Retinoic acid inhibits the infectivity and growth of Chlamydia pneumoniae in epithelial and endothelial cells through different receptors

Chlamydia pneumoniae is a human respiratory pathogen that has also been associated with cardiovascular disease. C. pneumoniae infection accelerates atherosclerotic plaque development in hyperlipidemic animals and promotes oxidation of low density lipoprotein in vitro. All-trans-retinoic acid (ATRA), an antioxidant, has been shown to inhibit C. pneumoniae infectivity for endothelial cells by preventing binding of the organism to the M6P/IGF2 receptor on the cell surface. This current study investigates whether ATRA similarly affects C. pneumoniae infectivity of epithelial cells, which are the primary site of infection in the respiratory tract, and the effects on intracellular growth in both endothelial and epithelial cells. Because ATRA binds to both the nuclear retinoid acid receptor (RAR) and the M6P/IGF2 receptor, 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid (TTNPB), an ATRA analog, which binds to the RAR but not the M6P/IGF2 receptor was used to differentiate the receptor mediating the effects of ATRA. The results of this study showed two separate effects of ATRA. The first effect is through interaction with the M6P/IGF2 receptor on the cell surface preventing attachment of the organism (inhibition by ATRA but not TTNPB) in endothelial cells and the second is through the nuclear receptor (inhibition by both ATRA and TTNPB) which inhibits growth in both epithelial and endothelial cells.     

Toxicological profile of cereulide, the Bacillus cereus emetic toxin, in functional assays with human, animal and bacterial cells.

Some strains of the endospore-forming bacterium Bacillus cereus produce a heat-stable ionophoric peptide, cereulide, of high human toxicity. We assessed cell toxicity of cereulide by measuring the toxicities of crude extracts of cereulide producing and non-producing strains of B. cereus, and of pure cereulide, using cells of human, animal and bacterial origins. Hepatic cell lines and boar sperm, with cytotoxicity and sperm motility, respectively, as the end points, were inhibited by 1 nM of cereulide present as B. cereus extract. RNA synthesis and cell proliferation in HepG2 cells was inhibited by 2 nM of cereulide. These toxic effects were explainable by the action of cereulide as a high-affinity mobile K+ carrier. Exposure to cereulide containing extracts of B. cereus caused neither activation of CYP1A1 nor genotoxicity (comet assay, micronucleus test) at concentrations below those that were cytotoxic (0.6 nM cereulide). Salmonella typhimurium reverse mutation (Ames) test was negative. Exposure of Vibrio fischeri to extracts of B. cereus caused stimulated luminescence up to 600%, independent on the presence of cereulide, but purified cereulide inhibited the luminescence with an IC(50% (30 min)) of 170 nM. Thus the luminescence-stimulating B. cereus substance(s) masked the toxicity of cereulide in B. cereus extracts to V. fischeri.     

Cognitive performance in relation to vitamin status in healthy elderly German women-the effect of 6-month multivitamin supplementation

BACKGROUND: Prior investigations have reported a link between poor status of antioxidants, folate, and cobalamin resulting in elevated total plasma homocysteine (tHcy) and methylmalonic acid (MMA) concentrations with an increased risk for reduced cognitive performance. The aim of the study was to evaluate the effect of a 6-month multivitamin supplementation on the cognitive performance of female seniors and to assess cognitive functioning in relation to vitamin status, tHcy, and MMA values at baseline. METHODS: The study was performed as a randomized placebo-controlled double-blind trial. 220 healthy, free-living women (aged 60-91 years) were included. Blood drawings and cognitive tests were performed at the Institute of Food Science of the University of Hanover, Germany. Vitamin and cognitive status have been evaluated prior to and 6 months after supplementation. Plasma ascorbic acid, serum concentrations of alpha-tocopherol, beta-carotene, and coenzyme Q10, serum and erythrocyte folate as well as serum cobalamin, serum MMA, and plasma tHcy concentrations were measured. Activity coefficient of erythrocyte alpha aspartic aminotransferase was used as functional index for vitamin B(6) status. The cognitive performance was assessed by the Symbol Search test, a subtest of the Wechsler Adult Intelligence Scale (WAIS-III) and the pattern-recognition test. Intelligence as assessed by the 'Kurztest für Allgemeine Intelligenz' (KAI) was a further variable. RESULTS: No significant differences in pattern-recognition and intelligence score were observed between vitamin and placebo group prior to and after multivitamin supplementation. In the Symbol Search test, the vitamin group exhibited better test results than the placebo group at both measure points. One-way ANOVA showed a marginally significant linear trend between the baseline tHcy concentration and the pattern-recognition score (P = 0.051) in the total sample. Multiple backward regression revealed only a significant influence of the school graduation on baseline cognitive function test results. A general linear model showed that the changes in cognitive function scores could not be explained by the type of treatment or blood parameters. CONCLUSIONS: Our data indicate that 6 months supplementation of physiological dosages of antioxidants and B vitamins have no effect on cognitive performance in presumedly healthy and well-nourished female seniors. An intervention period of only 6 months may be too short for improving cognitive performance in well-educated elderly women without dementia.     

Glycodelin responses to hyperinsulinaemic clamp vary according to basal serum glycodelin concentration

OBJECTIVE: Treatment with metformin, an insulin-lowering agent, increases serum glycodelin, a progesterone-regulated lipocalin protein of the reproductive axis that may play a role in foeto-maternal defence mechanisms. This finding led to the hypothesis that insulin might decrease serum glycodelin concentration. DESIGN, PATIENTS AND MEASUREMENTS: Euglycaemic hyperinsulinaemic clamp experiments (n = 50) were carried out on 28 women of reproductive age (range 25-47 years; mean +/- SEM 39 +/- 1.0 years), and the results were analysed with respect to their baseline serum progesterone (< 10 or > or = 10 nmol/l) and glycodelin (< 10 or > or = 10 microg/l, equivalent to < 357 or > or = 357 pmol/l) concentrations at the onset of the clamp. Ten clamp experiments were performed on five women wearing a levonorgestrel-releasing intrauterine device (IUD), and these were analysed as a separate group. RESULTS: Contrary to the hypothesis, no acute glycodelin-lowering effect of insulin was found in any of the groups studied. All the small rises in glycodelin levels detected during acute hyperinsulinaemia occurred in the comparisons of medians and not means, and all such changes took place within the limits seen in the women with no progesterone exposure. In the group with low progesterone/low glycodelin (n = 21), glycodelin showed a small but significant increase at 30 and 90 min of the clamp (P < 0.01). In the group with elevated progesterone/low glycodelin (n = 11), there was a slight glycodelin increase at 30 min (P < 0.05), whereas no increase was found in the group with elevated glycodelin levels (n = 8). In the clamp experiments on women with levonorgestrel-releasing IUD, the basal glycodelin level was low in all cases and, as in the other women with low glycodelin levels, glycodelin was slightly increased at 30, 60 and 90 min of hyperinsulinaemia (P < 0.01). CONCLUSIONS: The results rule out any acute glycodelin-reducing effects of insulin, although indirect long-term effects mediated by insulin on glycodelin secretion cannot be excluded.     

A syndrome with multiple malformations, mental retardation, and ACTH deficiency

We report on a patient with severe pre- and post-natal growth retardation, moderate mental retardation, microcephaly, unusual face with marked micrognathia and cleft palate, minor skeletal abnormalities, atrioseptal defect, hypospadias, hearing loss, and secondary adrenal insufficiency due to isolated ACTH deficiency diagnosed at 7 years of age. Family history was negative. Adrenal insufficiency is an uncommon feature in multiple malformation syndromes and may thus serve as a diagnostic handle for recognizing other possible patients with a similar syndrome.     

The incidence and survival of acute de novo leukaemias in Estonia and in a well defined region of Western Sweden during 1982-1996: a survey of patients aged 16-64 years

In the present work the incidence and survival of acute de novo leukaemias in two neighbouring countries, were studied retrospectively over three 5-year periods, 1982-1996. The aim was to compare the above variables, particularly with respect to political/socio-economic and environmental factors, in a well defined area of Sweden, the so-called Western Swedish Health Care Region, with Estonia. Population-wise the Western Swedish Region and Estonia are very similar; area-wise they are also well comparable. The present report covers only patients diagnosed between the ages of 16-64 years. The number of acute de novo leukaemias in the two regions was quite similar (Western Sweden n = 282 and Estonia n = 237). The age standardized incidence rate regarding total acute de novo leukaemias was slightly lower in Estonia than in Western Sweden (1.49/100,000 inhabitants/year for Estonia and 1.76 for Sweden, respectively), the difference being not statistically significant. However, the survival data for the two countries were highly different (P < 0.001). Thus, the relative survival for the total group of patients aged 16-64 years in Estonia at 1 year was 20.7% and at 5 years 3.6%, respectively. The corresponding figures for the Swedish patients were considerably higher, 65.2 and 29.4%, respectively. Further, the 5 year survival significantly (P < 0.05) increased for the Swedish patients over the 3 consecutive 5-year periods. No such improvement was recorded for the Estonian patients.     

Inhibition of cyclooxygenase-2 by NS-398 following hemorrhage and subsequent sepsis: no beneficial effects in either gender

BACKGROUND: Inhibition of cyclooxygenase-2 with a reduction of prostaglandin E(2)production by the specific antagonist NS-398 has been shown to have beneficial effects on immune function and survival in a trauma model. Immune function after experimental hemorrhagic shock and subsequent sepsis may be gender-related, with enhanced immunity and better survival in females. However, it remains unclear if the observed effect of NS-398 treatment is gender-related following hemorrhagic shock and subsequent sepsis. METHODS: Male and female CBA/J mice (age: 2-3 months) were subjected to hemorrhagic shock (35 +/- 5 mm Hg for 90 min and fluid resuscitation) or sham operation. At resuscitation and after 20 and 40 h each received either NS-398 10 mg/kg or placebo i.p. At 48 h after resuscitation, either splenocytes and peritoneal macrophages (pM phi) were harvested (n = 8 per group), or polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Following CLP, either 10-day survival (n = 15 per group) was determined or pM phi and splenocytes were harvested 4 h after CLP (n = 8 per group). Cytokine release of pM phi, and splenocyte proliferation and responsiveness in vitro were assessed. RESULTS: Treatment with NS-398 led to lower PGE(2) levels as compared to placebo-treated animals, reaching significance (p < 0.05) in males. Placebo-treated males had significantly depressed proinflammatory immune response (IL-1, IL-6, IL-2, IFN-gamma) after hemorrhagic shock and experienced further suppression by CLP (all, p < 0.05). In contrast, young females displayed unchanged cytokine release after hemorrhagic shock, but a comparable suppression following CLP. Treatment with NS-398 did not influence cytokine release nor survival. CONCLUSIONS: Despite a significant reduction of PGE(2) concentration, NS-398 treatment has no beneficial effects on cytokine release and survival in this model of hemorrhage and subsequent sepsis.     

Neuropsychological functions in variant Alzheimer's disease with spastic paraparesis

Few data exist on the effects of specific Alzheimer's disease (AD)-related mutations on cognitive function. We present neuropsychological test results in eight members of a large kindred with variant Alzheimer's disease (VarAD) due to a deletion of the presenilin 1 (PS-1) gene, encompassing exon 9. The disease was neuropathologically characterized by the presence of large, unusual, "cotton wool" plaques (CWP). Four surviving patients were prospectively tested, and retrospective neuropsychological data were collected from additional four deceased patients. The neuropsychological evaluation was based on tests of verbal and visual memory, abstract thinking, and visuoconstructive and spatial functions. In addition, psychiatric symptoms were evaluated. In four patients, brain glucose metabolism was examined by positron emission tomography (PET). PET showed temporoparietal hypometabolism typical of AD. In addition, variable patterns of hypometabolism (hemispherical asymmetry and occipital accentuation) were related to individual deficits of cognitive performance. However, all these early-onset patients (age range 43-63 years) with a deletion mutation of PS-1 gene showed prominent memory impairment and deficits in visuoconstructive and intellectual functions.