Mariana Jinga

Genetic correction of PSA values using sequence variants associated with PSA levels.

Sequence variants in the human genome are associated with serum levels of prostate-specific antigen. SNPping Away at Prostate Cancer Measuring prostate-specific antigen (PSA) in serum is the only diagnostic test for prostate cancer and is used as a screening tool for deciding whether to perform a biopsy. Yet, this diagnostic test is far from ideal, with more than a third of men with serum PSA levels of 10 ng/ml or greater having no evidence of prostate cancer at biopsy, and some men with very low PSA levels (less than the lower threshold of 2.5 ng/ml), who are not given a biopsy but yet end up having prostate cancer. The lack of specificity and sensitivity of the PSA test and the many confounding factors that influence the test result, including medications, inflammation, and, of course, genotype, have reduced the value of this screening tool. As with most cancers, early detection of prostate cancer leads to a greatly improved chance of survival, so improving the predictive accuracy of this test is of paramount importance. In an effort to investigate whether genome sequence variants can be used to make the PSA test more sensitive, Gudmundsson and colleagues have undertaken a genome-wide association study in 15,757 Icelandic men and 454 British men not yet diagnosed with prostate cancer to see whether they can tie sequence variants [single-nucleotide polymorphisms (SNPs)] to serum PSA levels. The authors identify six loci with SNPs that correlate with PSA levels. They then probed these data more deeply. They looked at these loci in 3834 men who underwent subsequent biopsy of the prostate and demonstrate that three of these loci (10q26, 12q24, and 19q13.33) are associated not only with higher PSA levels but also with a higher probability of a negative biopsy result. The authors suggest that this genotype information should be used to calculate a personalized “cutoff” value for serum PSA levels in each individual to improve the predictive accuracy of the test and to ensure that only men who need a prostate biopsy are subjected to this procedure. Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with Pcombined <3 × 10−10. Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.

Effects of lifestyle changes including specific dietary intervention and physical activity in the management of patients with chronic hepatitis C--a randomized trial.

BackgroundIn patients with chronic hepatitis C (CHC), obesity is involved in the pathogenesis of insulin resistance, fatty liver disease and progression of fibrosis. The objective of this study was to compare a normoglucidic low-calorie diet (NGLCD) with a low-fat diet (LFD) among participants with CHC. Aimed to measure the impact of dietary changes in reduction of insulin resistance, obesity but also in steatosis and fibrosis.MethodsRandomized, controlled trial in three medical centers with assessments at baseline, 6 months and 12 months. Participants were patients over 35 years with chronic hepatitis C (n = 120) with BMI over 25 kg/m2. We evaluated the effects of NGLCD vs. LFD in weight management and metabolic improvement. The primary endpoint was to measure the impact of dietary changes through nutritional intervention in reversibility of insulin resistance, obesity, steatosis, and fibrosis. We performed anthropometric measurements, fasting glucose profile, serum lipids, liver profile, blood count at baseline, 6 and 12 months. Steatosis was evaluated using ultrasonographic criteria. Liver fibrosis was non-invasively assessed.ResultsAfter 6 and 12 months of intervention, both groups had a significant decrease in caloric consumption. At 6 months, weight loss was greater in the NGLCD group (−5.02 ± 3.43 kg vs. −4.1 ± 2.6 kg; p = 0.002) compared to the LFD group. At 1-year, however, weight loss was similar in both groups (−3.9 ± 3.3 kg vs. −3.1 ± 2.6 kg; p = 0.139). At 12 months, fasting plasma glucose, fasting plasma insulin, and HOMA-IR had significant improvements in both groups. With both diets aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) decreased with significant differences; also there were significant improvements in AST/ALT ratio, Forns fibrosis index. The two diets were associated with reduction of both the prevalence and the severity of steatosis (all p < 0.001). At 12 months, total cholesterol, HDL-cholesterol, triglycerides improved in both groups (all p < 0.05).ConclusionsThe present study establishes the benefits of low-calorie diet and low-fat diet in management of patients with hepatitis C regarding improvement of insulin resistance, steatosis and also fibrosis.Overweight or obese patients with CHC undergoing a lifestyle intervention (specific dietary intervention and physical activity) for 1-year had significant improvements in body weight, lipid and hepatic profile.Trial registrationPNCI2-3343/41008/2007

Ratio of spleen diameter to red blood cell distribution width: a novel indicator for celiac disease.

AbstractCeliac disease (CD) is currently considerably underdiagnosed, setting the need for developing tools to select patients with probability of CD, who warrant further testing. Red blood cell distribution width (RDW) has been shown in previous studies to be a sensitive predictor for CD, but it lacks specificity. Splenic hypotrophy is also noted frequently in celiac patients.Our aim was to evaluate if spleen diameter to RDW ratio can be used as an indicator for CD.We evaluated 15 newly diagnosed CD patients, 52 patients with inflammatory bowel disease, and 35 patients with irritable bowel syndrome (IBS). We evaluated the differences in spleen diameter, RDW, and their ratio among the four groups.Two-thirds of the CD patients had elevated RDW, compared to 9% in the IBS group. A small spleen was seen in 80% of the celiacs, compared to 21.9% in the ulcerative colitis group, 10% in the Crohn disease group, and 9% in the IBS group. A spleen diameter to RDW ratio under 6 had a sensitivity of 73.3% and specificity of 88.5% in predicting CD, with an AUROC of 0.737.Spleen diameter to RDW ratio is a simple, widely available score, which can be used to select adult patients with probability of CD.

Harmonic contrast-enhanced endoscopic ultrasound fine-needle aspiration: Fact or fiction?

The negative predictive value of endoscopic ultrasonography fine-needle aspiration is relatively low. To achieve the improvement of the diagnostic yield, the following were proposed: a higher number of passes, the presence of the rapid on-site cytopathologist evaluation, the fanning technique, or the repetition of the fine needle biopsy. Harmonic contrast-enhanced endosonography may better identify the targeted area in the lesions by avoiding the inside necrosis and the vessels of fibrosis, so it can guide the fine-needle aspiration. Both techniques are complementary, not competitive, and they can be done in the same session. The combined technique is simple, safe, and requires only a few minutes with minimal extra costs compared to standard fine-needle aspiration. It minimally increases the diagnostic rate, and it permits the decrease of the number of passes. However, we will know its real clinical impact only in the future and whether it will be incorporated into the lesion assessment process.

Severe Refractory Anemia in Primary Intestinal Lymphangiectasia. A Case Report.

BACKGROUND Primary intestinal lymphangiectasia (Waldmanns disease) is a rare disease characterized by dilated lymphatics in the small bowel leading to an exudative enteropathy with lymphopenia, hypoalbuminemia and hypogammaglobulinemia. CASE PRESENTATION We report the case of a 23 year-old male who presented with chronic anemia and in whom primary intestinal lymphangiectasia was diagnosed. A low-fat diet along with nutritional therapy with medium-chain triglyceride supplementation improved the protein-losing enteropathy, but did not solve the anemia. Octreotide was also unsuccessful, and after attempting angiographic embolization therapy, limited small bowel resection together with antiplasmin therapy managed to correct the anemia and control the exudative enteropathy. CONCLUSIONS Although primary intestinal lymphangiectasia is usually adequately managed by nutritional therapy, complications such as anemia can occur and can prove to be a therapeutic challenge.

Rheumatologic manifestations in celiac disease: what we should remember?

Data regarding celiac disease (CD) have advanced greatly in the past years. Described initially as a gastroenterological entity with rare occurrence, we now admit for CD a prevalence of 1% and systemic involvement [1–4]. However, CD remains still an underdiagnosed disease [3, 4] and awareness should be raised especially for its nondigestive, non-classical clinical presentation [2, 5]. Therefore, we aim to shortly review here the musculoskeletal involvements described in or associated with adult CD, useful for internal medicine practice. CD has some specific features: it is an immune (anti-deamidated gliadin antibodies – DGP) and autoimmune (anti-endomysial antibodies – EMA, anti-tissue transglutaminase antibodies – tTG) condition that occurs in genetic susceptible individuals (90–95% HLA-DQ2 and for the rest HLA-DQ8) [1, 3]. The main pathogenic process is developing in the intestinal mucosa by lymphocytic infiltration with subsequent destruction of the intestinal villi architecture. CD diagnosis should be confirmed by intestinal biopsy in patients with positive serology before initiating the gluten-free diet (GFD). The GFD is easily accessible and has good rates of response for the CD symptoms [3, 4]. When the intestinal histology features suggestive for CD are found in seronegative patients, differential diagnosis should include also other autoimmune diseases that might mimics CD, like autoimmune enteropathy, Graves or Hashimoto disease, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome or type I diabetes [4]. During the last years, the systemic involvement in CD was more studied and musculoskeletal manifestations were also described. Jericho et al. identified extra-intestinal manifestations in 62% adults and 60% children known with CD (interestingly, 9% adults and 18% children presented only extraintestinal CD manifestations) [6]. In the same study, an important number of adult patients presented musculoskeletal manifestations: arthralgia (16%), arthritis (15%), and myalgia (8%). After the introduction of the GFD, the rates of clinical response were important: 69% for arthritis, 54% for arthralgia, and 50% for myalgia [6]. In a recent meta-analysis that comprised data up to August 2016, Daron et al. found cumulative incidence of 18.3 (4.7–38.1)% for osteomalacia, 22.1 (7.9–40.9)% for arthritis, 30.3 (19.2–42.8)% for arthralgia, and 6.1 (0.5–17.0)% for bone pain [7]. Moreover, they showed higher cumulative incidence in CD when compared to controls of 16.6% vs. 9.9%, 9.8% vs. 4.2%, and 18.1% vs. 5.0% for unspecified site, femoral, and spinal osteoporosis, respectively [7]. The relative risk of any site osteoporosis in CD patients when compared to controls was 2.7 (1.9– 4.0) [7]. Results of meta-analysis showed that there is an association between CD and bone fracture [8,9]: 30% (CI 1.1–1.5) for any site and 69% (CI 1.1–2.6) increase in risk for the hip fracture [9]. Furthermore, in middle-aged women, the tTG-IgA positivity was associated with bone mass density loss and osteoporosis; fractures were more prevalent in cases with high tTG-IgA levels [10]. Nuti et al. included in their research only women with osteoporosis and identified significant lower serum vitamin D in patients with positive AGA and tTG: 17.8 vs. 55.1 nmol/L [11]. The pathogenic mechanisms involved in osteopenia/ osteoporosis in CD are mainly related to vitamin D and calcium malabsorption due to villous atrophy. These are added to secondary hyperparathyroidism in patients with hypocalcemia, systemic inflammation with high serum levels of proinflammatory cytokines (IL-1, IL-6, TNF-alpha) as well as to hypogonadism and sexual hormones metabolism disturbances that also have impact on the bone turnover [1]. However, the risk of osteoporosis seems to be equal for both women and

Laparoscopic sleeve gastrectomy and gastroesophageal reflux

Abstract The prevalence of obesity is rising, becoming a medical problem worldwide. Also GERD incidence is higher in obese patients compared with normal weight, with an increased risk of 2.5 of developing symptoms and erosive esophagitis. Different treatment modalities have been proposed to treat obese patients, but bariatric surgery due to its complex interactions via anatomic, physiologic and neurohormonal changes achieved the best long-term results, with sustained weight loss and decrease of complications and mortality caused by obesity. The bariatric surgical procedures can be restrictive: laparoscopic adjustable gastric band (LAGB) and laparoscopic sleeve gastrectomy (LSG), or malabsorptive-restrictive such as Roux-en-Y gastric bypass (RYGB). These surgical procedures may influence esophageal motility and lead to esophageal complications like gastroesophageal reflux disease (GERD) and erosive esophagitis. From the literature we know that the RYGB can ameliorate GERD symptoms, and some bariatric procedures were finally converted to RYGB because of refractory reflux symptoms. For LAGB the results are good at the beginning, but some patients experienced new reflux symptoms in the follow-up period. Recently LSG has become more popular than other complex bariatric procedures, but some follow-up studies report a high risk of GERD after it. This article reviews the results published after LSG regarding gastroesophageal reflux and the mechanisms responsible for GERD in morbidly obese subjects.

Diagnostic accuracy of red blood cell distribution width-to-lymphocyte ratio for celiac disease

Abstract Background. Celiac disease (CD) is significantly underdiagnosed, despite significant efforts made in the last decades to increase its diagnostic rate. This has lead to a high need for developing new diagnostic strategies. Our aim was to evaluate the diagnostic performance of two routine hematologic indices for CD. Methods. In a prospective observational study, 34 newly diagnosed CD patients, 34 age-sex matched controls with irritable bowel syndrome (IBS) and 16 treated CD patients were assessed regarding the differences in mean lymphocyte count (LY), red blood cell distribution width (RDW) and their ratio (RDW/LY). Results. Elevated RDW (>14) and lymphopenia (<1.5 x 10e9/L) were more frequently seen in newly diagnosed CD patients compared to IBS control group and treated CD patients. Newly diagnosed CD patients had significantly higher mean values of RDW/LY - 10.09, compared to 7.72 in the CD-treated group and 6.79 in IBS controls (p<0.01). Subgroup analysis revealed that RDW/LY was higher in patients with destructive histology (Marsh≥3a), 10.54 vs. 7.99. For a value over 7, RDW/LY had a sensitivity of 88.24% (95% CI 72.55-96.70%) and AUROC of 0.785 (95% CI 0.683- 0.887). Conclusions. RDW/LY ratio is a widely available tool which could be used routinely in clinical practice for CD screening.

Essential in Genetic Etiology of Congenital Heart Diseases

Congenital heart disease (CHD) represent another unsolved problem of the present, although new techniques of exploration like fluorescence in situ hybridization (FISH), high resolution array-comparative genomic hybridization (array-CGH), single nucleotide polymorphisms (SNPs), comparative genomic hybridization (CGH) and spectral karyotyping (SKY) explain some genetic mechanisms implied in the genesis of this pathology. However, there are many unresolved issues. Structural modifications of chromosomes by duplication and also by deletion determine variable phenotypes depending on the altered structural site. Given that, the genetic defect affects only one gene or more but determines repercussions over the cardiac anatomy or/and other non-cardiac systems, as a result the phenotype can be syndromic or nonsyndromic. The raised or low number of chromosomes was the first explanation for CHD. Trisomy 21 (Down’s syndrome), 18 (Edward’s syndrome), 13 (Patau’s syndrome), monosomy X (Turner’s syndrome), deletion at chromosome 7q11.23 and 22q11.2, multiple gene mutations, are the most frequent chromosomal or sub-chromosomal destructuring along with syndromic phenotype. Copy number variations (CNVs) is defined as sub-chromosomal mechanism that by deletion or multiplication produces in general nonsyndromic phenotype. Transcription factors T-Box protein 5 (TBX5), mNK2 Homeobox 5 (NKX2.5), GATA-binding protein 4 (GATA4) are specific proteins that sending information from DNA to RNA messenger can undergo structural denaturations and if this happens these proteins cannot send correct messages resulting in alteration of the normal chain of cardiogenesis. Combination between these mechanisms and unitary action produce CHD in different forms, syndromic or nonsyndromic.

Endothelial Dysfunction in Aortic Aneurysm

Abstract The occurrence of aortic aneurysm has increased during the last decade. Even if, the relationship with atherosclerosis and thrombosis is almost clarified, endothelial dysfunction still has large unexplained issues. Molecular structures of endothelial cells comprise a large number of components, such as oxidative stress/nitric oxide, the relationship between telomere/telomerase, vascular smooth muscle cells proliferation, platelet aggregation, fibrinolysis, angiogenesis, inflammatory components, and so on, that are significant compounds of endothelial function. Moreover, in the case of aneurysm their function progressively deteriorates sequentially or concomitantly. Endothelialization of arterial grafts is difficult to achieve in the case of artificial vascular wall with normal function. Restoration and mostly the prevention of aorta aneurysm development include the delay of the endothelial dysfunction with angiotensin converting enzyme inhibitors, statins, antiplatelet medications and anticoagulants, reactive oxygen species and reactive nitrogen species formed by extracellular matrix, and decrease in proinflammatory cytokines and matrix metalloproteinases caused by leucocytes activity (Piechota-Polanczyk, 2015).