The prolactin receptor is expressed in macrophages within human carotid atherosclerotic plaques: a role for prolactin in atherogenesis?

Atherosclerotic vascular disease is the consequence of a chronic inflammatory process, and prolactin has been shown to be a component of the inflammatory response. Additionally, recent studies indicate that prolactin contributes to an atherogenic phenotype. We hypothesized that this may be the result of a direct effect of prolactin on atherogenesis through activation of the prolactin receptor. Human carotid atherosclerotic plaques were obtained from patients by endarteriectomies. The mRNA of prolactin receptor, but not of prolactin, was detected in these atherosclerotic plaques by quantitative real-time PCR. In situ hybridization confirmed the expression of the prolactin receptor in mononuclear cells. Analysis at the protein level using immunohistochemistry and immunoelectron microscopy revealed that the prolactin receptor was abundantly present in macrophages near the lipid core and shoulder regions of the plaques. Our findings demonstrate that the prolactin receptor is present in macrophages of the atherosclerotic plaque at sites of most prominent inflammation. We therefore propose that prolactin receptor signaling contributes to the local inflammatory response within the atherosclerotic plaque and thus to atherogenesis.     

Endothelial insulin receptor expression in human atherosclerotic plaques: Linking micro- and macrovascular disease in diabetes?

ObjectiveExogenous insulin use in patients with type 2 diabetes (DM2) has been associated with an increased risk of cardiovascular events. Through which mechanisms insulin may increase atherosclerotic plaque vulnerability is currently unclear. Because insulin has been suggested to promote angiogenesis in diabetic retinopathy and tumors, we hypothesized that insulin enhances intra-plaque angiogenesis.MethodsAn in vitro model of pathological angiogenesis was used to assess the potential of insulin to enhance capillary-like tube formation of human microvascular endothelial cells (hMVEC) into a three dimensional fibrin matrix. In addition, insulin receptor expression within atherosclerotic plaques was visualized in carotid endarterectomy specimens of 20 patients with carotid artery stenosis, using immunohistochemical techniques. Furthermore, microvessel density within atherosclerotic plaques was compared between 68 DM2 patients who received insulin therapy and 97 DM2 patients who had been treated with oral glucose lowering agents only.ResultsInsulin, at a concentration of 10^?8 M, increased capillary-like tube formation of hMVEC 1.7-fold (p < 0.01). Within human atherosclerotic plaques, we observed a specific distribution pattern for the insulin receptor: insulin receptor expression was consistently higher on the endothelial lining of small nascent microvessels compared to more mature microvessels. There was a trend towards an increased microvessel density by 20% in atherosclerotic plaques derived from patients using insulin compared to plaques derived from patients using oral glucose lowering agents only (p = 0.05).ConclusionExogenous insulin use in DM2 patients may contribute to increased plaque vulnerability by stimulating local angiogenesis within atherosclerotic plaques.     

Does leflunomide have a role in giant cell arteritis? An open-label study

Clinical Rheumatology - Glucocorticoid monotherapy has been the mainstay treatment of giant cell arteritis (GCA) for decades. We aimed to evaluate the role of leflunomide as a steroid-sparing agent...     

Fever and high lactate dehydrogenase in HIV-positive patients from the Antilles and Surinam: histoplasmosis?

We describe four cases of HIV-positive patients, two from Surinam, one from the Dutch Antilles and one from Nigeria, who presented with a febrile illness and a high lactate dehydrogenase plasma level. In all four, the diagnosis of disseminated histoplasmosis was made, in three of them by liver biopsy. Two patients had retinal abnormalities compatible with a systemic fungal infection. Three patients were treated successfully with antifungal agents. One patient died. Between 2000 and 2006, only 14 patients with HIV have been found to have histoplasmosis in the Netherlands. Although histoplasmosis is not endemic in the Netherlands, physicians are more likely to see cases because of a growing number of HIV -positive immigrants from endemic regions.     

Cerebral white matter lesions in primary Sj?gren's syndrome: a controlled study.

OBJECTIVE: To determine the prevalence of neurological and magnetic resonance imaging (MRI) abnormalities in a well defined population of unselected patients with primary Sj?gren's syndrome (SS) and age and sex matched healthy patients. METHODS: Thirty patients with SS and 29 age and sex matched controls were examined by a neurologist and subsequently underwent MRI scanning with a 1.0 Tesla Siemens Impact MR scanner. Scans were graded by a neuroradiologist blinded to the clinical status of each subject. The number and location of white matter lesions > 3 mm in long axis (to exclude non-specific perivascular changes) were recorded for each subject. RESULTS: There was a significant increase in lesions detected by MRI in SS patients versus controls (p = 0.02) including deep white matter lesions (p = 0.03) and subcortical white matter lesions (p = 0.02). The presence of white matter lesions did not correlate with serum IgG or rheumatoid factor levels, or with presence of anticardiolipin antibodies. No subjects had symptoms or signs of serious neurological disease including multiple sclerosis, and corpus callosal lesions commonly seen in multiple sclerosis were notably absent in this study. CONCLUSION: Cerebral white matter lesions detected by MRI are more frequent in patients with primary SS than control subjects, yet do not appear to be associated with significant clinical manifestations. Although the pathological nature of these lesions is yet to be defined, their presence should not be over-interpreted.     

Current opinion on aspirin in primary prevention of atherosclerotic cardiovascular diseases. Is there any difference between diabetic and non-diabetic patients?

Aspirin reduces vascular death by approximately 15% and nonfatal vascular events by about 30% in secondary prevention. The evidence in primary prevention in non-diabetic subjects is not so powerful. The benefit of aspirin primary prevention in type 2 diabetes remains to be advocated definitely.     

Pharmacological inhibition of NOX reduces atherosclerotic lesions,vascular ROS and immune–inflammatory responses in diabetic Apoe −/− mice

Aims/hypothesis

Enhanced vascular inflammation, immune cell infiltration and elevated production of reactive oxygen species (ROS) contribute significantly to pro-atherogenic responses in diabetes. We assessed the immunomodulatory role of NADPH oxidase (NOX)-derived ROS in diabetes-accelerated atherosclerosis.

Methods

Diabetes was induced in male Apoe ^?/? mice with five daily doses of streptozotocin (55 mg kg^?1 day^?1). Atherosclerotic plaque size, markers of ROS and immune cell accumulation were assessed in addition to flow cytometric analyses of cells isolated from the adjacent mediastinal lymph nodes (meLNs). The role of NOX-derived ROS was investigated using the NOX inhibitor, GKT137831 (60 mg/kg per day; gavage) administered to diabetic and non-diabetic Apoe ^?/? mice for 10 weeks.

Results

Diabetes increased atherosclerotic plaque development in the aortic sinus and this correlated with increased lesional accumulation of T cells and CD11c⁺ cells and altered T cell activation in the adjacent meLNs. Diabetic Apoe ^?/? mice demonstrated an elevation in vascular ROS production and expression of the proinflammatory markers monocyte chemoattractant protein 1, vascular adhesion molecule 1 and IFNγ. Blockade of NOX-derived ROS using GKT137831 prevented the diabetes-mediated increase in atherosclerotic plaque area and associated vascular T cell infiltration and also significantly reduced vascular ROS as well as markers of inflammation and plaque necrotic core area.

Conclusions/interpretation

Diabetes promotes pro-inflammatory immune responses in the aortic sinus and its associated lymphoid tissue. These changes are associated with increased ROS production by NOX. Blockade of NOX-derived ROS using the NOX inhibitor GKT137831 is associated with attenuation of these changes in the immune response and reduces the diabetes-accelerated development of atherosclerotic plaques in Apoe ^?/? mice.     

Environmental factors in a population-based inception cohort of inflammatory bowel disease patients in Europe — An ECCO-EpiCom study

Background and AimsThe incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe possibly due to changes in environmental factors towards a more “westernised” standard of living. The aim of this study was to investigate differences in exposure to environmental factors prior to diagnosis in Eastern and Western European IBD patients.MethodsThe EpiCom cohort is a population-based, prospective inception cohort of 1560 unselected IBD patients from 31 European countries covering a background population of 10.1 million. At the time of diagnosis patients were asked to complete an 87-item questionnaire concerning environmental factors.ResultsA total of 1182 patients (76%) answered the questionnaire, 444 (38%) had Crohn's disease (CD), 627 (53%) ulcerative colitis (UC), and 111 (9%) IBD unclassified. No geographic differences regarding smoking status, caffeine intake, use of oral contraceptives, or number of first-degree relatives with IBD were found. Sugar intake was higher in CD and UC patients from Eastern Europe than in Western Europe while fibre intake was lower (p < 0.01). Daily consumption of fast food as well as appendectomy before the age of 20 was more frequent in Eastern European than in Western European UC patients (p < 0.01). Eastern European CD and UC patients had received more vaccinations and experienced fewer childhood infections than Western European patients (p < 0.01).ConclusionsIn this European population-based inception cohort of unselected IBD patients, Eastern and Western European patients differed in environmental factors prior to diagnosis. Eastern European patients exhibited higher occurrences of suspected risk factors for IBD included in the Western lifestyle.     

Can older patients adopt and maintain a ketogenic diet? An observational study in support of clinical trials in older patients

Ketogenic diets appear promising for obesity, diabetes, cancer, and other illnesses. Because older patients are more likely to contend with such illnesses and because of a paucity of dietary outcomes among these patients, we examined ketogenic diets in older patients.This multisite study focused on patients (≥65 years of age) on a ketogenic diet. Medical records were identified with the keywords “keto,” “ketogenic,” and “Atkins.” Records were reviewed in detail with extraction of direct quotations to substantiate observations.We report on 200 consecutive patients with a median age of 70 years. Reasons for diet included weight loss, diabetes, and cancer; the majority remained on the diet for >1 month. In 134 (67%: 95% confidence interval: 60, 73%), the ketogenic diet appeared beneficial: 93 of 117 (79%) who sought weight loss lost weight (“She has lost 15 pounds and plans to lose another 8”); 36 of 67 (54%) who sought glucose control appeared to achieve the latter (“He has gone on a ketogenic diet and has been able to bring his sugars down significantly”); and 5 of 8 (63%) who sought improved cancer outcomes appeared to derive them (“He attributes part of the control of his cancer and increased QOL to adopting the keto for cancer diet”). Adverse events occurred in 30 patients (15%): dyslipidemia (n = 14), constipation (n = 9), sub-therapeutic international normalized ratio (n = 3), pancreatitis (n = 2), diarrhea (n = 1), and fatigue (n = 1).Trials that test ketogenic diets for a variety of illnesses should enroll older adults.     

Chlamydia pneumoniae in the atherosclerotic plaques of patients with unstable angina undergoing coronary artery bypass grafting: does it have prognostic implications?

Objective: This study sought to evaluate the prognostic significance of the presence of DNA of Chlamydia pneumoniae in the coronary atherosclerotic lesions of patients with unstable angina. Background: C. pneumoniae has been implicated in the pathogenesis of coronary artery disease by serological and pathological studies, but whether antichlamydial antibodies and the presence of this pathogen in the coronary atherosclerotic tissue are related to prognosis in unstable angina remains unclear. Methods: A total 76 coronary specimens from 45 patients with unstable angina undergoing bypass surgery were subjected to nested polymerase chain reaction (PCR) for C. pneumoniae. Antichlamydial immunoglobulin G (IgG), A (IgA) and M (IgM) were also examined by an enzyme immunoassay. Patients were followed during a 2-year period to determine the incidence of adverse cardiovascular events. Results: DNA of C. pneumoniae was detected in 57 (75%) of 76 atherosclerotic lesions: 39 patients showed a positive PCR result in at least one plaque. Of the 45 patients, 44 (97.7%) showed a positive serological result: IgG was positive in 39 (86.6%) patients, IgM in five (11.1%) patients and IgA in 42 (93.3%). Clinical characteristics and serologic results were similarly distributed in patients with and without infected lesions at enrollment. At least one adverse event occurred in 21 (46.6%) of the 45 patients at 2 years: death in nine (20%), recurrent angina in 12 (26.6%), revascularization in six (13.3%) and myocardial infarction in two (4.4%) patients. The composite endpoint of death, myocardial infarction, recurrent angina and revascularization at 2-year follow-up did not differ according to the PCR or serologic results. Conclusions: The presence of C. pneumoniae in coronary atherosclerotic plaques of patients with unstable angina undergoing coronary bypass grafting does not have prognostic significance. In addition, serology does not allow us to differentiate those patients with plaque infection by C. pneumoniae and also does not provide any prognostic information in these patients.     

What measure of carotid wall thickening is the best atherosclerotic loading score in the hypertensive patient: maximum or mean value?

Recent guidelines on arterial hypertension regard increased carotid intima-media thickness (IMT) as a marker of end-organ damage. However, these guidelines do not specify whether the maximum or mean IMT should be used as an indicator. The aim of this study was to compare these two measures and their relationship to atherosclerotic burden. The study involved 215 consecutive hypertensive patients who were divided into three groups according to their IMT: maximum IMT > 0.9 mm (with mean IMT < 0.9 mm); mean IMT > 0.9 mm (i.e. mean and maximum IMT > 0.9 mm); and normal IMT. Patients with a pathologically raised IMT (whether maximum or mean value) were more likely to be dyslipidemic, were older, had a longer history of hypertension, and had a poorer glomerular filtration rate and ankle-brachial index. Patients with a mean IMT > 0.9 mm were more likely to have carotid plaque, carotid stenosis and a low ankle-brachial index than those with a maximum IMT > 0.9 mm. The mean IMT provided a better indication of atherosclerotic burden in patients with hypertension.Full English text available from: www.revespcardiol.org