Fracture incidence and fracture-related mortality decreased with decreases in population mobility during the early days of the COVID-19 pandemic: an epidemiological study.

INTRODUCTION: We investigated the impact of coronavirus disease 2019 (COVID-19) social distancing measures on fracture incidence and fracture-related mortality, as well as associations with population mobility. METHODS: In total, 47 186 fractures were analysed across 43 public hospitals from 22 November 2016 to 26 March 2020. Considering the smartphone penetration of 91.5% in the study population, population mobility was quantified using Apple Inc's Mobility Trends Report, an index of internet location services usage volume. Fracture incidences were compared between the first 62 days of social distancing measures and corresponding preceding epochs. Primary outcomes were associations between fracture incidence and population mobility, quantified by incidence rate ratios (IRRs). Secondary outcomes included fracture-related mortality rate (death within 30 days of fracture) and associations between emergency orthopaedic healthcare demand and population mobility. RESULTS: Overall, 1748 fewer fractures than projected were observed during the first 62 days of COVID-19 social distancing (fracture incidence: 321.9 vs 459.1 per 100 000 person-years, P<0.001); the relative risk was 0.690, compared with mean incidences during the same period in the previous 3 years. Population mobility exhibited significant associations with fracture incidence (IRR=1.0055, P<0.001), fracture-related emergency department attendances (IRR=1.0076, P<0.001), hospital admissions (IRR=1.0054, P<0.001), and subsequent surgery (IRR=1.0041, P<0.001). Fracture-related mortality decreased from 4.70 (in prior years) to 3.22 deaths per 100 000 person-years during the COVID-19 social distancing period (P<0.001). CONCLUSION: Fracture incidence and fracture-related mortality decreased during the early days of the COVID-19 pandemic; they demonstrated significant temporal associations with daily population mobility, presumably as a collateral effect of social distancing measures.

Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Assessing natural infection with Zika virus in the southern house mosquito, Culex quinquefasciatus, during 2016 in Puerto Rico.

The epidemic of Zika in the Western hemisphere has led to intense investigations of all species important in the transmission of Zika virus (ZikV), including putative mosquito vectors. Although evidence points to Stegomyia (= Aedes) (Diptera: Culicidae) mosquitoes as the primary vectors in nature among humans, there remains the possibility that other common mosquito species may be implicated in the rapid spread of the virus. Herein, field-caught Culex quinquefasciatus (Diptera: Culicidae) collected during June 2016 in different neighbourhoods in San Juan, Puerto Rico were examined for the presence of natural infection with ZikV. Stegomyia aegypti (= Aedes aegypti) from the same locations were also analysed. None of the Cx. quinquefasciatus tested showed natural infection for ZikV, whereas S. aegypti tested positive at seven sites. The present results suggest that Cx. quinquefasciatus was not involved in the transmission of ZikV in San Juan, Puerto Rico in 2016.

Improvement in health-related quality of life in patients with haemophilia B treated with nonacog beta pegol, a new extended half-life recombinant FIX product.

INTRODUCTION: Health-related quality of life (HRQoL) of individuals with haemophilia has greatly improved with the use of factor replacement and routine prophylaxis. AIM: To explore the HRQoL of individuals with haemophilia B treated with nonacog beta pegol, an extended half-life recombinant factor IX, in a single-blind, randomized multinational phase III pivotal trial (paradigm(™) 2) and its open-label extension (paradigm(™) 4). METHODS: In the pivotal trial, adolescents and adults with haemophilia B were allocated to 28-week on-demand treatment or randomized to 52 weeks of prophylaxis with 10 or 40 IU kg(-1) nonacog beta pegol administered every seven days. In the extension trial, patients could continue on the same treatment or switch to the alternate dosing regimen at any time. HRQoL was assessed with the HAEMO-QOL/HAEM-A-QOL age-specific questionnaires and the EQ-5D. RESULTS: In the pivotal trial, adults receiving 40 IU kg(-1) prophylaxis reported significant improvements in the 'HAEM-A-QOL Total' score (-6.4 ± 8.5, P = 0.017) and in 'Sport' (-15.3 ± 8.5, P = 0.020), 'Feeling' (-15.2 ± 18.3, P = 0.010) and 'Partnership' (-9.6 ± 15.5, P = 0.046) domain scores; no significant improvements were seen in the other arms. At the pivotal trial end, fewer patients reported problems in the EQ-5D 'Mobility' and 'Pain/Discomfort' dimensions, in particular those receiving prophylaxis. In the extension trial, adult patients switching from 10 to 40 IU kg(-1) prophylaxis showed significant improvements in 'HAEM-A-QOL Total' score (-12.5 ± 8.7, P = 0.016) and 'Physical health' domain (-23.1 ± 14.4, P = 0.016). CONCLUSION: Prophylactic treatment with nonacog beta pegol 40 IU kg(-1) once weekly leads to HRQoL benefits in individuals with haemophilia B; this might be related to fewer bleeding episodes and higher FIX activity levels.

Estimation of Contaminant Loads from the Sacramento-San Joaquin River Delta to San Francisco Bay.

Contaminant concentrations from the Sacramento-San Joaquin River watershed were determined in water samples mainly during flood flows in an ongoing effort to describe contaminant loads entering San Francisco Bay, CA, USA. Calculated PCB and total mercury loads during the 6-year observation period ranged between 3.9 and 19 kg/yr and 61 and 410 kg/yr, respectively. Long-term average PCB loads were estimated at 7.7 kg/yr and total mercury loads were estimated at 200 kg/yr. Also monitored were PAHs, PBDEs (two years of data), and dioxins/furans (one year of data) with average loads of 392, 11, and 0.15/0.014 (OCDD/OCDF) kg/yr, respectively. Organochlorine pesticide loads were estimated at 9.9 kg/yr (DDT), 1.6 kg/yr (chlordane), and 2.2 kg/yr (dieldrin). Selenium loads were estimated at 16 300 kg/yr. With the exception of selenium, all average contaminant loads described in the present study were close to or below regulatory load allocations established for North San Francisco Bay.

Platelet function defects in adolescents with heavy menstrual bleeding.

Platelet function defects (PFD) are reported to occur frequently in adult women with heavy menstrual bleeding (HMB). Few studies on adolescent HMB report varying incidence rates (2-44%) for PFD. We reviewed our institutional experience in detecting and managing PFD in adolescent HMB. Postmenarchial girls and adolescents with HMB seen at our institution undergo a comprehensive bleeding disorder work-up by paediatric haematology and paediatric gynaecology providers. Whole blood platelet aggregometry (WBPA) is performed as a second tier test after excluding thrombocytopaenia, coagulation factor deficiencies and Von Willebrand disease (VWD). We retrospectively reviewed the medical records of adolescents with HMB seen between June 2009 and November 2010, as approved by the Institutional Review Board. Patient demographics, clinical features, laboratory results, therapy details and patient outcome information were analysed. Overall, 114 postmenarchial girls and adolescents with HMB were evaluated; 68 patients (59%) had WBPA study performed. Nineteen patients (28%) had at least one aggregation or secretion defect; 12 (18%) had two or more such defects. Treatment included hormonal therapy (13/19; 68%), antifibrinolytic agents (8/19; 42%) and intra-nasal DDAVP (3/19; 16%). Thirteen patients (81%) had improved outcome (median follow-up--15.6 months; range of 1-66 months). In this study, PFD were identified in nearly one-third of girls with HMB, with the majority of these having two or more defects as identified by WBPA. Further prospective studies are needed to better define the prevalence and address appropriate management of HMB and other bleeding complications of PFD in adolescents.

Interspecific competition of a new invasive mosquito, Culex coronator, and two container mosquitoes, Aedes albopictus and Cx. quinquefasciatus (Diptera: Culicidae), across different detritus environments.

The mosquito Culex coronator (Dyar and Knab) (Diptera: Culicidae) has undergone rapid range expansion in the United States since 2003, with its historical distribution in the southwest expanding eastward to the Atlantic coast. Although Cx. coronator nominally use small natural aquatic habitats for development, the use of containers (e.g., tires) makes it potentially important as container invasive. To determine the potential ecological effects of Cx. coronator on resident container species, we conducted a laboratory experiment to assess its competitive ability with two common tire-inhabiting species, Aedes albopictus (Skuse) and Culex quinquefasciatus (Say) (Diptera: Culicidae). Larvae were reared under a factorial design with each species alone and in combination (Cx. coronator + Ae. albopictus, Cx. coronator + Cx. quinquefasciatus) across three different resource environments (leaf detritus only, animal detritus only, animal + leaf). Mosquito performance (survival, adult male and female mass, and development time) was measured for each species across treatments. Female Cx. coronator developed slowest when grown with Ae. albopictus, or when grown with leaves only regardless of species combinations; similar patterns emerged for males although species effects were restricted to mass. Few differences were evident in performance for male and female Cx. coronator across detritus environments when grown with Cx. quinquefasciatus. Cx. quinquefasciatus did not vary in mass or development time in the presence of Cx. coronator compared with when grown alone. Ae. albopictus female mass was 15% lower in the presence of Cx. coronator. Survival of Cx. coronator was highest in animal and leaf detritus containers, although survival was generally lower when larvae were grown with Ae. albopictus. These findings suggest that the performance of Cx. coronator is similar to that of Cx. quinquefasciatus but it suffers in the presence of Ae. albopictus under some resource environments.

Behavioral differences among four co-occurring species of container mosquito larvae: effects of depth and resource environments.

Mosquito larvae often exhibit different behaviors depending on the aspects of the aquatic environment, including the presence of different physical factors and detrital food sources. Regardless of these physical differences, different genera also devote different amounts of time to different behaviors. To determine if differences existed among four focal mosquito species (Aedes albopictus (Singh), Aedes triseriatus (Say), Culex quinquefasciatus (Say), Culex coronator Dyar & Knab), we recorded behaviors under different food environments (animal detritus, leaf detritus, and inoculum + inert material) and depths (shallow and deep). Based on past work, we predicted that larval mosquitoes in the genus Culex would spend more time filtering or resting at the surface of containers, whereas Aedes mosquitoes would spend more time browsing on surfaces. Behaviors were recorded for 30 min and were used to generate instantaneous scan census of behavior (thrashing, browsing, and resting or filtering) and locations (top, middle, bottom, wall, and detritus) of each larva every minute. There were significant differences in behaviors among the three detritus types and the four species (Culex generally different than Aedes), as well as a significant interaction between depth and detritus type. Consistent with predictions, Culex species spent more time filtering or resting, whereas Aedes larvae spent more time browsing on detritus. However, all four species changed their behavior similarly among the different environments, and Cx. coronator exhibited some similar behaviors as the two Aedes species. These behavioral differences may aid in explaining performance differences between different species and outcomes of interspecific encounters, which in turn can affect adult emergence and patterns of disease.

Influence of resource levels, organic compounds and laboratory colonization on interspecific competition between the Asian tiger mosquito Aedes albopictus (Stegomyia albopicta) and the southern house mosquito Culex quinquefasciatus.

The mosquitoes Aedes albopictus (Stegomyia albopicta) (Skuse) and Culex quinquefasciatus (Say) (Diptera: Culicidae) are common inhabitants of tyres and other artificial containers, which constitute important peridomestic mosquito breeding habitats. We tested the hypotheses that interspecific resource competition between the larvae of these species is asymmetrical, that the concentration of chemicals associated with decomposing detritus affects the competitive outcomes of these species, and that wild and colonized strains of Cx. quinquefasciatus are affected differently by competition with Ae. albopictus. We conducted two laboratory competition experiments wherein we measured survivorship and estimated population growth (λ') in both species under multiple mixed-species densities. Under varying resource levels, competition was asymmetrical: Ae. albopictus caused competitive reductions or exclusions of Cx. quinquefasciatus under conditions of limited resources. In a second experiment, which used both wild and colonized strains of Cx. quinquefasciatus, organic chemical compounds associated with decomposing detritus did not affect the competitive outcome. The colonized strain of Cx. quinquefasciatus had greater survivorship and adult mass, and faster development times than the wild strain, but both strains were similarly affected by competition with Ae. albopictus. Competition between these species may have important consequences for vector population dynamics, especially in areas in which tyres and artificial containers constitute the majority of mosquito breeding habitats.

Implications of saline concentrations for the performance and competitive interactions of the mosquitoes Aedes aegypti (Stegomyia aegypti) and Aedes albopictus (Stegomyia albopictus).

Aedes albopictus (Stegomyia albopictus) (Diptera: Culicidae) has probably supplanted Aedes aegypti (Stegomyia aegypti) throughout most of its historical range in the U.S.A., although Ae. aegypti still exists in large coastal cities in southern Florida. We measured salt concentrations in field containers along an axis perpendicular to the coast and examined intraspecific outcomes in these species under different salt concentrations in a factorial study using varying intra- and interspecific densities in different conditions of salinity to order to determine if salt could mitigate the documented competitive superiority of Ae. albopictus. Salt in field containers declined away from the coast, with maximal values similar to our lower salt concentrations. Egg hatching and short-term survival of pupae and late instars were not affected by salt concentrations; survival of early instars of both species decreased at higher concentrations. In high salt conditions, Ae. aegypti achieved higher survival. In the longterm experiment, both species displayed longer development times. Salt did not affect interactions for either species; Ae. aegypti survived in the highest salt conditions, regardless of density. The tolerance of Ae. aegypti to high salt concentrations may allow it to use coastal containers, although because salt did not mediate interspecific interactions between Ae. aegypti and Ae. albopictus, the ultimate effects of salt on the coexistence of these species or exclusion of either species remain unknown.

Genotype-based screen for ENU-induced mutations in mouse embryonic stem cells.

The ability to generate mutations is a prerequisite to functional genetic analysis. Despite a long history of using mice as a model system for genetic analysis, the scientific community has not generated a comprehensive collection of multiple alleles for most mouse genes. The chemical mutagen of choice for mouse has been N-ethyl-N-nitrosourea (ENU), an alkylating agent that mainly causes base substitutions in DNA, and therefore allows for recovery of complete and partial loss-, as well as gain-, of-function alleles . Specific locus tests designed to detect recessive mutations showed that ENU is the most efficient mutagen in mouse with an approximate mutation rate of 1 in 1,000 gametes. In fact, several genome-wide and region-specific screens based on phenotypes have been carried out. The anticipation of the completion of the human and mouse genome projects, however, now emphasizes genotype-driven genetics--from sequence to mutants. To take advantage of the mutagenicity of ENU and its ability to create allelic series of mutations, we have developed a complementary approach to generating mutations using mouse embryonic stem (ES) cells. We show that a high mutation frequency can be achieved and that modulating DNA-repair activities can enhance this frequency. The treated cells retain germline competency, thereby rendering this approach applicable for efficient generation of an allelic series of mutations pivotal to a fine-tuned dissection of biological pathways.

Analysis of intraprostatic therapeutic effects in prostate cancer patients using [(11)C]-choline pet/ct after external-beam radiation therapy.

PURPOSE: The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. METHODS: The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. RESULTS: Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. CONCLUSIONS: Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.

Seasonal photoperiods alter developmental time and mass of an invasive mosquito, Aedes albopictus (Diptera: Culicidae), across its north-south range in the United States.

The Asian tiger mosquito, Aedes albopictus (Skuse), is perhaps the most successful invasive mosquito species in contemporary history. In the United States, Ae. albopictus has spread from its introduction point in southern Texas to as far north as New Jersey (i.e., a span of approximately 14 degrees latitude). This species experiences seasonal constraints in activity because of cold temperatures in winter in the northern United States, but is active year-round in the south. We performed a laboratory experiment to examine how life-history traits of Ae. albopictus from four populations (New Jersey [39.4 degrees N], Virginia [38.6 degrees N], North Carolina [35.8 degrees N], Florida [27.6 degrees N]) responded to photoperiod conditions that mimic approaching winter in the north (short static daylength, short diminishing daylength) or relatively benign summer conditions in the south (long daylength), at low and high larval densities. Individuals from northern locations were predicted to exhibit reduced development times and to emerge smaller as adults under short daylength, but be larger and take longer to develop under long daylength. Life-history traits of southern populations were predicted to show less plasticity in response to daylength because of low probability of seasonal mortality in those areas. Males and females responded strongly to photoperiod regardless of geographic location, being generally larger but taking longer to develop under the long daylength compared with short day lengths; adults of both sexes were smaller when reared at low larval densities. Adults also differed in mass and development time among locations, although this effect was independent of density and photoperiod in females but interacted with density in males. Differences between male and female mass and development times was greater in the long photoperiod suggesting differences between the sexes in their reaction to different photoperiods. This work suggests that Ae. albopictus exhibits sex-specific phenotypic plasticity in life-history traits matching variation in important environmental variables.

Constitutive differences between natural and artificial container mosquito habitats: vector communities, resources, microorganisms, and habitat parameters.

Aquatic containers, including tree holes and vehicle tires, harbor a diverse assemblage of mosquitoes capable of vectoring important diseases. Many studies have examined containers as a mosquito breeding site, although no data exist that have simultaneously compared mosquito communities between tree holes and tires, and few have quantified differences in environmental factors or food resources that may be important for explaining population or community differences. At two times (early and late summer 2009) we sampled two tire and two tree hole sites in south-central Mississippi, and for each container we enumerated mosquito larvae and measured several environmental parameters (canopy cover, water volume, and detritus), and biomass and productivity of fungi and bacteria, and species richness and abundance of protozoans. Tree holes held less water but were more shaded compared with tires; however, after correcting for volume differences, tree holes contained more detritus and were higher in some microorganism measures (protozoan richness, bacterial productivity in the water column). Based on community dissimilarity analysis of mosquitoes, strong differences existed between container types and sampling period; Aedes albopictus (Skuse) and Culex quinquefasciatus (Say) were dominant in tires, whereas Ae. triseriatus (Say) and Orthopodomyia signifera (Coquillett) were dominant in tree holes. This study also reports the use of tires by the invasive mosquito Cx. coronator (Dyar and Knab). Tree holes supported a higher density of larvae but fewer species than tires, though there was variation across time. Our work illustrates that detrital inputs and some microorganisms differ in fundamental ways between tires and tree holes, and because of compositional differences in mosquito communities, these small aquatic habitats cannot be considered to be homogeneous mosquito habitats.

Reducing methylmercury accumulation in the food webs of San Francisco Bay and its local watersheds.

San Francisco Bay (California, USA) and its local watersheds present an interesting case study in estuarine mercury (Hg) contamination. This review focuses on the most promising avenues for attempting to reduce methylmercury (MeHg) contamination in Bay Area aquatic food webs and identifying the scientific information that is most urgently needed to support these efforts. Concern for human exposure to MeHg in the region has led to advisories for consumption of sport fish. Striped bass from the Bay have the highest average Hg concentration measured for this species in USA estuaries, and this degree of contamination has been constant for the past 40 years. Similarly, largemouth bass in some Bay Area reservoirs have some of the highest Hg concentrations observed in the entire US. Bay Area wildlife, particularly birds, face potential impacts to reproduction based on Hg concentrations in the tissues of several Bay species. Source control of Hg is one of the primary possible approaches for reducing MeHg accumulation in Bay Area aquatic food webs. Recent findings (particularly Hg isotope measurements) indicate that the decades-long residence time of particle-associated Hg in the Bay is sufficient to allow significant conversion of even the insoluble forms of Hg into MeHg. Past inputs have been thoroughly mixed throughout this shallow and dynamic estuary. The large pool of Hg already present in the ecosystem dominates the fraction converted to MeHg and accumulating in the food web. Consequently, decreasing external Hg inputs can be expected to reduce MeHg in the food web, but it will likely take many decades to centuries before those reductions are achieved. Extensive efforts to reduce loads from the largest Hg mining source (the historic New Almaden mining district) are underway. Hg is spread widely across the urban landscape, but there are a number of key sources, source areas, and pathways that provide opportunities to capture larger quantities of Hg and reduce loads from urban runoff. Atmospheric deposition is a lower priority for source control in the Bay Area due to a combination of a lack of major local sources. Internal net production of MeHg is the dominant source of MeHg that enters the food web. Controlling internal net production is the second primary management approach, and has the potential to reduce food web MeHg in some habitats more effectively and within a much shorter time-frame. Controlling net MeHg production and accumulation in the food web of upstream reservoirs and ponds is very promising due to the many features of these ecosystems that can be manipulated. The most feasible control options in tidal marshes relate to the design of flow patterns and subhabitats in restoration projects. Options for controlling MeHg production in open Bay habitat are limited due primarily to the highly dispersed distribution of Hg throughout the ecosystem. Other changes in these habitats may also have a large influence on food web MeHg, including temperature changes due to global warming, sea level rise, food web alterations due to introduced species and other causes, and changes in sediment supply. Other options for reducing or mitigating exposure and risk include controlling bioaccumulation, cleanup of contaminated sites, and reducing other factors (e.g., habitat availability) that limit at-risk wildlife populations.

Stem cell deficiencies and thymic abnormalities in fetal mouse trisomy 16.

Mouse fetuses with trisomy 16 have severe abnormalities of several hematopoietic stem cell and precursor populations. The thymus is extremely hypoplastic, with a greater than or equal to 80% reduction in the number of thymocytes. This cellular deficiency appears to be the result of a deficiency in the number of precursor cells in the early thymus, since the rate of proliferation of thymocytes in explanted day-14 thymuses was normal. However, the functional maturation of thymocytes was delayed in vitro in day-17 organ explants, although the maximal response to the mitogenic and interleukin 2-stimulating effects of concanavalin A are quantitatively normal. B cells and pre-B cells in the fetal liver were moderately decreased, but the ability of fetal liver cells to be transformed by Abelson murine leukemia virus was nearly totally lost. There were also significant relative and absolute decreases in the number of spleen, culture, and erythroid colony-forming units (CFU-S, CFU-C, CFU-E) and of erythroid burst-forming units (BFU-E) in the trisomic liver, and the trisomic animals were anemic with small spleens and livers. However, unlike other genetically caused anemias, there was no reduction in the number of germ cells. The hematopoietic abnormalities in the trisomy 16 mouse, involving the lymphoid, myeloid, and erythroid cell lineages, are much more generalized than the abnormalities in any of the other described genetically caused immunodeficiencies or anemias in the mouse. They are also more severe than those in human trisomy 21 (Down syndrome), for which mouse trisomy 16 is a genetic model, but there does exist an interesting parallel between the thymic abnormalities in the two species.

Fluorescent tumour imaging of type I IGF receptor in vivo: comparison of antibody-conjugated quantum dots and small-molecule fluorophore.

BACKGROUND: The type I insulin-like growth factor receptor (IGF1R) is a transmembrane tyrosine kinase involved in cancer proliferation, survival, and metastasis. METHODS: In this study, we used two different fluorescent technologies (small-molecule fluorophores and quantum dot (QD) nanoparticles) to detect receptor expression and its downregulation by antibodies in vivo. RESULTS: After conjugation with AVE-1642, a humanised anti-IGF1R monoclonal antibody, both QDs (705 nm) or Alexa 680 (small-molecule fluorophore) detected expression and downregulation of IGF1R in vitro. To examine their utility in vivo, either AVE-1642 conjugates were intravenously delivered to mice bearing xenograft tumours of mouse embryo fibroblasts expressing human IGF1R or MCF-7 human breast cancer cells. Quantum dot fluorescence was mainly localised to the reticuloendothelial system in several organs and engulfed by macrophages, with only very small amount of QDs detected in the xenograft tumours. Depletion of macrophages by clodronate liposomes did not alter the nonspecific uptake of QDs. In contrast, AVE-1642-conjugated Alexa 680 solely targeted to xenograft tumour and was able to detect IGF1R downregulation, with little nonspecific targeting to other tissues or organs in mice. CONCLUSION: Taken together, our data suggest that small-molecule fluorophores, not QDs, are suitable to detect the expression and downregulation of IGF1R in vivo.

Feasibility of single-voxel MRS measurement of apparent diffusion coefficient of water in breast tumors.

We report initial results with single voxel spectroscopy (SVS) using diffusion weighting and localization by adiabatic selective refocusing (LASER) in breast tumors to measure the apparent diffusion coefficient of water (ADCw). This is a quick (30 s) and relatively easy method to implement compared with image-based diffusion measurements, and is insensitive to lipid signal contamination. The ADCw and concentration of total choline containing compounds [tCho] were evaluated for associations with each other and final pathologic diagnosis in 25 subjects. The average (+/- SD) ADCw in benign and malignant lesions was 1.96 +/- 0.47 mm(2)/s and 1.26 +/- 0.29 x 10(-3) mm(2)/s, respectively, P< 0.001. Receiver operating characteristic curve analysis showed an area under the curve of 0.92. Analysis of the single voxel (SV) ADCw and [tCho] showed significant correlation with a R(2) of 0.56, P< 0.001. Compared with more commonly used image-based methods of measuring water ADC, SV-ADCw is faster, more robust, insensitive to fat, and potentially easier to implement on standard clinical systems.