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We have used new gel pore-water profilers and conventional seepage meters to determine the advective flux of water from an underwater saline seep into Lake Kinneret. The gel probes sampled pore waters from medium to coarse sands that could not be sampled by conventional coring methods. The anions Cl, Br, and SO4 were constant at levels just above those for the lake for 3-5 cm into the sediment due to wave action or other turbulent mixing processes. There was then a sharp increase in concentration to values of approximately 8,000 mg Cl liter(-1), 370 mg SO4 liter(-1), and 120 mg Br liter(-1) at a depth of similar to 8.5 cm. Using an advection-diffusion model, the linear interstitial advection velocity (LIV) of the groundwater into the lake was calculated to vary between 140 and 275 cm yr(-1). The LN values from conventional seepage flux meters at the same site were 30 and 164 cm yr(-1). Differences between the LIV measurements of these two methods may be due to a number of possible factors, including groundwater flux heterogeneity.

A detailed hydrochemical study at two undisturbed Ordovician massive sulphide (Zn–Pb) deposits (Restigouche and Halfmile Lake deposits, Bathurst Mining Camp, New Brunswick) was initiated to elucidate the processes controlling the oxidation and dissolution of sulphide minerals, the subsequent dispersion of metals in ground and surface waters, and the precipitation of secondary minerals. Groundwater hydrogeochemical signatures are different for the two deposits. Elements that form sulphide minerals in the deposits correlate positively in surface waters and increase with proximity to the Restigouche deposit, whereas metal contents for Halfmile Lake surface waters are lower, though still typically higher than background levels. Variations in the composition of ground and surface waters draining the two deposits reflect in part differences in the depth and geometry of the massive sulphides and host lithologies. The Halfmile Lake deposit is deeper, more steeply dipping, and overturned compared to the shallower Restigouche deposit. Groundwaters at the Halfmile Lake deposit up to 760 m below surface are low-TDS (

The most appropriate and widely used source of drinking water for the populations of the upper regions of Ghana is groundwater. In general, groundwater quality is acceptable except for some parts of the Bolgatanga and Bongo Districts, where there are occurrences of elevated levels of natural groundwater fluoride. Concentrations of groundwater fluoride in excess of the World Health Organization (WHO) maximum guideline value (1.5 mg/l) in the Bongo area have been known since 1978. However, the effect of fluoride on people ingesting the water did not receive public and medical attention until October 1993, when health personnel were asked to investigate the cause of stained teeth in school children. The investigation established that 62% of the total population of school children in the Bongo area had dental fluorosis. Against this background, a study was initiated to understand the geochemistry, genesis, and distribution of fluoride in relation to the geology of the area. Groundwater fluoride in the upper regions ranges from 0.11 to 4.60 ppm, with the highest concentrations associated with the fluorine-enriched Bongo coarse-grained hornblende granite and syenite suite. The source of groundwater fluoride within the Bongo granitoids is dissolution of the mineral fluorite and dissolution of and anion exchange with micaceous minerals and their clay products. Applying the WHO recommended guideline values for fluoride in drinking water reveals that 49% of wells in the area deliver water below the optimum level of 0.5 mg/l F–; these populations are thus prone to dental caries. Twenty-eight percent of the wells fall within the optimum interval for good dental health (0.5–1.5 mg/l F–). Twenty-three percent of the wells have concentrations above the recommended maximum guideline limit of 1.5 mg/l F–; this population is susceptible to dental and possibly skeletal fluorosis. Climatic conditions of the area suggest that the individual water consumption is in the order of 3 to 4 l which is higher than the WHO estimate of 2 l/adult/day. In addition, dietary intake for the upper region population is probably higher than WHO baseline values (0.2–0.5 mg/day). This implies that a much higher population is susceptible to developing dental and skeletal fluorosis than originally suspected. Geochemical symbol plot maps help geochemists understand factors controlling the distribution and uptake of fluoride in the upper regions, but they are of minimal value to health officials responsible for planning epidemiological studies and dental health education programs in the region. By casting fluoride data into contoured 'geochemical health-risk maps' using intake interval guidelines more closely aligned to regional climatic and dietary conditions, health officals can better judge the impacts (regional and population based) of fluoride on segments of the population, such as various sex and age groups.

We have constructed a recombinant fowlpox virus (FPV) that expresses chicken myelomonocytic growth factor (cMGF). Administration of this construct (fp/cMGF) to 1-day-old chicks resulted in a marked and sustained increase in the number of circulating blood monocytes compared with chicks infected with the parental FPV strain (fp/M3). Blood monocyte numbers were elevated within 4 days of fp/cMGF infection, reached maximal levels at day 9, and returned to normal levels by day 16. During the peak response, approximately 35% of blood leukocytes were monocytes, compared with 4 to 7% in uninfected control birds. Infection with fp/M3 also resulted in a detectable increase in monocyte numbers; however, the effect was less dramatic. Compared with fp/M3, fp/cMGF consistently induced two- to threefold higher monocyte numbers, and the period of monocytosis was longer (10 vs 5 days). No other specific changes in white blood cell populations were observed. Associated with the increase in the number of monocytes was an increase in their state of activation, as measured by the ability to produce nitric oxide (NO) and to phagocytose latex beads. Blood monocytes from birds infected with fp/cMGF produced about 6 times as much NO per cell compared with monocytes from fp/M3-infected birds. Monocytes from normal birds failed to produce detectable levels of NO. Furthermore, cMGF treatment specifically induced enhanced phagocytic activity in blood monocytes. Overall, these results indicate that viral vectors are suitable for the delivery of biologically active cytokines and that they allow an assessment of cytokine activities in vivo.

Four new commercial grades of rubber toughened ABS (acrylonitrile-butadienestyrene) terpolymers were characterized by differential scanning calorimetry (DSC), mechanical analysis and gel permeation chromatography (GPC). These rubber toughened ABS molding compounds were manufactured by a new “blended technology” to yield resins which offer a broad range of flow properties and levels of toughness. Based upon DSC estimates of the level of rubber included, the four ABS compounds can be divided into two groups; the first has about 11 wt.% butadiene and the second near 18 wt.%. In addition, two styrene-acrylonitrile copolymers with different average molecular weights were found blended within each ABS group. By this blending process four resins are produced with impact strengths ranging from below three to near seven ft-lb in−1. These analytical results show that a resin's impact strength is enhanced not only by increasing the level of rubber particles in a given ABS compound but also by raising the molecular weight of the SAN which is blended into the terpolymer.

Several Au–Ag gossans occur over massive sulphide deposits in the Ordovician Tetagouche Group near Bathurst, New Brunswick. The Murray Brook and Heath Steele B zone goethite gossans were about 45 and 15 m thick, respectively, prior to mining. They contain no minerals suitable for radiometric age dating. Geologically they must be younger than the Devonian Acadian orogeny and older than the last glaciation. Paleomagnetic methods were used to analyse specimens from 29 sites, mostly from ore on the pit walls. Host rocks and sulphide mineralization retain characteristic remanent magnetization directions in magnetite and pyrrhotite with a variety of directions that include possible Devonian overprints. Fertile and barren gossan specimens at 21 sites retain antiparallel normal and reversed A characteristic remanence components in goethite and (or) hematite. The A direction is D = 357.7°, I = 61.7 °(α95 = 4.5°, k = 31). Its pole of 134.2°E, 85.2°N (dp = 5.4°, dm = 7.0°) falls on the North American apparent polar wander path and circumscribes the Earth's present rotational axis, indicating that the gossans formed during the Pliocene–Pleistocene. Examination of the site locations in the pits, along with the remanence polarity of their goethite and hematite A components, suggests the gossans formed during Chrons 1 and 2 only, or in the past 2.3 ± 0.3 Ma.

A lakebed seepage meter for measuring groundwater seepage rates in the nonlittoral zones of lakes was designed and field tested. Ease of installation and operation, sampling integrity, and year-round stability in ice-bound lake environments were the main factors governing design. The design of the meter incorporates a lake-bottom seepage meter connected by a flexible conduit hose to a sampling station -2 m below lake surface. The operation and design of the meter includes methods for minimizing and monitoring meter settlement, protecting meter components from trawling fishermen and nibbling fish (seepage bags), visually monitoring flux levels in seepage bags to determine optimum time for sampling, and easy detection by a small boat-mounted sonar unit. Results from a seepage meter survey in a small lake situated in complex glacial stratigraphy show that the system is effective in measuring very low flux rates and mapping complex inflow and outflow groundwater regimes in lake environments. Detailed lake studies in glaciated terrains allow classification of lakes, with regard to characteristics and relative contributions of groundwater and surface water inputs, into the six main types shown in Fig. 1. Although subtypes can be created within this classification, Fig. 1 shows the complexity of relationships that can exist between lakes and surrounding groundwater regimes. In some cases, lakes cannot be classed as one type year-round; for example, Jaquet’s (1976) studies of the groundwater regime around Snake Lake (Wisconsin) show that this lake has a hydrology much like type d (Fig. 1) in late summer, fall, and winter, but in spring the flow characteristics are represented better by type b. The lake I use to evaluate a new seepage meter design (Alexander Lake) was, from initial analyses, thought to be type d or type b. Later detailed seepage meter analysis showed it to be type b. Figure 2 schematically depicts two extremes of limnological regimes and groundwater processes on a continuum of lakes in glaciated environments. Although hydrologists generally accept that most groundwater that enters a lake system does so through the littoral zone

The Eighth Survey of Staffing in Cardiology was conducted with an index date of 30 September 1992. The total number of cardiologists in England and Wales, defined as individuals trained in the specialty and spending at least 40% of their professional time working in it, was 358. Of these 11 were part time, defined as six sessions or less, giving a number in whole time (or near whole time) equivalents of 352.5. The number of individuals increased from 1991 by 18 (5.3%). There were 71 cardiologists in Scotland and Northern Ireland, making a total for the United Kingdom of 429 individuals (423.5 whole time equivalents), which is 7.3 per million population. A total of 44 Districts serving 8.8 million people have no resident cardiologist. There has been little improvement since the 1991 survey. An additional 34 Districts with populations greater than 250,000 have only one cardiologist: we have clear evidence of inadequate provision of care in most of these, a situation that is inevitable within the resources provided. A wider threat to the provision of a satisfactory level of cardiological care throughout the United Kingdom will follow from changes in the organisation of the National Health Service and in the new requirements for training of future cardiologists because these changes will make major new demands on consultant time which cannot be met within existing resources. A crisis will be averted only if a rapid and major expansion of the consultant grade can be achieved.

We demonstrate the hohlraum radiation temperature and symmetry required for ignition-scale inertial confinement fusion capsule implosions. Cryogenic gas-filled hohlraums with 2.2 mm-diameter capsules are heated with unprecedented laser energies of 1.2 MJ delivered by 192 ultraviolet laser beams on the National Ignition Facility. Laser backscatter measurements show that these hohlraums absorb 87% to 91% of the incident laser power resulting in peak radiation temperatures of T(RAD)=300 eV and a symmetric implosion to a 100 μm diameter hot core.

Glycoprotein D (gD) of equine herpesvirus 1 (EHV-1) was expressed at the surface of insect cells infected by a recombinant baculovirus. EHV-1 gD was detected as multiple forms (56, 52, and 48 kDa) from 18 to 96 h postinfection. Laboratory animals inoculated with the recombinant EHV-1 gD developed neutralizing antibody responses against both EHV-1 and EHV-4.

There is evidence that many pathogens co-evolve with their hosts. This is often reflected in species specific virulence factors that can selectively interfere with host defense mechanisms, innate and acquired as well as a range of interactions with host homeostatic pathways that contribute to the course and severity of an infection. In this review, we highlight a number of select examples of these interactions and suggest that understanding of molecular pathogenesis requires a broad systems approach that can evaluate the multiple and dynamics interactions that are occurring during infection.

Genomics and bioinformatics are dynamic fields well-suited for capturing the imagination of undergraduates in both research laboratories and classrooms. Currently, raw nucleotide sequence is being provided, as part of several genomics research initiatives, for undergraduate research and teaching. These initiatives could be easily extended and much more effective if the source of the sequenced material and the subsequent focus of the data analysis were aligned with the research interests of individual faculty at undergraduate institutions. By judicious use of surplus capacity in existing nucleotide sequencing cores, raw sequence data could be generated to support ongoing research efforts involving undergraduates. This would allow these students to participate actively in discovery research, with a goal of making novel contributions to their field through original research while nurturing the next generation of talented research scientists.

The Sixth Biennial Survey of Staffing in Cardiology was conducted in July 1990. This report summarises the data that were collected, together with the results of a survey of facilities in cardiology made in 1989. The total number of cardiologists in the United Kingdom, defined as individuals trained in the specialty and spending at least 40% of their time working in it, is now 323. Six individuals work part time only, making 320 whole time posts. This number has increased over the two years from 1988 to 1990 by 32, of which 23 work only in the specialty and nine as general physicians with a major interest in cardiology. The rate of increase in numbers over the past decade has been reasonably consistent with an average of approximately 4.4% per year. Thirty one districts in England and Wales still have no cardiologist and 13 other districts have little provision with an average of three (visiting) sessions each per week. The population in these 44 districts is 8.3 million. Scotland also has an inadequate distribution of service in the specialty. If recommendations for cardiac surgery and angioplasty made in the Fourth Report of a Joint Cardiology Committee of the Royal College of Physicians of London and the Royal College of Surgeons of England are to be met, we calculate that we need 63 more cardiologists in our major centres. To provide one cardiologist in every district hospital and two for larger districts would require 94 more specialists, making a total shortfall of 157 individuals. We have no excess of senior registrars to provide for a major expansion at consultant level. Time spent within the senior registrar (or academic equivalent) grade has tended steadily to decline and very few now reach the end of their contracts. The need for more individuals to pass through the senior registrar grade will be met in part by a planned reduction in the training period to three years. This will be inadequate, however, because projected retirements show that the number of consultant vacancies will increase sharply from 1997. We believe that additional senior registrar posts must be created if a serious shortfall in service provision by consultants is to be avoided. The provision of non-invasive facilities in cardiology is reasonable. The need for additional equipment for invasive cardiology has not been assessed. The number of physiological measurement technicians varies considerably between regions and is generally inadequate.

The c protein (Ibc) of group B streptococci (GBS) is associated with at least four antigens (alpha, beta, gamma, delta). To assess the virulence potential of these antigens, 255 GBS isolates recovered from septic neonates, healthy neonates, and pregnant women were serotyped and surveyed for reactivity with sera to c protein and the four associated antigens. A radioimmunoassay using intact bacteria was used to detect the GBS antigens. In contrast to earlier reports, most (66%) of the type III strains expressed the c protein. Except for the gamma antigen, none of the other c protein-associated antigens showed an increased association with pathogenic strains independent of the polysaccharide antigens. The gamma antigen was expressed by 15 of 41 c protein-positive early-onset strains and by 4 of 38 c protein-positive late-onset strains (P = .007). This association was independent of the type-specific antigen, suggesting a potential role for the gamma antigen as a virulence factor in GBS strains causing early-onset sepsis.

Plasminogen receptors have been identified on the surface of a number of prokaryotic and eukaryotic cells. A receptor demonstrating high affinity for plasmin with minimal reactivity with the native zymogen Glu-plasminogen has been identified on the surface of certain group A streptococci. In this study the group A streptococcal plasmin receptor has been solubilized and purified to homogeneity. The isolated protein was an Mr approximately 41,000 molecule which retained its ability to bind plasmin following solubilization and affinity purification on a column of enzymatically inactivated human plasmin. The isolated plasmin receptor was compared functionally, antigenically, and physicochemically to the secreted plasminogen activator, streptokinase, produced by the same organism. The Mr approximately 41,000 surface plasmin receptor was shown to be functionally and antigenically distinct from the Mr approximately 48,000 streptokinase molecule produced by the same strain and lacked any plasminogen activator activity. The streptokinase molecule produced by this strain was shown to be closely related to the plasminogen activator protein secreted by other group A and C streptococci. This study represents the first report of the isolation of a plasmin receptor, either prokaryotic or eukaryotic, with functional activity.

The protein antigens synthesized by the malarial parasite change as the parasite matures, with a number of proteins showing strict stage-specificity. A detailed correlation between the stage-specificity of protein synthesis and parasite structure has yet to be established, but a number of proteins synthesized in the cycle are lost selectively during merozoite escape and reinvasion. These antigens are presumably associated with structures utilized and ultimately lost during this process. Particular interest has focused on some greater than 200K proteins identified as being on the surface of infected erythrocytes and internally and on the surface of merozoites. Smaller parasite proteins have also been identified in the erythrocyte membrane. The erythrocyte itself, including its membrane, is much modified by parasite growth. Changes include the presence of new cytoplasmic structures and differences in the surface labelling and isoantigenic characteristics of the surface membrane. An appreciation of the variability and specificity of exposed parasite antigens, and their relationship to newly exposed isoantigens, is central to our understanding of protective immunity to malaria.

This paper reports an assessment of the tolerance of STC’s bipolar, CMOS and ‘merged’ bipolar/CMOS processes to gamma total dose, dose rate and neutron fluence radiation effects. The objective of the assessment was to characterise process performance under worst case and near to worst case criteria when subjected to nuclear radiation up to the tactical level in accordance with BS 9000. Total dose irradiation was performed on the bipolar, CMOS and BiCMOS technologies with 9 Mrads (Si), 10-12 krads (Si) and 10-30 krads (Si) performance levels reported, respectively. Under dose rate conditions, transient upset, latch-up and photocurrent are reported with latch-up immunity reported for the bipolar 2 process and simultaneous latch-up and transient upset reported for both the bulk CMOS and BiCMOS processes. Neutron fluence testing was performed with the onset of failure for the CMOS reported at the 5 × 1014 neutrons/cm level and onset of failure for the bipolar and BiCMOS reported in the range 5 × 1014 to 5 × 1014 neutrons/cm2.

Eight commercial semiconductor grade epoxy compounds that are used to encapsulate 1C (integrated circuit) devices have been evaluated for their ability to minimize the development of thermal stresses which can cause failure during device temperature cycling. Thermal expansion, dynamic modulus and adhesion studies are used to describe the mechanical interaction between the plastic package and the silicon device it surrounds. A “figure of merit” is defined for the development of stress on the 1C device as it is cooled after the packaging process. The stress is shown to be proportional to the product of three terms: (αp-αs) Ep (Tanch-T) where αp and αs are the expansion coefficients for the plastic and silicon, respectively, Ep is the modulus of the epoxy and Tanch is the temperature at which the epoxy becomes anchored to the silicon device during transfer molding. In addition, the importance of good adhesion between the epoxy encapsulant and the silicon device to prevent package cracking has been demonstrated by finite element analysis and a novel adhesion test.

The role of cytotoxic T cells and NK cells in the recovery of immunodeficient, athymic, nude mice infected with a recombinant vaccinia virus (VV) encoding murine IL-2 was investigated. Kinetic studies with the IL-2-encoding recombinant (VV-HA-IL2) and control (VV-HA-TK) viruses excluded a role for cytotoxic T cells but suggested the possible involvement of NK cells. In athymic nude mice given VV-HA-IL2, NK activity was at least threefold higher than mice infected with VV-HA-TK and this activity persisted for at least 6 days after infection. The effectors mediating the NK-like activity were asialo-GM1+ (as-GM1+), Thy1.2+/-, CD4- and CD8-, the phenotype of conventional NK cells. Elevated NK activity coincided with the rapid clearance of VV-HA-IL2 from ovaries of infected normal CBA/H mice but not from ovaries of CBA beige mice which had no detectable NK activity in spleens or ovaries. The expression of IL-2 in recombinant VV infection probably induces a cascade of immunologic effects of which elevated NK activity is one. We speculate that the chemoattractant and NK activity augmenting effects of IL-2 may contribute to recovery from VV-infection.

[1] We report new Sr, S, and B isotopic data for evaporites (gypsum, anhydrite), carbonates, melt rocks, gneisses, and groundwaters recovered in and around the Lake St. Martin (LSM) impact structure, Interlake Region, Manitoba, Canada. The LSM meteorite impacted Devonian to Ordovician carbonates and sandstones of the eastern Williston Basin, resulting in partial melting of underlying Superior Province (∼2.5 Ga) gneisses of the Canadian Shield. Overlying the LSM melt rocks are red beds and evaporites (anhydrite/gypsum/glauberite) previously inferred to have been deposited during the Jurassic. The 87Sr/86Sr (lowest values cluster at 0.70836) and δ34SCDT (+23.7 ± 0.9‰) of the evaporites, combined with B isotope compositions of associated groundwaters (δ11BNBS951 = +25 to +28‰), are consistent with evaporite deposition within the impact structure near the edge of an ocean-connected salina. The establishment of a marine origin for the evaporites offers a method of age assignment using the secular variation of S and Sr isotopes in seawater. Comparison of Sr and S isotope results with the seawater curves precludes Jurassic deposition for the evaporites or correlation with Watrous and Amaranth formation evaporites, previously considered correlative with those at LSM. The lowest Sr and mean of S isotope values from the LSM evaporites are similar to seawater in the latest Devonian, consistent with conodonts recovered from carbonate breccia overlying melt rocks, and we suggest this as an alternative age of the evaporites. Data presented here preclude a Jurassic age for the evaporites and therefore for the impact event.

This document describes the development of a user-friendly and efficient groundwater management model of the Project Shoal Area (PSA and surrounding area that will allow the U.S. Department of Energy and State of Nevada personnel to evaluate the impact of proposed water-use scenarios. The management model consists of a simple hydrologic model within an interactive groundwater management framework. This framework is based on an object user interface that was developed by the U.S. Geological Survey and has been used by the Desert Research Institute researchers and others to couple disparate environmental resource models, manage temporal and spatial data, and evaluate model results for management decision making. This framework was modified and applied to the PSA and surrounding Fairview Basin. The utility of the management model was demonstrated through the application of hypothetical future scenarios including mineral mining, regional expansion of agriculture, and export of water to large urban areas outside the region. While the results from some of the scenarios indicated potential impacts to groundwater levels near the PSA and others did not, together they demonstrate the utility of the management tool for the evaluation of proposed changes in groundwater use in or near the PSA.

Cytokines are pivotal to a balanced innate or cell-mediated immune response, and can be indicative of disease progression and/or resolution. Methods to measure key cytokines rapidly with accuracy, precision, and sensitivity are consequently important. The current assay technologies, which are based on RT-PCR, immunoassays, or bioassays, are limited in their use in the clinic, in particular because of the long time (1-3 h) required to carry out the assays. An alternative, semi-quantitative approach described here, uses an immunological capture step and a mass spectral readout. The goal of the assay is speed rather than sensitivity or precision.

Evidence regarding a causal relationship between bacterial vaginosis and cervical intraepithelial neoplasia has so far been incomplete and conflicting. To determine whether bacterial vaginosis is associated with cervical intraepithelial neoplasia a retrospective study was conducted at the Genitourinary Medicine Clinic at Southlands Hospital, Shoreham-by-Sea, UK. Three hundred patients who presented to the clinic with a first diagnosis of genital warts in the absence of other sexually transmitted diseases were recruited. Results of cervical cytology and where abnormal, histology on colposcopically directed punch biopsies were collected. Bacterial vaginosis was diagnosed by the detection of clue cells on Gram-staining of a high vaginal swab, positive amine test, vaginal pH above 4.5 and the presence of characteristic vaginal discharge. Odds ratio showed an increased prevalence of cervical intraepithelial neoplasia associated with bacterial vaginosis. The results suggest that a prospective cross sectional study should be performed to formally test the hypothesis that bacterial vaginosis predisposes to cervical intraepithelial neoplasia.

Thallium (Tl) contamination in soils poses a significant threat to human health due to the high toxicity of Tl and its ready assimilation by crops. This study is focused on high concentrations of Tl in soils in the Lanmuchang area of southwest Guizhou, China, which is related to natural processes of Tl-rich sulfide mineralization. Thallium contents range from 40 to 124 mg/kg in soils originating from the mining area, from 20 to 28 mg/kg in slope wash materials, from 14 to 62 mg/kg in alluvial deposits downstream, from 1.5 to 6.9 mg/kg in undisturbed natural soils and0.2 to 0.5 mg/kg Tl in soils from the background area. These values indicate that both the erosion of natural soils from the Tl mineralized area and the mining activity are responsible for the distribution of high Tl concentrations in soils. Two other important toxic metals of interest, mercury and arsenic, also show high contents in soils, and are generally higher than Tl concentrations. Thallium concentration in plants exhibit species-dependent preferences. Thus, the enrichment of Tl in the edible parts of crop species decreases in the following order: green cabbagecarrotchiliChinese cabbagericecorn. The highest level of Tl in green cabbage is up to 500 mg/kg as dry wt., surpassing the values of Tl in the soils in which the green cabbages grow. In contrast, Hg and As are relatively less concentrated in local plants. The average daily uptake of Tl by the villagers of the Lanmuchang area through consumption of locally planted crops has been estimated to be 1.9 mg/person, which is 50 times the daily ingestion of individuals from the Tl-free background area. The daily ingestion of As and Hg from the study area are 0.03 and 0.01 mg, respectively. This indicates that Tl in the contaminated soils related to the natural Tl mineralization is being readily transferred to the human body through the food chain, and poses a significant threat to the health of the local villagers. Arsenic may pose a lesser health hazard, but mercury has an insignificant health risk. This study illustrates a real environmental concern related to land use and human health in areas containing high contents of Tl in soils associated with the natural occurrence of Tl-rich sulfides and coals, with or without mining activities. Thallium contamination in soils should be a critical parameter for proper land use and health related environmental planning and regulations.

This paper illustrates a real environmental concern and draws attention to the fact that natural processes can mobilize thallium (Tl), a highly toxic metal, which may enter the food chain as a “hidden health killer” with severe health impacts on local human population. Natural processes may be exacerbated by human activities such as mining and farming, and may cause enrichment of Tl in the environment. In geochemically anomalous areas with concentrated levels of Tl in the surface environment (bedrocks, waters, soils, and crops), such as the Lanmuchang area in southwestern Guizhou Province, China, it is essential to establish base-level values and to pay heed to the geological context of “natural contamination,” as high concentrations of Tl in bedrocks/ores (6–35,000 mg/kg) can lead to enrichment of Tl in the aquatic system (0.005–1100 μg/l in groundwaters and 0.07–31 μg/l in surface waters) and soil layers (1.5–124 mg/kg). In sensitive areas such as the Yanshang area of southwestern Guizhou, elevated natural levels of Tl from bedrocks may also cause higher concentrations of Tl in the surface environment, and thus more attention must be paid to geoenvironmental management of human activities if socio-economic catastrophes are to be avoided. Due to high uptake of Tl by crops, Tl can be transferred from soils to crops and remarkably concentrated in food crops. Concentrations of 1–500 mg/kg Tl based on dry weight (DW) were determined in many food crops growing on Tl-contaminated arable soils from the Lanmuchang area. The daily intake of 1.9 mg of Tl from consumed food crops was estimated for the local adult inhabitant of Lanmuchang. Thus, Tl is regarded as a latent health hazard with potential risk of toxicity in humans within areas of “natural” contamination by Tl. Keywords: Thallium, Geoenvironment, Health hazard, Contamination, Chronic poisoning, Guizhou, China

Previous in vitro studies with transgenic and gene-knockout mice have shown that lenses with elevated levels of glutathione peroxidase (GPX)-1 activity are able to resist the cytotoxic effect of H(2)O(2), compared with normal lenses and lenses from GPX-1-deficient animals. The purpose of this study was to investigate the functional role of this enzyme in antioxidant mechanisms of lens in vivo by comparing lens changes of gene-knockout mice with age-matched control animals.In vivo lens changes were monitored by slit lamp biomicroscopy, and enucleated lenses were examined under a stereomicroscope in gene-knockout animals and age-matched control animals ranging in age from 3 weeks to 18 months. Transmission (TEM) and confocal microscopy were performed on different regions of lenses after the mice were killed at various times.Slit lamp images showed an increase in nuclear light scattering (NLS) in gene-knockout mice compared with control animals. TEM revealed changes in the nucleus as early as 3 weeks of age by the appearance of waviness of fiber membranes. With increasing age, there was greater distortion of fiber membranes and distension of interfiber space at the apex of fiber cells compared with control mice. The changes in nuclear fiber membranes were even more dramatic, as observed by confocal microscopy, which was performed on thicker sections. In contrast to the changes in the lens nucleus, the morphology of the epithelium and superficial cortex remained unchanged in knockout animals during the same experimental period, consistent with slit lamp observations. Stereomicroscopy of ex vivo lenses demonstrated a significant increase in opacification in gene-knockout mice relative to control animals of the same age. This effect became evident in mice aged 5 to 9.9 months and persisted thereafter in older animals, resulting in mature cataracts after 15 months.The results demonstrate the critical role of GPX-1 in antioxidant defense mechanisms of the lens nucleus. The increased NLS appears to be associated with damage to fiber membranes in the nucleus, which is particularly susceptible to oxidative challenge because of the deficiency of GPX-1. It is suggested that the lens membrane changes in the knockout animals may be due to the formation of lipid peroxides, which serve as substrates for GPX-1. Cataract development in gene-knockout mice appeared to progress from focal opacities, apparent at an earlier age, to lamellar cataracts between 6 and 10 months, and finally to complete opacification in animals older than 15 months. This is the first reported phenotype in GPX-1-knockout mice.

To define the number of people in Tayside, Scotland (population 349 303) with Type 2 diabetes who use metformin, the incidence of contraindications to its continued use in these people and the proportion that discontinued metformin treatment following the development of a contraindication.Retrospective cohort study of the incidence of contraindications to metformin in all patients with Type 2 diabetes using metformin from January 1993 to June 1995. The contraindications of acute myocardial infarction, cardiac failure, renal impairment and chronic liver disease were identified by: the regional diabetes information system, biochemistry database and hospital admissions database and a database of all encashed community prescriptions.One thousand eight hundred and forty seven subjects (26.3% of those with Type 2 diabetes) redeemed prescriptions for metformin. Of these, 3.5% were admitted with an acute myocardial infarction (71 episodes); 4.2% were admitted with cardiac failure (114 episodes); 21.0% received metformin and loop diuretics for cardiac failure concurrently; 4.8% developed renal impairment; and 2.8% developed chronic liver disease. The development of contraindications rarely resulted in discontinuation of metformin, for example only 17.5% and 25% stopped metformin after admission with acute myocardial infarction and development of renal impairment, respectively. In total, 24.5% of subjects receiving metformin, 6.4% of all people with Type 2 diabetes, had contraindications to its use. There was one episode of lactic acidosis in 4600 patient years.This population-based study shows that 24.5% of patients prescribed metformin have contraindications to its use. Development of contraindications rarely results in discontinuation of metformin therapy. Despite this, lactic acidosis remains rare. Diabet. Med. 18, 483-488 (2001)

This study compared the pathology and infection pattern of streptococcal pyrogenic exotoxin B-positive (SpeB(+)) and SpeB-negative (SpeB(-)) isogenic variants of an M1 isolate of Streptococcus pyogenes in a mouse skin air sac model. SpeB(+) strains resulted in severe local tissue damage that extended from the epidermis through the subcutaneous layers, whereas isogenic SpeB(-) variants had reduced gross pathology. At the histologic level, differences in necrosis and host responses to each variant were apparent. Injection of purified SpeB alone into a skin air sac failed to induce any significant tissue damage; however, coinjection of the enzyme with either the wild-type or the speB mutant resulted in increased and accelerated tissue necrosis. Surprisingly, coinjection of the enzyme with the spleen-recovered SpeB(-) variant failed to induce a lesion.

Adenosine (ADO) is a homeostatic inhibitory autocoid that is released at sites of inflammation and tissue injury, and exerts anti-inflammatory effects via multiple interactions at ADO receptor subtypes. Inhibition of ADO kinase (AK) increases extracellular ADO concentrations and AK inhibitors have demonstrated ADO-mediated anti-inflammatory effects in acute models of inflammation. To evaluate the potential utility of this approach in chronic inflammation, a novel, potent, and selective non-nucleoside AK inhibitor, ABT-702, was tested in the rat adjuvant arthritis model. Animals were immunized with complete Freund's adjuvant on day 0 and were treated with vehicle or ABT-702 (20 mg/kg/b.i.d. p.o.) beginning on day 8. ABT-702 significantly inhibited arthritis as determined by paw volume. In addition, histologic and radiographic evidence of bone and cartilage destruction was significantly decreased in the treated group. Coadministration of the ADO receptor antagonist theophylline attenuated the anti-inflammatory effects of ABT-702, suggesting that this action was mediated through endogenous ADO release. To evaluate the mechanism of chondroprotection, Northern blot and electrophoretic mobility shift assays were performed on joints samples. These studies demonstrated that ABT-702 suppressed collagenase and stromelysin gene expression in treated animals. In addition, the activator protein-1 and nuclear factor-kappaB binding activity was also decreased. Therefore, ABT-702 inhibited clinical, radiographic, and histologic evidence of chronic inflammatory arthritis. The mechanism of joint protection is likely related to suppressed transcription factor activation and matrix metalloproteinase gene expression.

Preventive and/or therapeutic vaccines against Human Immunodeficiency Virus (HIV-1) are urgently required. Induction of cellular immunity is favoured since these responses correlate with control of HIV-1. Recombinant fowlpoxvirus (FPV) vaccines encoding both HIV-1 gag/pol and interferon-gamma (FPV gag/pol-IFNgamma) were hypothesised to enhance HIV-specific cellular immunity and were further evaluated in macaques previously infected with HIV-1. A novel assay to detect IFNgamma secretion following HIV antigen stimulation of whole blood was developed to further assess the safety and immunogenicity of the FPV gag/pol-IFNgamma vaccine. Immunisation with FPV gag/pol-IFNgamma safely enhanced HIV-specific IFNgamma secretion following ex vivo stimulation of whole blood, greater than that observed following FPV gag/pol vaccination not co-expressing IFNgamma. Both HIV-specific IFNgamma-spot-forming cells by ELISPOT and CD69 expression by CD4+ lymphocytes were also enhanced following FPV gag/pol-IFNgamma vaccination. Hence, the FPV-HIV vaccine co-expressing IFNgamma stimulated HIV-specific T cell responses in macaques, and should be further evaluated as a therapeutic or preventive HIV vaccine.

Traditionally investment casting of biomedical implants has utilized the lost wax process, this paper is an investigation into the possibilities of casting small lots of custom specific medical implants directly and indirectly from various rapid prototyping & tooling techniques. Small batch quantities for quick turn arounds cost and lead times are the main contributing factors for the purpose of this investigation. To directly produce parts means that a RP model will be used in the place of the wax pattern in the investment casting process. To indirectly produce parts means that a mould, which has been generated from RP&T techniques, will be used to manufacture wax patterns that will then in turn be used to investment cast the parts. The device to be manufactured is a non-sterile, referred to as ‘trial’ prosthetic implant. The implant is used by the operating surgeon to check the ‘fit’ of the cavity that will be made to receive the prosthesis plus bone cement that will be used to fix the implant in place.

A survey of sheep and goat producers in the state of Maharashtra, India, was undertaken to ascertain the extent and economic impact of sheep pox and goat pox (SGP). One thousand one hundred and sixteen owners were interviewed. Eighty owners (7.2%) reported that they had experienced an outbreak of the disease in the previous 6 years. The results showed that, while producers ranked SGP below other infectious diseases such as foot-and-mouth disease, rinderpest and enterotoxaemia, when SGP occurred it had a major impact, with average morbidity and mortality rates of 63.5% and 49.5%, respectively. Modelling studies suggested it would take about 6 years for a flock or herd to recover from an outbreak, with average annual losses in income of 30-43%, depending on flock type and the owner's actions. Statewide, it is estimated that around 5000 flocks and herds are affected by SGP annually in Maharashtra, costing up to INR 107.5 million. The highest losses occurred in the Aurangabad region.

To test the hypothesis that crystallin proteins may actively participate in the differentiation of lens epithelial cells into fiber cells.Primary epithelial cells from adult bovine lenses were cultured at 37 degrees C until reaching 95-100% confluency in approximately 4-7 days. Using osmotic lysis of pinocytic vesicles, cells were then loaded with proteins labeled or unlabeled with the fluorescent marker Texas Red (TR). Fetal bovine proteins loaded into cells were lens water soluble fractions, HPLC-purified alpha-, beta-, and gamma-crystallin fractions, or bovine serum albumin (BSA). Cultures were then monitored for morphological changes over a 7 day period.Both TR-labeled and unlabeled water-soluble and a-crystallin fractions from bovine lenses resulted in morphological changes to epithelial cells during the first two h postloading. These changes included aggregation of epithelial cells into raised multilayered cell masses, as well as several cells losing attachment to the dish. The initial changes were subsequently followed by elongation of cells within the mass and an increase in size of the mass, so that by 4 days postloading the multilayered, multicellular structures could be visualized with the unaided eye. Differentiation was confirmed within these structures by expression of MIP 26, beta- and gamma-crystallin. These changes did not occur in cultures containing cells originally loaded with beta- or gamma-crystallin fractions, or with cells loaded with BSA.The results support the hypothesis that alpha-crystallins may actively participate in the differentiation of lens epithelial cells into fiber cells.

The refolding of daniplestim, a human interleukin-3 variant (SC-55494) from Escherichia coli inclusion bodies, was optimized using a reversed-phase HPLC method developed to permit quantification of the reduced and oxidized forms of daniplestim. The presence of cysteine or dithiothreitol accelerated refolding of daniplestim from E. coli inclusion body slurries dissolved in urea or guanidine solutions and was complete in 4-6 h. Regardless of the dissolution and refolding protocol used to renature daniplestim, equivalently bioactive protein was produced. Under refolding conditions, no covalent modification of daniplestim by cysteine or cyanate was observed. The folding process was characterized further by following the unfolding of purified daniplestim by far-UV CD and fluorescence spectroscopies under both oxidizing and reducing conditions at pH values between 7 and 11. Formation of the single disulphide bond had a large stabilizing effect on daniplestim structure ( approximately 4-5 kCal at pH 9.5). This thermodynamic stabilization drove the refolding process towards the native form, even under conditions where the reduced protein was largely unfolded. From these data, scaleable refolding conditions for daniplestim were established.

NF-kappa B is a key regulator of inflammatory gene transcription and is activated in the rheumatoid arthritis (RA) synovium. In resting cells, NF-kappa B is retained as an inactive cytoplasmic complex by its inhibitor, I kappa B. Phosphorylation of I kappa B targets it for proteolytic degradation, thereby releasing NF-kappa B for nuclear translocation. Recently, two related I kappa B kinases (IKK-1 and IKK-2) were identified in immortalized cell lines that regulate NF-kappa B activation by initiating I kappa B degradation. To determine whether IKK regulates NF-kappa B in primary cells isolated from a site of human disease, we characterized IKK in cultured fibroblast-like synoviocytes (FLS) isolated from synovium of patients with RA or osteoarthritis. Immunoreactive IKK protein was found to be abundant in both RA and osteoarthritis FLS by Western blot analysis. Northern blot analysis showed that IKK-1 and IKK-2 genes were constitutively expressed in all FLS lines. IKK function in FLS extracts was determined by measuring phosphorylation of recombinant I kappa B in vitro. IKK activity in both RA and osteoarthritis FLS was strongly induced by TNF-alpha and IL-1 in a concentration-dependent manner. Activity was significantly increased within 10 min of stimulation and declined to near basal levels within 80 min. Activation of IKK in FLS was accompanied by phosphorylation and degradation of endogenous I kappa B alpha as determined by Western blot analysis. Concomitant activation and nuclear translocation of NF-kappa B was documented by EMSA and immunohistochemistry. Transfection with a dominant negative IKK-2 mutant prevented TNF-alpha-mediated NF-kappa B nuclear translocation, whereas a dominant negative IKK-1 mutant had no effect. This is the first demonstration that IKK-2 is a pivotal regulator of NF-kappa B in primary human cells.

Studies were performed to determine if p53 mutations identified in rheumatoid arthritis (RA) synovial tissue are dominant negative.Site-directed mutagenesis was used to produce 2 RA-derived mutants: asparagine--serine at codon 239 (N239S) and arginine--stop at codon 213 R213*). HS68 dermal fibroblasts were transfected with either empty vector, wild-type p53 cDNA (wt), or the N239S or R213* mutant p53 cDNA clones. Interleukin-6 (IL-6) and bax gene expression were determined by Northern blot analysis. Bax transcription was determined using a bax promoter/reporter gene construct (bax-luc).Transfection of HS68 cells with wt increased bax mRNA levels. This process was blocked by cotransfection with either mutant. The mutant p53 genes also increased IL-6 gene expression. Low levels of bax promoter activity were detected in HS68 cells co-transfected with bax-luc and empty vector, N239S, or R213*, indicating that the RA mutants lacked transcriptional activity. Transfection with wt and bax-luc led to a 10-fold increase in luciferase expression. When the wt gene was cotransfected with either of the mutants, there was a dose-dependent inhibition of bax promoter activity.These data indicate that at least 2 of the p53 mutants identified in RA joint samples are dominant negative and suppress endogenous wild-type p53 function.

The p53 tumor suppressor gene is overexpressed in synovial tissue (ST) from patients with longstanding rheumatoid arthritis (RA), and may contain somatic mutations. The aim of this study was to determine p53 expression in ST from RA patients in different stages of the disease, compared with disease controls.ST biopsy specimens were obtained from the knee joints of 31 RA patients in varying disease phases, 8 patients with reactive arthritis (ReA), 10 patients with inflammatory osteoarthritis (OA), and 6 control patients (4 with meniscus pathology, 2 with vascular insufficiency). ST was also obtained from the clinically uninvolved knee joints of 9 RA patients. Expression of p53 was determined by immunohistology with DO1 monoclonal antibody (mAb) in all patients and by Western blot analysis with DO7 mAb in a subgroup of the patients.The p53 protein was detected by immunohistology in 10 of the 13 patients with early RA (duration6 months) and in 12 of the 14 patients with longstanding RA (duration5 years). The p53 protein was also demonstrated in clinically uninvolved knee joints. Western blots revealed immunoreactive p53 in ST extracts from all RA patients. Expression of p53 was about twice as high in ST from patients with longstanding RA as in early RA samples, but the difference did not reach statistical significance. Small amounts of p53 were also detected in ST from ReA and OA patients, although the expression in RA synovium was significantly higher. Immunohistologic analysis of normal ST gave negative results for p53.This study shows that p53 overexpression is specific for RA, compared with OA and ReA. This phenomenon is probably secondary to increased production of wild-type p53 protein in response to DNA damage and secondary to somatic mutations caused by the genotoxic local environment in inflamed ST. Of interest, p53 overexpression can also be found in the earliest stages of RA and in clinically uninvolved joints.

The purpose of this article is to review information relative to the administration, stability, and compatibility of paclitaxel (Taxol, Mead Johnson Oncology Products, Princeton, NJ). The unique formulation used to solubilize paclitaxel has led to an increased awareness of plasticizer-leaching issues, paclitaxel stability in solution, and paclitaxel compatibility with other medications. Particularly with longer paclitaxel infusion schedules (greater than 48 hours), both drug stability in solution and pump apparatus congruence require careful consideration to minimize plasticizer-leaching problems and to ensure optimum drug delivery. Despite knowledge of the physical compatibility of paclitaxel with numerous drugs, a paucity of research has documented the specifics of paclitaxel's chemical compatibility with other medications.

With the end of the Cold War, the United States and Russia are reducing their nuclear weapons stockpiles. Deciding what to do with the materials from the thousands of retired nuclear weapons is an important international challenge. To help address this question and related issues, the US Department of Energy (DOE) and the State of Texas established the Amarillo National Resource Center for Plutonium in 1994.

Malignant ovarian tumours of the fibrothecoma group are rare. The clinicopathological features of a case of ovarian malignant fibrothecoma in which there was metastatic disease in the small intestine and peritoneum at presentation are described. A number of differential diagnoses were considered but positive immunohistochemical staining of the resected ovarian and small intestinal neoplasms with anti-inhibin was of value in confirming a sex cord-stromal tumour and in excluding other lesions. The two tumours were also ultrastructurally identical. Classical malignant fibrothecomas are said to show four or more mitotic figures per 10 high power fields (HPF). Although the intestinal secondary was mitotically active, the primary ovarian tumour contained only one to two mitoses per 10 HPF, showing that formal mitotic counts are not an absolute indicator of malignant behaviour in this group of tumours.