An analysis of the parental age effect for inv dup (15).

Parental ages and birth order were analysed in 16 sporadic cases of inv dup (15) using the method of Smith. A significant maternal age effect was apparent (dm = 5.989, SE 1.86; df = 2.02, SE 2.496; db = 0.138, SE 0.46).     

Effects of diphenylhydantoin and diazepam on hippocampal evoked responses

Diphenylhydantoin and diazepam were compared with regard to their effects on responses to single stimuli, and on post-tetanic potentiation of evoked potentials within the hippocampus of anaesthetized rats. Interhippocampal afferents to pyramidal cells were stimulated electrically, while extracellular field potentials were recorded at successive depths within the contralateral hippocampus. Recording electrodes penetrated perpendicularly from a surface point homotopic to the site of stimulation. The anticonvulsants (40 mg/kg diphenylhydantoin, 5 mg/kg diazepam), 30 min after intravenous infusion, depressed post-tetanic potentiation in the stratum radiatum. At these doses, responses to single stimuli were essentially unaltered. Doses nearer the toxic range (80 mg/kg diphenylhydantoin, 10 mg/kgdiazepam) also reduced post-tetanic potentiation in the stratum radiatum, but increased (up to 150%) post-tetanic potentiation recorded from granule cells in the area dentata. The results indicate that diphenylhydantoin and diazepam have: (1) selective actions on hippocampal post-tetanic potentiation which are site and dose dependent; (2) qualitatively similar end-effects on post-tetanic potentials in two hippocampal subregions; (3) minimal effects on responses to single stimuli at doses which depress or enhance hippocampal post-tetanic potentiation.     

Plasma and myocardial levels of cefonicid during open-heart surgery

To minimize the incidence of postoperative infections in patients undergoing open-heart surgery, antibiotics should maintain tissue concentrations greater than the minimal inhibitory concentration (MIC) for potential pathogens (eg, Staphylococcus) for the duration of the operation. The ability of cefonicid, a new β-lactamase-resistant parenteral cephalosporin, to attain plasma and myocardial levels greater than the MIC (4.8 to 5.0 μg/mL) for penicillin-resistant Staphylococci was assessed in 13 patients. Six patients were administered 1 g and seven patients were administered 2 g of cefonicid IM one hour prior to surgery. In all patients the plasma concentrations of the drug were determined at the start of surgery, 15 minutes after the patient was placed on cardiopulmonary bypass (CPB), and at the completion of CPB. In addition, the concentration of cefonicid was determined in a right atrial biopsy. It was found that both 1 g and 2 g of cefonicid administered one hour prior to surgery resulted in plasma and myocardial levels greater than the MIC for the organisms most frequently implicated in postoperative infections.     

Dendritic length in aged rats' occipital cortex: An environmentally induced response

The present investigation was the first to measure the lengths of dendrictic segments from aged animals in different environments to determine if the rates of retraction that occur with age can be influenced by the external environment. Our results show that the sixth-order segments, which represent the segments most distal to the cell body, are 86% longer in animals which have spent their final 30 days in an enriched environment compared with their littermates from standard laboratory conditions.     

Regulation of Hfe by stress factors in BV-2 cells

Mutations in the Hfe gene can be associated with the iron overload disorder known as hemochromatosis. A number of recent studies suggest that carrying an Hfe mutation is a risk factor or genetic modifier for Alzheimer's disease (AD). In AD, Hfe protein expression is induced on cells associated with neuritic plaques and on neurons in the periplaque area. In this study, the factors that may be responsible for induction of Hfe in AD brain were determined using BV-2 cells. Hfe expression was induced by serum deprivation, menadione and beta-amyloid. The labile iron pool was consistently decreased when Hfe expression increased. However, the changes in expression of Hfe appeared independent of the expression of transferrin receptor and ferritin. These data provide insight into the induction of Hfe in AD and indicate that Hfe expression may be a protective function to limit cellular iron exposure during cell stress. These results are the first in a series of studies to understand how mutations in Hfe can be a risk factor for AD.     

Humanizing mice: catching up with elusive B1 receptors

Bradykinin receptor activation plays an important role in pain arising following tissue inflammation, and recent studies have suggested that bradykinin B1 receptors in particular may be important in chronic pain related to arthritis and various neuropathies. The investigation of the function of the B1 receptors in vivo has been hampered by the lack of nonpeptide antagonists, and the development of such compounds made more difficult by the considerable species variation between human and rodent B1 receptors. In this issue, Fox and co-workers report the creation of a mouse that has had the human B1 gene inserted into the corresponding mouse locus, and they exploit this animal to study the effects of a novel, nonpeptide B1 receptor antagonist on measures of acute nociception and nociception following inflammation. By creating a platform that allows the study of human B1 receptors in vivo, these investigators have provided a tool to significantly advance the understanding of the kallikrein-kinin system in physiological and pathophysiological states.     

Determination of apoptosis, uracil incorporation, DNA strand breaks, and sister chromatid exchanges under conditions of thymidylate deprivation in a model of BER deficiency

Thymidylate synthase (TS) is an important target of several chemotherapeutic agents. During TS inhibition, dTTP levels decrease with a subsequent increase in dUTP. Uracil incorporated into the genome is removed by base excision repair (BER). BER has been hypothesized to play a role in the response to thymidylate deprivation, despite a lack of direct evidence. We previously found that beta-pol null murine fibroblasts were approximately six-fold more resistant than wild-type cells to raltitrexed, a folate-based inhibitor specific for TS. In this study, a number of endpoints were determined to understand the influence of BER and beta-pol during raltitrexed treatment. Raltitrexed induced apoptosis in wild-type cells to a greater extent than in beta-pol null cells. A PARP inhibitor decreased the sensitivity to raltitrexed, although the extent was not different between wild-type and beta-pol null cells. No evidence was seen for extensive strand break formation that preceded apoptosis, although raltitrexed induced more sister chromatid exchanges in wild-type cells. Increased levels of uracil in DNA were detected following treatment in wild-type and beta-pol null cells. However, uracil levels were only approximately two-fold higher in DNA from treated cells compared to untreated. Uracil DNA glycosylase activity was slightly higher in beta-pol null cells, although not sufficiently different to explain the difference in sensitivity to raltitrexed. Taken together, the data suggest that the sensitivity of the wild-type cells to raltitrexed is not associated with activation of PARP-1 dependent BER, extensive uracil incorporation into DNA and persistent strand breaks, but rather with changes suggestive of DNA recombination.     

Ozone-induced lung injury and sterile inflammation. Role of toll-like receptor 4

Inhalation of toxic doses of ozone is associated with a sterile inflammatory response characterized by an accumulation of macrophages in the lower lung which are activated to release cytotoxic/proinflammatory mediators that contribute to tissue injury. Toll-like receptor 4 (TLR4) is a pattern recognition receptor present on macrophages that has been implicated in sterile inflammatory responses. In the present studies we used TLR4 mutant C3H/HeJ mice to analyze the role of TLR4 in ozone-induced lung injury, oxidative stress and inflammation. Acute exposure of control C3H/HeOuJ mice to ozone (0.8ppm for 3h) resulted in increases in bronchoalveolar lavage (BAL) lipocalin 24p3 and 4-hydroxynonenal modified protein, markers of oxidative stress and lipid peroxidation. This was correlated with increases in BAL protein, as well as numbers of alveolar macrophages. Levels of surfactant protein-D, a pulmonary collectin known to regulate macrophage inflammatory responses, also increased in BAL following ozone inhalation. Ozone inhalation was associated with classical macrophage activation, as measured by increased NF-κB binding activity and expression of TNFα mRNA. The observation that these responses to ozone were not evident in TLR4 mutant C3H/HeJ mice demonstrates that functional TLR4 contributes to ozone-induced sterile inflammation and macrophage activation.