Seasonal variation in human fecundability

Seasonality of effective fecundability was investigated in a cohort of 402 women born in or near Rotterdam, The Netherlands, between 1873 and 1887, and married before the age of 40 years. Applying a newly developed method allowing simultaneous control for inherent couple fecundability, numbers at risk of pregnancy, and multiple confounders, we found a trend towards higher fecundability during the first half of June and the first half of December (P = 0.06). Seasonality of effective fecundability appeared to be strongest for women who married at <20 years of age. Potentially important implications for the study of seasonality of adverse reproductive outcome are discussed.     

The HHQK domain of beta-amyloid provides a structural basis for the immunopathology of Alzheimer's disease

The beta-amyloid peptide 1-42 (Abeta1-42), a major component of neuritic and core plaques found in Alzheimer's disease, activates microglia to kill neurons. Selective modifications of amino acids near the N terminus of Abeta showed that residues 13-16, the HHQK domain, bind to microglial cells. This same cluster of basic amino acids is also known as a domain with high binding affinity for heparan sulfate. Both Abeta binding to microglia and Abeta induction of microglial killing of neurons were sensitive to heparitinase cleavage and to competition with heparan sulfate, suggesting membrane-associated heparan sulfate mediated plaque-microglia interactions through the HHQK domain. Importantly, small peptides containing HHQK inhibited Abeta1-42 cell binding as well as plaque induction of neurotoxicity in human microglia. In vivo experiments confirmed that the HHQK peptide reduces rat brain inflammation elicited after infusion of Abeta peptides or implantation of native plaque fragments. Strategies which exploit HHQK-like agents may offer a specific therapy to block plaque-induced microgliosis and, in this way, slow the neuronal loss and dementia of Alzheimer's disease.     

Therapeutic actions of cyclosporine and anti-tumor necrosis factor alpha in collagen-induced arthritis and the effect of combination therapy

OBJECTIVE: To define the mechanisms of action of 2 novel drugs, cyclosporine and anti-tumor necrosis factor alpha (TNFalpha), in collagen-induced arthritis and to determine the effect of combination therapy. METHODS: Type II collagen-immunized DBA/1 mice with established arthritis were treated with cyclosporine alone, anti-TNFalpha alone, cyclosporine plus anti-TNFalpha, or saline. RESULTS: Cyclosporine was found to ameliorate arthritis, suppress interferon-gamma (IFNgamma) production by CD4+ T cells, and reduce TNFalpha expression in arthritic joints. However, cyclosporine did not directly inhibit TNFalpha production by macrophages, indicating that the decrease in TNFalpha expression observed in vivo was probably an indirect consequence of the reduction in type 1 T helper cell activity. Anti-TNFalpha also reduced IFNgamma production by T cells, indicating that TNFalpha is involved in the cellular immune response to collagen. Combined treatment with cyclosporine plus anti-TNFalpha had an additive therapeutic effect. CONCLUSION: Although cyclosporine and anti-TNFalpha target different points in the inflammatory pathway, there is an overlap in the consequences of their actions in vivo.     

Effect of probucol on LDL oxidation and atherosclerosis in LDL receptor-deficient mice

Probucol is a powerful inhibitor of atherosclerosis in a number of animal models. However, it is unknown whether this is due to the strong antioxidant protection of low density lipoprotein (LDL), to antioxidant effects in the artery wall, or to cellular effects not shared by other antioxidants. To investigate whether murine models are suitable to study the antiatherogenic mechanisms of probucol, three experiments following different protocols were carried out in 135 male and female LDL receptor-deficient (LDLR-/-) mice. Treatment groups received a high (0.5%) or low (0.025%) dose of probucol, or low-dose probucol plus a high dose (0.1%) of vitamin E for periods ranging from 6 to 26 weeks. In all experiments, probucol strongly protected LDL against ex vivo oxidation (lag times exceeding 1400 min in 0.5% probucol-treated mice). Treatment with 0.5% probucol significantly lowered both HDL-cholesterol and plasma apolipoprotein (apo)A-I concentrations. In all three experiments, treatment with 0.5% probucol consistently increased the size of lesions in the aortic origin, from 1.3-fold (n.s.) to 2.9-fold (P < 0.05) in female mice and from 3.6- to 3.7-fold in males (P < 0.001). Even treatment with 0.025% probucol increased atherosclerosis 1.6-fold in male mice (P < 0.01). Addition of the high dose of vitamin E did not attenuate the pro-atherogenic effect of 0.025% probucol. In conclusion, probucol not only failed to decrease but actively increased atherogenesis in LDLR-/- mice in a dose-dependent manner, even though it provided a very strong antioxidant protection of LDL. This suggests that the reduction of atherosclerosis observed in other animal models is due to intracellular effects of probucol not found in mice, to differences in the metabolism of probucol, and/or to an overriding atherogenic effect of the decrease in HDL in murine models.     

Prostaglandin E2 induced polymerization of human alpha-1-antichymotrypsin and suppressed its protease inhibitory activity: implications for Alzheimer''s disease

Different molecular forms of alpha-1-antichymotrypsin (ACT) in sera and cerebrospinal fluids from patients with Alzheimer's disease (AD) were detected. Monomeric and polymeric ACT were observed by polyacrylamide gel electrophoresis of both sera and cerebrospinal fluids. ACT polymers were increased in AD patients with the apolipoprotein E (APOE) 4 allele. Increased levels of inactive ACT molecules were also detected in brain homogenates of patients with the APOE 4 allele. Experimental conditions promoting in vitro polymerization of ACT and the effect of polymerization on the biological activity of this serpin were also explored. Incubation of this serpin with prostaglandins of E series (PGE 2) induced ACT polymerization and decreased its activity. Amyloid beta-peptide1-42 did not significantly affected the biological activity of ACT. Inactivation of protease inhibitors by inflammatory molecules such as PGE 2 released from activated microglia in AD brains may promote amyloid deposition and neurodegeneration.     

Managed care, school health programs, and adolescent health services: opportunities for health promotion

The rapid expansion of managed care creates opportunities and dilemmas for those involved in school health and adolescent health promotion. Managed care organizations (MCOs), public health agencies, and school and adolescent health providers share certain common goals and priorities including an emphasis on prevention, cost-effectiveness, and quality of care--and a willingness to explore innovative approaches to health promotion and disease prevention. However, MCOs often face conflicting challenges, balancing the goals of cost containment and investment in prevention. In considering support for school health programs, MCOs will be interested in evidence about the effectiveness of services in improving health and/or reducing medical expenditures. Mechanisms for improving prevention efforts within MCOs include quality assurance systems to monitor the performance of health plans, practice guidelines from professional organizations, and the contracting process between payers and health care providers. Development of partnerships between MCOs and schools will be a challenge given competing priorities, variation in managed care arrangements, structural differences between MCOs and schools, and variability in services provided by school health programs.     

Resistance to Leishmania major is linked to the H2 region on chromosome 17 and to chromosome 9

In Leishmaniasis, as in many infectious diseases, clinical manifestations are determined by the interaction between the genetics of the host and of the parasite. Here we describe studies mapping two loci controlling resistance to murine cutaneous leishmaniasis. Mice infected with L. major show marked genetic differences in disease manifestations: BALB/c mice are susceptible, exhibiting enlarging lesions that progress to systemic disease and death, whereas C57BL/6 are resistant, developing small, self-healing lesions. F2 animals from a C57BL/6 X BALB/c cross showed a continuous distribution of lesion score. Quantitative trait loci (QTL) have been mapped after a non-parametric QTL analysis on a genome-wide scan on 199 animals. QTLs identified were confirmed in a second cross of 271 animals. Linkage was confirmed to a chromosome 9 locus (D9Mit67-D9Mit71) and to a region including the H2 locus on chromosome 17. These have been named Imr2 and Imr1, respectively.     

Oxidation of LDL to a biologically active form by derivatives of nitric oxide and nitrite in the absence of superoxide. Dependence on pH and oxygen

A key factor in atherogenesis is oxidation of LDL in the subendothelial space. In the normal vessel wall or in the thickened intima of diseased vessels, this space is rich in nitric oxide (NO.) released from endothelial cells, smooth muscle cells, and macrophages. To determine whether NO. has a role in LDL oxidation, we exposed human LDL to NO. under aerobic and anaerobic conditions and at acidic and neutral pH. Spectrophotometric detection of beta-carotene in the LDL was used as a marker for LDL oxidation. Depletion of beta-carotene was observed in LDL treated with NO. under aerobic conditions but not under anaerobic conditions. In contrast, treatment of LDL with sodium nitrite did not require oxygen for beta-carotene depletion, although depletion was increased when O2 was present. Furthermore, low pH greatly accelerated LDL oxidation by either NO. gas or by nitrite (NO2-). Depletion of beta-carotene corresponded with formation of conjugated dienes, increased susceptibility to further oxidation, and aggregation of apolipoprotein B-100, but did not increase electrophoretic mobility of LDL. Also, nitrite-oxidized LDL demonstrated biological properties similar to minimally oxidized LDL, including stimulation of monocyte adhesion and inhibition of lipopolysaccharide-induced neutrophil binding to endothelium. These results indicate that NO. under certain circumstances may contribute to oxidative modification of LDL and may have a role in atherogenesis.     

A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance

In the present study, we analyzed the cytokine network among TNFalpha, IL-1beta, IL-8, and IL-1 receptor antagonist (IL-1Ra) in a rabbit experimental model of acute gout. The production of TNFalpha in synovial fluids reached the peak at 2 hours after the intra-articular injection of monosodium urate (MSU) crystals. The production of IL-1beta and IL-8 reached the first peak at 2 hours and the second peak at 9 and 12 hours, respectively. The production of endogenous IL-1Ra reached the peak at 9 hours. The source of TNFalpha and the first phase of IL-8 was synovial cells, whereas infiltrating leukocytes were the source of the second phase of IL-8 and also of IL-1beta and IL-1Ra. The production of TNFalpha was not altered by either anti-lL-8 IgG or IL-1Ra. The first IL-1beta peak was reduced only with a combination of anti-TNFalpha mAb and anti-lL-8 IgG, whereas the second peak was significantly reduced by either inhibitor. The first IL-8 peak was not altered with anti-TNFalpha mAb or IL-1 Ra, whereas the second IL-8 peak was reduced with IL-1Ra. Anti-TNFalpha mAb or anti-lL-8 IgG significantly reduced the peak level of endogenous IL-1Ra. These cytokine inhibitors also attenuated the maximal leukocyte accumulation at 9 hours, but not the initial phase, which occurred within 2 hours. These results provide evidence that IL-8 and TNFalpha were responsible for the production of IL-1beta and IL-1Ra, and that IL-1beta was responsible for the second phase of IL-1beta and IL-8 production. Our data also suggest that the initial and the maximal phases of leukocyte influx are differently regulated. Finally, the intravenous injection of colchicine inhibited neutrophil infiltration without affecting the production of TNFalpha or the first peak of IL-8, suggesting that colchicine inhibits MSU crystal-induced arthritis by directly inhibiting the migration of neutrophils.