Showing papers in "Polskie Archiwum Medycyny Wewnetrznej-polish Archives of Internal Medicine in 2015"

Effectiveness of probiotics in type 2 diabetes: a meta-analysis.

Abstract: INTRODUCTION An increasing number of studies suggest that the use of probiotics may have a beneficial effect in patients with type 2 diabetes. OBJECTIVES The aim of the study was to assess the ability of probiotics to modify selected cardiometabolic risk factors in subjects with type 2 diabetes. METHODS PubMed, Embase, Cochrane Library, and Scopus databases were thoroughly reviewed up to January 2015 to search for randomized controlled trials (RCTs) that examined the effect of probiotics on selected modifiable cardiometabolic parameters in patients with type 2 diabetes. The following endpoints were considered: fasting plasma glucose (FPG), insulin concentration, insulin resistance, hemoglobin A1c (HbA1c), as well as the levels of total cholesterol, triglycerides, low-density and high-density lipoprotein cholesterols, and C-reactive protein (CRP). A total of 571 RCTs were initially identified, of which 8 trials with 438 individuals were selected for meta-analysis. The effects of probiotics were calculated for each parameter. RESULTS The meta-analysis showed a significant effect of probiotics on reducing HbA1c levels (standardized mean difference [SMD], -0.81; confidence interval [CI], -1.33 to -0.29, P = 0.0023; I2 = 68.44%; P = 0.0421 for heterogeneity) and HOMA-IR (SMD, -2.10; CI -3.00 to -1.20, P <0.001; I2 = 82.91%; P = 0.0029 for heterogeneity). Supplementation with probiotics did not have a significant effect on FPG, insulin, and CRP levels as well as the lipid profile. CONCLUSIONS Our meta-analysis suggests that probiotic supplementation might improve, at least to some extent, metabolic control in subjects with type 2 diabetes. However, larger well-designed, longterm RCTs are needed to confirm any potentially beneficial relationship between the use of probiotics and modifiable cardiometabolic risk factors in patients with type 2 diabetes.

Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3-5.

Abstract: Introduction Observational studies have shown that high dietary intake of vitamin K2 is associated with reduced risk of coronary vascular disease and vascular calcification. Objectives We assessed the effect of vitamin K2 substitution on the progression of atherosclerosis and calcification in nondialyzed patients with CKD stages 3-5. Patients and methods The study included 42 nondialyzed patients with CKD. The following measurements were taken at baseline and after 270 ±12 days of supplementation with vitamin K2 at a dose of 90 μg (menaquinone, MK-7) together with 10 μg of cholecalciferol (K+D group) or 10 μg of cholecalciferol (group D): common carotid intima-media thickness (CCA-IMT), coronary artery calcification score (CACS), basic biochemical parameters, lipids, and calcification modulators: matrix Gla protein (MGP), desphosphorylated-uncarboxylated MGP (dp-ucMGP), osteoprotegerin (OPG), fetuin A, osteocalcin (OC), and fibroblast growth factor 23. Results The increase of CCA-IMT was significantly lower in the K+D group compared with the D group: from 0.95 ±0.2 mm to 1.01 ±0.3, P = 0.003 vs from 1.02 ±0.2 mm to 1.16 ±0.3, P = 0.003 (ΔCCA-IMT, 0.06 ±0.08 vs 0.136 ±0.05 mm, P = 0.005, respectively). The increase in CACS was slightly lower in the K+D group than in the D group (ΔCACS, 58.1 ±106.5 AU vs 74.4 ±127.1 AU, P = 0.7). In the K+D group, a significant decrease in the level of dp-ucMGP and total OC was observed. Conclusions A 270-day course of vitamin K2 administration in patients with CKD stages 3-5 may reduce the progression of atherosclerosis, but does not significantly affect the progression of calcification. Vitamin K2 significantly changes the levels of calcification promoters and inhibitors: dp-ucMGP, OC, and OPG.

Overuse of proton pump inhibitors

Abstract: Proton pump inhibitors (PPIs) are currently the most effective drugs inhibiting hydrochloric acid secretion. They have replaced histamine type 2 receptor antagonists in the majority of clinical indications, for example, functional dyspepsia, gastroesophageal reflux disease, or drug‑induced upper gastrointestinal tract injury. High prevalence of acid‑related upper gastrointestinal tract diseases, as well as the potency, good tolerance, and acceptable costs of treatment with PPIs have largely increased their use in hospitals and outpatient clinics. At present, PPIs are used more frequently, often long‑term and in high doses, and not necessarily according to the current recommendations. PPI‑induced inhibition of hydrochloric acid secretion causes iatrogenic hypochlorhydria and hypergastrinemia, which may result in parietal cell hypertrophy and enterochromaffin‑like cell hyperplasia, exposing patients to rebound hydrochloric acid hypersecretion. It is believed that this phenomenon may be responsible for failure to discontinue pharmacotherapy with PPIs and to their overuse. As a result, an inappropriate, especially chronic, treatment increases the risk of some side effects as well as individual and institutional expenditures. Therefore, a reasonable approach to clinical indications, dosing, and treatment regimen in each individual patient should be recommended.

General population reference values for 3-level EQ-5D (EQ-5D-3L) questionnaire in Poland.

Abstract: Introduction A Polish EQ-5D normative study published in 2010 was conducted in 2008 as a pilot study. The group of respondents was relatively small and had limited representativeness. Objectives The aim of the study was to derive population norms for the 3-level EQ-5D (EQ-5D-3L) questionnaire in Poland using a large, representative sample. Respondents and methods Stratified random sampling was used. A total of 3941 respondents (age, 18-87 years) completed the self-administered paper-based EQ-5D-3L questionnaire (3973 completed the visual analog scale, EQ VAS) and were included in this study. Utility index scores were derived using the Polish time trade-off value set. Results The study sample was representative of the general Polish population in terms of age, sex, geographical region, type and size of a given locality, level of education, and social and professional status. Mean EQ-5D-3L and visual analogue scale (EQ VAS) values decreased from 0.968 and 86.2 (age group, 18-24 years) to 0.730 and 54.0 (age group, ≥75 years), respectively. The most frequently reported complaints were pain/discomfort (45.8%) followed by anxiety/depression (33.3%), while the least commonly reported problem was self-care (9.4%). Conclusions Polish population norms developed for the EQ-5D-3L index, descriptive part of the EQ-5D-3L, and EQ VAS can be used as reference values. The availability of such normative data should encourage the use of EQ-5D-3L in health-related quality-of-life studies in Poland.

Genetic testing for monogenic diabetes using targeted next-generation sequencing in patients with maturity-onset diabetes of the young.

Abstract: Introduction Molecular diagnosis of monogenic diabetes mellitus is important for individualized patient care. Next-generation sequencing (NGS) enables a simultaneous analysis of multiple genes in a single test. Objectives We aimed to assess the feasibility of using NGS for detecting mutations in a set of known monogenic diabetes gene mutations in a cohort of Polish patients with maturity-onset diabetes of the young (MODY) with earlier negative Sanger sequencing results for HNF1A-MODY or GCK-MODY. Patients and methods We selected a panel of 28 chromosomal genes in which mutations have been reported to cause monogenic diabetes. The MiSeq platform was used for NGS. An exon-capture assay was designed to include coding regions and splice sites. A total of 54 patients with existing negative Sanger sequencing screening results for HNF1A or GCK gene mutations were selected for the study. Results NGS results were generated for all 54 patients and 9 positive controls with previously identified HNF1A or GCK gene mutation. All selected positive controls were confirmed by NGS. Among 28 genes, mutations were detected in 16. The type of the analyzed genetic changes was described in the NGS study as high (n = 3) or moderate (n = 76). Among the detected mutations, there were 4 known GCK gene mutations that had been previously missed in Sanger sequencing. So far, Sanger sequencing allowed us to confirm 21 gene mutations detected by NGS, and segregation with diabetes in 14 pedigrees. Conclusions Our pilot study using NGS for monogenic diabetes screening in the MODY cohort confirmed that it improves the detection of diabetes-related sequence differences. The screening with NGS should also include diabetic patients for whom Sanger-based screening for particular subtypes of MODY provided negative results.

Assessment of adherence to treatment in patients with resistant hypertension using toxicological serum analysis. A subgroup evaluation of the RESIST-POL study.

Abstract: Introduction Nonadherence to antihypertensive therapy is one of the main causes of resistant hypertension. Objectives The aim of our study was to evaluate adherence to therapy in patients with resistant hypertension by determining serum antihypertensive drug levels with the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS). Patients and methods The study included 36 patients with primary resistant hypertension selected from the RESIST-POL study (23 men and 13 women; mean age, 52.5 ±9.1 years; range, 22-67 years; mean number of antihypertensive drugs, 5.3 ±1.4), who met all 3 inclusion criteria: use of ≥4 antihypertensive drugs; average daytime ambulatory systolic blood pressure ≥140 mmHg; one of the clinical features suggesting nonadherence. All patients had their serum drug levels assessed using LC-MS/MS. Patients in whom the serum level of at least 1 drug was below the limit of quantification for the method used were regarded as nonadherent. Results Of all study patients, nonadherence was observed in 31 patients (86.1%), and none of the prescribed drugs was detected (complete nonadherence) in 5 patients (13.9%). In 26 patients (72.2%), at least 1 of the prescribed drugs could not be detected (partial nonadherence). Conclusions In our study, we documented a surprisingly low adherence to antihypertensive treatment in patients with resistant hypertension. Our results suggest that, particularly in those patients, the analysis of serum antihypertensive drug levels using LC-MS/MS might allow to avoid a comprehensive and costly diagnostic work-up including biochemical and imaging studies.

Associations between single-nucleotide polymorphisms of RFC-1, GGH, MTHFR , TYMS, and TCII genes and the efficacy and toxicity of methotrexate treatment in patients with rheumatoid arthritis.

Abstract: INTRODUCTION The differences in drug efficacy and adverse reactions may be caused by genetic variations in drug metabolism between individuals. OBJECTIVES The aim of the study was to evaluate the effect of gene polymorphisms on the efficacy of therapy and side effects in patients with rheumatoid arthrit s (RA) treated with methotrexate (MTX). PATIENTS AND METHODS A total of 273 Caucasian patients with RA were treated with MTX for at least 6 months or stopped MTX because of adverse effects. Seven polymorphisms (RFC-1 c.80G>A, GGH c.-401C>T, MTHFR c.1298A>C and c.677C>T, TYMS 2R/3R, TYMS 6-bp deletion, and TCII c.593T>C) were examined for their effects on MTX efficacy and toxicity. Genomic DNA was obtained from peripheral blood leukocytes. RESULTS Of all patients, 53% reported some adverse effects during at least 1 visit, which led to MTX withdrawal in 17% of the patients. Adverse effects were more frequent in patients with the MTHFR 677T allele than in those with the 677CC genotype (odds ratio [OR], 1.97; P = 0.01) and in those with the GGH 401CC genotype than in those with the GGH 401CT and TT genotypes (OR, 3.8; P = 0.05). Furthermore, the MTHFR 677T allele was associated with increased activity of aminotransferases (OR, 3.4; P = 0.02). MTX-related hepatotoxicity and alopecia were more common in patients with the RFC-1 80AA genotype (OR, 3.5, P = 0.01; OR, 2.4, P = 0.04; respectively). A more rapid positive response to MTX therapy was demonstrated in MTHFR 677CC homozygotes (OR, 3.4; P = 0.001). There were no other associations between single -nucleotide polymorphisms and the efficacy of MTX treatment. CONCLUSIONS The MTHFR 677CC and GGH 401TT and CT genotypes were associated with a reduction in the number of MTX-related adverse events. Future allele and genotype analyses may help identify the subsets of RA patients with an increased risk of adverse effects.

The biomarker paradigm: between diagnostic efficiency and clinical efficacy.

Abstract: The interest in biomarker research has been growing exponentially, and this trend is not expected to reverse soon. Although the clinical usefulness of laboratory tests is conventionally defined in terms of diagnostic efficiency or clinical efficacy (or effectiveness), these notions are complementary but not interchangeable. The former concept is an expression of diagnostic accuracy but does not entail outcome assessment. Conversely, clinical efficacy investigates whether or not a certain test can produce significant changes in managed care and an improvement of clinical outcomes. The vast majority of published studies were mainly focused on diagnostic efficacy rather than on clinical efficacy, and this seems no longer sustainable in a world with limited resources. Although bridging the gap between efficiency and efficacy is not a trivial endeavour, a paradigm shift is necessary, wherein the laboratory community should focus on what clinicians need rather than pursuing an endless search for analytically perfect tests. In the foreseeable future, efficacy should be improved by translating this concept into a simple "six R" paradigm, namely, performing the Right test, with the Right method, at the Right time, to the Right patient, at the Right cost, for the Right outcome.

Prevalence of acquired von Willebrand syndrome during essential thrombocythemia: a retrospective analysis of 170 consecutive patients.

Abstract: Introduction The identification of patients with essential thrombocythemia (ET) who are at increased risk of acquired von Willebrand syndrome (AVWS) would likely facilitate individualization of treatment and improve its outcomes. Objectives The aim of the study was to determine the prevalence of AVWS in patients with ET and to verify whether individuals with and without this bleeding disorder differ in terms of their baseline clinical parameters. Patients and methods The study included 170 consecutive patients with ET. AVWS was diagnosed on the basis of reduced levels of von Willebrand factor and abnormal results of other routine tests. Patients with and without concomitant AVWS were compared in terms of their demographic characteristics, past and current medical histories, and laboratory parameters. Results Concomitant AVWS was found in 34 patients (20%). Individuals with AVWS were diagnosed with ET at a significantly younger age than those without the syndrome. In addition, these patients significantly less often were in remission at the time of testing, had significantly higher erythrocyte and platelet counts, and showed abnormalities of the coagulation profile corresponding to defects of primary hemostasis as well as abnormal values of most parameters used i n the routine diagnosis of AVWS. Conclusions Even every fifth patient with ET may develop AVWS. Young age at diagnosis of ET and the lack of response to its previous treatment are potential risk factors for AVWS that should be considered during the management of the primary condition. All patients with ET and signs of a bleeding disorder, irrespective of the platelet count, should be tested for the presence of AVWS.

Exosomes as mediators of intercellular communication: clinical implications.

Abstract: Cells of multicellular organisms exchange informative signals by diverse mechanisms. Recent findings uncovered the special role of extracellular vesicles, especially exosomes, in intercellular communication. Exosomes, present in all tested human bodily fluids, carry various functional compounds including proteins, lipids, and diverse RNA molecules. The composition of exosome cargo in vivo is likely formed by a regulated selection of specific components and can express the current status of the exosome-secreting cell. Therefore, particular emphasis is now placed on the extremely high potential of exosomes as essentially noninvasive prognostic and diagnostic biomarkers, but also as therapeutic nanocarriers, especially after the discovery that their cargo as well as cell-targeting specificity could be shaped in vitro. In addition, targeting the exosomes mediating pathological intercellular communication may also express high therapeutic potential. Hence, numerous studies are conducted to explore the profile and function of exosomes and their cargo in health and disease and to shape their properties to facilitate their clinical application. The present review summarizes the current knowledge on the role of exosomes in different physiological and pathological mechanisms of intercellular communication with a particular focus on the use of exosomes in the diagnosis and treatment of various inflammatory, cardiovascular, metabolic, and neurodegenerative disorders as well as malignant neoplasms.

New insight into the mechanisms of gastroduodenal injury induced by nonsteroidal anti-inflammatory drugs: practical implications.

Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs), especially acetylsalicylic acid (ASA), are commonly used in the therapy of various diseases. However, the serious side effects of these drugs, such as bleedings, acute lesions, gastric ulcers, and even intestinal perforations, are widely recognized. NSAIDs inhibit cyclooxygenase (COX) activity resulting in the suppression of mucosal generation of gastroprotective prostaglandins (PGs) derived from a constitutive isoform, COX-1, as well as an inducible isoform, COX-2. COX-1-derived PGs are responsible for gastroprotection, while PGs generated via COX-2 activity also play an important role in gastroprotection and ulcer healing. Recently, a new class of NSAIDs has been developed by adding NO moiety to conventional NSAIDs. In contrast to native NSAIDs, their NO-releasing derivatives such as NO-ASA were found to exhibit lower gastric toxicity despite inhibiting both COX-1 and COX-2 activity in the gastric mucosa. Similar limited gastrointestinal toxicity and protective actions were observed with a new class of hydrogen sulfide (H₂S)-releasing NSAIDs, such as H₂S-releasing naproxen (ATB-346). Dual antiplatelet therapy with ASA and clopidogrel increases the risk of gastrointestinal bleeding in patients with acute coronary syndrome in whom concomitant treatment with a proton-pump inhibitor (PPI) was less effective owing to the interaction of clopidogrel and PPI with the same hepatic cytochrome P-450. In conclusion, new derivatives of NSAIDs releasing vasoactive gaseous mediators NO or H₂S are associated with fewer gastrointestinal adverse effects, suggesting that, in the future, they may be used as a safer alternative in everyday clinical practice and antithrombotic therapy.

Prognostic significance of PD-1 expression on peripheral blood CD4+ T cells in patients with newly diagnosed chronic lymphocytic leukemia.

Abstract: INTRODUCTION Recent studies in a mouse model of chronic lymphocytic leukemia (CLL) demonstrated that inhibition of the programmed death receptor 1 (PD‑1)–PD‑L1 axis resulted in correction of leuke‑ mia‑induced CD8 + T cell‑related immune dysfunction and protected mice against CLL development. However, it remains unclear whether CLL development and progression can be also associated with CD4 + T cells expressing PD‑1. OBJECTIVES We aimed to analyze whether a quantitative assessment of CD4 + PD‑1 + T cells performed at the time of diagnosis can have prognostic significance in patients with CLL. PATIENTS AND METHODS We examined 56 patients with newly diagnosed CLL at different stages of the disease. The quantitative assessment of PD‑1‑expressing CD4 + T cells was performed in all patients, using multicolor flow cytometry. RESULTS We demonstrated that CLL patients with an advanced (high and intermediate risk) stage had a significantly higher number of CD4 + PD‑1 + T cells compared with subjects with low‑grade disease. Importantly, we showed that the number of PD‑1‑expressing CD4 + T cells in the peripheral blood of patients referred for immediate treatment due to the advanced stage of the disease was significantly higher compared with subjects on watchful waiting. Finally, we found that treatment‑naive patients with higher numbers of CD4 + PD‑1 + T cells at baseline showed a significantly shortened time to the first treatment compared with patients with a low number of CD4 + PD‑1 + T cells. CONCLUSIONS Our study showed that the quantative assessment of CD4 + PD‑1 + T cells in peripheral blood using flow cytometry can facilitate prognostication of patients with newly diagnosed CLL.

Risk of left atrial appendage thrombus in patients scheduled for ablation for atrial fibrillation: beyond the CHA2DS2VASc score.

Abstract: Introduction Atrial fibrillation (AF) increases the risk of thromboembolic events by promoting clot formation in the left atrial appendage (LAA). Transesophageal echocardiography (TEE) is routinely used to exclude the presence of an LAA thrombus before AF ablation. So far, it has not been established what is the optimal combination of noninvasive parameters for thromboembolic risk stratification in this setting and whether patients at very low risk require TEE. Objectives The aim of the study was to assess predisposing factors for an LAA thrombus in patients scheduled for AF ablation and to identify those patients in whom preprocedural TEE is not necessary. Patients and methods In consecutive 151 patients (107 men; mean age, 57 ±10 years) the type of AF and renal function were assessed in addition to the CHA2DS2VASc score to improve thromboembolic risk stratification. Results An LAA thrombus or dense echo contrast with a strong suspicion of a probable thrombus was detected in 15 patients (10%). Diabetes, age of 65 years or older, persistent AF, and estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2 were predictors of the LAA thrombus. A multivariate logistic regression analysis showed that only persistent AF and an eGFR of less than 60 ml/min/1.73 m2 were independent predictors of the LAA thrombus. The receiver operating characteristic curves showed that the greatest area under the curve (0.845) was achieved for the CHA2DS2VASc-AFR (CHA2DS2VASc plus the type of AF and renal function); the difference was not significant. A CHA2DS2VASc-AFR score of 2 or greater or a CHA2DS2VASc score of 1 or greater identified patients with the LAA thrombus with a sensitivity of 100% (and specificity of 54% and 36%, respectively). Conclusions In patients scheduled for AF ablation, an LAA thrombus or dense echo contrast is a relatively common finding despite routine anticoagulant treatment. The addition of AF type and renal function to the CHA2DS2VASc score slightly improves thromboembolic risk stratification and may help identify patients who do not need preprocedural TEE.

Association of adipokines and inflammatory markers with lipid control in type 2 diabetes.

Abstract: INTRODUCTION Data regarding the effect of certain adipokines on lipid metabolism are equivocal. OBJECTIVES The aim of this study was to evaluate the association of lipid control with adipokines and inflammatory markers in patients with type 2 diabetes. PATIENTS AND METHODS The analysis included 195 patients with type 2 diabetes. The achievement of treatment targets in terms of total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides was assessed in accordance with the current guidelines. Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) index as well as concentrations of highmolecular-weight (HMW) adiponectin, leptin, resistin, high-sensitivity C-reactive protein, interleukin 6, and tumor necrosis factor α (TNF-α) were measured in all patients. Logistic regression analyses were performed to determine the risk factors for inadequate lipid control. RESULTS Optimal control in terms of total cholesterol, LDL, HDL, and triglycerides was achieved in 61%, 43%, 53%, and 68% of the patients, respectively. In multivariate analyses, female sex, lower resistin concentrations, and the absence of statin treatment were predictors of total cholesterol levels above the treatment target; older age and lower statin dose--of LDL cholesterol levels above the treatment targets; female sex, higher HOMA-IR index, lower HMW adiponectin concentrations, and higher TNF-α concentration-o-f HDL levels below the treatment targets; and higher HOMA-IR, lower HMW adiponectin concentration, and the absence of statin treatment--of triglycerides above the treatment target. CONCLUSIONS In type 2 diabetes, lower HMW adiponectin concentrations are associated with inadequate triglyceride and HDL control; higher TNF-α, with inadequate HDL control, and lower resistin concentrations, with inadequate total cholesterol control.

Factors associated with resistant hypertension in a large cohort of hypertensive patients: the Pol-Fokus study.

Abstract: INTRODUCTION Patients with resistant hypertension (RHT) are at high risk for coronary artery disease (CAD) and cerebrovascular disease (CVD), compared with the general hypertensive population OBJECTIVES The aim of the study was to evaluate factors associated with RHT in a large sample of hypertensive patients under the care of general practitioners and specialists in Poland PATIENTS AND METHODS We included 12 375 patients (mean age, 640 ±123 years; age range, 18-98 years; women, 59%) with hypertension treated for at least 1 year Patients were divided into 3 groups: with controlled hypertension, uncontrolled hypertension (not fulfilling the criteria for RHT), and RHT RESULTS Controlled hypertension, uncontrolled hypertension, and RHT were found in 473%, 279%, and 247% of the patients, respectively The RHT rate was higher in patients visiting specialist offices (298%) and in patients with diabetes (325%), CAD (315%), CVD (333%), and impaired renal function (319%) Patients with RHT were characterized by the highest rate of high (235%) and very high (605%) added cardiovascular risk An underuse of preferred antihypertensive drug combinations and aldosterone antagonists in patients with uncontrolled hypertension and RHT was observed In a multivariate analysis, RHT was independently associated with male sex, higher pulse pressure, metabolic syndrome, diabetes, CAD, CVD, diseases requiring treatment with nonsteroidal anti-inflammatory drugs and an estimated glomerular filtration rate of less than 60 ml/min/173 m2 CONCLUSIONS The vast majority of patients with RHT carry a high or very high cardiovascular risk In addition, the underuse of preferred antihypertensive drug combinations and aldosterone antagonists has been observed

Diagnosis and therapy of antiphospholipid syndrome.

Abstract: Antiphospholipid syndrome (APS) is a clinical condition that has not been well defined yet. Although the clinical component is well established, the laboratory part is a mood issue. According to current guidelines, 3 tests (lupus anticoagulant, anticardiolipin, and anti β2-glycoprotein I antibodies) are officially recommended to assess the presence of antiphospholipid antibodies. According to test positivity, patients are classified into categories in clinical studies. However, it is now clear that classification categories have a different impact on the clinical course of APS. Indeed, patients and healthy carriers with a full positive antibody profile (triple positivity) are those at the highest risk of events. Patients with a single test positivity are those at a lower risk. In this review, on the basis of a laboratory profile, we grade the diagnosis of APS into definite, probable/possible, and uncertain. We also discuss secondary prevention of thrombotic APS, prevention of pregnancy morbidity, and treatment of catastrophic APS. Finally, new tools in laboratory diagnosis and treatment are highlighted.

Malignant hypertension: new aspects of an old clinical entity.

Abstract: Malignant hypertension (MHT), also known as accelerated-malignant hypertension or malignant-phase hypertension, is the most severe form of arterial hypertension. It is defined clinically as high blood pressure (BP) levels associated with lesions of the retinal fundus (flame-shaped hemorrhages, exudates, or cotton wool spots, with or without papilledema). Despite the availability of a vast range of antihypertensive agents, MHT continues to be a significant clinical challenge. Although its prevalence is very low, the absolute number of new cases has not changed over the past decades. While the role of the activation of the renin-angiotensin-aldosterone system and endothelial dysfunction in the pathogenesis of MHT has been well described, recent studies have indicated that the immune system may also play an important role in the development of this condition. Patients with MHT are characterized by pronounced target organ damage, including structural and functional cardiac abnormalities. MHT is frequently complicated by renal insufficiency and end-stage renal disease. The survival rates for patients with MHT have improved considerably with increased availability of antihypertensive treatment. However, renal insufficiency and end-stage renal disease still remain a significant cause of morbidity and mortality in this patient group. In conclusion, MHT is not a "vanishing disease" because there is a relatively stable number of new cases per year. Nonetheless, prognosis and survival rates in these patients have improved significantly owing to earlier detection, stricter BP control, lower BP targets, better choice of antihypertensive drugs, and availability of hemodialysis and renal transplantation.

Comparison of conventional and ultrasound-guided needle biopsy techniques in the diagnosis of sarcoidosis: a randomized trial.

Abstract: Introduction Endoscopic biopsy techniques are useful in the diagnosis of sarcoidosis. There is a need for randomized trials to establish where these procedures fit in the diagnosis of sarcoidosis. Objectives The aim of the study was to compare the diagnostic yield of conventional transbronchial needle aspiration (TBNA) with endobronchial ultrasound-guided TBNA (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in stages I and II of pulmonary sarcoidosis. Patients and methods Patients suspected of sarcoidosis were randomized to undergo TBNA or EBUS-TBNA or EUS-FNA. Patients with negative TBNA and EBUS-TBNA results underwent EUS-FNA and those with negative EUS-FNA results—EBUS-TBNA. If both tests were negative, patients in stage I were scheduled for mediastinoscopy (MS) and those in stage II—for transbronchial lung biopsy (TBLB). Results In 100 patients, 34 TBNA, 30 EBUS-TBNA, and 36 EUS-FNA procedures were performed at baseline. TBNA was positive in 20 patients (58.8%); EBUS-TBNA, in 23 (76.7%); and EUS-FNA, in 31 patients (86.1%). In patients with negative biopsy results, the second procedure was performed. The results of EUS-FNA were positive in 9 patients and of EBUS-TBNA—in none. Of 17 patients with negative results of both procedures, MS was performed in 6 patients and was positive in 2. In the remaining 11 patients, sarcoidosis was confirmed by TBLB. Sensitivity and accuracy of TBNA compared with EBUS-TBNA and EUS-FNA were 62.5% and 64.7%, 79.3% and 80%, and 88.6% and 88.9%, respectively. Sensitivity and accuracy of EBUS-TBNA were higher (P = 0.139) and of EUS-FNA were significantly higher compared with TBNA (P = 0.012). Conclusions In stages I and II of pulmonary sarcoidosis, endoscopic ultrasound is a reasonable approach but EUS-FNA seems to be the method of choice.

Clinical outcomes in patients after surgical and transcatheter aortic valve replacement.

Abstract: Introduction Transcatheter aortic valve implantation (TAVI) and minimally invasive aortic valve replacement (minithoracotomy and ministernotomy) have become a valuable alternative to conventional surgical treatment of severe aortic stenosis (AS) in high-risk patients. Objectives The aim of the study was to evaluate long-term results and complications in patients with symptomatic AS treated with TAVI, surgical aortic valve replacement (SAVR), minithoracotomy, or ministernotomy. Patients and methods A total of 173 patients with symptomatic AS were enrolled to the study between the years 2011 and 2013. Propensity scores were calculated for TAVI and each surgical method separately. Differences in clinical outcomes between patients treated with TAVI and those treated with surgical methods were adjusted for propensity scores using a logistic regression analysis and presented as adjusted odds ratios with 95% confidence intrervals. Results A median follow-up was 583.5 days (interquartile range, 298-736 days). Before aortic valve replacement (AVR), no significant differences in ejection fraction (EF) were observed between the groups. At 1 week after AVR, mean EF values were significantly higher in patients after TAVI in comparison with the other groups (TAVI, 50.2% ±13.1%; minithoracotomy, 44.1% ±13.4%; ministernotomy, 37.8% ±12.8%; SAVR, 40.3% ±12.5%; P = 0.001). There were no differences in the longest available follow-up mortality between the analyzed groups (P = 0.8). To our best knowledge, this is the first study comparing minithoracotomy, ministernotomy, and SAVR with TAVI in terms of long-term outcomes such as the longest available follow-up mortality, left ventricular (LV) function, complications after the procedure, and conduction disturbances and arrhythmias after the procedure. Conculsions Patients undergoing TAVI show more beneficial long-term outcomes in comparison with patients undergoing minithoracotomy, ministernotomy, and SAVR and do not differ in terms of the longest available follow-up mortality. TAVI seems to have a more favorable effect on LV function and an increase in EF in comparison with the surgical methods.

Treatment of iron deficiency anemia: practical considerations.

Abstract: Iron deficiency anemia is a common problem worldwide, and doctors of all specialties need to be competent in its treatment. While most patients respond well to oral iron preparations, a substantial minority have side effects that make them adhere poorly to their treatment. For oral iron‑intolerant patients, those responding poorly despite good adherence, and those with severe and/or symptomatic anemia, intravenous iron is an excellent alternative. It is, however, more expensive and carries a very small but potentially life‑threatening risk of severe infusion‑related hypersensitivity reactions. After outlining the main features of iron metabolism, in this review we compare the indications for therapy with oral and intravenous iron, and then focus on how to maximize the efficacy and safety of the two different routes.

Changes in urine proteome accompanying diabetic nephropathy progression.

Abstract: Introduction Owing to the prevalence of type 2 diabetes, diabetic kidney disease (DKD) becomes the major cause of end-stage renal disease. The current markers of diabetic nephropathy are based on albuminuria and clinical signs of retinopathy. Sensitive and specific noninvasive diagnostic tools, unbiased by the presence of comorbidities, are needed, especially to detect the early stages of diabetic complications. Objectives The aim of the study was to analyze changes in urinary protein excretion based on the stage of DKD using quantitative proteomics. Patients and methods A total of 27 healthy controls were age- and sex-matched to 72 diabetes patients classified into 3 groups: no signs of retinopathy or nephropathy (n = 33), retinopathy but no microalbuminuria (n = 15), and diabetic nephropathy (DN) based on overt albuminuria or microalbuminuria with retinopathy (n = 24). To assess the intergroup differences, samples were partially pooled, tagged using 8-plex iTRAQ reagents, and the resulting peptide mixture was resolved by isoelectrofocusing. The obtained fractions were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Data were analyzed using the MASCOT software and dedicated in-house proteomic data analysis programs. Results The changes in the urine proteome following DKD progression involved some known protein markers of DN and several other proteins. Decreased levels of some proteins are presumably related to impaired secretory function of other organs affected by diabetes. In particular, a diminished excretion of pancreatic amylase and deoxyribonuclease I suggested exocrine pancreatic insufficiency (EPI), coexisting with type 2 diabetes. Conclusions A decrease in the urinary excretion of some pancreatic enzymes suggests EPI associated with diabetes. This hypothesis is yet to be verified; nevertheless, renal and extrarenal confounders must be considered when interpreting the results of quantitative urinary proteomics.

Risk factors for anaphylaxis in patients with mastocytosis.

Abstract: Introduction Symptoms resulting from the activation and release of mediators from the mast cells are observed in about 30% of the patients with mastocytosis. Objectives The aim of the study was to assess the prevalence of anaphylactic reactions and to identify the risk factors for anaphylaxis in patients with mastocytosis depending on the type of the disease. Furthermore, we analyzed a response to treatment of mediator-related symptoms in this patient group. Patients and methods The study group included 152 adult patients with mastocytosis. The diagnostic workup included a histopathological examination, flow cytometry, KIT mutation analysis, and measurement of tryptase levels. The diagnosis of allergy was confirmed by the skin prick test and serum immunoglobulin E levels. Results The prevalence of anaphylactic reactions in the study group was 50% and was higher in patients with systemic mastocytosis (P = 0.007), specifically in its indolent variant (P = 0.026), than in patients with cutaneous mastocytosis. The most frequent triggers of anaphylaxis were food (29%), insect stings (22%), and drugs (15%). Tryptase levels were higher in patients with a history of anaphylaxis (P = 0.029) as well as in those with symptoms provoked by physical factors (P = 0.002). Such symptoms were reported in 112 patients (74%) and were more common in patients with systemic mastocytosis compared with those with cutaneous mastocytosis (P = 0.026). The treatment was ineffective in 8 patients (10.5%) and resulted only in partial remission in 14 patients (18.4%). Conclusions The study showed a significant incidence of symptoms related to physical factors in patients with mastocytosis and anaphylaxis in history. Risk factors for anaphylaxis included increased serum tryptase levels and indolent variant of systemic mastocytosis. Standard pharmacological treatment was ineffective in 10% of the patients, who may require biological treatment.

Reflections on the Institute of Medicine’s systemic exertion intolerance disease

Abstract: The Institute of Medicine (IOM) in the United States has recently proposed that the term systemic exertion intolerance disease (SEID) replace chronic fatigue syndrome. In addition, the IOM proposed a new case definition for SEID, which includes substantial reductions or impairments in the ability to engage in pre‑illness activities, unrefreshing sleep, postexertional malaise, and either cognitive impairment or orthostatic intolerance. Unfortunately, these recommendations for a name change were not vetted with patient and professional audiences, and the new criteria were not evaluated with data sets of patients and controls. A recent poll suggests that the majority of patients reject this new name. In addition, studies have found that prevalence rates will dramatically increase with the new criteria, particularly due to the ambiguity revolving around exclusionary illnesses. Findings suggest that the new criteria select more patients who have less impairment and fewer symptoms than several other criteria. The implications of these findings are discussed in the current review.

Gastroenteropancreatic neuroendocrine neoplasms: a 10-year experience of a single center.

Abstract: Introduction: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) constitute a rare and heterogeneous group of tumors with varied biology. Objectives: The aim of this study was to establish the clinical characteristics of patients with GEP-NEN and identify factors influencing their 5-year survival. Patients and methods: The study included 122 patients living in Krakow or its administrative region, who were diagnosed with GEP-NEN between 2002 and 2011. Results: The mean follow-up period was 4.9 ±2.8 years. The most frequent primary site of the tumor was the small intestine (n = 25; 20%), followed by pancreas (n = 23; 19%), rectum (n = 23; 19%), stomach (n = 21; 17%), appendix (n = 19; 16%), and colon (n = 11; 9%). There were 84 tumors classified as NEN G1; 31, as NEN G2; 5, as neuroendocrine carcinoma; and 1, as mixed adenoneuroendocrine carcinoma. Most well-differentiated GEP-NENs (n = 57; 57%) were diagnosed at stage I according to the American Joint Committee on Cancer / Union for International Cancer Control (AJCC/UICC) classification; 77% of NEN G1 (n = 64) were diagnosed at stage I, but the majority of NEN G2—at stage IV (n = 18; 58%). Metastases at diagnosis were found in 38 patients (34%). In 90% of the cases (n = 101), tumors were hormonally nonfunctional. The overall 5-year survival was 85%. In the univariate analysis, NEN G2 (P = 0.003), higher stage according to the AJCC/UICC classification (P <0.001), and metastases at diagnosis (P <0.001) were associated with poorer prognosis. In standardized multivariate models, higher stage (P = 0.02) and metastases at diagnosis (P = 0.02) were independent risk factors for death. Conclusions: The most important factors affecting survival of patients with GEP-NENs are tumor stage and the presence of metastases at diagnosis. The analysis of single-center data improves identification of patients with poorer prognosis requiring a more aggressive approach.

Results of an open-access lung cancer screening program with low-dose computed tomography: the Gdańsk experience.

Abstract: INTRODUCTION Lung cancer screening with low-dose computed tomography (LDCT) is one of the most promising tools for reducing mortality from lung cancer. OBJECTIVES The aim of the study was to evaluate the results of an open-access lung cancer screening program with LDCT. PATIENTS AND METHODS In total, 8649 asymptomatic volunteers between 50 and 75 years of age with a smoking history of at least 20 pack-years underwent LDCT screening. The presence of lung nodules with a diameter of less than 5 mm required a follow-up control visit after 12 months, and with a diameter of 5 to 10 mm--after 3, 6, and 12 months. Patients with a nodule of more than 10 mm in diameter required further diagnostic workup. RESULTS Lung nodules were detected in 4694 individuals (54%). Lung cancer was diagnosed in 107 patients (1.24%). Of 8649 participants, 300 (3.5%) were referred for further diagnostic workup, and 125 (1.5%) underwent surgical resection (81 because of malignant lesions; 44, benign lesions). Eighty-one participants (75%) underwent surgery with a curative intent, and 26 participants underwent oncological treatment. There were no perioperative deaths. The majority of surgical patients underwent lobectomy (video-assisted, in 30 patients; and open, in 38 patients). Stage I non-small cell lung cancer was detected in 64 of the surgical patients (79%). CONCLUSIONS The detection rate of lung cancer in the screening program with low-dose computed tomography is relatively low but patients were diagnosed at a very early stage of the disease compared with standard clinical practice.

Stroke prevention in asymptomatic carotid artery disease: revascularization of carotid stenosis is not the solution.

Abstract: Asymptomatic carotid stenosis (ACS) exceeding 50% is present in about 2% of 60-year-old patients and an even higher fraction of older individuals. The major independent risk factors include advancing age, male sex, tobacco smoking, and a history of vascular disease. The best available evidence does not support either population screening for ACS or routine carotid revascularization when ACS is discovered. There is an urgent need to identify patients with ACS and a sufficiently high risk of ipsilateral stroke (despite contemporary medical management) to warrant invasive treatment. The mainstays of medical management are antiplatelet therapy (usually low-dose aspirin), high-dose statins, blood pressure control, and smoking cessation. Patients with ACS should be periodically educated about symptoms of transient ischemic attack and stroke that require emergent medical attention. Current guidelines vary widely in recommendations regarding revascularization (ie, endarterectomy or carotid stenting). The benefits of revascularization strategies remain uncertain for patients with ACS who receive contemporary medical management.

Insect sting allergy in adults: key messages for clinicians.

Abstract: During their lifetime, 945% of people are stung by wasps, honeybees, hornets, or bumblebees (order Hymenoptera) After a sting, most people show typical local symptoms, 5% to 15% develop local allergic reactions, and 3% to 89%--systemic allergic reactions (SARs), which may be potentially life-threatening in about 10% of them In mild forms of Hymenoptera-venom allergy (HVA), the leading symptoms are urticaria and edema (grades I and II, respectively, according to the Mueller classification) Severe SARs are classified as grade III (respiratory symptoms) and IV (cardiovascular symptoms) Rare manifestations of HVA are Kounis syndrome and takotsubo cardiomyopathy All patients after an SAR require standard (skin test, IgE, tryptase) or comprehensive (component diagnosis, basophil activation test) allergy testing All patients with severe systemic symptoms (hypertension, disturbances in consciousness) should be tested for mastocytosis Additionally, a relationship was found between the severity of HVA symptoms and intake of angiotensin-converting enzyme inhibitors (ACEIs) There is a similar concern, although less well-documented, about the use of β-blockers Patients with HVA who have experienced a SAR are potential candidates for venom immunotherapy (VIT), which is effective in 80% to 100% of individuals treated for 3 to 5 years An increased risk of a VIT failure has been reported in patients with systemic mastocytosis and those treated with ACEIs In certain groups (beekeepers, patients who develop a SAR to stings during a VIT with a standard dose, as well as those with a SAR to maintenance doses of VIT), a twice higher maintenance dose is recommended Indications, contraindications, treatment protocols, and vaccine doses are regulated by the international guidelines of allergy societies

CHA2DS2-VASc and R2CHA2DS2-VASc scores have predictive value in patients with acute coronary syndromes.

Abstract: INTRODUCTION The CHA2DS2-VASc and R2CHA2DS2-VASc scoring systems were designed to stratify thromboembolic risk in patients with atrial fibrillation. The R2CHA2DS2-VASc score, compared with the CHA2DS2-VASc, was modified by adding reduced creatinine clearance. OBJECTIVES The aim of the study was to assess the long-term predictive value of these scores in patients with acute coronary syndrome (ACS) and to compare their utility with TIMI and GRACE scores in this patient group. PATIENTS AND METHODS We performed a pooled analysis of 5 independent populations with ACS with a long-term follow-up available. The primary endpoint was defined as all-cause mortality. The following risk scores were calculated: TIMI-STEMI or TIMI-NSTEMI, GRACE, CHA2DS2-VASc, and R2CHA2DS2-VASc RESULTS A total of 2557 patients were included in the final analysis with a median follow-up of about 5 years. The CHA2DS2-VASc and R2CHA2DS2 -VASc scores were significant predictors of total mortality in the pooled analysis. After correction for heart rate and systolic blood pressure on admission as well as previous myocardial infarction, the scores were still significantly predictive of mortality (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.39–1.54; P <0.0001 for CHA2DS2-VASc; and HR, 1.41; 95%CI, 1.35–1.47; P <0.0001 for R2CHA2DS2-VASc). At all time points (1, 3, and 5 years), the TIMI-STEMIscore was a significantly better predictor than the CHA2DS2-VASc and R2CHA2DS2-VASc scores. The predictive value of the R2CHA2DS2-VASc score was comparable to that of the GRACE score at 3 and 5 years. CONCLUSIONS The CHA2DS2-VASc and R2CHA2DS2-VASc scores are significant predictors of all-cause mortality in a long-term follow-up in patients with ACS. These simple risk scores may be easily applied in clinical practice in this patient group.

Atrial fibrillation in outpatients with stable coronary artery disease: results from the multicenter RECENT study.

Abstract: INTRODUCTION Atrial fibrillation (AF) frequently coexists with other cardiovascular diseases. OBJECTIVES The aim of this study was to assess the prevalence of AF in outpatients with stable coronary artery disease (CAD) and to determine clinical and laboratory parameters associated with the higher prevalence of this arrhythmia. In addition, we compared the indications for antithrombotic treatment using the older CHADS₂ and the currently used CHA₂DS₂-VASc scores. PATIENTS AND METHODS We studied the clinical data of 2578 Polish patients with stable CAD participating in the multicenter RECENT study (age, 65 ±10 years; men, 55%; Canadian Cardiovascular Society class I/II/III+IV, 38%/48%/14%). RESULTS AF was present in 19% of patients with CAD. Advanced age, longer history of CAD, and concomitant heart failure were independently associated with the higher prevalence of AF (all P <0.05). Among patients with CAD and AF, 73% of the patients required antithrombotic treatment according to the CHADS₂ score (≥2), and 94%-according to the CHA₂DS₂-VASc score (≥2). A CHA₂DS₂-VASc score of 2 or higher was found in 47% of the patients with a CHADS₂ score of 0 and 85% of those with a CHADS2 score of 1. Twenty-one percent of patients with CAD and AF did not have unequivocal indications for antithrombotic treatment according to the CHADS₂ score (0-1), while they had strong indications for such treatment on the basis of the CHA₂DS₂-VASc score (≥2). CONCLUSIONS AF affects every fifth ambulatory patient with CAD. According to the CHA₂DS₂-VASc score, almost all patients with CAD and AF require antithrombotic treatment, which may complicate coronary revascularization and related antiplatelet treatment.

Effects of genetic polymorphisms of glutathione S-transferase genes (GSTM1, GSTT1, GSTP1) on the risk of diabetic nephropathy: a meta-analysis.

Abstract: INTRODUCTION Glutathione S-transferases (GSTs) belong to a family of ubiquitous and multifunctional enzymes that protect the cells against oxidative stress. OBJECTIVES The aim of the study was to evaluate the association between the polymorphisms of glutathione-S-transferase (GST) genes and diabetic nephropathy (DN). PATIENTS AND METHODS PubMed, EMBASE, and Google Scholar databases were systematically searched to identify relevant studies. The odds ratio (OR) for the association was determined using a fixed or random effects model. Tests for heterogeneity of the results and sensitivity analyses were performed. RESULTS A total of 9 publications (874 patients in the study group, 966 controls) were included. With the exception of 1 study, GSTT1 and GSTM1 genotypes were not assessed by methods that measure a gene copy number. A significantly increased risk of DN was found for the GSTM1(–) genotype (OR, 1.27; 95% CI, 1.02–1.58) and the combination of GSTT1(–)/GSTM1(–) (OR, 2.02; 95% CI, 1.22–3.36). We did not observe a correlation between DN and the GSTT1(–) genotype or the presence of Val alleles. In a subgroup analysis, an association between DN and the GSTM1(–) genotype was significant in Asians but not in Caucasians. CONCLUSIONS Our results indicate that the GSTM1(–) genotype and the combination of GSTT1(–)/GSTM1(–) increase the risk of DN. The combination of the GST polymorphisms rather than individual polymorphism should be investigated. Genotyping allowing a trimodular determination of the GST copy number variations may better describe an association between the risk of disease and a given genotype.