving combination therapy. Median overall survival (OS) for monotherapy and combination therapy from the start of second-line therapy was 5.5 months (confidence interval [CI] 4.3, 7.8) and 7.4 months (CI 6.6, 8.8), respectively. CONCLUSIONS: The results showed that patients who received ramucirumab monotherapy started ramucirumab therapy later after diagnosis and were older than those who received ramucirumab in combination. Additionally, survival data suggest that outcomes observed in community oncology practices are similar to data from phase 3 clinical trials.

Transcriptome analysis provides insight into venom evolution in a seed-parasitic wasp, Megastigmus spermotrophus.

One of the most striking host range transitions is the evolution of plant parasitism from animal parasitism. Parasitoid wasps that have secondarily evolved to attack plants (ie gall wasps and seed-feeders) demonstrate intimate associations with their hosts, yet the mechanism of plant-host manipulation is currently not known. There is, however, emerging evidence suggesting that ovipositional secretions play a role in plant manipulation. To investigate whether parasites have modified pre-existing adaptations to facilitate dramatic host shifts we aimed to characterize the expression of venom proteins in a plant parasite using a collection of parasitoid venom sequences as a guide. The transcriptome of a seed-feeding wasp, Megastigmus spermotrophus, was assembled de novo and three putative venoms were found to be highly expressed in adult females. One of these putative venoms, aspartylglucosaminidase, has been previously identified as a major venom component in two distantly related parasitoid wasps (Asobara tabida and Leptopilina heterotoma) and may have originated via gene duplication within the Hymenoptera. Our study shows that M. spermotrophus, a specialized plant parasite, expresses putative venom transcripts that share homology to venoms identified in Nasonia vitripennis (both superfamily Chalcidoidea), which suggests that M. spermotrophus may have co-opted pre-existing machinery to develop as a plant parasite.

An open-label study of pemigatinib in cholangiocarcinoma: final results from FIGHT-202.

BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period. PATIENTS AND METHODS: The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently. CONCLUSIONS: Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202.

Systemic therapy for advanced carcinoid tumors: where do we go from here?

Carcinoid tumors are relatively indolent, but the treatment of advanced disease remains a challenge. Liver-directed therapies are a consideration in patients with liver-dominant disease. Somatostatin analogs (SSTa) are routinely used to control hormone-mediated symptoms (carcinoid syndrome), but the identification of systemic agents with antitumor efficacy has proven difficult. Aside from octreotide for small bowel carcinoid (which is associated with delayed progression), no treatment has proven antitumor activity. Chemotherapy seems to be of limited value. The role of interferon is also controversial; it is typically used after failure of octreotide. Peptide receptor radionuclide therapy may have activity in patients with SST receptor-expressing tumors, but randomized controlled trials are lacking. Advances in the understanding of the mechanisms underlying tumor progression have led to the identification of several potential therapeutic targets (including the vascular endothelial growth factor [VEGF] and mammalian target of rapamycin [mTOR] signaling pathways), but none has been definitively validated in carcinoid. Everolimus is associated with a trend toward improved progression-free survival in patients with progressive carcinoid, but is not approved for this indication. Therefore, a serious unmet need remains for additional therapeutic strategies for patients with advanced disease. Several avenues are under study, including the use of novel SSTa; VEGF and mTOR inhibitors; and agents that interfere with insulin growth factor 1 receptor and AKT signaling. Moving forward, optimizing patient selection based on clinical features or biomarkers holds promise for identifying individuals most likely to benefit from therapy.

Antimicrobial activity of cyclodextrin entrapped allyl isothiocyanate in a model system and packaged fresh-cut onions.

The aim of this work was to determine the antimicrobial effect of allyl isothiocyanate (AIT) entrapped in alpha and beta cyclodextrin inclusion complexes (ICs). In model experiments, AIT formulations were applied to filter paper discs fixed inside the lid of Petri dishes, where the agar surface was inoculated with the target organism (Penicillium expansum, Escherichia coli or Listeria monocytogenes). Solid phase microextraction coupled with gas chromatography was used to determine static headspace concentrations of AIT formulations. The antimicrobial effect of beta IC was determined during aerobic storage of packaged fresh-cut onions at 5 °C for 20 days. AIT entrapped in beta IC exhibited a significantly (p < 0.05) better antimicrobial effect compared to unentrapped AIT. AIT vapour concentrations in the static system were highest for unentrapped AIT followed by beta IC and alpha IC. Application of beta IC (200 µl/l) to packaged fresh-cut onions effectively decreased numbers of L. monocytogenes, which were also decreased at slower rates to undetectable levels on untreated cut onion. After 10 days, total aerobic counts were ca. 4 log CFU/g lower on onions treated with beta IC (100 and 200 µl/l) compared to untreated controls. This work demonstrates the utility of beta IC as an antimicrobial treatment with potential applications in packaged fresh-cut vegetable products.

Rethink Vape: Development and evaluation of a risk communication campaign to prevent youth E-cigarette use.

INTRODUCTION: E-cigarettes are now the most common form of tobacco use among adolescents, and use is associated with increased risk of initiation of cigarette smoking. This project used a community-engaged research process to develop and pilot a risk communication campaign to prevent youth vaping. METHOD: The research team worked with a 36-member Teen Advisory Council and a 19-member Expert Panel. Together, the team employed survey (N = 674) and focus group (N = 82) methodologies, and hired a marketing company to partner on development of the campaign. Campaign concepts were developed, eliminated, and/or modified through an iterative process of feedback and refinement. The final campaign included video ads (https://bit.ly/2QMR8gH) a microsite (rethinkvape.org), and social media sites (@rethinkvape). The campaign communicated three messages to teens: what's in the vapor, health risks, and connections to big tobacco. Prior to launch of the campaign, a randomized controlled 2 (time) × 2 (group) online experiment was conducted to evaluate the campaign (N = 268). RESULTS: Repeated measures mixed analyses of variance indicated that vaping knowledge, perceptions of risk, and anti-vape intentions significantly increased among teens viewing the Rethink Vape Materials compared to their own baseline, while control participants did not change. Following evaluation, the team launched a 6-week online media campaign with a teen-targeted geo-fence radius to deliver 3,838,465 impressions, 770,443 completed video views, and 18,316 clicks in mobile app, Snapchat, YouTube, and Spotify platforms. The majority of placements exceeded industry standards, with mobile pre-roll and Snapchat as top performers. CONCLUSIONS: The e-cigarette campaign showed promising signs of effectiveness and scalability.

Treatment Patterns and Clinical Outcomes in Patients With Metastatic Gastroenteropancreatic Neuroendocrine Tumors Treated in the Community Practice Setting in the United States.

OBJECTIVE: This study was conducted to understand treatment patterns and clinical outcomes in metastatic gastroenteropancreatic neuroendocrine tumor patients treated in a large community oncology network. METHODS: This retrospective study used the McKesson Specialty Health/US Oncology Network iKnowMed electronic health record database with supplemental chart review. Eligibility criteria included a metastatic neuroendocrine tumor diagnosis between January 1, 2008, and to December 31, 2012; at least 2 US Oncology Network visits; and age at least 18 years. Follow-up was through October 31, 2014. RESULTS: Among the 229 patients identified, median age was 64.0 years, 52.4% were male, 69.4% were white, and 62.9% were overweight/obese. Primary tumor sites included small bowel (47.6%), pancreas (31.4%), and stomach/colorectum (21.0%). There were 16.2% under observation without treatment, 52.4% received only somatostatin analogs (SSAs), and 31.4% received chemotherapy/targeted therapy during treatment. In the first-line setting (n = 192), 77% received SSAs, 12% received chemotherapy, and 10.9% received targeted therapy. Fifty percent of patients receiving octreotide had a relative dose intensity of less than 85%, and 16.7% received above-label dose. Toxicities of SSAs included diarrhea (18.2%), abdominal pain (16.9%), and fatigue (13.5%). Median overall survival from diagnosis was 68.0 months (95% confidence interval, 57.1 to not reached). CONCLUSIONS: Most metastatic gastroenteropancreatic neuroendocrine tumor patients received systemic treatment with SSAs. Patient treatment used an individualized dosing approach. Overall survival and toxicity were consistent with the published literature.

The association between heroin use and anxiety sensitivity among inner-city individuals in residential drug use treatment.

The current study represents an initial investigation of the association between heroin use and anxiety sensitivity (AS). Within a sample of 172 inner-city treatment seeking drug users, AS was compared across past year (1) heroin users with no crack/cocaine use (n=12); (2) crack/cocaine users with no heroin use (n=66); (3) users of both heroin and crack/cocaine (n=45); and (4) individuals with no use of heroin or crack/cocaine (n=49). Consistent with expectations, primary heroin users evidenced higher levels of AS than all other groups, with these differences also evidenced for the physical and social subscales. Differences in AS total score and physical subscale score persisted after controlling for demographic variables, depressive symptoms, and primary use of drugs other than heroin and crack/cocaine including alcohol, nicotine, marijuana, and hallucinogens. Findings suggest a unique relationship between AS and heroin, and set the stage for future work explicating the direction of the observed association.

Some physical and microstructural properties of genipin-crosslinked gelatin-maltodextrin hydrogels.

The physical properties and microstructure of gelatin-maltodextrin hydrogels fixed with genipin (GP) were investigated as a function of pH (3-7), maltodextrin (MD) (0-9%, w/w) and GP (0-10 mM levels), at a constant gelatin (G) concentration (10%, w/w). Network strength (elastic modulus, E) and swelling behavior were characterized by large deformation testing and by swelling index (SI). In general, network strength increased and swelling decreased at higher pH, MD and GP levels, except at pH 3, where E was independent of the GP concentration until approximately 7.5 mM, above which it declined. Confocal scanning laser microscopy (CLSM) images showed phase separation to be suppressed at pH 3, whereas at pH 7, separation into a self-similar dispersed phase was apparent. Overall, the judicious use of GP to crosslink G was an appropriate means of kinetically trapping MD within the gelatin network.

Kinetic and mechanistic considerations in the gelation of genipin-crosslinked gelatin.

The gelling properties (gel time (t(gel)) and gel strength) of a 10% (w/w) gelatin sol were investigated as a function of genipin (GP) concentration (0-15 mM) and temperature (25-55 degrees C) to discern mechanisms and optimal conditions for fixation. Gel time increased with increasing temperature, reached a maximum, and then declined as temperature was raised further. By contrast, network strength data followed the opposite trend. From the thermal behavior of t(gel) and network strength, it was inferred that gelation in the low-temperature regime was dominated by hydrogen bonding, while in the high-temperature regime it was dominated by covalent crosslinking. At higher temperatures, crosslinking was described by an Arrhenius rate law expression, with activation energies between 63.2 and 67.8 kJ/mol, depending on GP concentration. In the low temperature regime, an Arrhenius plot resulted in negative activation energies of -75.8 and -64.4 kJ/mol in the presence of 10 and 15 mM GP, respectively. With an increase in both GP concentration and temperature, the gelatin network gradually shifted from being dominated by hydrogen bonds (physical crosslinks) to covalent crosslinking (chemical crosslinks).

Relationship of hair dye use, benign breast disease, and breast cancer.

An epidemiologic case-control study of 118 breast cancer patients and 233 controls was conducted to test the hypothesis that hair dyes are related to breast cancer. Matched controls were selected by "random digit dialing," and all epidemiologic data were collected by telephone interviews. No overall association was detected. On a prospective basis, the interaction between hair dye exposure and six variables known to be risk factors for breast cancer then were examined: previous benign breast disease (BBD), "ever" versus "never" pregnant, age at first pregnancy, menopause induced by operation, age at menarche, and education. A statistically significant increased risk of breast cancer was found for women with a history of BBD and exposure to hair dyes as compared to women with BBD but no hair dye exposure: The relative risk (RR) was 4.5, and the 95% confidence intervals (C) were 1.20 and 15.78. A total of 24 women (19 patients and 5 controls) reported a history of BBD and hair dye use. Further analysis revealed a significant association between hair dye use and breast cancer among women 40-49 years of age (RR = 3.33; 95% CI: 1.1 and 10.85) and a highly significant (P = 0.0008) dose-response relationship among women who used hair dyes for changing their natural color as opposed to covering gray hair. The numbers of patients and controls included in this study were small and several hypotheses were tested. Additional epidemiologic studies are needed before firm conclusions can be reached concerning the nature of these associations.

SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model.

Somatic mutations or deletions of TP53 and PTEN in ductal carcinoma in situ lesions have been implicated in progression to invasive ductal carcinomas. A recent molecular and mutational analysis of breast cancers revealed that inactivation of tumor suppressors, p53 and PTEN, are strongly associated with triple negative breast cancer. In addition, these tumor suppressors have important roles in regulating self-renewal in normal and malignant stem cells. To investigate their role in breast carcinogenesis, we knocked down these genes in human mammary cells and in non-transformed MCF10A cells. p53 and PTEN knockdown synergized to activate pro-inflammatory interleukin-6 (IL6)/Stat3/nuclear factor κB signaling. This resulted in generation of highly metastatic epithelial-to-mesenchymal transition-like cancer stem cells resulting in tumors whose gene expression profile mimicked that found in basal/claudin-low molecular subtype within the triple negative breast tumors. Constitutive activation of this loop in transformed cells was dependent on proteolytic degradation of suppressor of cytokine signaling 3 (SOCS3) resulting in low levels of this protein in basal/claudin-low cell lines and primary tumors. In non-transformed cells, transient activation of the IL6 inflammatory loop induced SOCS3 expression leading to pathway inactivation. In transformed cells, enforced expression of SOCS3 or interfering with IL6 pathway via IL6R blockade inhibited tumor growth and metastasis in mouse xenograft models. Furthermore, circulating tumor cells were significantly reduced in tumor-bearing animals when treated with anti-IL6R antibodies. These studies uncover important connections between inflammation and carcinogenesis and suggest that blocking pro-inflammatory cytokines may be utilized as an attractive strategy to target triple negative breast tumors, which currently lacks molecularly targeted therapies.

Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients.

ONYX-015 is an adenovirus that selectively replicates in p53 dysfunctional or mutated malignant cells. We performed a pilot trial to determine the safety and feasibility of treatment with ONYX-015 delivered intravenously in patients with advanced malignancy. One cohort of five patients received ONYX-015 once a week for 6 weeks at a dose of 2 x 10(12) particles per infusion in combination with weekly infusions of irinotecan (CPT11, 125 mg per week) and 5-fluorouracil (5FU, 500 mg per week). A second cohort of five patients received the combination of ONYX-015 at a dose of 2 x 10(11) particles per week for 6 weeks in combination with interleukin 2 (IL 2, 1.1 x 10(6) units daily via subcutaneous injection for 5 days each week for 4 weeks). Toxicity attributable to ONYX-015 was limited to transient fever. All patients demonstrated elevations in neutralizing antibody titers within 4 weeks of the infusion of ONYX-015. Serum levels of IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma increased within 6 hours of viral infusion, suggesting immune activation. This response was more pronounced in the cohort of patients who received 2 x 10(12) particles per infusion. Two patients demonstrated uptake of viral particles in malignant tissue by quantitative PCR. Electron microscopy confirmed selective cytoplasmic viral particles within malignant cells but not within adjacent normal tissue in a third patient. In conclusion ONYX-015 can be administered safely in combination with CPT11, 5FU or low-dose IL 2 and is able to access malignant tissue following intravenous infusion. Further investigation of ONYX-015, possibly with agents that may modulate replication activity, or duration of virus survival, is indicated.

Respiration and gene expression in germinating ascospores of Neurospora tetrasperma.

Cellular proteins were not synthesized by germinating ascospores of Neurospora tetrasperma until 90 min after spore activation. Nevertheless, immediately after activation these ascospores developed a cyanide-sensitive respiration which increased throughout this 90-min period. At 90 min the respiratory rates accelerated rapidly, protein synthesis was initiated, and transcripts for a subunit of the mitochondrial ATPase, employed here as a representative mRNA, began to accumulate.

Heat shock gene expression in germinating ascospores of Neurospora tetrasperma.

The activated ascospores of Neurospora tetrasperma were inactive in protein synthesis and did not accumulate transcripts for a constitutive protein until after 90 min of incubation. These spores were blocked even longer in the expression of a gene encoding a heat shock protein, hsp30, which could not be induced until after 300 min of spore germination. Early in germination the ascospores were highly susceptible to damage from moderately high temperatures. At the same time that spores became capable of expressing the hsp30 gene, there was a loss of cytosine methylation from the gene.

Modeling of orthokinetic flocculation of Saccharomyces cerevisiae.

This study examined the flocculation behavior of two Saccharomyces cerevisiae strains expressing either Flo1 (LCC1209) genotype or NewFlo (LCC125) phenotype in a laminar flow field by measurement of the fundamental flocculation parameter, the orthokinetic capture coefficient. This orthokinetic capture coefficient was measured as a function of shear rate (5.95-223 s(-1)) and temperature (5-45 degrees C). The capture coefficients of these suspensions were directly proportional to the inverse of shear rate, and exhibited an increase as the temperature was increased to 45 degrees C. The capture coefficient of pronase-treated cells was also measured over similar shear rate and temperature range. A theory, which predicts capture coefficient values due to zymolectin interactions, was simplified from that developed by Long et al. [Biophys. J. 76: (1999) 1112]. This new modified theory uses estimates of: (1) cell wall densities of zymolectins and carbohydrate ligands; (2) cell wall collision contact area; and (3) the forward rate coefficient of binding to predict theoretical capture coefficients. A second model that involves both zymolectin interactions and DLVO forces was used to describe the phenomenon of yeast flocculation at intermediate shear ranges, to explain yeast flocculation in laminar flow.

Reproductive dysfunction in women with epilepsy: antiepileptic drug effects on sex-steroid hormones.

Women with epilepsy are at risk for reproductive health dysfunction. Sex-steroid hormone abnormalities have been reported in women with epilepsy, but it has been difficult to determine whether these abnormalities are due to epilepsy-related hypothalamic-pituitary axis dysfunction, or to pharmacokinetic actions of antiepileptic drugs (AEDs). Sex-steroid hormones were evaluated in 84 reproductive-aged women with epilepsy receiving an AED in monotherapy, and in 20 nonepileptic controls. Estrone, free testosterone, and androstenedione were significantly lower in subjects receiving enzyme-inducing AEDs than in nonepileptic controls. Free testosterone was significantly elevated in subjects receiving valproate compared to nonepileptic controls. Subjects with epilepsy receiving gabapentin or lamotrigine were no different from the nonepileptic controls in any of the endocrine variables. Subjects with epilepsy who are receiving AEDs that alter cytochrome P450 enzymes are at risk for significant abnormalities in sex-steroid hormones. In contrast, subjects receiving AEDs that do not alter cytochrome P450 enzymes show no differences in sex-steroid hormones compared with nonepileptic controls. With new AEDs available that do not alter cytochrome P450 enzymes, physician selection of therapy should consider not only seizure control, but also potential effects on reproductive physiology.

Biogeochemical removal of Zn and Cd in the Coeur D'Alene River (Idaho, USA), downstream of a mining district.

The conservative biogeochemical behavior of dissolved Zn and Cd in a 17-km, free-flowing reach of the Coeur d'Alene River downstream of a mining district is typical of watersheds in which suspended matter concentrations are low. For watersheds impacted by acid-rock drainage (ARD), low suspended matter concentrations are more likely to be found when acid rock drainage travels through soils because much of the Fe and Al that could form adsorbing surfaces is retained within the soils. In the absence of additional sources of solid substrates, metals can be transported great distances downstream once this Fe- and Al-poor ARD seeps into surface waters. In a 46-km backwater reach of the Coeur d'Alene River, it appears that biological activity increased pH and provided the organic matter solid substrate which removed approximately 50% of the Zn and Cd. Zn removal was partially reversible as pH decreased. These observations reinforce the concept that both inorganic and organic carbon chemistry must be measured if significant. advances in our understanding of the attenuation of Zn and Cd from ARD sources are to be made.

Separate dissolved and particulate trace metal budgets for an estuarine system: an aid for management decisions.

The sources and sinks of dissolved and particulate Pb, Cu and Zn were determined for the main basin of Puget Sound to understand the effect man has had on metal concentrations in both the water column and in the sediments. Municipal, industrial and atmospheric sources contributed about 66% of the total Pb added to the main basin of Puget Sound during the early 1980s. Advective inputs were the major sources of total Cu and Zn (approximately 40%) while riverine and erosional sources contributed about 30%. The discharge of the particle-bound trace metals from rivers minimized the influence of particulate anthropogenic sources, which constituted 50%, 23% and 18% of the total particulate Pb, Cu and Zn inputs, respectively. While advective transport was the major source of dissolved Cu and Zn (approximately 60% of all dissolved inputs), industrial, municipal and atmospheric inputs contributed about 85%, 30% and 38% of the dissolved Pb, Cu and Zn inputs, respectively. The sources of dissolved and particulate Cu and Zn were comparable with the sinks within the errors of the analyses indicating their quasi-conservative nature. Advection removed about 60% of the total Cu and Zn added to the main basin while 40% was deposited in the sediments of Puget Sound. Because of this quasi-conservative nature of Cu and Zn, anthropogenic inputs of Cu and Zn were dispersed from the system more than they were contained within main basin sediments. About 75% of the dissolved Pb discharged into the main basin of Puget Sound was lost from the dissolved phase and was balanced by a similar gain in the particulate phase. Because of this extensive scavenging and the effective retention of particles within the main basin, about 70% of the total Pb added to the main basin was retained within its sediments. These separate mass balances have utility in management decisions because they show the relative contributions from different sources and demonstrate whether the influences of dissolved and particulate inputs are reflected solely in the water column or the sediments, respectively.