Relationships between cardiovascular risk factors and white-coat hypertension diagnosed by home blood pressure recordings in a middle-aged population.

OBJECTIVE: To study risk in white-coat hypertension (WCH) by measurement of coronary artery calcium score (CACS), carotid--femoral pulse-wave velocity (PWV) and carotid plaques. METHODS: Cross-sectional population-based cohort with randomized selection of participants from Linköping, Sweden. An Omron m10-IT oscillometric device was used for clinic and home blood pressures (HBP) in the morning and evening for 1 week. RESULTS: We recruited 5029 middle-aged and mainly defined WCH as SBP at least 140 mmHg and/or DBP at least 90 mmHg with HBP less than 135/85 mmHg. There were 2680 normotensive participants and 648 had WCH after exclusion of treated participants. More women (59.5%) than men (42.8%, P < 0.001) had WCH. We found higher prevalence of CACS greater than 100 compared with less than 100 (12.4 vs. 7.2%, P < 0.001), PWV (11.5 ±â€Š1.5 vs. 10.4 ±â€Š1.3 m/s, P < 0.001) and a higher prevalence of one or more carotid plaques (59.5 vs. 48%, P < 0.001) in participants with WCH than in normotension. Participants with WCH also had more dyslipidemia and higher glucose levels. Normotensive women scored lower on nervousness than women with WCH (P = 0.022). After matching of 639 participants with WCH to normotensive participants according to age, gender and systolic HBP the prevalence of a high CACS (12.1 vs. 8.6%, P = 0.003,) PWV (11.0 ±â€Š0.068 vs. 11.5 ±â€Š0.068 m/s, estimated marginal means ±â€ŠSE, P < 0.001 by ANOVA) but not more carotid plaques (59.5 vs. 55.6%, P = 0.23), remained in the participants with WCH compared with the matched normotensive participants. CONCLUSION: WCH is particularly common in middle-aged women, and it displays metabolic dysfunction and increased prevalence of arteriosclerotic manifestations in both genders. As markers of increased cardiovascular risk were present also after matching normotensive and WCH participants according to systolic HBP, age and gender, the presence of WCH signals an increased cardiovascular risk burden that is not fully explained by elevated BP levels at home.

Circulating TNFrII levels predict incidence of ischemic heart disease and total mortality, independently of intima media thickness and pulse wave velocity in male with type 2 diabetes.

New and clinically useful markers of cardiovascular risk are of great importance in patients with type 2 diabetes since cardiovascular disease is a major cause of death in these patients. We analyzed inflammatory markers and other risk factors for heart disease in 761 patients who participated in the CARDIPP-study, Cardiovascular Risk factors in Patients with Diabetes-a Prospective study in Primary care. All participants had type 2 diabetes and were 55-66 years old at recruitment during the years 2005-2008. Patients were followed for incidence of stroke, myocardial infarction, or death from cardiovascular disease until the end of the year 2018 using the national Swedish Cause of Death and Hospitalization Registries. Besides traditional risk-markers for vascular disease, we also measured carotid-femoral pulse-wave velocity and intima-media thickness of carotid arteries. During a median period of 13 years, 165 men and 65 women died or were hospitalized for ischemic heart disease and stroke. TNFrII showed statistically significance as a risk factor for stroke, ischemic heart disease, and total mortality in male patients with diabetes type 2, independently of age, diabetes duration, BMI, Hba1c, systolic blood pressure, triglycerides, IMT and PWV (p = 0.002, HR 2.70, CI 1.42:5.13, p = 0.002). Circulating TNFrII levels failed to present a similar correlation in women (p = 0.48, CI 0.48:4.84). TNFrII stayed significant in males when HDL/LDL-ratio, CRP and smoking were added to the statistical analysis. Our data support the use of serum TNFrII in male type 2 diabetes patients to add independent prognostic information in terms of mortality and heart disease independently of other strong and well-established risk markers including cholesterol, inflammatory cytokines, PWV and IMT.Trial registration: ClinicalTrials.gov NCT01049737.

Intestinal, adipose, and liver inflammation in diet-induced obese mice.

Chronic inflammation and increased visceral adipose tissue (VAT) are key elements of the metabolic syndrome. Both are considered to play a pathogenic role in the development of liver steatosis and insulin resistance. The aim of the present study was to investigate the hypothesis that an inflamed intestine, induced both by diet and chemical irritation, could induce persistent inflammation in VAT. Female C57BL/6JOlaHsd mice were used. In study I, groups of mice (n = 6 per group) were given an obesity-inducing cafeteria diet (diet-induced obesity) or regular chow only (control) for 14 weeks. In study II, colitis in mice (n = 8) was induced by 3% dextran sulfate sodium in tap water for 5 days followed by 21 days of tap water alone. Healthy control mice (n = 8) had tap water only. At the end of the studies, all mice were killed; and blood and tissues were sampled and processed for analysis. Body weight of diet-induced obese mice was greatly increased, with evidence of systemic inflammation, insulin resistance, and liver steatosis. Tissue inflammation indexed by proinflammatory cytokine expression was recorded in liver, mesenteric fat, and proximal colon/distal ileum, but not in subcutaneous or perigonadal fat. In dextran sulfate sodium-induced colitis mice, mesenteric fat was even more inflamed than the colon, whereas a much milder inflammation was seen in liver and subcutaneous fat. The studies showed both diet- and colitis-initiated inflammation in mesenteric fat. Fat depots contiguous with intestine and their capacity for exaggerated inflammatory responses to conditions of impaired gut barrier function may account for the particularly pathogenic role of VAT in obesity-induced metabolic disorders.

Semen activates the female immune response during early pregnancy in mice.

Insemination elicits inflammatory changes in female reproductive tissues, but whether this results in immunological priming to paternal antigens or influences pregnancy outcome is not clear. We have evaluated indices of lymphocyte activation in lymph nodes draining the uterus following allogeneic mating in mice and have investigated the significance of sperm and plasma constituents of semen in the response. At 4 days after mating, there was a 1b7-fold increase in the cellularity of the para-aortic lymph node (PALN) compared with virgin controls. PALN lymphocytes were principally T and B lymphocytes, with smaller populations of CD3(+) B220(lo), NK1.1(+) CD3(-) (NK) and NK1.1(+) CD3(+) (NKT) cells. CD69 expression indicative of activation was increased after mating and was most evident in CD3(+) and NK1.1(+) cells. Synthesis of cytokines including interleukin-2, interleukin-4 and interferon-gamma was elevated in CD3(+) PALN cells after exposure to semen, as assessed by intracellular cytokine fluorescence-activated cell sorting, immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction. Matings with vasectomized males indicated that the lymphocyte activation occurs independently of sperm. However, in contrast, males from which seminal vesicle glands were surgically removed failed to stimulate PALN cell proliferation or cytokine synthesis. Adoptive transfer experiments using radiolabelled lymphocytes from mated mice showed that lymphocytes activated at insemination home to embryo implantation sites in the uterus as well as other mucosal tissues and lymph nodes. These findings indicate that activation and expansion of female lymphocyte populations occurs after mating, and is triggered by constituents of seminal plasma derived from the seminal vesicle glands. Moreover, lymphocytes activated at insemination may help mediate maternal tolerance of the conceptus in the implantation site.

Effect of interleukin-10 null mutation on maternal immune response and reproductive outcome in mice.

Interleukin-10 (IL-10) is an anti-inflammatory and immune-deviating cytokine expressed in the endometrium and placenta. IL-10 null mutant (IL-10-/-) mice have been employed to examine the role of IL-10 in regulating immune events in early pregnancy and its significance in implantation and pregnancy success. The inflammatory response elicited in endometrial tissue by insemination was amplified in IL-10-/- mice, with a 66% increase in leukocytes in the endometrial stroma on Day 3 of pregnancy. Despite this, no evidence of abnormal type 1/type 2 skewing was seen in T-lymphocytes from lymph nodes draining the uterus. On Day 18 of gestation, IL-10-/- females mated with IL-10-/- males had 15% more implantation sites and 27% more viable fetuses than pregnant wild-type (IL-10+/+) mice. Placental weight was unaffected, but fetal weight and the fetal:placental weight ratio were higher in IL-10-/- pregnancies. Similar data were obtained in allogeneic pregnancies when IL-10-/- females were mated with major-histocompatibility complex (MHC) disparate IL-10-/- males. Pups delivered by IL-10-/- mothers had increased birth weight and followed an altered growth trajectory, with growth impairment evident from early postnatal life into adulthood, which was reflected in alterations in body composition at 14 wk of age. This study shows that although IL-10 is not essential for maternal immune tolerance or successful pregnancy irrespective of MHC disparity in the fetus, maternal IL-10 is a determinant of growth trajectory in progeny in utero and after birth.

Immunology of the human genital tract.

PURPOSE OF REVIEW: Despite much interest in the mechanisms of immune protection against sexually transmitted diseases (STDs), little is known about the role of the immune system in the genital tract. A better knowledge is needed to understand not only host protection against STDs, but also how tolerance is established in pregnancy to avoid rejection of the foetus. RECENT FINDINGS: The immune system of the genital tract displays characteristic features that are unique, and therefore distinct from those of other mucosal and systemic immune sites. It is functionally separate from the mucosal immune systems of the lung or intestine, and contrary to these systems, antibodies in the genital tract are dominated by IgG and not IgA. Most of the IgA is polymeric and consists of equal proportions IgA1 and IgA2. Polymeric IgA is actively transported via the polymeric immunoglobulin receptor on the basolateral surface of the epithelial cell, whereas it is not known how IgG antibodies are secreted. Antibody levels and isotypes exhibit strong hormonal dependence. Less is known about cell-mediated immune responses in the genital tract. Interest has focused on adhesion molecules, the existence of regulatory T and natural killer cells, and whether innate and early adaptive immune responses may be stimulated by local vaginal, intranasal or intestinal vaccinations. These topics are reviewed here and the most recent developments in these areas are reported. SUMMARY: A greater knowledge of immune activation and the homing of leukocytes to the genital tract is important for future attempts to design vaccines against STDs, as well as in understanding foetal tolerance.

A unique population of extrathymically derived alpha beta TCR+CD4-CD8- T cells with regulatory functions dominates the mouse female genital tract.

A better understanding of the regulatory role of genital tract T cells is much needed. In this study, we have analyzed the phenotype, distribution, and function of T lymphocytes in the female genital tract of naive, pregnant, or Chlamydia trachomatis-infected C57BL/6 mice. Unexpectedly, we found that the dominant lymphocyte population (70-90%) in the genital tract was that of CD3(+)alphabetaTCR(int)CD4(-)CD8(-) T cells. Moreover, these cells were CD90(low) but negative for the classical T cell markers CD2 and CD5. The CD3(+)B220(low) cells were NK1.1 negative and found in nude mice as well as in mice deficient for MHC class II, beta(2)-microglobulin, and CD1, indicating extrathymic origin. They dominated the KJ126(+)Vbeta8.2(+) population in the genital tract of DO11.10 OVA TCR-transgenic mice, further supporting the idea that the CD3(+)B220(low) cells are truly T cells. The function of these T cells appeared not to be associated with immune protection, because only CD4(+) and CD8(+) T cells increased in the genital tract following chlamydial infection. Notwithstanding this, the infected, as well as the uninfected and the pregnant, uterus was dominated by a high level of the CD3(+)CD4(-)CD8(-)B220(low) cells. Following in vitro Ag or polyclonal stimulation of the CD3(+)CD4(-)CD8(-)B220(low) cells, poor proliferative responses were observed. However, these cells strongly impaired splenic T cell proliferation in a cell density-dependent manner. A large fraction of the cells expressed CD25 and produced IFN-gamma upon anti-CD3 plus anti-CD28 stimulation, arguing for a strong regulatory role of this novel T cell population in the mouse female genital tract.