Political history of recent times, 1816-1875,

Translated from the German.

Intermediary equatorial orbits of an artificial satellite,

"NBS project 1104-12-11440."

Geology and ore deposits of the Afterthought Mine : Shasta County, California.

Mode of access: Internet.

Reproductive and feeding ecology of parasitic gnathiid isopods of epaulette sharks (Hemiscyllium ocellatum) with consideration of their role in the transmission of a haemogregarine

Epaulette sharks Hemiscyllium ocellatum were surveyed on Heron Island, Great Barrier Reef, Australia for gnathiid isopods and protozoan (haemogregarine) parasites to determine the prevalence and intensity of infection and to investigate the potential role of gnathiids as vectors of these haemogregarines, the first such study carried out on elasmobranchs. Juvenile gnathiids were collected and quantified using a novel non-invasive and chemical-free technique and gnathiid squashes were examined for haemogregarine developmental stages. The feeding and reproductive ecology of the Gnathia spp. was investigated to better understand the relationship between gnathiids and haemogregarines. Gnathiids were found on all sharks and intensities ranged between two and 66. Only third-stage gnathiid juveniles were found, which fell into two size groups (A and B). These juveniles remained attached to H. ocellatum for up to 17 days, the longest period of attachment yet recorded for gnathiids. Group A female gnathiids produced broods of 45-187 (median = 120) first stage juveniles from between 54 and 82 days (median = 63 days) after detachment. First stage juveniles survived for an average of 15.8 +/- 0.1 (SEM) days without feeding. The prevalence (6.7%) and parasitaemia (usually

The effects of intra-amniotic injection of periodontopathic lipopolysaccharides in sheep

Objective: Periodontal disease may cause several complications of pregnancy, including fetal death. The purpose of this study was to investigate in sheep the effects of the intra-amniotic injection of lipopolysaccharide from 3 periodontopathic organisms and to compare these effects with those resulting from similar injection of Escherichia coli lipopolysaccharide. The outcomes that were studied included the rates of fetal death and the features of inflammation and lung maturation in survivors. Study design: At 118 days of pregnancy, ewes that were bearing single fetuses were allocated at random to receive intra-amniotic injections of saline solution (n = 13 fetuses), or lipopolysaccharide from Porphyromonas gingivalis (in doses from 0.1 to 10 tug [n = 22 fetuses]), Actinobacillus actinomycetemcomitans (10 mg [n = 6 fetuses]; 1 mg [n = 6 fetuses]), Fusobacterium nucleation (10 mg [n = 6 fetuses]) or Escherichia coli (10 mg [n = 14 fetuses]; 1 mg [n = 7 fetuses]). Surviving fetuses were delivered abdominally at 125 days of gestation (term, 150 days). Results: When compared with Escherichia coli lipopolysaccharide at similar dosages, periodontopathic lipopolysaccharides had high rates of fetal lethality. Only 6 of 22 fetuses that were exposed to intra-amniotic Porphyromonas gingivalis lipopolysaccharide survived doses of 0.1 to 10 mg, and only 3 of 6 fetuses survived 10-mg Actinobacillus actinomycetemcomitans lipopolysaccharide. Escherichia coli lipopolysaccharide did not cause fetal loss when given at doses of 10 mg (n = 14 fetuses) or l mg (n = 7 fetuses). Fetuses that survived exposure to these lipopolysaccharides showed features of inflammation in amniotic fluid and cord blood at birth and enhanced lung maturation. Conclusion: Lipopolysaccharides from these 3 periodontopathic organisms have much higher rates of fetal lethality than Escherichia coli lipopolysaccharide but can cause similar intrauterine inflammatory responses and improvements in lung volumes in survivors. Sources of inflammation that are distant from the uterus may underlie a proportion of unexplained stillbirth and other complications of pregnancy. (c) 2005 Mosby, Inc. All rights reserved.

Motorcycle accident risk could be inflated by a time to arrival illusion

Purpose. Drivers adopt smaller safety margins when pulling out in front of motorcycles compared with cars. This could partly account for why the most common motorcycle/car accident involves a car violating a motorcyclist's right of way. One possible explanation is the size-arrival effect in which smaller objects are perceived to arrive later than larger objects. That is, drivers may estimate the time to arrival of motorcycles to be later than cars because motorcycles are smaller. Methods. We investigated arrival time judgments using a temporal occlusion paradigm. Drivers recruited from the student population (n = 28 and n = 33) saw video footage of oncoming vehicles and had to press a response button when they judged that vehicles would reach them. Results. In experiment 1, the time to arrival of motorcycles was estimated to be significantly later than larger vehicles (a car and a van) for different approach speeds and viewing times. In experiment 2, we investigated an alternative explanation to the size-arrival effect: that the smaller size of motorcycles places them below the threshold needed for observers to make an accurate time to arrival judgment using tau. We found that the motorcycle/car difference in arrival time estimates was maintained for very short occlusion durations when tau could be estimated for both motorcycles and cars. Conclusions. Results are consistent with the size-arrival effect and are inconsistent with the tau threshold explanation. Drivers estimate motorcycles will reach them later than cars across a range of conditions. This could have safety implications.

Genomewide Linkage Scan of 409 European-ancestry and African American Families with Schizophrenia: Suggestive Evidence of Linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the Combined Sample

We report the clinical characteristics of a schizophrenia sample of 409 pedigrees-263 of European ancestry ( EA) and 146 of African American ancestry ( AA)-together with the results of a genome scan ( with a simple tandem repeat polymorphism interval of 9 cM) and follow-up fine mapping. A family was required to have a proband with schizophrenia ( SZ) and one or more siblings of the proband with SZ or schizoaffective disorder. Linkage analyses included 403 independent full-sibling affected sibling pairs ( ASPs) ( 279 EA and 124 AA) and 100 all-possible half-sibling ASPs ( 15 EA and 85 AA). Nonparametric multipoint linkage analysis of all families detected two regions with suggestive evidence of linkage at 8p23.3-q12 and 11p11.2-q22.3 ( empirical Z likelihood-ratio score [ Z(lr)] threshold >= 2.65) and, in exploratory analyses, two other regions at 4p16.1-p15.32 in AA families and at 5p14.3-q11.2 in EA families. The most significant linkage peak was in chromosome 8p; its signal was mainly driven by the EA families. Z(lr) scores >= 2.0 in 8p were observed from 30.7 cM to 61.7 cM ( Center for Inherited Disease Research map locations). The maximum evidence in the full sample was a multipoint Z(lr) of 3.25 ( equivalent Kong-Cox LOD of 2.30) near D8S1771 ( at 52 cM); there appeared to be two peaks, both telomeric to neuregulin 1 ( NRG1). There is a paracentric inversion common in EA individuals within this region, the effect of which on the linkage evidence remains unknown in this and in other previously analyzed samples. Fine mapping of 8p did not significantly alter the significance or length of the peak. We also performed fine mapping of 4p16.3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Z(lr) scores was observed for 5p14.1-q12.1, where the maximum Z(lr) increased from 2.77 initially to 3.80 after fine mapping in the EA families.

Overexpression of Leucyl Aminopeptidase in Plasmodium falciparum Parasites. Target for the antimalarial activity of bestatin

Malaria aminopeptidases are important in the generation and regulation of free amino acids that are used in protein anabolism and for maintaining osmotic stability within the infected erythrocyte. The intraerythrocytic development of malaria parasites is blocked when the activity of aminopeptidases is specifically inhibited by reagents such as bestatin. One of the major aminopeptidases of malaria parasites is a leucyl aminopeptidase of the M17 family. We reasoned that, when this enzyme was the target of bestatin inhibition, its overexpression in malaria cells would lead to a reduced sensitivity to the inhibitor. To address this supposition, transgenic Plasmodium falciparum parasites overexpressing the leucyl aminopeptidase were generated by transfection with a plasmid that housed the full-length gene. Transgenic parasites expressed a 65-kDa protein close to the predicted molecule size of 67.831 kDa for the introduced leucyl aminopeptidase, and immunofluorescence studies localized the protein to the cytosol, the location of the native enzyme. The product of the transgene was shown to be functionally active with cytosolic extracts of transgenic parasites exhibiting twice the leucyl aminopeptidase activity compared with wildtype parasites. In vitro inhibitor sensitivity assays demonstrated that the transgenic parasites were more resistant to bestatin (EC50 64 mu M) compared with the parent parasites (EC50 25 mu M). Overexpression of genes in malaria parasites would have general application in the identification and validation of targets for antimalarial drugs.

Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc

Aqueous semi-solid polymeric gels, such as those based on hydroxyethylcellulose (HEC) and polyacrylic acid (e.g. Carbopol®), have a long history of use in vaginal drug delivery. However, despite their ubiquity, they often provide sub-optimal clinical performance, due to poor mucosal retention and limited solubility for poorly water-soluble actives. These issues are particularly pertinent for vaginal HIV microbicides, since many lead candidates are poorly water-soluble and where a major goal is the development of a coitally independent, once daily gel product. In this study, we report the use of a non-aqueous silicone elastomer gel for vaginal delivery of the HIV-1 entry inhibitor maraviroc. In vitro rheological, syringeability and retention studies demonstrated enhanced performance for silicone gels compared with a conventional aqueous HEC gel, while testing of the gels in the slug model confirmed a lack of mucosal irritancy. Pharmacokinetic studies following single dose vaginal administration of a maraviroc silicone gel in rhesus macaques showed higher and sustained MVC levels in vaginal fluid, vaginal tissue and plasma compared with a HEC gel containing the same maraviroc loading. The results demonstrate that non-aqueous silicone gels have potential as a formulation platform for coitally independent vaginal HIV microbicides.

Sustained release of the CCR5 inhibitors CMPD167 and maraviroc from vaginal rings in rhesus macaques

Antiretroviral entry inhibitors are now being considered as vaginally administered microbicide candidates for the prevention of the sexual transmission of human immunodeficiency virus. Previous studies testing the entry inhibitors maraviroc and CMPD167 in aqueous gel formulations showed efficacy in the macaque challenge model, although protection was highly dependent on the time period between initial gel application and subsequent challenge. In this paper, we describe the sustained release of maraviroc and CMPD167 from matrix-type silicone elastomer vaginal rings both in vitro and in vivo. Both inhibitors were released continuously during 28 days from rings in vitro at rates of 100 to 2,500 µg/day. In 28-day pharmacokinetic studies in rhesus macaques, the compounds were measured in the vaginal fluid and vaginal tissue; steady-state fluid concentrations were ~10(6)-fold greater than the 50% inhibitory concentrations (IC(50)s) for simian human immunodeficiency virus 162P3 inhibition in macaque lymphocytes in vitro. Plasma concentrations for both compounds were very low. The pretreatment of macaques with Depo-Provera (DP), which is commonly used in macaque challenge studies, was shown to significantly modify the biodistribution of the inhibitors but not the overall amount released. Vaginal fluid and tissue concentrations were significantly decreased while plasma levels increased with DP pretreatment. These observations have implications for designing macaque challenge experiments and also for ring performance during the human female menstrual cycle.