Long-term effects of prenatal stress on HPA axis activity in juvenile rhesus monkeys

The effect of stress to the pregnant mother on hormonal responses of the offspring to stressful events was investigated in juvenile rhesus monkeys. Six pregnant monkeys were repeatedly removed from their home cages and exposed to unpredictable noise during mid- to late gestation (Days 90–145 postconception), while six undisturbed pregnant mothers served as controls. Blood samples were collected from the juvenile offspring under anesthesia on four occasions and assayed for ACTH and cortisol. In a second experiment, blood samples were collected from the awake offspring under a baseline and four progressively stressful conditions. Offspring of stressed mothers showed higher ACTH and cortisol levels than control offspring at all four anesthesia samples and at a nonanesthesized home cage baseline. Prenatally stressed offspring also showed higher ACTH values in all four stress conditions. Cortisol values were similar for the two groups under the stress conditions. The disparity between the two groups in the relationship between ACTH and cortisol was greatest in the most stressful condition, suggesting regulatory differences between the two groups. These results indicate that offspring of primate mothers stressed during pregnancy show enhanced HPA axis responsivity to stressors later in life, and concur with rodent findings indicating that prenatal stress may have long-term effects on HPA axis regulation. © 1994 John Wiley & Sons, Inc.     

Microwear phenomena of ultrahigh molecular weight polyethylene cups and debris morphology related to gamma radiation dose in simulator study

Ultrahigh molecular weight polyethylene (PE) cups with 0, 2.5, 50, 100, and 150 Mrad radiation treatments were run in a hip simulator for comparison of the microwear phenomena on the cup surfaces with the corresponding debris morphology. In general, the size and frequency of the PE surface fibrils and the size of the retrieved PE debris decreased with increasing radiation dose. The fibril size and shape on the cup surfaces were well correlated with the radiation dose. The fibrillar shape and size were found to be proportional to the square root of the radiation dose. However, the trend for size and shape factors of the wear debris related to the radiation dose was weak at best. Thus, the morphology of the PE fibrils on the cup surfaces was more sensitive to variations in the radiation dose than the actual wear debris. The wear response appeared to be a three-step process, which was dependent on the formation of surface nodules or ripples, the teasing out of surface fibrils, and the toughness of the PE matrix in releasing a wear fibril to form a debris particle. The tougher PE became with increasing radiation dose, the harder it was for the PE fibrils to break out into wear particles.     

Molecular epidemiology of pneumococcal colonization in response to pneumococcal conjugate vaccination in children with recurrent acute otitis media

A randomized double-blind trial with a 7-valent pneumococcal conjugate vaccine was conducted in The Netherlands among 383 children, aged 1 to 7 years, with a history of recurrent acute otitis media. No effect of vaccination on the pneumococcal colonization rate was found. However, a shift in serotype distribution was clearly observed (R. Veenhoven et al., Lancet 361:2189-2195, 2003). We investigated the molecular epidemiology of 921 pneumococcal isolates retrieved from both the pneumococcal vaccine (PV) and control vaccine (CV) groups during the vaccination study. Within individuals a high turnover rate of pneumococcal restriction fragment end labeling genotypes, which was unaffected by vaccination, was observed. Comparison of the genetic structures before and after completion of the vaccination scheme revealed that, despite a shift in serotypes, there was clustering of 70% of the pneumococcal populations. The remaining isolates (30%) were equally observed in the PV and CV groups. In addition, the degree of genetic clustering was unaffected by vaccination. However, within the population genetic structure, nonvaccine serotype clusters with the serotypes 11, 15, and 23B became predominant over vaccine-type clusters after vaccination. Finally, overall pneumococcal resistance was low (14%), and, albeit not significant, a reduction in pneumococcal resistance as a result of pneumococcal vaccination was observed. Molecular surveillance of colonization in Dutch children shows no effect of pneumococcal conjugate vaccination on the degree of genetic clustering and the genetic structure of the pneumococcal population. However, within the genetic pneumococcal population structure, a clear shift toward nonvaccine serotype clusters was observed.     

Evidence for association and epistasis at the DAOA/G30 and D-amino acid oxidase loci in an Irish schizophrenia sample.

The D-amino acid oxidase (DAO) signaling pathway has been implicated in schizophrenia pathogenesis. This may be mediated through modulation of NMDA function by DAO, which is in turn activated by DAO activator (DAOA, formerly G72). Chumakov et al. (2002); PNAS 99: 13675-13680, identifying the novel schizophrenia susceptibility gene DAOA/G30 and a number of independent studies have since reported evidence of association between the DAOA and DAO genes and schizophrenia. However, at least two studies have failed to replicate the epistatic interaction between these loci described in the original report and there have been differences in the associated alleles/haplotypes reported at each locus. In this study, we performed association and epistasis analyses of the DAOA/G30 and DAO loci in a sample of 373 cases with DSM-IV schizophrenia/schizoaffective disorder and 812 controls from the Republic of Ireland. Corrected for the number of tests performed, we found evidence for association between markers at both genes and schizophrenia: DAOA/G30 (P = 0.005, OR = 1.34 (1.09, 1.65)) and DAO (P = 0.003, OR = 1.43 (1.12, 1.84). The data suggest that evidence for association at DAO (marker rs2111902) is more consistent than previously realized, particularly in Caucasian schizophrenia populations. We identified evidence for epistatic interaction between the associated SNPs at DAOA and DAO genes in contributing to schizophrenia risk (OR = 9.3 (1.4, 60.5). Based on these data, more systematic investigation of genes involved in DAO signaling is required.     

Biased immunoglobulin variable region gene expression by Ly-1 B cells due to clonal selection

Most, if not all, autoantibodies specific for bromelain-treated mouse erythrocytes recognize the common membrane phospholipid, phosphatidyl choline (PtC). Anti-PtC antibodies are produced by 5%-15% of CD5+ Ly-1 B cells of normal unimmunized mice, but not by detectable numbers of conventional CD5- B cells. At 1 week of age PtC-specific B cells are undetectable but then increase dramatically over the next 3 to 4 weeks to reach adult numbers. We report here that PtC-specific Ly-1 B cells in B10.H-2aH-4bp/Wts mice predominantly express either of two heavy and kappa chain variable (V) region gene combinations. In addition, the sequence and length of DH genes are conserved among cells expressing the same V gene combination, and the V kappa-J kappa junctions of one group involve unusual splice sites. Preferential V gene rearrangement models are insufficient to explain the DH and V kappa-J kappa junctional sequences or the delayed appearance of this specificity, and so they cannot solely account for the high frequency of PtC-specific cells. These characteristics are more consistent with antigen selection. We therefore attribute the frequent use of the two V region gene combinations to selection for cells that express them and conclude that the expressed V gene repertoire of Ly-1 B cells in adult mice is influenced by antigen selection. Apparently, there is no selection for mutant anti-PtC antibodies of higher affinity during the formation of the Ly-1 B repertoire because the V region genes expressed by PtC-specific cells are unmutated. Our findings are consistent with an important, germ line-encoded function for the immunoglobulin products of these gene combinations.     

In vitro activity of the novel cephalosporin GR69153

The in vitro activity of GR69153 was compared to that of ceftazidime, ceftriaxone, imipenem and gentamicin against a total of 702 recent clinical isolates. MICs were determined by a standard agar dilution procedure and two inocula (10⁴ and 10⁸ cfu) were used throughout. GR69153 inhibited 90 % of isolates ofEscherichia coli, Klebsiella pneumonia andProteus mirabilis at 0.25 mg/l and 90 % of isolates ofPseudomonas aeruginosa at 1 mg/l.Citrobacter freundii (MIC90 16 mg/l),Morganella morganii (MIC90 128 mg/l) andEnterobacter spp. (MIC90>128 mg/l) were considerably more resistant to GR69153. GR69153 was four-fold more active than ceftazidime against methicillin-sensitiveStaphylococcus aureus but was inactive against methicillin-resistantStaphylococcus aureus, Enterococcus faecalis andBacteroides fragilis group.     

Conversion of isoaspartyl peptides to normal peptides: implications for the cellular repair of damaged proteins.

The hypothesis that cellular protein carboxyl-methylation reactions recognize altered aspartyl residues as part of a protein repair pathway has been tested in an in vitro system using tetragastrin (Trp-Met-Asp-Phe-NH2) as a model sequence. The L-isoaspartyl form of tetragastrin, where the phenylalanine residue is linked to the side-chain carboxyl group of the aspartate residue ([iso-Asp3]tetragastrin), is a substrate for the erythrocyte protein carboxyl methyltransferases, while the normal form is not. The enzymatically produced alpha-methyl ester of [iso-Asp3]tetragastrin, [iso-Asp(OMe)3]tetragastrin, is unstable at pH 7.4 and 37 degrees C and spontaneously demethylates with a half-time of 41 min to an intermediate L-succinimide form ([Asu3]tetragastrin) that, in turn, spontaneously hydrolyzes with a half time of 116 min to give a mixture of normal tetragastrin (20%) and [iso-Asp3]tetragastrin (80%). This sequence of enzymatic and nonenzymatic reactions can be coupled in a single reaction mixture; the [iso-Asp3]tetragastrin that is produced upon succinimide hydrolysis can reenter the reaction sequence by enzymatic methylation, and the net result of the process is the conversion of the isomerized peptide to the normal peptide. The efficiency of this "repair" reaction is limited by a side reaction of racemization at the alpha-carbon of the succinimide (half-time = 580 min). In a 24-hr time period, normal L-aspartyl-containing tetragastrin is obtained in about 50% yield from the coupled reaction mixture; other products include [D-iso-Asp3]tetragastrin and [D-Asp3]tetragastrin. The versatile chemistry of succinimide peptides suggests that methylated L-isoaspartyl sites (and possibly methylated D-aspartyl sites) in cellular polypeptides can eventually yield "repaired" normal L-aspartyl sites through succinimide intermediates.     

The natural history of sensitivity to jack jumper ants (Hymenoptera formicidae Myrmecia pilosula) in Tasmania

There are no records of the natural history of allergic reactions to "jack jumper ant" (Myrmecia pilosula) stings, but a letter to Tasmanian newspapers asked that persons who had not received prophylactic injections for such stings to report any reactions that they had experienced. Two hundred replies were received from a population of 400,000 persons, which shows that these reactions are widespread and that victims are often terrified at the thought of a further sting. Persons who responded were sent a circular and their reactions were classified. The first 100 replies were analysed: 49 persons reported an immediate generalized reaction from the first sting; 31 of these 49 persons and 18 others had a generalized reaction to further stings; and there was a tendency for local reactions at the sting site to become generalized to the whole body. Of the 15 persons who had had no reaction to a first sting, 12 claimed to have developed a generalized reaction on receiving a subsequent sting. Although self-selection may have provided an exaggerated view of the frequency with which reactions to the stings of jack jumper ants become generalized, the problem is clearly one of considerable magnitude which requires further research and attention.