Changes in tissue levels of sorbitol, myo-inositol, and Na+-K+-ATPase enzyme activity have been implicated in the development of diabetic complications in animal models of the disease and in humans. ...The ability of the aldose reductase inhibitor sorbinil to reverse the hyperglycemia-induced changes in these lenticular metabolite and enzyme-activity levels in the streptozocin-induced diabetic rat was examined to determine what, if any, relationship exists between these changes. Two weeks of untreated diabetes did not change ouabain-inhibitable ATPase enzyme activity assayed in lens homogenates but did result in a decrease in the Na+-K+-ATPase transport activity as measured by 86Rb uptake in the intact lens. This was accompanied by a 100-fold increase in the levels of sorbitol and significant decreases in the levels of myo-inositol, ATP, and glutathione in the lens. Whereas all of these changes could be reversed by sorbinil treatment, the dose required for restoration of the depleted myo-inositol level (ED50 greater than 20 mg.kg-1.day-1) was much higher than the dose required to reverse the other changes (ED50 range 2-5 mg.kg-1.day-1). These results suggest that the restoration of lenticular Na+ -K+ -ATPase activity is not secondary to a normalization of myo-inositol levels and may provide evidence that the two parameters are not strictly associated in diabetic tissues.
Differences in newborn outcome measures for human immunodeficiency virus (HIV)-1-infected and HIV-1-exposed but uninfected infants have been found in several studies, but not in others. Eighty-four ...infected and 248 uninfected children born to HIV-1-seropositive mothers followed prospectively in a multicenter, perinatal HIV-1 transmission cohort study were compared for differences in maternal demographics, health status, and newborn outcome measures, including delivery complications, physical examination findings, neonatal complications, and laboratory results.
Mothers of HIV-1-infected infants were more likely than those of uninfected infants to have acquired immunodeficiency syndrome (AIDS) diagnosed through 2 weeks postpartum (21% vs 11%, P = .04); the transmission rate for the 38 women with AIDs was 37% compared with 22% for the 245 women without AIDS. Two of 27 (7%) women receiving zidovudine during pregnancy had infected infants compared with 73 (27%) of 275 women who did not receive zidovudine (P = .033). Mean gestational age was significantly lower among HIV-1-infected (37 weeks) than among uninfected infants (38 weeks; P < .001). Infected infants had significantly higher rates of prematurity (gestational age less than 37 weeks) (33% vs 19%, P = .01) and extreme prematurity (gestational age less than 34 weeks) (18% vs 6%, P = .001) than uninfected infants. Infection was associated with lower birth weight (2533 g vs 2862 g, P < .001) and smaller head circumference (32.0 cm vs 33.1 cm, P = .001). HIV-1-infected infants were significantly more likely to be small for gestational age (26% vs 16%, P = .04) and low birth weight (less than 2500 g) (45% vs 29%, P = .006) than infants who were uninfected. Twenty-two (26%) HIV-1-infected children died during a median follow-up of 27.6 months (range 1.9 to 98.3 months). Prematurity was predictive of survival: by Kaplan-Meier, an estimated 55% (95% confidence interval, 31% to 72%) of preterm infected children survived to 24 months compared with 84% (95% confidence interval, 70% to 92%) of full-term infected children (P = .005).
Infants born to women with AIDS are at higher risk for HIV-1 infection than are infants born to HIV-1-infected women with AIDS not yet diagnosed. Women receiving zidovudine appear less likely to transmit HIV-1 to their infants. Significantly higher rates of prematurity and intrauterine growth retardation were found among HIV-1-infected infants than among those in the uninfected, HIV-1-exposed control group. Prematurity was associated with shortened survival in HIV-1-infected infants. Measures of intrauterine growth and gestation appear to be important predictors of HIV-1 infection status for seropositive infants and of prognosis for the infected infant.
Modeling studies revealed that progesterone, testosterone, and estradiol are stereochemically complementary to the cavity formed between base pairs in the DNA sequence, 5'-dTdG-3' X 5'-dCdA-3'. Each ...steroid aligned precisely with the topography of the cavity and formed 2 stereospecific hydrogen bonds linking phosphate oxygens on adjacent DNA strands. Hydrogen bonding donor-acceptor relationships were different for each hormone. The remarkable stereochemical specificity of the hormone-DNA complexes was demonstrated by the lack of complementarity of steroid enantiomers and steroid analogs having alternate ring systems and/or changes in the position of functional groups. Fit of molecules into DNA in the manner of the parent hormone correlated with biological activity. Antagonists also fit into the cavity but differed from agonists in their hydrogen bonding linkages to DNA and/or extended out of the cavity beyond the helix. Unlike flat intercalating agents which form stable complexes with DNA, wedge shaped steroids may thus be capable of forming reversible sequence-specific complexes with DNA. We conclude that the stereochemistry of DNA can be used to predict hormonal activity.
This analysis sought to identify characteristics of pregnant human immunodeficiency virus type 1 (HIV-1)-infected women that predict mother-to-child HIV-1 transmission. Pregnant and immediately ...postpartum women at risk for HIV were enrolled at obstetric and pediatric care settings in New York City from 1986 to 1992. Demographic and behavioral characteristics, clinical illness, T lymphocyte subsets, immunoglobulin concentration and syphilis serology were collected on the women. Infants were followed to determine HIV infection classification according to Centers for Disease Control and Prevention criteria for HIV-1 in children. Transmission rates were calculated for women who gave birth more than 15 months before the analysis. Of 172 HIV-1-infected women with known outcome 49 (28%) had infected infants. The transmission rate (TR) was significantly higher among women with < 280 CD4+ cells/microliters (lowest CD4+ quartile) than with CD4+ counts > 280 (48% vs. 22%; P = 0.004; odds ratio, 3.4; 95% confidence interval (1.5, 7.8)); a similar trend was seen by CD4+% quartile. No difference in TR was seen comparing women by CD8+ count quartile but marginally higher TR was seen among women with CD8+% > or = 51% than with CD8+% < 51% (TR = 41% vs. 24%; P = 0.076; odds ratio, 2.2; confidence interval (1.0, 5.1)). The highest TR, 62% was seen in women with both CD8+ count above the median and CD4+ count in the lowest quartile. No significant difference in TR was seen between women with and without HIV-related illness, although the TR was 53% among women hospitalized in the previous year for pneumonia compared with 25% in others (P = 0.03). TR was somewhat lower in women who delivered by cesarean section than vaginally (entire cohort: 18% vs. 32%, P = 0.11; prenatal enrollees only, 17% vs. 38%, P = 0.045). No factor or combination of factors was both highly sensitive and specific for predicting mother-to-child HIV transmission. A possible relationship between transmission and mode of delivery deserves further investigation.
A simplified human immunodeficiency virus 1 (HIV-1)-specific IgA capture enzyme immunoassay (IgA-CEIA) was evaluated and compared with IgA-Western blot assay for early diagnosis of HIV-1 infection in ...infants born to seropositive women. A total of 232 coded sera collected prospectively from 70 infants were tested. All 25 sera from 10 HIV-1-negative infants born to seronegative mothers (negative controls) were negative by both assays. All 111 sera from 37 seroreverting, uninfected infants were negative by IgA-CEIA (specificity, 100%), whereas 110 of 111 sera were negative by IgA-Western blot assay (specificity, > 99%). Overall IgA-CEIA detected HIV-IgA in 20 (87%) of 23 infected infants, and IgA-Western blot assay detected HIV-IgA in 21 (91.3%) of 23 infants; specimen-wise agreement between the 2 assays was > 80%. Analysis of results by age group indicated that after 2 months of age both assays were equivalent with sensitivity ranging from 60 to 80%. Quantitative data provided by IgA-CEIA suggests that the bulk of HIV-1 IgA synthesis in most HIV-1-infected infants occurs after 2 months of age.
The isolated cultured rat lens has been used to examine the effects of the aldose reductase inhibitor sorbinil on lenticular polyol accumulation and sugar cataract formation. Lenses incubated in ...medium containing 35 mmol/L glucose accumulated sorbitol over a seven-day period without the appearance of overt opacities. Sorbitol accumulation was inhibited in a dose response fashion by sorbinil with an IC50 of 3.1 X 10(-6) mol/L. In lenses incubated in the presence of 29.5 mmol/L xylose, xylitol accumulation was accompanied by an increase in the water content of the lens and the development of a classical sugar cataract. All of these effects could be prevented by the addition of sorbinil to the culture medium. Complete inhibition of cataract formation required greater than an 80% inhibition of the xylitol accumulation. Reversal of a preformed xylose cataract by sorbinil could be achieved if the inhibitor was added at the stage of cortical opacities (20 h). Cataract progression proceeded normally over the next 48 hours and then the lens slowly began to clear. The rate of the reversal was dependent on the dose of sorbinil.
We have used a human immunodeficiency virus type 1 (HIV-1)-specific IgG-Fc capture enzyme immunoassay (IgG-CEIA) to elucidate the dynamics of HIV-1 maternal antibody decay and de novo synthesis of ...HIV-1 antibodies in infants. Two hundred and thirty-nine serum specimens from 77 infants were analyzed by the IgG-CEIA and by two different conventional EIAs. With the IgG-CEIA, IgG was captured by an anti-human IgG monoclonal antibody (3C8) that reacts with all subclasses and was detected by recombinant HIV-1 envelope protein (CBre3)-peroxidase conjugate. Unlike the conventional EIAs, the IgG-CEIA showed a rapid decay of HIV-1-specific antibody in uninfected infants, with decline to background levels by 6 months (T1/2 half-life = 28-30 days). All 69 specimens collected from 39 uninfected infants between 6 and 15 months of age were negative by IgG-CEIA. However, HIV-1 antibodies remained high in infected infants; 20/22 infants (90.9%) with specimens between the ages of 6 to 23 months were positive by IgG-CEIA. Subtracting mean IgG-CEIA optical density values of seroreverting infants from those of HIV-1-infected infants in corresponding age groups provided a model for seroconversion in infected infants, with detectable IgG antibody synthesis starting about 3 months after birth. The IgG-CEIA may be a simple and important tool for early diagnosis of HIV-1 infection in infants at 6 months of age.
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Excavation of the Schöningen lignite mine in Germany produced the earliest examples of hunting spears to date, and a large assemblage of anthropogenically fragmented faunal remains deposited in ...anaerobic lacustrine silt sediments during the Middle Pleistocene. The exceptional preservation of the assemblage makes the site of prime importance to our understanding of the behavioural, social and economic patterns of hominins in the Lower Palaeolithic of the Middle Pleistocene in Europe. This chapter describes the digital refitting analysis, part of the AHRC-funded Fragmented Heritage project, undertaken to address the logistical challenge posed by manually comparing individual bone fragments within the assemblage to identify refitting sequences. This logistical refit challenge uses the Schöningen assemblage to investigate the effectiveness of a digital refit approach to the analysis of large faunal assemblages. We describe the process from digitisation of the bone fragments by macro structured light scanning, digital segmentation of refitting surfaces, and digital comparison of the refitting and non-refitting surfaces to produce statistical matches. We discuss how taphonomic data can be visualised from the analysis and can be used to inform interpretation of the taphonomic histories of these faunal remains and the human behaviours associated with the formation of this unique assemblage.
The research was funded through an AHRC doctoral award as part of the AHRC Digital Transformations funded Theme Large Grant Fragmented Heritage (AH/L00688X/1) and through in-kind contributions from MONREPOS.
