The involvement of interdigitating (antigen-presenting) cells in the pathogenesis of rheumatoid arthritis.

Macrophage like cells expressing high concentrations of HLA-DR antigen have been identified in situ within the synovium of patients with rheumatoid arthritis. The characteristics of these cells have been determined using immunohistological analysis and combined cytochemical techniques. It was found that the majority (greater than 80%) of these cells were interspersed within the perivascular lymphocytic infiltrates occurring in the synovium. These cells did not stain with antisera against surface immunoglobulin or any Mc Abs to T lymphocyte markers. Further combined staining demonstrated that the HLA-DR + ve cells did stain with an anti-monocyte monoclonal (FMC-17), but could not be stained with a Mc Ab against C3b receptors. The interfacing of cytochemical reactions for acid phosphatase (ACP) and adenosine triphosphatase (ATPase) with immunofluorescence staining for HLA-DR demonstrated that these cells were ACP - ve ATPase + ve. This analysis led to the conclusion that the HLA-DR + ve cells found in abundance in the rheumatoid synovium expressed identical characteristics to the interdigitating cells of the normal lymph node paracortex. The possible significance of the presence of large numbers of such antigen presenting cells in the rheumatoid synovium is discussed.     

IMPT1, an imprinted gene similar to polyspecific transporter and multi- drug resistance genes

Human chromosome 11p15.5 and distal mouse chromosome 7 include a megabase-scale chromosomal domain with multiple genes subject to parental imprinting. Here we describe mouse and human versions of a novel imprinted gene, IMPT1 , which lies between IPL and p57 KIP2 and which encodes a predicted multi-membrane-spanning protein similar to bacterial and eukaryotic polyspecific metabolite transporter and multi- drug resistance pumps. Mouse Impt1 and human IMPT1 mRNAs are highly expressed in tissues with metabolite transport functions, including liver, kidney, intestine, extra-embryonic membranes and placenta, and there is strongly preferential expression of the maternal allele in various mouse tissues at fetal stages. In post-natal tissues there is persistent expression, but the allelic bias attenuates. An allelic expression bias is also observed in human fetal and post-natal tissues, but there is significant interindividual variation and rare somatic allele switching. The fact that Impt1 is relatively repressed on the paternal allele, together with data from other imprinted genes, allows a statistical conclusion that the primary effect of human chromosome 11p15.5/mouse distal chromosome 7 imprinting is domain-wide relative repression of genes on the paternal homolog. Dosage regulation of the metabolite transporter gene(s) by imprinting might regulate placental and fetal growth.      

Comparative virulence of blood and stool isolates of Shigella sonnei.

Shigellemia is rare in developed countries and might result from the emergence of unusually virulent strains. We compared systemic invasiveness markers of isolates from the blood of 3 temporally clustered patients with Shigella sonnei bacteremia in Boston with those of 11 unrelated contemporaneous strains from stools of people in New England. We found no difference between the two groups in O-chain length by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, mouse 50% lethal dose, in vivo response to iron, and susceptibility to serum, which varied from moderately susceptible to ultrasusceptible. Mean intraperitoneal 50% lethal doses of smooth form I colonies for mice were equally low (10(5.8) CFU) in both groups, and the 50% lethal doses were lowered equally further in the two groups by predosing with iron to levels useful in mouse model sepsis studies. S. sonnei bacteremia may reflect compromised host defenses, not bacterial virulence.     

Gene conversion,unequal crossing-over and mispairing at a non-tandem duplication during meiosis of Saccharomyces cerevisiae

Summary We have developed a novel system to examine conversion, exchange and mispairing involving a nontandem duplication of the ade8 locus in yeast by monitoring the segregation of heterozygous markers between the duplicated sequence. Plasmid Yrp 17 carries the yeast selectable markers URA3 ⁺ and TRP1 ⁺. Yrpl7 derivatives with a 4 kb insert carrying ade8-18 were used to clone the mutations trpl-1 and ura3-1 by gap repair. Integrants of the resulting plasmids at the Ade8 locus were crossed to yield diploid hybrids with a non-tandem duplication of Ade8 and heterozygosity for the plasmid markers between the duplicated sequences. 1192 complete, unselected asci were analyzed and 270 exhibiting recombination of the markers contributed by the plasmid were analyzed by Southern transfers to detect changes in plasmid sequences. Twenty-seven tetrads had unequal homologous exchanges and five had unequal sister-chromatid exchanges. Seven tetrads carry an additional copy of the integrated plasmid and ten are missing one. We propose that these two classes represent conversions of the entire 11 kb plasmid, which occur after misalignment and formation of an unpaired loop. Mispairing is a frequent event, and occurs in approximately fifty percent of all meioses. The system described provides a means to determine the meiotic rules of conversion, exchange and pairing for duplicated DNA sequences.     

Behavioral and hormonal responses to stress in the newborn mouse: Effects of maternal deprivation and chlordiazepoxide

These studies investigated behavioral and hormonal responses to stress in developing mice. Experiment 1 examined the effects of 24-hr maternal deprivation on corticosterone (CORT) secretion and ultrasonic vocalization (UVZ) rate in 4-, 8-, and 12-day-old mice. At these ages, exposure to a novel environment resulted in minimal changes in CORT secretion. Maternal deprivation increased pups′ CORT secretion in an age-dependent fashion but did not affect their UVZ rate. The aim of experiment 2 was to test the effects of cholordiazepoxide (CDP), an anxyolytic compound, on CORT secretion and UVZ in both normally reared and in maternally deprived 8-day-old mice. CDP administration elevated CORT increases in deprived (DEP) animals. CDP affected UVZ only in nondcprived (NDEP) animals: UVZ ratewas decreased by high CDP doses Overall, these findings demonstrate that the infant mouse shows a period of stress hyp9oresponsiveness similar to the rat and that maternal presence contributes to inhibit adrenocorticalactivity. CDP administration, butnot novelty exposure, increased CORT secretion in 8-day- old normally reared mice suggesting that during the stress hyporesponsive period, the HPA axis is capable of responding only to specific stimuli. Changes in HPA axis activity and UVZ rateresulting from maternal deprivation and/or CDP challenge do not seem to be directly related. ©1994 John Wiley & Sons, Inc.     

Mental illness in the biological and adoptive families of adopted individuals who have become schizophrenic

In a sample of 5483 adults who had been legally adopted early in life by persons not biologically related to them, 33 were identified, from mental hospital records, for whom a diagnosis of definite schizophrenia (chronic, latent, or acute) could be agreed upon by four raters. An equal number of matched controls were selected from the sample of adopted individuals who had never been admitted to a mental hospital. Ninety percent of the living parents, siblings, and half-siblings, biological and adoptive, cooperated in an extensive psychiatric interview permitting a consensus diagnosis by three blind raters. Schizophrenia and uncertain schizophrenia were found to be significantly concentrated in the population genetically related to the schiziphrenic adoptees. Their adoptive relatives did not differ from the control populations in the prevalence of schizophrenic illness.This was presented at the Annual Meeting of the American Society of Human Genetics, Portland. Oregon, October 18, 1974.     

Maternal pituitary-adrenal responsiveness as a function of differential treatment of rat pups

The effects of litter separation and pup treatment on the maternal pituitary-adrenal system were investigated in 3 experiments. Lactating females did not show a pituitary-adrenal response to separation from their pups. However, the lactating females showed an increase in plasma corticosterone when their pups had been briefly removed and then returned. If, in addition, the pups were subjected to a noxious stimulus (electric shock) during the 2-min separation, mothers showed a further increase in corticosterone. When pups were returned after 3 hr of separation, mothers again showed a differential pattern of corticoid responsiveness. The magnitude of the mother's pituitary adrenocortical response depended upon the intensity of treatment given to the pups. These data lend physiological support to behavioral studies which have shown that maternal behavior is differentially influenced by pup-produced stimuli.