Mässlingsvaccin kan ges vid 6 månaders ålder i särskilda fall - Vid risk för smitta kan off label-användning övervägas, enligt en litteraturgenomgång.

MMR vaccination in 6-9 month olds Vaccination against measles using the MMR vaccine is licensed from 9 months of age, but is used off-label from 6 months of age during or when travelling to areas with an ongoing measles outbreak. In this review of the published literature, studies on MMR vaccination in this age group are limited and small in size. Immunogenicity studies indicate that infants under 9 months respond with lower antibody titres but comparable T cell responses against measles. The safety profile of the vaccine does not appear to differ between infants vaccinated earlier or later. Vaccination from 6 months of age should be recommended if the risk of being infected with measles is considered greater than the risk of not attaining full vaccination protection.

Leptin Deficiency Shifts Mast Cells toward Anti-Inflammatory Actions and Protects Mice from Obesity and Diabetes by Polarizing M2 Macrophages.

Mast cells (MCs) contribute to the pathogenesis of obesity and diabetes. This study demonstrates that leptin deficiency slants MCs toward anti-inflammatory functions. MCs in the white adipose tissue (WAT) of lean humans and mice express negligible leptin. Adoptive transfer of leptin-deficient MCs expanded ex vivo mitigates diet-induced and pre-established obesity and diabetes in mice. Mechanistic studies show that leptin-deficient MCs polarize macrophages from M1 to M2 functions because of impaired cell signaling and an altered balance between pro- and anti-inflammatory cytokines, but do not affect T cell differentiation. Rampant body weight gain in ob/ob mice, a strain that lacks leptin, associates with reduced MC content in WAT. In ob/ob mice, genetic depletion of MCs exacerbates obesity and diabetes, and repopulation of ex vivo expanded ob/ob MCs ameliorates these diseases.

Cathepsin G activity lowers plasma LDL and reduces atherosclerosis.

Cathepsin G (CatG), a serine protease present in mast cells and neutrophils, can produce angiotensin-II (Ang-II) and degrade elastin. Here we demonstrate increased CatG expression in smooth muscle cells (SMCs), endothelial cells (ECs), macrophages, and T cells from human atherosclerotic lesions. In low-density lipoprotein (LDL) receptor-deficient (Ldlr(-/-)) mice, the absence of CatG reduces arterial wall elastin degradation and attenuates early atherosclerosis when mice consume a Western diet for 3months. When mice consume this diet for 6months, however, CatG deficiency exacerbates atherosclerosis in aortic arch without affecting lesion inflammatory cell content or extracellular matrix accumulation, but raises plasma total cholesterol and LDL levels without affecting high-density lipoprotein (HDL) or triglyceride levels. Patients with atherosclerosis also have significantly reduced plasma CatG levels that correlate inversely with total cholesterol (r=-0.535, P<0.0001) and LDL cholesterol (r=-0.559, P<0.0001), but not with HDL cholesterol (P=0.901) or triglycerides (P=0.186). Such inverse correlations with total cholesterol (r=-0.504, P<0.0001) and LDL cholesterol (r=-0.502, P<0.0001) remain significant after adjusting for lipid lowering treatments among this patient population. Human CatG degrades purified human LDL, but not HDL. This study suggests that CatG promotes early atherogenesis through its elastinolytic activity, but suppresses late progression of atherosclerosis by degrading LDL without affecting HDL or triglycerides.

Pharmaceutical stabilization of mast cells attenuates experimental atherogenesis in low-density lipoprotein receptor-deficient mice.

Mast cells (MCs) contribute to atherogenesis by releasing pro-inflammatory mediators to activate vascular cells and other inflammatory cells. This study examined whether MC activation or stabilization affects diet-induced atherosclerosis in low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. When Ldlr(-/-) mice consumed an atherogenic diet for 3 or 6 months, MC activation with compound 48/80 (C48/80) increased aortic arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels, whereas MC stabilization with cromolyn reduced these parameters. There were significant differences in arch intima and total lesion areas, and plasma total cholesterol, LDL, and triglyceride levels between C48/80-treated and cromolyn-treated mice. To examine a therapeutic application of cromolyn in atherosclerosis, we fed Ldlr(-/-) mice an atherogenic diet for 3 months followed by giving mice cromolyn for additional 3 months. Cromolyn did not affect aortic arch intima area, but significantly reduced lipid deposition in the thoracic-abdominal aortas. In aortic arches, however, cromolyn treatment significantly reduced lesion contents of Mac-3(+) macrophages, CD4(+) T cells, activated MCs, and lesion cell proliferation. While plasma total cholesterol and LDL levels increased and high-density lipoprotein (HDL) levels decreased from 3 months to 6 months of an atherogenic diet, cromolyn treatment decreased significantly plasma total cholesterol, LDL, and triglyceride levels and increased HDL levels above those of 3-month time point. These observations demonstrate that MC stabilization reduces lesion inflammation, ameliorates plasma lipid profiles, and may serve as a potential therapy for this cardiovascular disease.

A guanidine-rich regulatory oligodeoxynucleotide improves type-2 diabetes in obese mice by blocking T-cell differentiation.

T lymphocytes exhibit pro-inflammatory or anti-inflammatory activities in obesity and diabetes, depending on their subtypes. Guanidine-rich immunosuppressive oligodeoxynucleotides (ODNs) effectively control Th1/Th2-cell counterbalance. This study reveals a non-toxic regulatory ODN (ODNR01) that inhibits Th1- and Th17-cell polarization by binding to STAT1/3/4 and blocking their phosphorylation without affecting Th2 and regulatory T cells. ODNR01 improves glucose tolerance and insulin sensitivity in both diet-induced obese (DIO) and genetically generated obese (ob/ob) mice. Mechanistic studies show that ODNR01 suppresses Th1- and Th17-cell differentiation in white adipose tissue, thereby reducing macrophage accumulation and M1 macrophage inflammatory molecule expression without affecting M2 macrophages. While ODNR01 shows no effect on diabetes in lymphocyte-free Rag1-deficient DIO mice, it enhances glucose tolerance and insulin sensitivity in CD4(+) T-cell-reconstituted Rag1-deficient DIO mice, suggesting its beneficial effect on insulin resistance is T-cell-dependent. Therefore, regulatory ODNR01 reduces obesity-associated insulin resistance through modulation of T-cell differentiation.

Cathepsin K deficiency reduces elastase perfusion-induced abdominal aortic aneurysms in mice.

OBJECTIVE: Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown. METHODS AND RESULTS: Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days postperfusion. CatK deficiency significantly reduced lesion CD4(+) T-cell content, total lesion and medial cell proliferation and apoptosis, medial smooth muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but it did not affect AAA lesion Mac-3(+) macrophage accumulation or CD31(+) microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4(+) T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMCs and endothelial cells but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice. CONCLUSIONS: This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation and by affecting vascular cell protease expression and activities.

Cathepsin L activity is essential to elastase perfusion-induced abdominal aortic aneurysms in mice.

OBJECTIVE: The development of abdominal aortic aneurysms (AAA) requires extensive aortic wall matrix degradation. Human AAA lesions express high levels of cathepsin L (CatL), one of the most potent mammalian elastases. Whether this protease participates directly in AAA pathogenesis, however, is unknown. METHODS AND RESULTS: We generated experimental AAA with aortic elastase perfusion in mice and established an essential role of CatL in AAA formation. After 14 days postperfusion, most wild-type (Ctsl(+/+)) mice developed AAA, but none of the CatL-deficient (Ctsl(-/-)) mice did. AAA lesion macrophage contents, CD4(+) T cell numbers, CD31(+) and laminin-5 angiogenic fragment γ2(+) microvessel numbers, and elastin fragmentation were all significantly lower in Ctsl(-/-) mice than in Ctsl(+/+) mice. While lesions from Ctsl(-/-) mice contained fewer Ki67(+) proliferating cells than did Ctsl(+/+) mice, the absence of CatL did not affect lesion apoptotic cell contents or medial smooth-muscle cell loss significantly. Mechanistic studies indicated that the absence of CatL reduced lesion chemokine monocyte chemotactic protein-1 content, macrophage and T-cell in vitro transmigration, and angiogenesis, and altered the expression and activities of matrix metalloproteinases and other cysteinyl cathepsins in inflammatory cells, vascular cells, and AAA lesions. CONCLUSION: CatL contributes to AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, and protease expression.

IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe-/- mice.

IgE has a key role in the pathogenesis of allergic responses through its ability to activate mast cells via the receptor FcεR1. In addition to mast cells, many cell types implicated in atherogenesis express FcεR1, but whether IgE has a role in this disease has not been determined. Here, we demonstrate that serum IgE levels are elevated in patients with myocardial infarction or unstable angina pectoris. We found that IgE and the FcεR1 subunit FcεR1α were present in human atherosclerotic lesions and that they localized particularly to macrophage-rich areas. In mice, absence of FcεR1α reduced inflammation and apoptosis in atherosclerotic plaques and reduced the burden of disease. In cultured macrophages, the presence of TLR4 was required for FcεR1 activity. IgE stimulated the interaction between FcεR1 and TLR4, thereby inducing macrophage signal transduction, inflammatory molecule expression, and apoptosis. These IgE activities were reduced in the absence of FcεR1 or TLR4. Furthermore, IgE activated macrophages by enhancing Na+/H+ exchanger 1 (NHE1) activity. Inactivation of NHE1 blocked IgE-induced macrophage production of inflammatory molecules and apoptosis. Cultured human aortic SMCs (HuSMCs) and ECs also exhibited IgE-induced signal transduction, cytokine expression, and apoptosis. In human atherosclerotic lesions, SMCs and ECs colocalized with IgE and TUNEL staining. This study reveals what we believe to be several previously unrecognized IgE activities that affect arterial cell biology and likely other IgE-associated pathologies in human diseases.

Cysteine Protease Cathepsins in Atherosclerosis and Abdominal Aortic Aneurysm.

Extracellular matrix remodeling is an important mechanism in the initiation and progression of cardiovascular diseases. Cysteine protease cathepsins are among the important proteases that affect major events in the pathogenesis of atherosclerosis and abdominal aortic aneurysm, including smooth muscle cell transmigration through elastic lamina, macrophage foam cell formation, vascular cell and macrophage apoptosis, and plaque rupture. These events have been studied in cathepsin deficiencies and cathepsin inhibitor deficiencies in mice and have provided invaluable insights regarding the roles of cathepsins in cardiovascular diseases. Pharmacological inhibitions for cathepsins are under evaluation for other human diseases and may be used as clinical treatments for cardiovascular diseases in the near future. This article reviews different mechanisms for cathepsins in atherosclerosis and abdominal aortic aneurysm that could be targeted by selective cathepsin inhibitors.

CD44-deficiency on hematopoietic cells limits T-cell number but does not protect against atherogenesis in LDL receptor-deficient mice.

OBJECTIVE: Vascular and inflammatory cells express adhesion molecule CD44. We demonstrated previously that enhanced CD44 localizes in human atherosclerotic lesions. Apolipoprotein E/cd44 double-deficient mice and apolipoprotein E-deficient mice transplanted with CD44-deficient bone marrow (BM) exhibit reduced atherosclerosis. Since CD44 is a novel factor in atherogenesis, it is imperative that it is investigated in more than one animal model to conclusively determine its role in this particular disease pathology. To test the hypothesis that CD44 expressed by hematopoietic cells plays a critical role in atherogenesis in the low density lipoprotein (LDL) receptor-deficient mouse model, we performed BM reconstitution experiments. METHODS: Lethally irradiated LDL receptor-deficient mice were transplanted with either CD44-deficient or wild-type BM. Beginning 10 weeks after successful reconstitution, mice consumed a cholesterol-enriched atherogenic diet for 6 or 11 weeks. RESULTS: Surprisingly, CD44-deficiency on BM-derived inflammatory cells did not affect lesion size. Additionally, neither group displayed differences in smooth muscle cell, macrophage, collagen, or elastin content as well as lipoprotein levels. However, lesions in CD44-deficient BM-recipient mice contained fewer T-cells compared to wild-type BM mice. Interestingly, CD44-deficient T-cells expressed less chemokine receptor-5 mRNA. Furthermore, in vivo leukocyte adhesion decreased in CD44-deficient mice compared to wild-type mice. CONCLUSION: This study surprisingly revealed that atherogenesis does not require CD44 expression on hematopoietic cells in the LDL receptor-deficient mouse model. However, CD44 promotes T-cell recruitment, downregulates chemokine receptor-5, and participates critically in leukocyte adhesion in vivo. Consequently, the anti-atherogenic role of CD44 may require CD44-deficiency on cell types other than inflammatory cells in the LDL receptor-deficient mouse model.

CD44 - a new cardiovascular drug target or merely an innocent bystander?

CD44, short for cluster of differentiation 44, is an adhesion molecule of the hyaluronate receptor family. Expressed on the surface of most vertebrate cells, it functions as a receptor for several extracellular matrix components, e.g., hyaluronan, collagen, laminin, fibronectin, and osteopontin. CD44 has in recent years been intensively studied in connection with different forms of cancer, where CD44 may regulate invasiveness and tumor progression. Although major functions involve adhesion and migration, CD44 also affects leukocyte homing and recruitment, phagocytosis, matrix remodeling, proliferation, and apoptosis. As such, CD44 is an interesting putative molecule in cardiovascular drug therapy. Accumulating evidence from human studies point to CD44 as involved in inflammatory diseases such as atherosclerosis and human abdominal aneurysms. To date, several animal studies have shown that the role of CD44 in atherogenesis may vary depending on experimental model. In this Review, we trace CD44 and its potential role in the context of cardiovascular diseases by highlighting both human and animal studies that may help us understand; is CD44 a new cardiovascular drug target or merely an innocent bystander?

The endogenous estradiol metabolite 2-methoxyestradiol reduces atherosclerotic lesion formation in female apolipoprotein E-deficient mice.

Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17beta-estradiol (6 microg/d), or 2-methoxyestradiol [6.66 microg/d (low-dose) or 66.6 microg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.

Augmented levels of CD44 in macrophages from atherosclerotic subjects: a possible IL-6-CD44 feedback loop?

The cell-adhesion molecule CD44 likely participates in atherosclerosis development. We have shown previously that pro-inflammatory cytokines affect CD44 expression. Therefore, this work examined the role of elevated CD44 levels in human macrophages. Macrophages from human atherosclerotic subjects (n=15) showed elevated levels of CD44 transcript and protein (1.5-fold) compared to matched controls (n=15) (P=0.050 and 0.044, respectively). To test whether genetic factors influence CD44 expression, two single nucleotide polymorphisms in the CD44 gene were analyzed but these were not associated with coronary artery disease. We also examined the potential connection between plasma cytokine levels and CD44 expression. In atherosclerotic subjects, elevated CD44 expression correlates (P=0.012) with enhanced macrophage IL-6 secretion (3.13+/-2.5 pg/mL versus 0.32+/-0.16 pg/mL in controls, P=0.021). Additionally, CD44-deficient mice exhibit less circulating IL-6 than wild-type controls (9.8+/-0.7 pg/mL versus 14.3+/-0.7 pg/mL; P=0.032). Furthermore, IL-6 augments CD44 expression in primary human macrophages after 24 h (P=0.038) and 48 h (P=0.015). Taken together, our data show an IL-6-CD44 feedback loop in macrophages. Such a positive feedback loop may aggravate atherosclerosis development.

Circulating soluble CD44 is higher among women than men and is not associated with cardiovascular risk factors or subclinical atherosclerosis.

In the present study, the associations between the plasma concentration of soluble CD44 (sCD44), sex, cardiovascular risk factors, and ultrasound-assessed measures of carotid atherosclerosis were examined in 2 groups of 61- and 64-year-old men and women from population-based samples. Women had higher levels of circulating sCD44 than men. There were no associations between sCD44 and cardiovascular risk factors or subclinical atherosclerosis.

Applying the theory of planned behavior to fruit and vegetable consumption by older adults.

This study applied the Theory of Planned Behavior to fruit and vegetable intake among older adults. A cross-sectional questionnaire was administered to older adults (N = 205, mean age = 77 years) at senior centers. Most were women (74%), white (77%), and had >/= 12 years of education. Regression analyses showed that the theory constructs explained more than 40% and 18% (p < 0.0001) of the variance in intention and reported intake of fruits and vegetables, respectively. Perceived behavioral control was most important in explaining both intention and intake, followed by attitudes and subjective norms. Important control beliefs were related to convenience, preferences, time, and availability when eating out. These beliefs should be addressed in education for older adults to increase fruit and vegetable intake.

Applying the theory of planned behavior to predict dairy product consumption by older adults.

OBJECTIVE: The purpose of this study was to explain intention to consume dairy products and consumption of dairy products by older adults using the Theory of Planned Behavior (TPB). The factors examined were attitudes, subjective norms, and perceived behavioral control. DESIGN: A cross-sectional questionnaire was administered. SETTING: Community centers with congregate dining programs, group classes, and recreational events for older adults. SUBJECTS: One hundred and sixty-two older adults (mean age 75 years) completed the questionnaire. Subjects were mostly women (76%) and white (65%), with about half having less than a high school education or completing high school. VARIABLES MEASURED: Variables based on the TPB were assessed through questionnaire items that were constructed to form scales measuring attitudes, subjective norms, perceived behavioral control, and intention to consume dairy products. Dairy product consumption was measured using a food frequency questionnaire. ANALYSIS: Regression analyses were used to determine the association between the scales for the 3 variables proposed in the TPB and intention to consume and consumption of dairy products; the alpha level was set at.05 to determine the statistical significance of results. RESULTS: Attitudes toward eating dairy products and perceived behavioral control contributed to the model for predicting intention, whereas subjective norms did not. Attitudes toward eating dairy products were slightly more important than perceived behavioral control in predicting intention. In turn, intention was strongly related to dairy product consumption, and perceived behavioral control was independently associated with dairy product consumption. CONCLUSIONS AND IMPLICATIONS: These results suggest the utility of the TPB in explaining dairy product consumption for older adults. Nutrition education should focus on improving attitudes and removing barriers to consumption of dairy products for older adults.