HDL-C concentration is related to markers of absorption and of cholesterol synthesis: Study in subjects with low vs. high HDL-C

Background: The antiatherogenic functions of high density lipoprotein (HDL-C) include its role in reverse cholesterol transport, but to what extent the concentration of HDL-C interferes with the whole-body cholesterol metabolism is unknown. Therefore, we measured markers of body cholesterol synthesis (desmosterol and lathosterol) and of intestinal cholesterol absorption (campesterol and beta-sitosterol) in healthy subjects that differ according to their plasma HDL-C concentrations. Methods: Healthy participants presented either low HDL-C (<40 mg/dl, n = 33,17 male and 16 female) or high HDL-C (>60 mg/dl, n = 33, 17 male and 16 female), BMI <30 kg/m(2), were paired according to age and gender, without secondary factors that might interfere with their plasma lipid concentrations. Plasma concentrations of non-cholesterol sterols were measured by the combined GC-MS analysis. Results: Plasma desmosterol did not differ between the two groups; however, as compared with the high HDL-C participants, the low HDL-C participants presented higher concentration of lathosterol and lower concentration of the intestinal cholesterol absorption markers campesterol and beta-sitosterol. Conclusion: Plasma concentrations of HDL, and not the activities of LCAT and CETP that regulate the reverse cholesterol transport system, correlate with plasma sterol markers of intestinal cholesterol absorption directly, and of cholesterol synthesis reciprocally. (C) 2010 Elsevier B.V. All rights reserved.

Sensitization to foods in gastroesophageal reflux disease and its relation to eosinophils in the esophagus: is it of clinical importance?

Background: Refractory gastroesophageal reflux disease (GERD) can be related to greater sensitization to foods. Objective: To evaluate sensitization to foods in patients with refractory GERD. Methods: Patients with refractory GERD after using at least 40 mg of a proton pump inhibitor were given a restriction diet based on the results of skin prick testing and atopy patch testing with foods. The characteristics of sensitized patients were compared with those of nonsensitized patients in relation to atopy and number of eosinophils in the esophageal mucosa. Results: The prevalence of sensitization to foods was 27.7%. Asthmatic patients showed higher sensitization to foods (P = .008). Eosinophils were determined to be present in the esophageal mucosa in 15.8% of patients, and this correlated with greater sensitization to foods (P = .01). One case of eosinophilic esophagitis was confirmed. A diet excluding identified sensitizing foods led to clinical improvement regarding GERD symptoms (P = .004). Conclusion: The presence of eosinophils in esophageal mucosa associated with greater sensitization to foods and the response to a restriction diet in patients with positive test results suggest that refractory GERD can represent an initial stage of eosinophilic esophagitis. Ann Allergy Asthma Immunol. 2010;105:359-363.

High sucrose intake in rats is associated with increased ACE2 and angiotensin-(1-7) levels in the adipose tissue

Sucrose-fed rats, a model of metabolic syndrome, are characterized by insulin resistance, obesity, hypertension, and high plasma levels of triacylglycerols and angiotensin II (Ang II). However, whether tissue renin-angiotensin system (RAS) is altered in metabolic syndrome is unclear. To study this issue, food ad libitum and water (C) or 20% sucrose solution (SC) were given to adult male Wistar rats, for 30 days. Body weight (BW), blood pressure (BP), epididymal adipose tissue (EPI) mass, rate of in vivo fatty acid (FA) synthesis in EPI, circulating glucose, insulin, leptin, angiotensins I and II, triacylglycerols, and plasma renin (PRA) and angiotensin-converting enzyme (ACE) activities were evaluated. In kidneys and EPI, gene and protein expression of type 1 (AT(1)) and 2 (AT(2)) Ang II receptors, ACE, angiotensinogen (ACT) as well as protein expression of angiotensin-converting enzyme 2 (ACE2) were determined. In both tissues, Ang I, Ang II and Ang-(1-7) contents were also measured by HPLC. In SC rats higher BP, EPI mass, circulating triacylglycerols, insulin, leptin, PRA and, Ang II were found. In EPI, the rate of in vivo FA synthesis was associated with increased Ang-(1-7), protein expression of AT(1) and AT(2) receptors, ACE2, ACT, and gene expression of ACT although a reduction in ACE activity and in adipose Ang I and Ang II contents was observed. In kidneys, AT(1) and AT(2), ACE and ACT gene and protein expression as well as protein expression of ACE2 were unaltered while Ang II, Ang-(1-7) and ACE activity increased. These RAS component changes seem to be tissue specific and possibly are related to enhancement of FA synthesis, EPI mass and hypertension. (C) 2010 Elsevier B.V. All rights reserved.

Mandibular Function is Severely Impaired in Systemic Sclerosis Patients

Aims: To evaluate the presence of temporomandibular disorders (TMD) in systemic sclerosis (SSc) patients and its possible association with the severity of skin involvement. Methods: The presence of TMD was evaluated in 35 SSc women and 30 age- and sex-matched healthy controls by means of the anamnestic (A(i)) and clinical (D(i)) Helkimo indices; the jaw mobility was further analyzed (M(I)). Skin involvement was scored by the Modified Rodnan Skin Score (MRSS). Results: Signs and symptoms of TMD were more frequent in SSc patients than in controls, the frequency distribution of the different clinical dysfunction indices differing significantly (P < .001) between patients (D(i)0 8.6%, D(i)I 48.6%, D(i)II 22.8%, and D(i)III 20%) and controls (D(i)0 50%, D(i)I 33.3%, and D(i)II 16.7%). Cyclophosphamide for severe and rapidly progressive cutaneous fibrosis was prescribed in six out of seven patients with severe signs (D(i)III), in contrast this treatment was indicated for only two out of 25 patients with mild to moderate signs (D(i)I and D(i)II, P <. 001). Impaired jaw mobility was more frequent in SSc patients than controls (P < .001). It was severe in 77.1% (M(I)II) and mild in 22.9% (M(1)I) of the cases, in contrast to controls (M(I)0 33.4%, M(I)I 53.3%, and M(I)II 13.3%; P < .001). Approximately half of SSc patients with severe (M(I)II) but none of those with mild impairment were on cyclophosphamide treatment for severe cutaneous fibrosis (P = .02). Conclusion: Severe signs of TMD according to the anamnestic and clinical Helkimo indices were very frequent in SSc patients. J OROFAC PAIN 2010;24:197-202

Collagen is reduced and disrupted in human aneurysms and dissections of ascending aorta

In ascending aorta aneurysms, there is an enlargement of the whole vessel, whereas aortic dissections (ADs) are characterized by the cleavage of the wall into 2 sheets at the external half. We searched if alterations in collagen could be related to these diseases. Sections of aortas from 14 case patients with acute dissections, 10 case patients with aneurysms, and 9 control subjects were stained with picrosirius. Slides were analyzed under polarized microscopy to evaluate the structure of collagen fibers. The proportion of collagen was calculated in each half of the medial layer by color detection in a computerized image analysis system. Collagen appearance under polarized light was consistent with collagenolysis. The mean collagen proportions at the inner and outer halves, respectively, were 0.50 +/- 0.13 and 0.40 +/- 0.08 in the control group, 0.20 +/- 0.10 and 0.18 +/- 0.12 in the AD group, and 0.33 +/- 0.12 and 0.19 +/- 0.12 in the aneurysm group. The AD (P < .01) and control (P = .04) groups had less collagen at the external half, no difference was found in the aneurysm group (P = .71). In both halves, there was less collagen in the case patients than in the control subjects (all P < .01), but at the internal half, the decrease was significantly greater in the case patients with aneurysms than in those with dissections (P = .03; at the external half, P = .99). Aortic dissections and aneurysms show a decrease in collagen content that could be related to a weakness of the wall underlying the diseases, but the locations of the decrease differ: in dissections, it is situated mostly at the external portion of the media (site of cleavage), whereas in aneurysms, it is more diffuse, consistent with the global enlargement. (c) 2008 Elsevier Inc. All rights reserved.

Human leukocyte antigen-G expression after kidney transplantation is associated with a reduced incidence of rejection

HLA-G is a non-classic Human Leukocyte Antigen (HLA-G) Class I of low polymorphism and restricted tissue distribution that displays tolerogenic functions. In heart transplantation and in combined liver/renal allograft transplantation, the expression of HLA-G has been associated with a lower incidence of acute graft rejection episodes and absence of chronic dysfunction. Since the expression of HLA-G in renal biopsies has been investigated only in few patients who received a combined kidney and liver transplant, in this study we performed a cross-sectional study, systematically comparing the expression of HLA-G in post-transplanted renal grafts, stratifying patients according to the presence or absence of rejection. Patients and Methods: Seventy-three renal specimens (10 with acute rejection and 13 with chronic allograft nephropathy, and 50 with no signs of rejection) were immunohistochemically evaluated for HLA-G expression. Results: In the group as a whole, HLA-G molecules were detected in 40 cases (54.8%). Among specimens that presented HLA-G expression, 2 out of 40 (5%) exhibited acute rejection, 2 (5%) exhibited chronic allograft nephropathy, and the remaining 36 (90%) exhibited no signs of rejection. The comparison between patients with rejection and those without rejection showed that the expression of HLA-G was significantly increased in specimens exhibiting no signs of rejection (p<0.0001). Considering only patients with acute rejection, 8 out of 10 patients showed no HLA-G expression in their kidney biopsies when compared to patients exhibiting no signs of rejection and absence of HLA-G was observed in 14 out of 50 (p=0.0032). Similarly, considering only patients with chronic allograft nephropathy, absence of HLA-G expression was observed in I I out of 13 specimens, whereas in patients without rejection absence of HLA-G was observed in 14 out of 50 (p=0.003). Therapy with tacrolimus was significantly associated with the expression of HLA-G and a better graft prognosis. Conclusions: Our results suggest that HLA-G expression in the kidney allograft and the use of tacrolimus are associated with a lower frequency of acute renal rejection and chronic allograft nephropathy. (c) 2007 Elsevier B.V. All rights reserved.

Severe Periodontitis Is Associated With Diastolic Blood Pressure Elevation in Individuals With Heterozygous Familial Hypercholesterolemia: A Pilot Study

Background: This pilot study evaluates the association of severe periodontitis with pulse wave velocity (PWV), carotid artery intima-medial thickness (IMT), and clinical, metabolic, and atherogenic inflammatory markers in 79 subjects with heterozygous familial hypercholesterolemia (hFH). All subjects were free of previous vascular disease manifestations. Methods: The body mass index (in kilograms per square meter), plasma lipids, glucose, C-reactive protein, and white blood cell counts were evaluated. After full-mouth periodontal examinations, patients were categorized into the severe periodontitis group (SPG) or non-severe periodontitis group (NSPG). Results: The SPG showed significantly higher values of cholesterol-year scores, triglycerides, glucose, PWV, IMT, and diastolic blood pressure (DBP) (P <= 0.05) than the NSPG. After adjustment for traditional risk factors for atherosclerosis, only the association between severe periodontitis and DBP (odds ratio: 3.1; 95% CI: 1.1 to 8.5; P = 0.03) was confirmed. Conclusion: In individuals with hFH, severe periodontitis was associated with a higher DBP, which suggests that severe periodontitis, itself, may contribute to the increased cardiovascular risk profile in this population. J Periodontol 2011;82:683-688.

Native LDL-Cholesterol Mediated Monocyte Adhesion Molecule Overexpression is Blocked by Simvastatin

Aim of the study This study sought to evaluate the effect of nLDL concentrations on monocyte adhesion molecule expression in hypercholesterolemic patients with stable corollary artery disease (CAD) and to determine whether lipid-lowering therapy with simvastatin Would change this effect. Methods Blood samples from patients with hypercholesterolemia (mean LDL 152 mg/dL) and CAD (HC, n = 23) were collected before and after a 12-week treatment with 40 mg of simvastatin. Healthy individuals (mean LDL 111 mg/dL) were used as controls (CT, n = 15). Isolated nLDL, at a fixed concentration of 100 mg/dL, was added to monocyte suspensions obtained before and after the simvastatin treatment. Monocyte activation was determined by changes in cellular adhesion molecule expression. Results In response to nLDL, CD11b and CD14 adhesion molecule expression was higher in HC patients than in CT patients before treatment (174.2+/-8.4 vs 102.2+/-6.3, P<0.03 and 140.4+/-5.0 vs 90.4+/-6.7, P<0.04). After simvastatin treatment, CD11b expression decreased to 116.9+/-12.5 (P< 0.03) and CD14 expression to 107.5+/-6.2 (P<0.04). Alternatively, L-selectin expression was lower in HC patients than in CT patients before therapy (46.0+/-3.5 vs 62.1+/-5.5, P<0.04), and it increased markedly after lipid reduction to 58.7+/-5.0 (P<0.04 vs baseline). After simvastatin treatment, LDL was reduced to mean 101.5 mg/dL. Conclusions These data demonstrate that monocytes from HC patients are more prone to marked nLDL-mediated changes of adhesion molecule expression than monocytes from controls. Simvastatin is capable of inhibiting such nLDL effects. This proinflammatory response to nLDL may have a role in the early onset of atherosclerosis.

Pressure-Frequency Sensing Subxiphoid Access System for Use in Percutaneous Cardiac Electrophysiology: Prototype Design and Pilot Study Results

We have designed, built, and tested an early prototype of a novel subxiphoid access system intended to facilitate epicardial electrophysiology, but with possible applications elsewhere in the body. The present version of the system consists of a commercially available insertion needle, a miniature pressure sensor and interconnect tubing, read-out electronics to monitor the pressures measured during the access procedure, and a host computer with user-interface software. The nominal resolution of the system is <0.1 mmHg, and it has deviations from linearity of <1%. During a pilot series of human clinical studies with this system, as well as in an auxiliary study done with an independent method, we observed that the pericardial space contained pressure-frequency components related to both the heart rate and respiratory rate, while the thorax contained components related only to the respiratory rate, a previously unobserved finding that could facilitate access to the pericardial space. We present and discuss the design principles, details of construction, and performance characteristics of this system.

NFAT1 transcription factor is central in the regulation of tissue microenvironment for tumor metastasis

Members of the nuclear factor of activated T cell (NFAT) family of transcription factors were originally described in T lymphocytes but later shown to be expressed in several immune and non-immune cell types. NFAT proteins can modulate cellular transformation intrinsically, and NFAT-deficient (NFAT1-/-) mice are indeed more susceptible to transformation than wild-type counterparts. However, the contribution of an NFAT1-/- microenvironment to tumor progression has not been studied. We have addressed this question by inoculating NFAT1-/- mice with B16F10 melanoma cells intravenously, an established model of tumor homing and growth. Surprisingly, NFAT1-/- animals sustained less tumor growth in the lungs after melanoma inoculation than wild-type counterparts. Even though melanoma cells equally colonize NFAT1-/- and wild-type lungs, tumors do not progress in the absence of NFAT1 expression. A massive mononuclear perivascular infiltrate and reduced expression of TGF-beta in the absence of NFAT1 suggested a role for tumor-infiltrating immune cells and the cytokine milieu. However, these processes are independent of an IL-4-induced regulatory tumor microenvironment, since lack of this cytokine does not alter the phenotype in NFAT1-/- animals. Bone marrow chimera experiments meant to differentiate the contributions of stromal and infiltrating cells to tumor progression demonstrated that NFAT1-induced susceptibility to pulmonary tumor growth depends on NFAT1-expressing parenchyma rather than on bone marrow-derived cells. These results suggest an important role for NFAT1 in radio-resistant tumor-associated parenchyma, which is independent of the anti-tumor immune response and Th1 versus Th2 cytokine milieu established by the cancer cells, but able to promote site-specific tumor growth.

Activation of the Wnt/Beta-catenin Signaling Pathway during Oral Carcinogenesis Process Is Not Influenced by the Absence of Galectin-3 in Mice

Background/Aim: Galectin-3 has been associated with activated Wnt pathway, translocating beta-catenin into the nucleus. However, it is still unknown whether this lectin drives the Wnt signaling activation in lesions from galectin-3-deficient (Gal3(-/-)) mice. The purpose was to study beta-catenin expression in tongue lesions from Gal3(-/-) and wildtype (Gal3(+/+)) mice and the status of Wnt signaling. Materials and Methods: Twenty Gal3(-/-) and Gal3(+/+) male mice were challenged with 4-nitroquinolin-1-oxide and killed at week 16 and 32. Tongues were processed and stained with H&E to detect dysplasias and carcinomas. An imunohistochemical assay was performed to evaluate beta-catenin expression. Results: Carcinomas were more evident in Gal3(+/+) than Gal3(-/-) mice (55.5% vs. 28.5%, respectively; p>0.05). Elevated expression of non-membranous beta-catenin was observed in dysplasias and carcinomas from both groups (p>0.05). Conclusion: Absence of galectin-3 does not interfere in the pattern of beta-catenin expression and therefore in the mediation of the Wnt signaling pathway.

Silencing of LRRC49 and THAP10 genes by bidirectional promoter hypermethylation is a frequent event in breast cancer

Previously we found that levels of LRRC49 (leucine rich repeat containing 49; FLJ20156) transcripts were elevated in ER-positive breast tumors compared with ER-negative breast tumors. The LRRC49 gene is located on chromosome 15q23 in close proximity to the THAP10 (THAP domain containing 10) gene. These two genes have a bidirectional organization being arranged head-to-head on opposite strands, possibly sharing the same promoter region. Analysis of the promoter region of this gene pair revealed the presence of potential estrogen response elements (EREs), suggesting the potential of this promoter to be under the control of estrogen. We used quantitative real-time PCR (qPCR) to evaluate the expression of LRRC49 and THAP10 in a series of 72 primary breast tumors, and found reduced LRRC49 and THAP10 expression in 61 and 46% of the primary breast tumors analyzed, respectively. In addition, the occurrence of LRRC49/THAP10 promoter hypermethylation was examined by methylation specific PCR (MSP) in a sub-group of the breast tumors. Hypermethylation was observed in 57.5% of the breast tumors analyzed, and the levels of mRNA expression of both genes were inversely correlated with promoter hypermethylation. We investigated the effects of 17 beta-estradiol on LRRC49 and THAP10 expression in MCF-7 breast cancer cells and found both transcripts to be up-regulated 2- to 3-fold upon 17 beta-estradiol treatment. Our results show that the transcripts of LRRC49/THAP10 bidirectional gene pair are co-regulated by estrogen and that hypermethylation of the bidirectional promoter region simultaneously silences both genes. Further studies will be necessary to elucidate the role of LRRC49/THAP10 down-regulation in breast cancer.

Altered Ex Vivo Expression of Caspase 8, Caspase 9, and Bcl-2 Is Associated with T-Cell Hyporeactivity in Patients with Paracoccidioidomycosis

To better understand the T-cell hyporesponsiveness of patients with paracoccidioidomycosis, we tested the hypothesis that the T cells were committed to apoptosis. We show here that T cells of patients with paracoccidioidomycosis overexpress caspase 9 and caspase 8 but express low Bcl-2 levels and that interleukin-2 was unable to revert the hyporesponsiveness. These data suggest that the T cells would in vivo be driven to a tolerant state and apoptosis.

FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC(3) program

Background & Aims: EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon-alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Methods: Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Results: Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2 = 0.80 (p<0.00001). Five baseline factors were associated (p<0.001) with SVR in UV and MV analyses (odds ratio: UV/MV): fibrosis stage estimated using FT (4.5/5.9) or biopsy (1.5/1.6), genotype 2/3 (4.5/5.1), BVL (1.5/1.3), prior relapse (1.6/1.6), previous treatment with non-PEG-IFN (2.6/2.0). These same factors were associated (p <= 0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis (p <= 0.001): genotype 2/3 (odds ratio = 2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). Conclusions: FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12 weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Screening Anal Dysplasia in HIV-Infected Patients: Is There an Agreement Between Anal Pap Smear and High-Resolution Anoscopy-Guided Biopsy?

PURPOSE: The purpose of this study was to analyze the agreement between anal Pap smear and high-resolution anoscopy-guided biopsy in diagnosing anal dysplasia in HIV-infected patients. METHODS: We conducted cross-sectional analysis of HIV-infected patients receiving anal dysplasia screening as part of routine care. Agreement between measures was estimated by weighted kappa statistics, using a three-tiered cytologic and histologic grading system (normal, low-grade dysplasia, and high-grade dysplasia). Estimates of sensitivity, specificity, and predictive values were calculated using a two-tiered cytologic and histologic grading system (""without dysplasia"" and ""with dysplasia of any grade""). Estimates were also calculated for the detection of high-grade dysplasia. RESULTS: During a one-year period, 222 patients underwent 330 anal Pap smears followed by high-resolution anoscopy-guided biopsies. There were 311 satisfactory Pap smears with concurrent biopsies. Considering histology the standard, the frequency of anal dysplasia was 46%. Kappa agreement between anal Pap smear and biopsy was 0.20. For detection of anal dysplasia of any grade, anal Pap smear showed sensitivity of 61%, specificity of 60%, positive predictive value of 56%, and negative predictive value of 64%. For high-grade dysplasia, anal Pap smear showed sensitivity of 16% and specificity of 97%. CONCLUSION: Anal Pap smears alone were not sensitive enough to rule out anal dysplasia. We recommend that high-resolution anoscopy-guided biopsy be incorporated as a complementary screening test for anal dysplasia in high-risk patients. Following baseline high-resolution anoscopy, these individuals could be followed with serial anal cytology to dictate the need for future high-resolution anoscopy-guided biopsies.