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Flack J.M.,Wayne State University | Bakris G.,University of Chicago | Brown A.L.,University of Washington | Ferdinand K.C.,Emory University | And 9 more authors.
Hypertension | Year: 2010

Since the first International Society on Hypertension in Blacks consensus statement on the "Management of High Blood Pressure in African American" in 2003, data from additional clinical trials have become available. We reviewed hypertension and cardiovascular disease prevention and treatment guidelines, pharmacological hypertension clinical end point trials, and blood pressure-lowering trials in blacks. Selected trials without significant black representation were considered. In this update, blacks with hypertension are divided into 2 risk strata, primary prevention, where elevated blood pressure without target organ damage, preclinical cardiovascular disease, or overt cardiovascular disease for whom blood pressure consistently <135/85 mm Hg is recommended, and secondary prevention, where elevated blood pressure with target organ damage, preclinical cardiovascular disease, and/or a history of cardiovascular disease, for whom blood pressure consistently <130/80 mm Hg is recommended. If blood pressure is ≤10 mm Hg above target levels, monotherapy with a diuretic or calcium channel blocker is preferred. When blood pressure is >15/10 mm Hg above target, 2-drug therapy is recommended, with either a calcium channel blocker plus a renin-angiotensin system blocker or, alternatively, in edematous and/or volume-overload states, with a thiazide diuretic plus a renin-angiotensin system blocker. Effective multidrug therapeutic combinations through 4 drugs are described. Comprehensive lifestyle modifications should be initiated in blacks when blood pressure is ≥115/75 mm Hg. The updated International Society on Hypertension in Blacks consensus statement on hypertension management in blacks lowers the minimum target blood pressure level for the lowest-risk blacks, emphasizes effective multidrug regimens, and de-emphasizes monotherapy. © 2010 American Heart Association, Inc.


Sanz J.M.,Section of Internal Medicine | Falzoni S.,University of Ferrara | Rizzo R.,University of Ferrara | Cipollone F.,University of Chieti Pescara | And 2 more authors.
Experimental Gerontology | Year: 2014

Inflammation is a key factor in the onset and progression of Alzheimer's disease (AD). The P2X7 receptor (P2X7R) is increasingly recognized as key pro-inflammatory receptor. A recent study has shown that activation of microglia by amyloid β (Aβ) and associated release of IL-1β, requires P2X7R expression. In this study we assessed by RT-PCR in genomic DNA samples, the frequency of two single-nucleotide polymorphisms (SNP) of P2X7R in AD patients compared to age-matched non demented elderly. Our data show that the 489C>T SNP was significantly less frequent in AD patients than in controls (p. =. 0.01), whereas there was no statistical difference in 1513A>C frequency in either groups. In addition, presence of the 1513C allele and absence of the 489C allele decreased the probability of having AD by about four fold. In conclusion, our data show a strong negative association between the P2X7R 489C>T polymorphism and AD, especially in the presence of the 1513C allele. © 2014.


Mazzocca A.,Section of Internal Medicine | Dituri F.,Section of Internal Medicine | Lupo L.,University of Bari | Quaranta M.,Italian National Cancer Institute | And 2 more authors.
Hepatology | Year: 2011

Hepatocellular carcinoma (HCC) occurs in fibrotic liver as a consequence of underlying cirrhosis. The goal of this study was to investigate how the interaction between HCC cells and stromal fibroblasts affects tumor progression. We isolated and characterized carcinoma-associated fibroblasts (CAFs) and paired peritumoral tissue fibroblasts (PTFs) from 10 different patients with HCC and performed coculture experiments. We demonstrated a paracrine mechanism whereby HCC cells secrete lysophostatidic acid (LPA), which promotes transdifferentiation of PTFs to a CAF-like myofibroblastic phenotype. This effect is mediated by up-regulation of specific genes related to a myo/contractile phenotype. After transdifferentiation, PTFs expressed α-smooth muscle actin (α-SMA) and enhanced proliferation, migration, and invasion of HCC cells occur. A pan-LPA inhibitor (α-bromomethylene phosphonate [BrP]-LPA), or autotaxin gene silencing, inhibited this PTF transdifferentiation and the consequent enhanced proliferation, migration, and invasion of HCC cells. In vivo, PTFs coinjected with HCC cells underwent transdifferentiation and promoted tumor progression. Treatment with BrP-LPA blocked transdifferentiation of PTFs, down-regulated myofibroblast-related genes, and slowed HCC growth and progression. Patients with larger and metastatic HCC and shorter survival displayed higher serum levels of LPA. Analysis of microdissected tissues indicated that stroma is the main target of the LPA paracrine loop in HCC. As a consequence, α-SMA-positive cells were more widespread in tumoral compared with paired peritumoral stroma. Conclusion: Our data indicate that LPA accelerates HCC progression by recruiting PTFs and promoting their transdifferentiation into myofibroblasts. Inhibition of LPA could prove effective in blocking transdifferentiation of myofibroblasts and tumor progression. © 2011 American Association for the Study of Liver Diseases.


Farahnak P.,Section of Surgery | Farahnak P.,Karolinska Institutet | Larfars G.,Section of Internal Medicine | Larfars G.,Karolinska Institutet | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: The extent and clinical significance of cardiovascular (CV) abnormalities associated with mild primary hyperparathyroidism (PHPT) are still matters for discussion. Objective: The main objective of the present study was to evaluate biochemical CV risk markers in PHPT patients before and after parathyroidectomy (PTX) in comparison with controls. Design and Subjects: In a prospective case-control design, 49 patients with PHPT and 49 healthy matched controls were included. Methods: Blood pressure (BP), 25-OH-D, plasminogen activator inhibitor-1 activity, von Willebrand factor antigen, homocysteine, high-sensitivity C-reactive protein, IGF-I, and lipid profile were evaluated at baseline and 15 ± 4 months after PTX. Results: At baseline, the level of 25-OH-D was significantly lower in patients compared with controls (40.1 ± 16.5 vs. 64.6 ± 20.8 nmol/liter, P < 0.001) and increased after PTX (58.9 ± 19.5, P < 0.001). Postoperatively, 25-OH-D was inversely correlated to the PTH level (r = -0.34; P < 0.05). Systolic BP (127.2 ± 17.4 vs. 119.3 ± 12.5mmHg, P < 0.05) and triglyceride (TG; 1.04 ± 0.60 vs. 0.86 ± 0.43 mmol/liter, P < 0.05) were higher in patients compared with controls and decreased slightly in patients after PTX (BP, 124.4 ± 16.8mmHg, and TG, 0.94 ± 0.50 mmol/liter, P < 0.05). Otherwise, there were no intergroup differences in coagulation, inflammatory, metabolic, and lipid status. Conclusions: Except for a lower 25-OH-D level and slightly higher systolic BP and TG levels, patients with mild PHPT without other CV risk factors did not differ from healthy controls as regards biomarkers predicting CV diseases. PTX had an overall positive effect on TG level, BP, and vitamin D status. Copyright © 2011 by The Endocrine Society.


Zuliani G.,Section of Internal Medicine | Donnorso M.P.,University of Rome Tor Vergata | Bosi C.,Section of Internal Medicine | Passaro A.,Section of Internal Medicine | And 5 more authors.
BMC Neurology | Year: 2011

Background: In central nervous system cholesterol cannot be degraded but is secreted into circulation predominantly in the form of its polar metabolite 24(S)-hydroxycholesterol (24S-OH-Chol). Some studies suggested an association between 24S-OH-Chol metabolism and different neurological diseases including dementia. A possible decrease in 24S-OH-Chol plasma levels has been reported late onset Alzheimer's disease (LOAD) and vascular dementia (VD), but results of previous studies are partially contradictory.Methods: By high-speed liquid chromatography/tandem mass spectrometry we evaluated the plasma levels of 24S-OH-Chol in a sample of 160 older individuals: 60 patients with LOAD, 35 patients with VD, 25 subjects affected by cognitive impairment no-dementia (CIND), and 40 (144 for genetics study) cognitively normal Controls. We also investigated the possible association between PPARgamma Pro12Ala polymorphism and dementia or 24S-OH-Chol levels.Results: Compared with Controls, plasma 24S-OH-Chol levels were higher in LOAD and lower in VD; a slight not-significant increase in CIND was observed (ANOVA p: 0.001). A positive correlation between 24S-OH-Chol/TC ratio and plasma C reactive protein (CRP) levels was found in the whole sample, independent of possible confounders (multiple regression p: 0.04; r2: 0.10). This correlation was strong in LOAD (r: 0.39), still present in CIND (r: 0.20), but was absent in VD patients (r: 0.08). The PPARgamma Pro12Ala polymorphism was not associated with the diagnosis of LOAD, VD, or CIND; no correlation emerged between the Ala allele and 24S-OH-Chol plasma levels.Conclusions: Our results suggest that plasma 24S-OH-Chol levels might be increased in the first stages of LOAD, and this phenomenon might be related with systemic inflammation. The finding of lower 24S-OH-Chol concentrations in VD might be related with a more advanced stage of VD compared with LOAD in our sample, and/or to different pathogenetic mechanisms and evolution of these two forms of dementia. © 2011 Zuliani et al; licensee BioMed Central Ltd.


Roth B.,Section of Internal Medicine | Manjer J.,Skåne University Hospital | Ohlsson B.,Section of Internal Medicine
Drug Target Insights | Year: 2013

Microscopic colitis (MC) is a disease with intestinal mucosal inflammation causing diarrhea, affecting predominantly middle-aged women. The etiology is unknown, but increased prevalence of autoimmune diseases in these patients has been described, although not compared with controls or adjusted for confounding factors. The aim of this study was to examine the prevalence of common diseases in patients with MC and controls from the general population. Hypertension, rheumatoid arthritis, asthma or bronchitis, ischemia, and diabetes mellitus were more prevalent in patients than in controls. The prevalence of gastric ulcer and cancer did not differ between the groups. Besides corticosteroids, many patients were also being treated with proton pump inhibitors, antidepressant drugs, angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, statins, thyroid hormones, and beta-blockers. More patients than controls were former or current smokers (72.5% versus 57.7%). Thus, MC patients have an increased prevalence of several diseases, not only of autoimmune origin. © the author(s), publisher and licensee Libertas Academica Ltd.


Murdolo G.,Assisi Hospital | Bartolini D.,University of Perugia | Tortoioli C.,Section of Internal Medicine | Piroddi M.,University of Perugia | And 2 more authors.
Free Radical Biology and Medicine | Year: 2013

The expansion of adipose tissue (AT) is, by definition, a hallmark of obesity. However, not all increases in fat mass are associated with pathophysiological cues. Indeed, whereas a "healthy" fat mass accrual, mainly in the subcutaneous depots, preserves metabolic homeostasis, explaining the occurrence of the metabolically healthy obese phenotype, "unhealthy" AT expansion is importantly associated with insulin resistance/type 2 diabetes and the metabolic syndrome. The development of a dysfunctional adipose organ may find mechanistic explanation in a reduced ability to recruit new and functional (pre)adipocytes from undifferentiated precursor cells. Such a failure of the adipogenic process underlies the "AT expandability" paradigm. The inability of AT to expand further to store excess nutrients, rather than obesity per se, induces a diabetogenic milieu by promoting the overflow and the ectopic deposition of fatty acids in insulin-dependent organs (i.e., lipotoxicity), the secretion of various metabolically detrimental adipose-derived hormones (i.e., adipokines and lipokines), and the occurrence of local and systemic inflammation and oxidative stress. Hitherto, fatty acids (i.e., lipokines) and the oxidation by-products of cholesterol and polyunsaturated fatty acids, such as nonenzymatic oxysterols and reactive aldehyde species, respectively, emerge as key modulators of (pre)adipocyte signaling through Wnt/β-catenin and MAPK pathways and potential regulators of glucose homeostasis. These and other mechanistic insights linking adipose dysfunction, oxidative stress, and impairment of glucose homeostasis are discussed in this review article, which focuses on adipose peroxidation as a potential instigator of, and a putative therapeutic target for, obesity-associated metabolic dysfunctions. © 2013 Elsevier Inc.


Rydman R.,Karolinska University Hospital | Soderberg M.,Section of Internal Medicine | Larsen F.,Karolinska University Hospital | Caidahl K.,Karolinska University Hospital | Alam M.,Karolinska Institutet
Echocardiography | Year: 2010

Assessment of right ventricular (RV) function is a challenge due to complex anatomy. We studied systolic and diastolic tricuspid annular excursion and longitudinal RV fractional shortening as geometry-independent measures in patients with acute pulmonary embolism (PE). Forty patients with PE were studied within 24 hours after admission and after 3 months, and compared to 23 healthy subjects used as controls. We recorded tricuspid annular plane systolic (TAPSE) and diastolic (TAPDE) excursion from the four-chamber view and calculated RV fractional shortening as TAPSE/RV diastolic length. The diastolic RV function was defined as the ratio of the amplitude of tricuspid annular plane excursion during atrial systole to total tricuspid annular plane diastolic excursion (atrial/total TAPDE). In the acute stage, the TAPSE was decreased in PE compared to healthy subjects (19 ± 5 vs. 26 ± 4 mm, P < 0.001), with greater reduction in patients with increased, compared to normal, RV pressure (16.6 ± 5 vs. 20.5 ± 5 mm, P < 0.05). The atrial/total TAPDE was increased in patients compared to healthy subjects (47 ± 13% vs. 38 ± 7%, P < 0.001) and normalized during the follow-up. Although the patients were asymptomatic after 3 months, the TAPSE recovered incompletely as compared to healthy subjects (21.4 ± 4 vs. 26 ± 4 mm, P < 0.001). Both systolic and diastolic RV function are impaired in acute PE. Diastolic function recovers faster than systolic; therefore, the atrial contribution to RV filling may be a useful measure to follow changes in diastolic function in PE. © 2010, Wiley Periodicals, Inc.


Franceschini A.,University of Ferrara | Capece M.,University of Ferrara | Chiozzi P.,University of Ferrara | Falzoni S.,University of Ferrara | And 5 more authors.
FASEB Journal | Year: 2015

The P2X7 receptor (P2X7R) is a known and powerful activator of the NOD-like receptor (NLR)P3 inflammasome; however, the underlying pathways are poorly understood. Thus, we investigated the molecular mechanisms involved. The effect of P2X7R expression and activation on NLRP3 expression and recruitment was investigated by Western blot, RT-PCR, coimmunoprecipitation, and confocal microscopy in microglial mouse cell lines selected for reduced P2X7R expression and in primary cells from P2X7R-/- C57BL/6 mice. We show here that P2X7R activation by ATP (EC50 = 1 mM) or benzoyl-ATP (EC50 = 300 μM) and P2X7R down-modulation caused a 2- to 8-fold up-regulation of NLRP3 mRNA in mouseN13microglial cells. Moreover, NLRP3 mRNA was also up-regulated in primary microglial and macrophage cells from P2X7R-/- mice. Confocal microscopy and immunoprecipitation assays showed that P2X7R and NLRP3 closely interacted at discrete subplasmalemmal sites. Finally, P2X7R stimulation caused a transient (3-4 min) cytoplasmic Ca2+ increase localized to small (2-3 mm wide) discrete subplasmalemmal regions. The Ca2+ increase drove P2X7R recruitment and a 4-fold increase in P2X7R/NLRP3 association within 1-2 min. These data show a close P2X7R and NLRP3 interaction and highlight the role of P2X7R in the localized cytoplasmic ion changes responsible for bothNLRP3 recruitment and activation. © FASEB.


Trotta F.,University of Ferrara | Colina M.,Section of Internal Medicine
Best Practice and Research: Clinical Rheumatology | Year: 2012

Multicentric reticulohistiocytosis (MRH) and fibroblastic rheumatism (FR) are uncommon disorders with similar joint and skin manifestations. They are usually included among the non-Langerhans histiocytoses, but recent insights drive some criticism. The diagnosis is often challenging and must be confirmed by the histological typical features. If the skin manifestations are missing, the arthritic complaints may be confused with those of other rheumatic disorders. In these cases, only a careful clinical and radiological evaluation leads to the correct diagnosis. The natural course of the diseases may rapidly develop into disabling manifestations, making an aggressive treatment strongly recommendable. There is emerging evidence that anti-tumour necrosis factor-α agents and bisphosphonates are promising drugs for MRH, while a course of methotrexate and steroids seems to be the best option for FR. Finally, the clinician should be aware that in many cases MRH, but not FR, is associated with a large number of systemic manifestations and with malignancy. This eventuality must be accurately ruled out. © 2012 Elsevier Ltd. All rights reserved.

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