Effects of social stress and intrauterine position on sexual phenotype in wild-type house mice (Mus musculus)

Wild-type house mice were used to test the effect of intrauterine position on anogenital distance (AGD) and to verify whether crowding stress would masculinize female pups, developing at all intrauterine positions, as has been demonstrated in CF-1 mice stressed by restraint, heat, and light. Stress of crowding was documented by comparing aggressive behavior, litter birth weights, and plasma corticosterone levels among females in different densities. AGDs were recorded from pups born to females housed from day 12 to 19 of gestation either individually with their mate (nonstressed) or in one of two group-housed densities. Female pups from nonstressed dams positioned between two males in utero (2M females) had longer AGDs than females positioned between two females (0M females). AGDs of males from nonstressed dams did not differ on the basis of intrauterine position. Group-housed pregnant females in the higher of two densities had female pups with longer AGDs than female pups of other dams. However, variance in female pup AGD was no different among dams in different densities. These results extend to the wild house mouse previous findings in albino mice that intrauterine position influences sexual phenotype. In addition, social stress can induce masculinization of female pups in wild mice as physical stress has been shown to do in albinos. This suggests that intrauterine position effects and their modification by crowding stress can potentially influence the dynamics of wild house mouse populations.     

Bilateral simultaneous tubal sextuplets: pregnancy after in-vitro fertilization--embryo transfer following salpingectomy

The presence of a damaged tube has been suggested in recent studies to have a negative effect on in-vitro fertilization (IVF) outcome. Performing bilateral salpingectomy prior to IVF to maximize pregnancy rates may also result in unnecessary surgery. This case is also an example of the occurrence of interstitial pregnancy after salpingectomy. This unusual type of ectopic pregnancy must be kept in mind when evaluating a patient suspected of a possible early abnormal gestation after assisted reproductive technolologies.      

The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell- mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ- specific autoimmune disease.      

Effects of leflunomide on immune responses and models of inflammation

Conclusions Leflunomide is an antiphlogistic and immunomodulating agent that has been shown to be effective in preventing and healing autoimmune disorders and reactions leading to organ graft rejection. From our preliminary clinical data [4], we now have hopes that these effects, observed in experimental animals, can truly be transferred to humans.Although we are far from understanding the mode of action of leflunomide, we are slowly gathering some insight. A good many of the immunosuppressive effects of leflunomide can be attributed to the antagonistic effects it has on responses to many cytokines, most likely through receptor expression and signal transduction (tyrosine kinase inhibition). The inhibition of transplant rejection could be explained by interference with the activity of IL-2 and IL-4, i.e. the interference of cytotoxic T cell formation. Considering, further, that increased IL-3-like activity has been reported in autoimmune MRL/lpr mice [23], and that it is felt that this amplified activity may contribute to the pathology of their illness [23], then the interference of leflunomide with IL-3 may, together with the antagonistic activity of TRF and specifically IL-4, explain some of the disease modifying properties of this drug in animals with SLE-like and other autoimmune diseases. Also, interference with responses to IL-6 (Germann, personal communication) could be responsible for the suppression of acute-phase proteins observed in adjuvant-diseased rats [24].Our data concerning tyrosine kinase inhibition as a hypothetical mechanism for the non-cytotoxic and reversible antiproliferative activity of A77 1726 are in many ways, intriguing. First of all, many known receptors for growth factors are associated with tyrosine kinase, i.e. EGF [35], IL-2 (the high binding, 75 kDa chain) [21], IL-3 [26], G-CSF, GM-CSF and TNF- [9]. Leflunomide antagonizes all of these mediators. On the other hand, IL-1, which is not antagonized by leflunomide, is not associated with tyrosine kinase, but with threonine and serine kinase [11]. Much more work must be conducted before we can be sure that tyrosine kinase inhibition is important for the mode of action of leflunomide.Another important aspect of this drug is its inhibitory effect on the release of histamine from basophils and mast cells, because of its role in inflammatory reactions. Relating to our findings on the activity of leflunomide on murine SLE-like disorders, it has been reported recently that SLE patients often exhibit abnormal production of antibodies to IgE, and that these autoantibodies may, by activating mast cells and basophils, play a consequential part in the release of vasoactive amines, thus leading to generalized tissue injury [15].We are confident that leflunomide will prove to be an effective drug in combating human autoimmune disorders. Indeed, we already have preliminary evidence for this, from studies of its effects on humans suffering from autoimmune diseases. Moreover, this drug provides a tool for gaining new insights into both the mechanisms leading to such ailments and their therapeutic control, and as such may facilitate the discovery of even more proficient drugs or other means to modulate these malfunctioning immune reactions.     

IL-10 has a protective role in experimental autoimmune uveoretinitis

The role of IL-10 in the regulation of ocular autoimmune disease was studied in experimental autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN- gamma. A concomitant treatment with IL-4 further reduced disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the autoimmune response towards a non-pathogenic Th2 pathway.      

Natural killer cell activity and antibody-dependent cellular cytotoxicity in patients under various immunosuppressive regimens

The influence of various modes of immunosuppression using cyclosporin A (CyA), corticosteroids (Cort), azathioprine (AZA), and antithymocyte globulin (ATG) alone or in combination with each other upon natural killer (NK) cell activity and antibody-dependent cellular cytotoxicity (ADCC) was assessed. CyA given alone did not influence either NK or ADCC activity; in contrast, the administration of Cort resulted in a significant decline (P less than 0.01) of ADCC but not of NK activity (P greater than 0.1). The combination of the two drugs led to a significant impairment of NK activity (P less than 0.01). The combination of AZA and Cort was found to produce an even more pronounced reduction in NK activity compared to both healthy controls (P less than 0.001) as well as patients from the CyA + Cort group (P less than 0.001). A similar decrease was found also after the addition of ATG to CyA + Cort (P less than 0.001, compared both with patients on CyA + Cort and with controls). In these instances, ADCC showed an overall similar pattern. We conclude that the administration of either CyA or Cort does not influence NK activity, while the combination of CyA with Cort and of AZA with Cort leads to a decrease in both NK and ADCC activities. The monotherapy with Cort only leads to a reduction of ADCC. These findings may explain the higher incidence of malignancies in patients undergoing combined immunosuppressive treatment.     

Decline in perinatal HIV transmission in New York State (1997-2000)

BACKGROUND: Perinatal HIV transmission has declined significantly in New York State (NYS) since implementation of a 3-part regimen of zidovudine prophylaxis in the antenatal, intrapartum, and newborn periods. This study describes the factors associated with perinatal transmission in NYS from 1997 to 2000, the first 4 years of NYS's comprehensive program in which all HIV-exposed newborns were identified through universal HIV testing of newborns. METHODS: This population-based observational study included all HIV-exposed newborns whose infection status was known and their mothers identified in NYS through the universal Newborn HIV Screening Program (NSP) from February 1997 to December 2000. Antepartum, intrapartum, newborn, and pediatric medical records of HIV-positive mothers/infants were reviewed for history of prenatal care, antiretroviral therapy (ART), and infant infection status. Risks associated with perinatal HIV transmission were examined. RESULTS: Perinatal HIV transmission declined significantly from 11.0% in 1997 to 3.7% in 2000 (P < 0.05). Prenatal ART was associated with a decline in perinatal HIV transmission both for monotherapy (5.8%, relative risk [RR] = 0.3, 95% confidence interval: 0.2%-0.5%) and combination therapy [2.4%, RR = 0.1, 95% confidence interval: 0.1%-0.2%) compared with no prenatal antiretroviral prophylaxis (P < 0.05). CONCLUSIONS: Public health policies to improve access to care for pregnant women and advances in clinical care, including receipt of appropriate preventive therapies, have contributed to declines in perinatal HIV transmission in NYS.