Usefulness of liver biopsy in chronic hepatitis C

Major requirements for performance of liver biopsy (LB) are the benefits for the patient and the impossibility of having the same information by less invasive procedures. In the last two decades physicians have faced the difficult task of convincing a patient positive for hepatitis C, with minimal clinical or laboratory alterations to be submitted to LB in order to evaluate the status of the disease for therapeutic management. The characteristics of the needle used for percutaneous LB interferes with the accuracy of diagnosis. In chronic hepatitis C (CHC), validity is achieved with liver fragments about 25mm in length containing more than 10 portal tracts. Morbidity due to LB is mainly related to bleeding but death is very rare. Severe complications are also uncommon, increasing with number of passes and decreasing with experience of operator and ultrasound guidance. Although CHC is a diffuse disease, the various areas of the liver may not be equally affected and sampling errors are possible. Another potential limitation of LB is the discordance between pathologists in its interpretation. To replace LB, many panels of surrogate markers have been described, aiming to identify extent of fibrosis and inflammation. All of them have used LB as their ""gold standard"". Liver biopsy continues to be the most reliable method to evaluate the possibility of therapy for CHC. Universal treatment of all patients with diagnosis of CHC would be ideal. But, there are mainly three drawbacks. Overall efficacy is as low as 50%, side effects are common and may be severe and treatment is prolonged and expensive. The acceptability of the biopsy by the patient is highly dependent on the physician`s conviction of its usefulness.

A pilot double-blind sham-controlled trial of repetitive transcranial magnetic stimulation for patients with refractory schizophrenia treated with clozapine

Schizophrenia is a complex and heterogeneous psychiatric disorder. Auditory verbal hallucinations occur in 50-70% of patients with schizophrenia and are associated with significant distress, decreased quality of life and impaired social functioning. This study aimed to investigate the effects of active compared with sham 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal-parietal cortex in patients with schizophrenia treated with clozapine. Symptom dimensions that were evaluated included general psychopathology, severity of auditory hallucinations, quality of life and functionality. Seventeen right-handed patients with refractory schizophrenia experiencing auditory verbal hallucinations and treated with clozapine were randomly allocated to receive either active rTMS or sham stimulation. A total of 384 min of rTMS was administered over 20 days using a double-masked, sham-controlled, parallel design. There was a significant reduction in Brief Psychiatric Rating Scale (BPRS) scores in the active group compared with the sham group. There was no significant difference between active and sham rTMS on Quality of Life Scale (QLS), Auditory Hallucinations Rating Scale (AHRS), Clinical Global Impressions (CGI) and functional assessment staging ( FAST) scores. Compared with sham stimulation, active rTMS of the left temporoparietal cortex in clozapine-treated patients showed a positive effect on general psychopathology. However, there was no effect on refractory auditory hallucinations. Further studies with larger sample sizes are needed to confirm these findings. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Reaching C-Reactive Protein and Low-Density Lipoprotein Cholesterol Goals in Dyslipidemic Patients (from the Lipid Treatment Assessment Project [L-TAP] 2)

The purpose of the present substudy of the Lipid Treatment Assessment Project 2 was to assess dual C-reactive protein (CRP) and low-density lipoprotein (LDL) cholesterol goal attainment across a spectrum of low-, moderate-, and high-risk patients with dyslipidemia in 8 countries in North America, Latin America, Europe, and Asia. Of the 9,518 patients studied overall, 45% were women, 64% had hypertension, 31% had diabetes, 14% were current smokers, 60% were high risk, and 79% were taking a statin. The median CRP level was 1.5 mg/L (interquartile range 0.2 to 2.8). On multivariate analysis, higher CRP levels were associated with older age, female gender, hypertension, current smoking, greater body mass index, larger waist circumference, LDL cholesterol level, and triglyceride/high-density lipoprotein cholesterol ratio. In contrast, being from Asia or taking a statin was associated with lower levels. Across all risk groups, 59% of patients attained the CRP target of <2 mg/L, and 33% had <1 mg/L. Overall, 44% of patients attained both their National Cholesterol Education Program Adult Treatment Panel III LDL cholesterol target and a CRP level of <2 mg/L, but only 26% attained their LDL cholesterol target and a CRP level of <1 mg/L. In the very high-risk group with coronary heart disease and >= 2 risk factors, only 19% attained both their LDL cholesterol goal and a CRP level of <2 mg/L and 12% their LDL cholesterol goal and a CRP level of <1 mg/L. In conclusion, with current treatment, most dyslipidemic patients do not reach the dual CRP and LDL cholesterol goals. Smoking cessation, weight reduction, and the greater use of more potent statins at higher doses might be able to improve these outcomes. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:1639-1643)

Use of AST platelet ratio index (APRI Score) as an alternative to liver biopsy for treatment indication in chronic hepatitis C

Chronic hepatitis C (CHC) is one of the most important causes of chronic liver disease in the world, potentially resulting in cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. Liver biopsy is currently performed before therapy indication. Although, it is the golden standard there are many reasons to avoid or delay the procedure. APRI Score is an easy, low cost and practice alternative method which was described as an alternative for assessing structural changes in chronic hepatitis C (CHC). The rationale of this study was to observe the accuracy of APRI Score in comparison to liver biopsy in 400 patients divided into two groups of 200 carriers (Validation and Experimental groups respectively) selected at random or according to liver fibrosis staging (METAVIR). The ROC curves showed a concordance among these two methods of 92% and 88.5% when 1.05 was the cut off (F3 and F4), and 87% and 83%, on 0.75 cut offs (F2-F4). The discordance in advanced fibrosis staging (F3 and F4) was only 16 (8%) and 22 (11%) out of 200 patients in the experimental and validation groups, respectively. In 26 (13%) out of 200 patients in the experimental group and 34 (17%) out of 200 patients in the validation group, there was discordance between APRI Score and liver biopsy in moderate and advanced fibrosis (F2-F4). In conclusion APRI is a serological marker that has satisfactory sensitivity and specificity together with a high predictive value and it can be useful either in the absence of a biopsy or to reduce the frequency with which biopsies need to be carried out to monitor the evolution of chronic hepatitis C and the right moment for treatment indication.

Mannan-binding lectin MBL2 gene polymorphism in chronic hepatitis C: association with the severity of liver fibrosis and response to interferon therapy

Hepatitis C virus (HCV) is a major cause of hepatic disease and of liver transplantation worldwide. Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement activating molecule in HCV persistence and liver injury. We assessed the MBL2 polymorphism in 102 Euro-Brazilian patients with moderate and severe chronic hepatitis C, paired for gender and age with 102 HCV seronegative healthy individuals. Six common single nucleotide polymorphisms in the MBL2 gene, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction with fluorescent hybridization probes. The concentration of MBL in plasma was measured by enzyme-linked immunosorbent assay. The frequency of the YA/YO genotype was significantly higher in the HCV patients compared with the controls (P = 0.022). On the other hand, the genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4), when compared with the patients with moderate fibrosis (stage F2) (P = 0.04) and to the control group (P = 0.011). Furthermore, MBL2 genotypes containing X or O mutations were found to be associated with non-responsiveness to pginterferon and ribavirin treatment (P = 0.023). MBL2 polymorphisms may therefore be associated not only with the development of chronic hepatitis C, but also with its clinical evolution and response to treatment.

The Role of Prostate Specific Membrane Antigen and Pepsinogen C Tissue Expression as an Adjunctive Method to Prostate Cancer Diagnosis

Purpose: The diagnosis of prostate cancer in men with persistently increased prostate specific antigen after a negative prostate biopsy has become a great challenge for urologists and pathologists. We analyzed the diagnostic value of 6 genes in the tissue of patients with prostate cancer. Materials and Methods: The study was comprised of 50 patients with localized disease who underwent radical prostatectomy. Gene selection was based on a previous microarray analysis. Among 4,147 genes with different expressions between 2 pools of patients 6 genes (PSMA, TMEFF2, GREB1, TH1L, IgH3 and PGC) were selected. These genes were tested for diagnostic value using the quantitative reverse transcription polymerase chain reaction method. Initially malignant tissue samples from 33 patients were analyzed and in the second part of the study we analyzed benign tissue samples from the other 17 patients with prostate cancer. The control group was comprised of tissue samples of patients with benign prostatic hyperplasia. Results: Analysis of malignant prostatic tissue demonstrated that prostate specific membrane antigen was over expressed (mean 9 times) and pepsinogen C was under expressed (mean 1.3 X 10(-4) times) in all cases compared to benign prostatic hyperplasia. The other 4 tested genes showed a variable expression pattern not allowing for differentiation between benign and malignant cases. When we tested these results in the benign prostate tissues from patients with cancer, pepsinogen C maintained the expression pattern. In terms of prostate specific membrane antigen, despite over expression in most cases (mean 12 times), 2 cases (12%) presented with under expression. Conclusions: Pepsinogen C tissue expression may constitute a powerful adjunctive method to prostate biopsy in the diagnosis of prostate cancer cases.

Voiding Dysfunction in Patients With Parkinson`s Disease: Impact of Neurological Impairment and Clinical Parameters

Aims: We assessed the lower urinary tract symptoms (LUTS) of patients with Parkinson`s disease (PD) and their association with different clinical parameters. Methods: We prospectively evaluated 110 patients (84 men), with a mean age of 61.8 +/- 9.6 years. Mean duration of the disease was 12.3 +/- 7.2 years. Neurological impairment was assessed by the Hoehn-Yahr and the Unified Parkinson Disease Rating scales. LUTS were assessed by the International Continence Society questionnaire. We evaluated the impact of age, PD duration, neurological impairment, gender, and use of anti-Parkinsonian drugs on the voiding function. Results: On multivariate analysis, voiding dysfunction increased with the neurological impairment, but not with patient`s age or disease duration. Quality of life (QOL) was affected by the severity of LUTS, and the symptoms with the worst impact were frequency and nocturia. Sixty-three (57.2%) patients were symptomatic. They did not differ with the asymptomatic as to age and disease duration, but had more severe neurological impairment. No impact on LUTS was associated with the use of levodopa, anticholinergics, and dopamine receptor agonists. Men and women were similarly affected by urinary symptoms. Conclusions: The severity of the neurological disease is the only predictive factor for the occurrence of voiding dysfunction, which affects men and women alike. Neztrourol. Urodynam. 28.510-515, 2009. (C) 2009 Wiley-Liss, Inc.

SINGLE MEASUREMENTS OF C-REACTIVE PROTEIN AND DISEASE ACTIVITY SCORES ARE NOT PREDICTORS OF CAROTID ATHEROSCLEROSIS IN RHEUMATOID ARTHRITIS PATIENTS

Background: Although inflammation has a defined role in the pathogenesis of atherosclerosis, the link between rheumatoid arthritis (RA) parameters of disease activity and atherosclerotic findings are not defined. Objective: To investigate the association between subclinical carotid atherosclerosis and clinical/laboratorial parameters of RA systemic inflammatory activity. Methods: Seventy-one RA patients were consecutively selected and compared to 53 healthy controls. Smoking, diabetes and hypertension were excluded, as well as the use of statins or fibrates. B-mode carotid ultrasound was performed in all subjects. CRP, ESR and fibrinogen were determined in both groups. Clinical assessment of RA activity included DAS 28 and SDAI. Correlation between plaques and intima-media thickness (IMT) of common carotid arteries and inflammatory parameters was evaluated. Results: Carotid plaques were more prevalent in RA patients than in controls (14.1% vs. 1.9 %, p=0.02) and marginally increased IMT was observed (0.72 +/- 0.17 vs. 0.67 +/- 0.15mm, p=0.07). RA patients with plaques had older age (p=0.001) and increased IMT (p<0.001), but low SDAI (p=0.025) compared to those without plaques. RA patients with plaques had also longer disease duration, although this difference did not reach statistical significance (p=0.06). No significant correlations were found between IMT and ESR (p=0.80), CRP (p=0.75), fibrinogen (p=0.94), HAQ (p=0.89) and DAS 28 (p=0.13). Conclusions: Carotid atherosclerosis is more frequently detected in RA but its prevalence was not correlated with isolated inflammatory markers measurement or noncumulative activity scores. These findings reinforce the need to evaluate subclinical atherosclerosis in RA patients, and to find predictors of atherosclerotic lesions.

Macromolecular assembly of polycystin-2 intracytosolic C-terminal domain

Mutations in PKD2 are responsible for approximately 15% of the autosomal dominant polycystic kidney disease cases. This gene encodes polycystin-2, a calcium-permeable cation channel whose C-terminal intracytosolic tail (PC2t) plays an important role in its interaction with a number of different proteins. In the present study, we have comprehensively evaluated the macromolecular assembly of PC2t homooligomer using a series of biophysical and biochemical analyses. Our studies, based on a new delimitation of PC2t, have revealed that it is capable of assembling as a homotetramer independently of any other portion of the molecule. Our data support this tetrameric arrangement in the presence and absence of calcium. Molecular dynamics simulations performed with a modified all-atoms structure-based model supported the PC2t tetrameric assembly, as well as how different populations are disposed in solution. The simulations demonstrated, indeed, that the best-scored structures are the ones compatible with a fourfold oligomeric state. These findings clarify the structural properties of PC2t domain and strongly support a homotetramer assembly of PC2.

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.

A 12-month randomized controlled trial of balance training in elderly women with ostebporosis: Improvement of quality of life

Objective: Physical and psychological incapacity, including fear of falling is related to decreased satisfaction with life in osteoporosis (OP). The impact of a balance exercise program on improving the quality of life is not well established. We have, therefore, investigated the effect of 12-month Balance Training Program in quality of life, functional balance and falls in elderly OP women. Methods: Sixty consecutive women with senile OP were randomized into a Balance Training Group (BT) of 30 patients and no intervention control group (CG) of 30 patients. The BT program included techniques to improve balance over a period of 12 months (1 h exercise session/week and home-based exercises). The quality of life was evaluated before and at the end of the trial using the Osteoporosis Assessment Questionnaire (OPAQ), functional balance was evaluated by Berg Balance Scale (BBS). Falls in the preceding year were noted and compared to the period of study. Results: The comparison of OPAQ variations (INITIAL-FINAL) revealed a significant improvement in quality of life in all parameters for BT compared to CG: well-being (1.61 +/- 1.44 vs. -1.46 +/- 1.32, p < 0001), physical function (1.30 +/- 1.33 vs. -0.36 +/- 0.82, p < 0.001), psychological status (1.58 +/- 1.36 vs. -1.02 +/- 0.83, p < 0.001), symptoms (2.76 +/- 1.96 vs. -0.63 +/- 0.87, p < 0.001), social interaction (1.01 +/- 1.51 vs. 0.35 +/- 1.08, p < 0.001). Of note, this overall benefit was paralleled by an improvement of BBS (-5.5 +/- 5.67 vs. +0.5 +/- 4.88 p < 0.001) and a reduction of falls in 50% in BT group vs. 26.6% for the CG (RR: 1.88, p < 0.025). Conclusion: The long-term Balance Training Program of OP women provides a striking overall health quality of life improvement in parallel with improving functional balance and reduced falls. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Most of the patients presenting myocardial infarction would not be eligible for intensive lipid-lowering based on clinical algorithms or plasma C-reactive protein

Objective: The study we assessed how often patients who are manifesting a myocardial infarction (MI) would not be considered candidates for intensive lipid-lowering therapy based on the current guidelines. Methods: In 355 consecutive patients manifesting ST elevation MI (STEMI), admission plasma C-reactive protein (CRP) was measured and Framingham risk score (FRS), PROCAM risk score, Reynolds risk score, ASSIGN risk score, QRISK, and SCORE algorithms were applied. Cardiac computed tomography and carotid ultrasound were performed to assess the coronary artery calcium score (CAC), carotid intima-media thickness (cIMT) and the presence of carotid plaques. Results: Less than 50% of STEMI patients would be identified as having high risk before the event by any of these algorithms. With the exception of FRS (9%), all other algorithms would assign low risk to about half of the enrolled patients. Plasma CRP was <1.0 mg/L in 70% and >2 mg/L in 14% of the patients. The average cIMT was 0.8 +/- 0.2 mm and only in 24% of patients was >= 1.0 mm. Carotid plaques were found in 74% of patients. CAC > 100 was found in 66% of patients. Adding CAC >100 plus the presence of carotid plaque, a high-risk condition would be identified in 100% of the patients using any of the above mentioned algorithms. Conclusion: More than half of patients manifesting STEMI would not be considered as candidates for intensive preventive therapy by the current clinical algorithms. The addition of anatomical parameters such as CAC and the presence of carotid plaques can substantially reduce the CVD risk underestimation. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Bone marrow cell therapy prevents infarct expansion and improves border zone remodeling after coronary occlusion in rats

Background: Since the cell therapy benefits for myocardial infarction are mainly related to infarct reduction by regenerating lost myocardium or increasing survival of tissues at risk, we evaluated the effects of bone marrow-derived mononuclear cells (MNC), implanted after the completion of necrosis, on infarct progression and cardiac remodeling. Methods: After 48 h of induction of myocardial infarction (MI), Lewis-inbred rats were injected with 6 x 10(6) cells (MI + MNC) or saline (MI). After six weeks, scar dimension, ventricular morphology and function were analyzed by echocardiography followed by histomorphology of the infarcted and border zones. Results: After therapy, the relative size of the infarct was smaller in MI + MNC (37 +/- 1% of the left ventricle) than in MI (43 +/- 1%). While the MI group exhibited parallel elongation of the infarcted (31.6 +/- 3.8% increase) and reminiscent ventricular portions (33.5 +/- 3.7%), MNC therapy preserved the initial infarct length. Infarcted walls were thicker (979 +/- 31 mm) in the MNC group than in the untreated group (709 +/- 41 mm), also demonstrating an absence of infarct expansion. In the border zones, MNC led to increased capillary densities and capillary/myocyte ratios. The cardiac systolic function remained depressed in MI, but improved by 19 +/- 5% in MI + MNC which reduced the incidence of pulmonary arterial hypertension (37.5% in MI and 6.25% in MI + MNC). Conclusion: MNC therapy prevented the infarct expansion and thinning related to cardiac remodeling and was associated with an improvement of border zone microcirculation: as a result, MNC therapy reduced typical MI dysfunctional repercussions. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

A Randomized Trial of a Skin Sealant to Reduce the Risk of Incision Contamination in Cardiac Surgery

Background. Immobilizing skin microbes is a rational approach to reducing contamination of surgical sites by endogenous microorganisms. Methods. This randomized, controlled, parallel-group, multicenter, open-label clinical trial (ClinicalTrials.gov NCT00467857) enrolled 300 adults scheduled for elective coronary artery bypass graft surgery. Patients received iodine-based skin preparations followed by a cyanoacrylate-based skin sealant or skin preparations alone. Microbiological samples collected from sternal and graft incision sites immediately before any skin preparation, at the wound border after skin incision, and at the incision after fascial closure were evaluated quantitatively. Results. In evaluable patients, mean microbial counts in collected samples increased at the sternal site after fascial closure compared with after skin incision by 0.37 log(10) colony-forming units (CFU)/mL in the skin sealant group (n = 120) and by 0.57 log10 CFU/mL in the control group (n = 132) (p = 0.047, Wilcoxon rank sum test). At the graft site, mean microbial counts increased by 0.09 (n = 119) and 0.27 (n = 127) log(10) CFU/mL, respectively (p = 0.037). There was a 35.3% relative risk reduction in surgical site infection (SSI) occurring in the skin sealant group (9 of 146 patients, 6.2%) versus the control group (14 of 147 patients, 9.5%). In obese patients (body mass index [BMI] > 30.0 to <= 37.0 kg/m(2)), the relative risk reduction for SSI associated with skin sealant was 83.3%. Conclusions. Pretreatment with skin sealant protects against contamination of the surgical incision by migration of skin microbes. Further data are needed to confirm the impact of this technology on SSI rates in clinical practice. (Ann Thorac Surg 2011;92:632-7) (C) 2011 by The Society of Thoracic Surgeons ADULT CARDIAC

Aerobic Exercise Training-Induced Left Ventricular Hypertrophy Involves Regulatory MicroRNAs, Decreased Angiotensin-Converting Enzyme-Angiotensin II, and Synergistic Regulation of Angiotensin-Converting Enzyme 2-Angiotensin (1-7)

Aerobic exercise training leads to a physiological, nonpathological left ventricular hypertrophy; however, the underlying biochemical and molecular mechanisms of physiological left ventricular hypertrophy are unknown. The role of microRNAs regulating the classic and the novel cardiac renin-angiotensin (Ang) system was studied in trained rats assigned to 3 groups: (1) sedentary; (2) swimming trained with protocol 1 (T1, moderate-volume training); and (3) protocol 2 (T2, high-volume training). Cardiac Ang I levels, Ang-converting enzyme (ACE) activity, and protein expression, as well as Ang II levels, were lower in T1 and T2; however, Ang II type 1 receptor mRNA levels (69% in T1 and 99% in T2) and protein expression (240% in T1 and 300% in T2) increased after training. Ang II type 2 receptor mRNA levels (220%) and protein expression (332%) were shown to be increased in T2. In addition, T1 and T2 were shown to increase ACE2 activity and protein expression and Ang (1-7) levels in the heart. Exercise increased microRNA-27a and 27b, targeting ACE and decreasing microRNA-143 targeting ACE2 in the heart. Left ventricular hypertrophy induced by aerobic training involves microRNA regulation and an increase in cardiac Ang II type 1 receptor without the participation of Ang II. Parallel to this, an increase in ACE2, Ang (1-7), and Ang II type 2 receptor in the heart by exercise suggests that this nonclassic cardiac renin-angiotensin system counteracts the classic cardiac renin-angiotensin system. These findings are consistent with a model in which exercise may induce left ventricular hypertrophy, at least in part, altering the expression of specific microRNAs targeting renin-angiotensin system genes. Together these effects might provide the additional aerobic capacity required by the exercised heart. (Hypertension. 2011;58:182-189.).