Metabolism and biochemical effects of 3,3',4,4'-tetrachlorobiphenyl in pregnant and fetal rats

The metabolism and distribution of a single oral dose of 25 mumol 14C-labelled 3,3',4,4'-tetrachlorobiphenyl (14C-TCB) were investigated in pregnant female Wistar rats and their fetuses. TCB was administered on day 13 of gestation and the elimination was followed for 7 days. Non-pregnant rats were treated similarly for comparison. Fecal elimination of 14C-TCB derived radioactivity was significantly lower in pregnant rats than in non-pregnant rats. The major metabolite found in adult liver and plasma, placental tissue, whole fetuses and fetal plasma was 3,3',4',5-tetrachloro-4-biphenylol (4-OH-TCB). Tissue levels (liver, abdominal fat, skin, skeletal muscle, kidney and plasma) of 14C-TCB-derived radioactivity declined by 65-85% over a 7-day period following administration in the adult animals. However, 14C-TCB-derived radioactivity accumulated more than 100-fold in the fetuses over the same time period, and GC/MS analysis revealed that the fetal accumulation in radioactivity was due primarily to 4-OH-TCB, and not the parent compound. On day 20 of gestation, concentrations of 4-OH-TCB were 14 times greater in fetal plasma than maternal plasma. Treatment with 14C-TCB significantly reduced plasma thyroxine levels by at least 28% up to 7 days after administration in non-pregnant animals and up to 4 days after administration in pregnant rats (31% decrease). By 7 days after administration plasma thyroxine levels had returned to control levels in the TCB-treated pregnant rats. However, fetal plasma thyroxine levels were significantly decreased by 35% in fetuses from 14C-TCB-treated dams 7 days after TCB administration. Hepatic microsomal ethoxyresorufin-O-deethylase (EROD) activity was significantly induced in TCB-treated dams relative to controls at 4 and 7 days after administration, while no EROD activity was detected in hepatic microsomes from control or TCB treated fetal rats at day 20 of gestation. These data suggest that hydroxylated metabolites of polychlorinated biphenyls may play a role in the development toxicity of these compounds.     

Behavioral factors affecting exposure potential for household cleaning products

Variation in repeated nucleotide sequences (RNSs) at the level of entire families assayed by Southern blot hybridization is remarkably low within species and is a powerful tool for scrutinizing the origin of allopolyploid taxa. Thirty-one clones from RNSs isolated from different Triticeae genera were used to investigate the genome constitution of South American Elymus. One of these clones, pHch2, preferentially hybridized with the diploid H genome Hordeum species. Hybridization of this clone with a worldwide collection of Elymus species with known genome formulas showed that pHch2 clearly discriminates Elymus species with the H genome (StH, StHH, StStH, and StHY) from those with other genome combinations (StY, StStY, StPY, and StP). Hybridization with pHch2 indicates the presence of the H genome in all South American Elymus species except Elymus erianthus and Elymus mendocinus. Hybridization with additional clones that revealed differential restriction fragments (marker bands) for the H genome confirmed the absence of the H genome in these species. Differential restriction fragments for the Ns genome of Psathyrostachys were detected in E. erianthus and E. mendocinus and three species of Leymus. Based on genome constitution, morphology, and habitat, E. erianthus and E. mendocinus were transferred to the genus Leymus.     

Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial

CONTEXT: Although the long-term health benefits of good glycemic control in patients with diabetes are well documented, shorter-term quality of life (QOL) and economic savings generally have been reported to be minimal or absent. OBJECTIVE: To examine short-term outcomes of glycemic control in type 2 diabetes mellitus (DM). DESIGN: Double-blind, randomized, placebo-controlled, parallel trial. SETTING: Sixty-two sites in the United States. PARTICIPANTS: A total of 569 male and female volunteers with type 2 DM. INTERVENTION: After a 3-week, single-blind placebo-washout period, participants were randomized to diet and titration with either 5 to 20 mg of glipizide gastrointestinal therapeutic system (GITS) (n = 377) or placebo (n = 192) for 12 weeks. MAIN OUTCOME MEASURES: Change from baseline in glucose and hemoglobin A1c (HbA1c) levels and symptom distress, QOL, and health economic indicators by questionnaires and diaries. RESULTS: After 12 weeks, mean (+/-SE) HbA1c and fasting blood glucose levels decreased with active therapy (glipizide GITS) vs placebo (7.5% 0.1% vs 9.3%+/-0.1% and 7.0+/-0.1 mmol/L [126+/-2 mg/dL] vs 9.3+/-0.2 mmol/L [168+/-4 mg/ dL], respectively; P<.001). Quality-of-life treatment differences (SD units) for symptom distress (+0.59; P<.001), general perceived health (+0.36; P= .004), cognitive functioning (+0.34; P=.005), and the overall visual analog scale (VAS) (+0.24; P=.04) were significantly more favorable for active therapy. Subscales of acuity (+0.38; P=.002), VAS emotional health (+0.35; P=.003), general health (+0.27; P=.01), sleep (+0.26; P=.04), depression (+0.25; P=.05), disorientation and detachment (+0.23; P= .05), and vitality (+0.22; P=.04) were most affected. Favorable health economic outcomes for glipizide GITS included higher retained employment (97% vs 85%; P<.001), greater productive capacity (99% vs 87%; P<.001), less absenteeism (losses = $24 vs $115 per worker per month; P<.001), fewer bed-days (losses = $1539 vs $1843 per 1000 person-days; P=.05), and fewer restricted-activity days (losses = $2660 vs $4275 per 1000 person-days; P=.01). CONCLUSIONS: Improved glycemic control of type 2 DM is associated with substantial short-term symptomatic, QOL, and health economic benefits.     

Correlations in a General Theory of Quantum Measurement

The paper investigates correlations in a general theory of quantum measurement based on the notion of instrument. The analysis is performed in the algebraic formalism of quantum theory in which the observables of a physical system are described by a von Neumann algebra, and the states—by normal positive normalized functionals on this algebra. The results extend and generalise those obtained for the classical case where one deals with the full algebra of operators on a Hilbert space.     

Identification of spherical virus particles in digitized images of entire electron micrographs

Interferon-gamma (IFN-gamma) has the most potent immunomodulatory activity of all the interferons. This phase II-B study was performed to define time- and dose-dependent immunomodulatory effects mediated by IFN-gamma in a subset of patients with melanoma treated in the dose-seeking therapeutic trial conducted by the Eastern Cooperative Oncology Group E4687 (13). The effects of IFN-gamma (Genentech, San Francisco, CA) were evaluated for phenotype and function of peripheral blood lymphocytes obtained twice prestudy, and on days 2, 9, and 29 of IFN-gamma therapy for 50 patients. Early significant increases in CD4/CD8 ratio (p = 0.001) were noted, largely due to a rise in CD4+ and fall in CD8+ T-cell populations sustained through day 29 at only the lowest dosage. Increased natural killer cell (NK) activity (p = 0.001 on day 9; p = 0.01 on day 29) was accompanied by durable increases in circulating activated NK cells (CD56+DR+% p = 0.001, day 9; p = 0.001, day 29). After initial depression of CD56+ and CD16+ cells on day 2, the total percent of CD56+ and CD16+ cells increased significantly by day 29. Increases in NK cell activity were maximal at doses > or =0.1 mg. Monocyte CD14+ expression of DQ+ rose early (p = 0.011 and 0.001 on days 2 and 9), accompanied by elevation in CD14+DR+ cells that was less significant. Immunomodulatory effects of IFN-gamma reported in this trial have major implications for interpretation of past and current clinical trials, and the design of future trials. This is the first trial in which IFN-gamma has been shown to have significant effects on the T-cell compartment of the immune system.     

Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors

Only two tumor suppressor gene loci, one on 3p25 and the MEN1 gene on 11q13, have thus far been implicated in the pathogenesis of sporadic human pancreatic endocrine tumors (PETs). A genome-wide allelotyping study of 28 human PETs was undertaken to identify other potential tumor suppressor gene loci. In addition to those on chromosomes 3p and 11q, frequent allelic deletions were identified on 3q (32%), 11p (36%), 16p (36%), and 22q (29%). Finer deletion mapping studies localized the smallest regions of common deletion to 3q27, 11p13, and 16p12.3-13.11. Potential candidate genes at these loci include WT1 (11p13), TSC2 (16p13), and NF2 (22q12), but no known tumor suppressor gene localizes to 3q27. The mean fractional allelic loss among these human PETs is 0.126, and no correlation was observed between allelic loss and clinical parameters, including age, sex, hormonal subtype, and disease stage. These findings highlight novel locations of tumor suppressor gene loci that contribute to the pathogenesis of human PETs, and several of these on 3p, 3q, and 22q are syntenic with loci on mouse chromosomes 9 and 16 that are implicated in a murine transgenic model of PETs.     

Geographic distribution and clinical description of leishmaniasis cases in Peru

Asymmetric acetylcholinesterase (AChE) is anchored to the basal lamina (BL) of cholinergic synapses via its collagenic tail, yet the complement of matrix receptors involved in its attachment remains unknown. The development of a novel overlay technique has allowed us to identify two Torpedo BL components that bind asymmetric AChE: a polypeptide of approximately 140 kDa and a doublet of 195-215 kDa. These were found to stain metachromatically with Coomassie blue R-250, were solubilized by acetic acid, and were sensitive to collagenase treatment. Upon sequence analysis, the 140 kDa polypeptide yielded a characteristic collagenous motif. Another AChE-binding BL constituent, identified by overlay, corresponded to a heparan sulfate proteoglycan. Lastly, we established that this proteoglycan, but not the collagenous proteins, interacted with at least one heparin binding domain of the collagenic tail of AChE. Our results indicate that at least two BL receptors are likely to exist for asymmetric AChE in Torpedo electric organ.     

Mapping the active sites of 3-phosphoglycerate kinase and glycerol kinase with monoammine chromium(III) ATP

The 12 isomers of monoammine chromium(III) ATP have been used to probe the ATP binding sites of yeast 3-phosphoglycerate kinase and glycerol kinase from Candida mycoderma. Inhibition studies of 3-phosphoglycerate kinase show a dramatic decrease in isomer binding only when the ammonia is in the Delta axial facial anti position. This suggests an open site architecture with only one strong contact point between the coordination sphere and the enzyme surface. These results agree well with the computer modeling studies of bidentate chromium ATP into the nucleotide site determined by X-ray crystallography [McPhillips, T., et al. (1996) Biochemistry 35, 4118-4127]. Both methods describe an open site strongly supporting the validity of the inhibition studies. Inhibition studies of glycerol kinase show significant decreases in binding for all the tested ammonia positions, suggesting a closed site architecture with many contacts between the coordination sphere and the surface of the enzyme. This is in good agreement with X-ray studies [Hurley, T., et al. (1993) Science 259, 673-677] on the Escherichia coli glycerol kinase. Inhibition studies of hexokinase previously reported [Rawlings, J., et al. (1993) Biochemistry 32, 11204-11210] more closely resemble those of 3-phosphoglycerate kinase, suggesting the surprising result that however closely hexokinase and glycerol kinase are related structurally the site around the coordination sphere in hexokinase is functionally open like that of 3-phosphoglycerate kinase.