Behavior of major and trace elements in a transient surface water/groundwater system following removal of a long-term wastewater treatment facility source.

In many aquatic environments, municipal wastewater treatment facility (WWTF) effluent discharges influence local hydrologic and chemical connectivity between the surface-water and adjacent alluvial shallow-groundwater systems. Fourmile Creek located in Polk County, Iowa received effluent from the Ankeny WWTF for nearly forty years before it was shut down in November 2013. The decommissioning of the municipal WWTF provided a unique opportunity to characterize the recovery from impacts of treated wastewater discharge on water quality at the surface-water/groundwater interface in a shallow, unconfined alluvial aquifer. Dissolved major element and trace element concentrations in Fourmile Creek surface water, hyporheic-zone water, and shallow, unconfined groundwater were monitored upstream and downstream from the WWTF discharge before and after the shutdown. Multivariate statistical techniques including principal component analysis (PCA) and agglomerative hierarchical clustering (AHC) were used to differentiate source-water contributions, characterize elemental components, and describe surface-water/groundwater interaction dynamics. During the post-closure assessment, there was subsurface attenuation of wastewater constituents including Al, B, Cu, Gd, K, Mo, Na, P, Pb, Sb, and Zn. During the same time, groundwater concentrations increased for As, Ba, Ca, Fe, Mg, Mn, SiO2, Sr, and U and represented a profile characteristic of the shallow alluvial aquifer. Hydrologic conditions transitioned from predominantly wastewater infiltration and hyporheic exchange before the WWTF shutdown, to predominantly discharge of native groundwater. Precipitation-driven streamflow events created fluctuations in the groundwater water-table elevations, resulting in variable contact between the saturated and unsaturated zones within the unconfined, alluvial aquifer and intermittent exposure to constituents stored in the sediments. The inorganic fingerprint of municipal wastewater was flushed relatively quickly (≤19 weeks) from the hyporheic zone indicating that processes like diffusion or sorption/desorption that might extend recovery may not be important for many trace elements in this system.

Impact of concomitant medication use on belimumab efficacy and safety in patients with systemic lupus erythematosus.

Practicing physicians have requested efficacy and safety data for belimumab, when used with specific systemic lupus erythematosus (SLE) medications. This was a post hoc analysis of pooled efficacy and safety data from patients who received belimumab 10 mg/kg plus standard of care (SoC) or placebo (SoC) in two Phase III, randomized trials, BLISS-52 and BLISS-76. Patients were categorized into four groups based on baseline concomitant medication usage: steroids only; antimalarials (AM) only; steroids + AM; or steroids + AM + immunosuppressants (IS). The primary endpoint was the SLE Responder Index (SRI) at Week 52. SRI over time and individual SRI components were secondary endpoints. Time to first flare and changes in concomitant medications were exploratory endpoints. Safety was assessed using adverse event (AE) reporting. Across 834 patients, steroids + AM was the largest group (n = 346, 41.5%) and AM only was the smallest (n = 77, 9.2%). Disease duration was shortest in the steroids + AM group (5.7 years vs 6.4-7.1 years); SELENA-SLEDAI scores were similar across groups. At Week 52, the percentage of SRI responders was greatest in the steroids + AM group for belimumab 10 mg/kg (59%) compared with placebo (44%); treatment response and SRI component improvements were also observed across other groups. The probability of experiencing an SLE flare was reduced in the steroids-only group for patients who received belimumab 10 mg/kg compared with placebo (64.3% vs 78.1%; hazard ratio 0.64; 95% confidence interval: 0.42-0.96). There was little or no change in daily AM or IS dose in any group. For all groups, there was a general decrease in steroid dose over time; a quarter to a third of patients experienced decreased steroid doses at Week 52. The overall safety profile was similar across treatment arms and concomitant medication groups, with the exception of serious AEs in the steroids + AM group (belimumab 10 mg/kg 16%, placebo 8%). The efficacy and safety of belimumab in combination with SoC was demonstrated for various groupings of steroids, AM and IS. These findings may improve the understanding of the safety and efficacy of adding belimumab to different treatments.

Elevated BLyS levels in patients with systemic lupus erythematosus: Associated factors and responses to belimumab.

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) with B-lymphocyte stimulator (BLyS) levels ≥ 2 ng/mL are at increased risk of flare. A regression analysis was undertaken to identify routine clinical measures that correlate with BLyS ≥ 2 ng/mL. Efficacy and safety of belimumab 10 mg/kg were examined in patients with BLyS ≥ 2 ng/mL and < 2 ng/mL. METHODS: Data from BLISS-52 and -76 (N = 1684) were pooled post hoc. A univariate logistic regression was employed to identify factors predictive of baseline BLyS ≥ 2 ng/mL. Factors significant at the 0.05 level then entered a stepwise logistic regression as covariates. Efficacy endpoints included SLE responder index (SRI), ≥ 4-point reduction in Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) and risk of severe flare over 52 weeks. Adverse events (AEs) were analyzed for each treatment arm and BLyS subgroup. RESULTS: Baseline predictors of BLyS ≥ 2 ng/mL included positive anti-Smith (≥ 15 U/mL), low complement (C) 3 (< 900 mg/L), anti-double-stranded DNA (anti-dsDNA) 80-200 and ≥ 200 IU/mL, immunosuppressant usage, proteinuria, elevated C-reactive protein (CRP), and low total lymphocyte count for all patients. Belimumab 10 mg/kg led to significantly greater SRI responses over 52 weeks versus placebo in both BLyS subgroups, though treatment differences were numerically greater at Week 52 in the BLyS ≥ 2 ng/mL group (24.1%, p < 0.0001) compared with BLyS < 2 ng/mL (8.2%, p = 0.0158). Results were similar for ≥ 4-point reduction in SELENA-SLEDAI. Risk of severe flare over 52 weeks was significantly reduced with belimumab 10 mg/kg versus placebo in the BLyS ≥ 2 ng/mL group (p = 0.0002). AEs were similar across treatment arms and BLyS subgroups. CONCLUSIONS: Positive anti-Smith, low C3, anti-dsDNA ≥ 80 IU/mL, immunosuppressant usage, proteinuria, elevated CRP, and low total lymphocyte count were predictors of BLyS ≥ 2 ng/mL. Monitoring these factors could identify patients with BLyS ≥ 2 ng/mL who are at risk of flare.

Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE.

A pooled post-hoc analysis of the phase 3, randomized, placebo-controlled BLISS trials (1684 patients with active systemic lupus erythematosus (SLE)) was performed to evaluate the effect of belimumab on renal parameters in patients with renal involvement at baseline, and to explore whether belimumab offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. In addition to belimumab or placebo, all patients received standard SLE therapy. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement (assessed by Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index and British Isles Lupus Assessment Group), proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, although the between-group differences in most renal outcomes were not significant. Among the 267 patients with renal involvement at baseline, those receiving mycophenolate mofetil or with serologic activity at baseline had greater renal organ disease improvement with belimumab than with placebo. Limitations of this analysis included the small patient numbers and the post-hoc nature of this pooled analysis. The results suggest that belimumab may offer renal benefit in patients with SLE. Further study is warranted in patients with severe active lupus nephritis.

Selected trace elements in the Sacramento River, California: occurrence and distribution.

The impact of trace elements from the Iron Mountain Superfund site on the Sacramento River and selected tributaries is examined. The concentration and distribution of many trace elements-including aluminum, arsenic, boron, barium, beryllium, bismuth, cadmium, cerium, cobalt, chromium, cesium, copper, dysprosium, erbium, europium, iron, gadolinium, holmium, potassium, lanthanum, lithium, lutetium, manganese, molybdenum, neodymium, nickel, lead, praseodymium, rubidium, rhenium, antimony, selenium, samarium, strontium, terbium, thallium, thulium, uranium, vanadium, tungsten, yttrium, ytterbium, zinc, and zirconium-were measured using a combination of inductively coupled plasma-mass spectrometry and inductively coupled plasma-atomic emission spectrometry. Samples were collected using ultraclean techniques at selected sites in tributaries and the Sacramento River from below Shasta Dam to Freeport, California, at six separate time periods from mid-1996 to mid-1997. Trace-element concentrations in dissolved (ultrafiltered [0.005-µm pore size]) and colloidal material, isolated at each site from large volume samples, are reported. For example, dissolved Zn ranged from 900 µg/L at Spring Creek (Iron Mountain acid mine drainage into Keswick Reservoir) to 0.65 µg/L at the Freeport site on the Sacramento River. Zn associated with colloidal material ranged from 4.3 µg/L (colloid-equivalent concentration) in Spring Creek to 21.8 µg/L at the Colusa site on the Sacramento River. Virtually all of the trace elements exist in Spring Creek in the dissolved form. On entering Keswick Reservoir, the metals are at least partially converted by precipitation or adsorption to the particulate phase. Despite this observation, few of the elements are removed by settling; instead the majority is transported, associated with colloids, downriver, at least to the Bend Bridge site, which is 67 km from Keswick Dam. Most trace elements are strongly associated with the colloid phase going downriver under both low- and high-flow conditions.

BDDrFVIII (Moroctocog alfa [AF-CC]) for surgical haemostasis in patients with haemophilia A: results of a pivotal study.

SUMMARY: Moroctocog alfa (AF-CC) (Xyntha, BDDrFVIII) is manufactured by a process designed to enhance the theoretical viral safety profile relative to ReFacto, its predecessor, and to provide alignment with clinical monitoring by the one-stage clotting assay. To evaluate the efficacy and safety of B-domain-deleted recombinant factor VIII (BDDrFVIII) was given as bolus injection (BI) or continuous infusion (CI) in haemophilia patients undergoing major surgery. BDDrFVIII was administered by BI or CI per investigator discretion peri-operatively for at least 6 days. Thirty patients enrolled and were treated with at least one dose of BDDrFVIII. Twenty-five patients were evaluable for efficacy. Outcomes were favourable against a background of multiple major surgical procedures. All haemostatic efficacy ratings were 'excellent' or 'good'. End-of-surgery haemostasis ratings, the primary efficacy endpoint, were excellent for 72% (18/25) and good for 28% (7/25) of patients. Haemostasis ratings following the initial postoperative period were excellent for 92% (23/25) and good for 8% (2/25) of patients. Intra-operative blood loss was rated as normal in all patients. Thirteen patients had postoperative blood loss; in 10, this was rated as normal. A low frequency of transfusion was reported in both the intra-operative and postoperative settings. Adverse events (AEs) were consistent with surgery; three were considered related to BDDrFVIII. One patient had a related AE of postoperative haemorrhage. A clinically silent low-titre inhibitor was detected in one patient, and one patient had a false-positive inhibitor titre. This study demonstrates that BDDrFVIII is safe and efficacious for surgical prophylaxis in haemophilia A patients undergoing major surgery.

Safety and efficacy of investigator-prescribed BeneFIX prophylaxis in children less than 6 years of age with severe haemophilia B.

Prophylaxis is increasingly prescribed in treatment of haemophilia and its benefit is believed to be most significant for the youngest patients as haemophilic arthropathy may be prevented if prophylaxis is initiated prior to recurrent haemarthroses. While clinical prophylaxis data are readily available for haemophilia A, analogous data for haemophilia B are relatively limited. A prospective clinical study of recombinant factor IX (BeneFIX; rFIX), designed to allow investigator prescribed prophylaxis according to customary practices, was conducted in children <6 years old with severe haemophilia B. Nearly all children were prescribed prophylaxis (22/25; 88%) for all or part of their study participation. Favourable efficacy and safety profiles were reported. Routine prophylaxis with 1 or 2 rFIX infusions per week over an average of greater than 6 months of therapy resulted in near complete prevention of spontaneous breakthrough haemorrhages (<1 per year), with most children (77%) having none, including seven patients (32%) who had no bleeding episodes at all. Haemorrhages in joints were less common than those outside joints (27% vs. 73% of haemorrhages). In a patient population that included children with multiple prior haemarthroses, 68% of children had no joint bleeding. Breakthrough haemorrhages resolved with 1 or 2 infusions in 89% of episodes. The absence of changes in prophylaxis infusion schedules suggests that 1 or 2 rFIX infusion(s) per week were well-tolerated by these young patients, including those with (41%) and without (59%) central venous access devices. Safety was established by the low incidence of treatment-related adverse events.

Clinical evaluation of moroctocog alfa (AF-CC), a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full-length recombinant factor VIII.

BDDrFVIII is a B-domain deleted recombinant factor VIII (rFVIII) product for haemophilia A. Manufacture uniquely includes purification chromatography by synthetic-affinity ligand rather than murine-based monoclonal antibody, as well as an albumin-free cell culture process. BDDrFVIII was studied in 204 patients, including 62 subjects <16 years old, in two studies. A double-blind, randomized, pharmacokinetic (PK) crossover study, utilizing a central laboratory assay (one-stage (OS)) for both drug potency assignment and plasma FVIII-activity measurements, demonstrated that BDDrFVIII was PK-equivalent to a full-length rFVIII. Favourable efficacy and safety were observed: during defined routine prophylaxis in a patient population significant for preexisting target joints, nearly half (45.7%) of patients had no bleeding, and a low-annualized bleed rate (ABR) was achieved (median 1.9); 92.5% of haemorrhages (n = 187) required < or =2 infusions. Three subjects (1.5%, across both studies) developed de novo inhibitors (low-titre, transient), and the primary safety endpoint, based on a prospective Bayesian analysis, demonstrated the absence of neoantigenicity for BDDrFVIII. The PK-equivalence, based on central testing to align test and reference articles, and the novel Bayesian analysis of inhibitor safety in these investigations reflect robust experimental designs with relevance to future studies. This extensive dataset demonstrates the safety and efficacy of BDDrFVIII for haemophilia A.

Reformulated BeneFix: efficacy and safety in previously treated patients with moderately severe to severe haemophilia B.

BeneFix, the only recombinant factor IX (FIX), has been reformulated. The reformulation involves a change in diluent and allows for more concentrated infusions of recombinant FIX. A double-blind, randomized, pharmacokinetic (PK) crossover study demonstrated that reformulated BeneFix was bioequivalent to original BeneFix and follow-up PK evaluation after 6 months of treatment demonstrated the PK stability of reformulated BeneFix after multiple exposures. Favourable efficacy and safety profiles, consistent with those already well-established for original BeneFix, were observed: 81.1% of haemorrhages resolved with only a single infusion; 85.3% of initial treatment response ratings were Excellent or Good; more than half of the subjects using reformulated BeneFix for routine prophylaxis (11 of 17, 64.7%) had no spontaneous haemorrhages during their 6-12 month course of prophylactic treatment, with an overall spontaneous bleeding rate of 0.72 year(-1); and for the single surgical procedure (knee washing), treatment was rated Useful. In addition, there was no FIX inhibitor development, allergic-type manifestations, or thrombogenic complications with more than 1100 infusions (nearly 5.2 million IUs) administered in this trial. All efficacy and safety outcomes from this study were achieved with more concentrated recombinant protein infusions than that possible with original BeneFix, and utilization of the 2000 IU per vial dosage strength, newly introduced with the reformulated product, was high (>62%). The reformulation of BeneFix allows smaller delivery volumes and an increased choice of dosage strengths without altering the PK properties (including incremental recovery and half-life) or the established efficacy and safety profile of recombinant FIX.

B-domain deleted recombinant factor VIII preparations are bioequivalent to a monoclonal antibody purified plasma-derived factor VIII concentrate: a randomized, three-way crossover study.

BACKGROUND: Deletion of the B-domain of recombinant blood coagulation factor VIII (BDDrFVIII) increases the manufacturing yield of the product but does not impair in vitro or in vivo functionality. BDDrFVIII (ReFacto) has been developed with the additional benefit of being formulated without human albumin. OBJECTIVE: The primary objective of this three-way crossover-design study was to compare the pharmacokinetic (PK) parameters of two BDDrFVIII formulations (one reconstituted with 5 mL of sterile water, the other reconstituted with 4 mL sodium chloride 0.9% USP) with those of a plasma-derived, full-length FVIII preparation (Hemofil M) in patients with haemophilia A to determine bioequivalence. METHODS: A series of blood samples were collected over a period of 48 h after i.v. administration of each of the FVIII preparations. Plasma FVIII activity was determined using a validated chromogenic substrate assay. Plasma FVIII activity vs. time curves was characterized for a standard set of PK parameter estimates. Two parameter estimates, the maximum plasma concentration (Cmax) and the area under plasma concentration vs. time curves (AUCs), were used to evaluate bioequivalence. The two preparations were considered bioequivalent if the 90% confidence intervals for the ratio of geometric means for Cmax and AUCs fell within the bioequivalence window of 80% to 125%. RESULTS/CONCLUSION: Results show that each BDDrFVIII formulation is bioequivalent to Hemofil M and the two formulations of BDDrFVIII are bioequivalent to each other.

A Bayesian approach to the assessment of inhibitor risk in studies of factor VIII concentrates.

The assessment of inhibitor risk is a crucial component in the clinical development of new and modified factor VIII (FVIII) preparations. There has been a recent discussion about the design of studies and the assessment of inhibitors and inhibitor risk in such studies at a recent FDA-sponsored FVIII Inhibitor Workshop, and new requirements for the success of these trials have been proposed to evaluate inhibitor data based on the use of an upper 95% confidence bound. We review the consequences of these requirements and demonstrate that for any product to succeed, it must have an extremely low underlying risk of inhibitor development. Furthermore, several existing commercially available FVIII products with an excellent safety record would not necessarily pass these endpoints. As a result, we propose an alternative set of acceptance criteria based on a Bayesian statistical paradigm. This approach is based on the determination of a probability that the product in question actually has an inhibitor risk below some pre-set limit, a concept that we believe is more intuitive than the traditional confidence interval method. We show that all existing products would pass this approach, but a product (Bisinact) with known inhibitor risk would not.

High resolution TDL spectroscopy of the Ar-CH4 complex.

The spectrum of the weakly bound complex Ar-CH4 in the 7 microm region was discovered, analysed, and compared with a spectrum, predicted from ab initio calculations. The measurements were made by probing a supersonic gas expansion with a tunable diode laser (TDL). Several bands of Ar-CH4 associated with different ro-vibrational transitions of the v4 vibration of CH4 were recorded and analysed in a spectral region from 1295 to 1330 cm(-1). In particular the following transitions were studied: j = 1 <-- 0 (at 1311 cm(-1)) reported in Pak et al. [Z. Naturforsch. 53 (1998) 725], j = 0 <-- 1 (at 1301 cm(-1)), j = 2 <-- 1 (at 1316 cm(-1)), and j = 3 <-- 2 transitions (at 1322 cm(-1)). Here, j denotes the angular momentum of the methane unit inside the complex. Analysis of the recently recorded j = 1 <-- 1 transitions at about 1306 cm(-1) in the region of methane Q(1) is in progress. The experimental results are compared with ab initio calculations. The close agreement between observed and ab initio spectra is convincingly demonstrated with respect to the gross spectral features, including many details of the spectra.

Influence of natural organic matter on the adsorption of metal ions onto clay minerals.

The influence of natural organic matter (NOM) on the adsorption of Al, Fe, Zn, and Pb onto clay minerals was investigated. Adsorption experiments were carried out at pH = 5 and pH = 7 in the presence and absence of NOM. In general, the presence of NOM decreased the adsorption of metal ions onto the clay particles. Al and Fe were strongly influenced by NOM, whereas Zn and Pb adsorption was only slightly altered. The interaction of the metal ions with the minerals and the influence of NOM on this interaction was investigated by coupling SdFFF with an inductively coupled plasma mass spectrometer (ICPMS) or an inductively coupled plasma atomic emission spectrometer (ICPAES). Quantitative atomization of the clay particles in the ICP was confirmed by comparing elemental content determined by direct injection of the clay into the ICPMS with values from acid digestion. Particle sizes of the clays were found to be between 0.1 and 1 microm by sedimentation field-flow fractionation (SdFFF) with UV detection. Aggregation of particles due to metal adsorption was observed using SdFFF-ICPMS measurements. This aggregation was dependent on the specific metal ion and decreased in the presence of NOM and at higher pH value.

Absence of germline infection in male mice following intraventricular injection of adenovirus.

The possibility of inadvertent exposure of gonadal tissue to gene therapy vectors has raised safety concerns about germline infection. We show here that the receptor for coxsackie B viruses and adenoviruses 2 and 5 (CXADR) is expressed in mouse germ cells, suggesting the possibility that these viruses could infect germ cells. To directly assess the risk of germline infection in vivo, we injected an adenovirus carrying the germ-cell-specific protamine promoter fused to the bacterial lacZ reporter gene into the left ventricular cavity of mice and then monitored expression of the reporter gene in germ cells. To differentiate between infection of stem cells and differentiating spermatogenic cells, we analyzed expression of the reporter cassette at different times after viral delivery. Under all conditions tested, mice did not express the Escherichia coli beta-galactosidase protein in developing spermatids or in mature epididymal spermatozoa. Primary germ cells cultured in vitro were also refractory to adenoviral infection. Our data suggest that the chance of vertical germline transmission and insertional mutagenesis is highly unlikely following intracoronary adenoviral delivery.

Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates.

Human plasma-derived factor IX (pdFIX) concentrates are routinely used to treat patients with hemophilia B, an X-linked bleeding disorder that affects 1 in 30 000 males, but concerns remain regarding transmission of blood-borne pathogens. Therefore, the safety and efficacy of recombinant human factor IX (rFIX) were evaluated. A 20-center international trial was conducted in previously treated patients with severe or moderate (< 5 IU/dL factor IX activity) hemophilia B. Participants received rFIX for pharmacokinetic studies, treatment of or prophylaxis against hemorrhage, or surgical hemostasis, and were assessed at 3-month intervals for 2 years. Fifty-six subjects were treated. Mean incremental rFIX recovery was 0.75 IU/dL per IU/kg, 30% lower than expected for pdFIX, although the mean half-life was similar. Pharmacokinetic parameters were stable over time. Somewhat lower recoveries were seen in subjects younger than 15 years of age and in those with no detectable factor IX antigen. A total of 7362 infusions of rFIX were administered. All 1796 hemorrhages were controlled, 80.9% of which required only one rFIX infusion. Effective hemostasis was also achieved in prophylactic and surgical settings. One individual developed a low titer (1.2 Bethesda unit) transient inhibitor that spontaneously resolved. rFIX was not associated with serious adverse events, thrombogenicity, or virus transmission. rFIX is safe and effective for the treatment of hemophilia B. Despite a lower recovery compared with pdFIX, rFIX controlled hemorrhage in a wide variety of settings and may provide a safety advantage in terms of risk from blood-borne pathogens.

Cognitive-behavioral models of social anxiety disorder.

In 1985, Liebowitz et al labeled SAD the "neglected anxiety disorder." Clearly, times have changed. Although it took 10 years after this pronouncement for the first cognitive-behavioral model of SAD to be introduced, a great deal of research has been carried out and a great deal has been learned since then. The core features of these models seem to hold a great deal of validity. Perhaps the greatest "learning curve" has been seen in work done on the processing of the self as social object, a component of both cognitive-behavioral models of SAD. A great deal of empiric evidence now suggests that people with SAD see themselves as they believe they are seen by others. Unfortunately, their perception of how they are seen by others is often grossly distorted, likely contributing to the distress they feel about social situations and their concomitant avoidance of them. Recent work by Hirsch and Mathews has gone so far as to suggest that people with the disorder may not attend at all to social information while social events are ongoing but rather may judge them later based on preexisting notions about themselves as social beings. In Rapee and Heimberg's model, preferential allocation of attentional resources is emphasized, and this has been another great area of progress over the past few years. While people with SAD may be hypervigilant to social threat in their environments, once they find it, they tend to divert their attention away from it--as has been most clearly demonstrated in the studies of processing of facial expressions. The data suggest that both angry and happy faces may be perceived as threatening and attention is diverted as a means of avoiding them--again having important implications for social behavior and for maintenance of the disorder over time. Important strides have also been made in understanding judgment biases in SAD. Studies on this issue have suggested that individuals with the disorder see positive social outcomes as unlikely and see negative social outcomes as highly likely. When presented with ambiguous scenarios, people with SAD are more likely to select negative interpretations for them, even when they are given the option of selecting positive interpretations and neutral interpretations that they could find at least somewhat believable. Furthermore, people with SAD see both negative social outcomes and positive social outcomes as coming at a higher emotional cost than do people without the disorder. Hirsch and Mathews suggest that the core of social anxiety may be a failure to (over-)emphasize the positive. However, people with the disorder may not adequately distinguish between positive and negative cues, seeing them as equal in valence. Gilboa-Schechtman et al and Wallace and Alden, using very different approaches, have also suggested that both positive and negative outcomes in social situations come at a great emotional cost for people with SAD. Studies of facial expressions suggest that positive and negative faces are perceived as threatening, leading people with SAD to divert attention away from both. Finally, the studies on the observer perspective suggest, also in line with the research of Hirsch and Mathews, that people with SAD do not pay sufficient attention to what is going on around them in social situations. In effect, they are looking at the wrong thing (or through the wrong eyes) and missing important social cues, both positive and negative. Perhaps, as suggested by Hirsh and Mathews, people with the disorder come away from social situations with very little information at all (this notion is supported by older studies that asked socially anxious people what they remembered from social situations after they had participated in them), forcing them to draw conclusions about their performance based on blanket assumptions about themselves as social beings rather than about what actually occurred during that single event. These conclusions have very important implications for treatment. First, it is clear that clinicians need to help their patients learn to pay attention in social situations and, furthermore, to attend to the "right" things. Studies that have included that manipulations of attention suggest that this is a positive direction to pursue. Furthermore, clinicians have to help their patients to make judgments based on what really occurred in a single situation, rather than drawing blanket conclusions for all situations based on preconceived notions of the self as social being. Again, some very preliminary evidence suggests that this approach (through the use of video feedback and other techniques) could be of great benefit.

Auditory backward masking and the effect of training in normal hearing adults.

Recent renewed interest in auditory backward masking has stemmed from studies of children with language impairments who were found to have significant, elevated thresholds for this paradigm, compared to normal cohorts. There are, however, many unresolved theoretical and procedural issues. The present study was conducted to investigate some of these issues. Specific purposes were: 1) To establish the differences between backward masking and simultaneous masking in normal hearing subjects; 2) To investigate the effect of listening conditions, i.e., monaural versus binaural; 3) To measure the effect of training on the performance of a backward masking paradigm; and 4) To measure generalization of the trained condition to untrained conditions. Two experiments were conducted: In experiment I, we compared the performance of 10 normal-hearing adult subjects for backward masking and simultaneous masking paradigms in both monaural and binaural modes of presentation. Stimuli consisted of a 1000 Hz pure-tone and bandpass masker (600-1400 Hz). Tone thresholds for backward masking were significantly lower than those of the simultaneous masking. The binaural mode of presentation yielded lower thresholds than those of the monaural mode only for the backward masking condition. A significantly large inter- and intra-subject variability was observed in the backward masking paradigm. Experiment II was conducted to measure the effects of training and generalization. Two groups of subjects were included: a trained group and a control group of six and eight normal hearing adults, respectively. The trained group received 10 sessions of backward masking training with feedback. The control group was tested only twice, with a 2-week interval between testing. Only the trained group showed a significant improvement in backward masking thresholds, which amounted to an average of 10.7 dB. No significant improvement was observed in the non-trained group. A nonsignificant trend of generalization occurred for the trained task to the untrained ear. No generalization was evident in the untrained condition (simultaneous masking). The data have important clinical and theoretical implications regarding the ability to train for auditory tasks in general, and for backward masking in particular.

The occurrence and distribution of selected trace elements in the Upper Rio Grande and tributaries in Colorado and northern New Mexico.

Two sampling trips were undertaken in 1994 to determine the distribution of trace elements in the Upper Rio Grande and several of its tributaries. Water discharges decreased in the main stem of the Rio Grande from June to September, whereas dissolved concentrations of trace elements generally increased. This is attributed to dilution of base flow from snowmelt runoff in the June samples. Of the three major mining districts (Creede, Summitville, and Red River) in the Upper Rio Grande drainage basin, only the Creede District appears to impact the Rio Grande in a significant manner, with both waters and sediments having elevated concentrations of some trace elements considerably downriver. For example, dissolved zinc concentrations upriver of Willow Creek, which primarily drains the Creede District, were about 2-3 microg/L; immediately downstream of the Willow Creek confluence, concentrations were above 20 microg/L; and elevated concentrations occurred in the Rio Grande for the next 100 km. The Red River District does not significantly impact the Upper Rio Grande for most trace elements. Because of current water management practices, it is difficult to assess the impact of the Summitville District on the Upper Rio Grande. There are, however, large increases in many dissolved trace element concentrations as the Rio Grande passes through the San Luis Valley, coincident with elevated concentrations of those same trace elements in tributaries. Among these elements are As, B, Cr, Li, Mn, Mo, Ni, Sr, U, and V. None of the trace elements exceeded U.S. EPA primary drinking water standards in either survey, with the exception of cadmium in Willow Creek. Secondary drinking water standards were frequently violated, especially in tributaries draining areas where mining has occurred. Dissolved zinc (in Willow Creek in both June and September) was the only element that exceeded the EPA Water Quality Criteria for aquatic life of 120 microg/L.

Attenuation of age-related declines in glucagon-mediated signal transduction in rat liver by exercise training.

This study investigated alterations in glucagon receptor-mediated signal transduction in rat livers from 7- to 25-mo-old animals and examined the effects of exercise training on ameliorating these changes. Sixty-six young (4 mo), middle-aged (12 mo), and old (22 mo) male Fischer 344 rats were divided into sedentary and trained (treadmill running) groups. Isolated hepatic membranes were combined with [(125)I-Tyr(10)]monoiodoglucagon and nine concentrations of glucagon to determine maximal binding capacity (B(max)) and dissociation constant (K(d)). No alterations were found in B(max) among groups; however, middle-aged trained animals had significantly higher glucagon affinity (lower K(d); 21.1 +/- 1.8 nM) than did their untrained counterparts (50.2 +/- 7.1 nM). Second messenger studies were performed by measuring adenylyl cyclase (AC) specific activity under basal conditions and with four pharmacological stimulations to assess changes in receptor-dependent, G protein-dependent, and AC catalyst-dependent cAMP production. Age-related declines were observed in the old animals under all five conditions. Training resulted in increased cAMP production in the old animals when AC was directly stimulated by forskolin. Stimulatory G protein (G(s)) content was reduced with age in the sedentary group; however, training offset this decline. We conclude that age-related declines in glucagon signaling capacity and responsiveness may be attributed, in part, to declines in intrinsic AC activity and changes in G protein [inhibitory G protein (G(i))/G(s)] ratios. These age-related changes occur in the absence of alterations in glucagon receptor content and appear to involve both G protein- and AC-related changes. Endurance training was able to significantly offset these declines through restoration of the G(i)/G(s) ratio and AC activity.