Sensitive, High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Analysis of Atorvastatin and Its Pharmacologically Active Metabolites in Serum for Supporting Precision Pharmacotherapy.

The antihyerlipidemic drug atorvastatin (ATR) is used worldwide as part of the strategy to prevent cardiovascular events. The high prevalence of patient nonadherence remains an important challenge which could be addressed efficiently by precision pharmacotherapy based on therapeutic drug monitoring (TDM). ATR is metabolized to pharmacologically active metabolites, and evidence shows that the sums of ATR acid and lactone form concentrations (ATR + ATRL), or of ATR and hydroxylated metabolites (ATR + MET) should be assayed. A method is presented for the analysis of these substances in serum. Method validation included the estimation of the quantitative relationship between the concentrations and the standard deviations (SD), which supports the optimal incorporation of TDM results into nonparametric pharmacokinetic models. The concentrations of the analytes were evaluated in human subjects receiving ATR. The method's performance improved by taking the sums of acid and lactone concentrations into account. The concentration-SD relationship was linear, and we recommend applying Theil's regression for estimating the assay error. All analytes could be detected by 2 h post dose in the samples of human subjects. The changes in metabolite/parent drug concentration ratios in time depended on the dose. The method is suitable for the TDM of ATR with a focus on precision pharmacotherapy.

Flow-mediated vasodilation assay indicates no endothelial dysfunction in hereditary angioedema patients with C1-inhibitor deficiency.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare, potentially life-threatening disorder characterized by recurrent edematous attacks. The edema formation is the consequence of interaction of bradykinin and various vasoactive peptides with endothelium. Besides these agents, danazol, a modified testosterone derivative used in these patients to prevent edematous attacks, can also affect the function of the endothelium, because it shifts the blood lipid profile to a pro-atherogenic phenotype. OBJECTIVE: To assess the endothelial function in C1-INH-HAE patients and in healthy matched controls. METHODS: To evaluate the endothelial function, we used the flow-mediated dilation method measured in the region of the brachial artery in 33 C1-INH-HAE patients and in 30 healthy matched controls. Laboratory measurements of standard biochemical parameters were performed on computerized laboratory analyzers. RESULTS: No difference was found in endothelial function (reactive hyperemia, RH) between patients (median, 9.0; 25%-75% percentile, 6.3-12.9) and controls (median, 7.37; 25%-75% percentile, 4.52-9.93). Although we found elevated cardiovascular risk (high body mass index and low-density lipoprotein/high-density lipoprotein ratio) in danazol-treated C1-INH-HAE patients, RH values did not differ between danazol-treated and nontreated patients. Furthermore, risk factors correlated with the endothelial function only in healthy controls and patients not treated with danazol. CONCLUSION: In summary, our results did not indicate any signs of endothelial dysfunction in C1-INH-HAE patients. Moreover, the normal endothelial function in danazol-treated patients with pro-atherogenic lipid profile suggests that elevated bradykinin level or other factor(s) involved in the pathogenesis of edematous attacks may have a protective role against endothelial dysfunction and atherosclerosis.

Novel electrocardiographic dyssynchrony criteria improve patient selection for cardiac resynchronization therapy.

Aims: We hypothesized that the greater the intra- or interventricular dyssynchrony (intraD, interD), the more effective cardiac resynchronization therapy (CRT) is. We sought to improve patient selection for CRT by using novel ECG dyssynchrony criteria. Methods and results: Left ventricular (LV) intraD was estimated by the absolute time difference between the intrinsicoid deflections (ID) in leads aVL and aVF divided by the QRS duration (QRSd): [aVLID - aVFID]/QRSd (%). InterD was estimated from the formula: [V5ID - V1ID]/QRSd (%). Their >25% value indicated electrical dyssynchrony present (ED+) and ≤25% value electrical dyssynchrony absent (ED-) diagnoses. Using the intraD + interD criteria (intra + interDC) together, if at least one of them indicated ED+ diagnosis, a final ED+ diagnosis, if both indicated ED- diagnosis, a final ED- diagnosis was made. Two authors, blinded to CRT response, retrospectively analysed pre-CRT ECGs of 124 patients with known CRT outcome. CRT response was defined as improvement of ≥ 1 NYHA class, being alive and having no hospitalizations for heart failure during 6 months of follow-up. 35/124 (28%) patients were non-responders (NRs), using the traditional criteria (TC) correct diagnosis was made in the remaining 89/124 (72%) responder (R) cases. The test accuracy (TA) of intra + interDC + TC [100/124 (81%), P < 0.001] was superior to that of TC [89/124 (72%)] due to its superior TA [36/43 (84%) vs. 29/43 (67%), respectively, P = 0.0156] in the non-specific intra-ventricular conduction disturbance (NICD) subgroup [43/124 (35%)]. In the left bundle branch block subgroup [70/124 (56%)] there was no between-criteria difference in TA. Conclusion: The intra + interDC + TC predicts clinical response after CRT more accurately than TC alone, due to greater TA in the NICD subgroup.

Long-Term Survival and Apolipoprotein A1 Level in Chronic Heart Failure: Interaction With Tumor Necrosis Factor α -308 G/A Polymorphism.

BACKGROUND: Apolipoprotein A1 (ApoA1), a major constituent of high-density lipoprotein (HDL), has antiinflammatory and antioxidative properties and plays a prognostic role in chronic heart failure (CHF). Despite increased tumor necrosis factor α (TNFα) levels being linked to worse outcome of HF, the results are ambiguous about the association of functionally active 308 promoter polymorphism of the TNFα gene. The aims of our study were to investigate the association of ApoA1 and TNFα levels with mortality and to evaluate potential interaction between these factors and TNFα -308 polymorphism. METHODS: Together with several parameters ApoA1, TNFα levels and TNFα-308 polymorphism were determined in a cohort of 195 patients with CHF who were followed for 5 years. RESULTS: Low ApoA1 and high TNFα levels were associated with more severe disease, and ApoA1 showed the strongest relationship with HDL, total cholesterol, C-reactive protein, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). TNFα -308 A carriers had significantly higher ApoA1 levels than wild-type (GG) patients (1.41 ± 0.268 vs 1.29 ± 0.324 g/L; P = .007), whereas levels of TNFα were the same in these groups. Decreased ApoA1 levels were significant predictors of 5-year mortality (NT-proBNP-adjusted HR for 1 decile decrease in ApoA1 level was 1.10 (P = .011). Interaction was found between the ApoA1 level and TNFα -308 polymorphism, because in patients with GG haplotype the adverse effect of low ApoA1 level on survival was more prevalent. CONCLUSIONS: Lower ApoA1 levels were strongly associated with adverse outcome in CHF patients in a TNFα -308 polymorphism dependent manner. These observations support the complex involvement of malnutrition and inflammation in the pathogenesis of CHF.

[Up to date lipid lowering treatment]. / Korszeru lipidcsökkento kezelés.

Considerable evidence suggests that "the lower the better" is a reasonable approach for reducing cardiovascular risk by lowering LDL cholesterol levels. Despite the reduction in cardiovascular events and mortality achieved by statin therapy, significant residual risk remains, especially in severe hereditary hypercholesterolemia, such as familial hypercholesterolemia. Some new strategies to achieve even lower LDL levels are now available, including the addition of cholesterol absorption inhibitor ezetimibe, and the recently available Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies. In addition, new LDL drugs may be effectively administrated in those individuals who are unable to tolerate statins. The authors summarize the efficacy and clinical indications of these new agents and review the currently available guidelines. Orv. Hetil., 2016, 157(31), 1219-1223.

Metastasis blood test by flow cytometry: in vivo cancer spheroids and the role of hypoxia.

Cancer hypoxia correlates with therapeutic resistance and metastasis, suggesting that hypoxic adaptation is a critical survival advantage for cancer stem cells (CSCs). Hypoxic metabolism, however, may be a disadvantage in aerobic circulation as the extremely low incidence of metastasis-compared to the high circulating tumor-cell numbers (CTCs)-appears to suggest. As rare metastatic CSCs still survive, we searched for a mechanism that protects them from oxygen in circulation. CSCs form multicellular spheroids in vitro from virtually all cancers tested. We asked, therefore, whether cancers also form spheroids in vivo and whether circulating spheroids play a role in metastasis. We used metabolic, apoptotic and hypoxia assays, we measured aerobic barriers and calculated hypoxia vs. spheroid-size correlations. We detected metabolic/oxidative stress in spheroids, we found correlation between stem cell presence and hypoxia and we showed that the size of hypoxic spheroids is compatible with circulation. To detect spheroids in patients, we worked out a new light-scatter flow cytometry blood test and assayed 67 metastatic and control cases. We found in vivo spheroids with positive stem cell markers in cancer blood and they showed exclusive correlation with metastasis. In conclusion, our data suggest that metastatic success depends on CSC-association with in vivo spheroids. We propose that the mechanism involves a portable "micro-niche" in spheroids that may support CSC-survival/adaptation in circulation. The new assay may establish a potential early marker of metastatic progression.

Copeptin (C-terminal pro arginine-vasopressin) is an independent long-term prognostic marker in heart failure with reduced ejection fraction.

BACKGROUND: The level of copeptin, a stable fragment of pro-arginine-vasopressin (AVP), correlates with disease severity. It is an established, short-term prognostic marker for patients with heart failure with reduced ejection fraction (HFREF). We aimed to examine the association between copeptin and long-term mortality. We also studied the clinical usefulness of copeptin as a prognostic biomarker by analysing the improvement of net reclassification. METHODS: Copeptin concentrations were measured in a cohort of 195 consecutive patients with HFREF. Disease severity and clinical parameters were determined at baseline, and all-cause mortality was recorded after five-year follow-up. RESULTS: One hundred and ten patients died during the five-year follow-up (five-year mortality rate: 0.56). Univariate analysis identified copeptin (HR 2.168 [95% CI 1.740-2.700]) as a predictor of mortality. The final, multivariable Cox survival model identified a number of independent predictors of death. These included higher NHYA functional class, previous MI, at least one hospitalisation for worsening HF (within the two years before inclusion into the study), elevated blood urea nitrogen, NT-proBNP-, and copeptin levels, as well as increased red blood cell distribution width, and decreased GFR. The addition of copeptin alone to the baseline predictive model (NT-proBNP only) resulted in a minor (8.21%) improvement, whereas the final, multivariable model showed a significant increase in net reclassification (10.26%, p=0.015). CONCLUSIONS: These data indicate that copeptin is an independent long-term prognostic marker in HFREF, with possible clinical relevance for multimarker risk prediction algorithms.

Chloroquine cardiotoxicity mimicking connective tissue disease heart involvement.

The authors report a case of rare chloroquine cardiotoxicity mimicking connective tissue disease heart involvement in a 56-year-old woman with mixed connective tissue disease (MCTD) manifested suddenly as third degree A-V block with QT(c) interval prolongation and short torsade de pointes runs ultimately degenerating into ventricular fibrillation. Immunological tests suggested an MCTD flare, implying that cardiac arrest had resulted from myocardial involvement by MCTD. However, QT(c) prolongation is not a characteristic of cardiomyopathy caused by connective tissue disease, unless anti-Ro/SSA positivity is present, but that was not the case. Therefore, looking for another cause of QT(c) prolongation the possibility of chloroquine cardiotoxicity emerged, which the patient had been receiving for almost two years in supramaximal doses. Biopsy of the deltoid muscle was performed, because in chloroquine toxicity, specific lesions are present both in the skeletal muscle and in the myocardium, and electron microscopy revealed the accumulation of cytoplasmic curvilinear bodies, which are specific to antimalarial-induced myocyte damage and are absent in all other muscle diseases, except neuronal ceroid lipofuscinosis. Thus, the diagnosis of chloroquine cardiotoxicity was established. It might be advisable to supplement the periodic ophthalmological examination, which is currently the only recommendation for patients on long-term chloroquine therapy, with ECG screening.

Persistence of initial oral antidiabetic treatment in patients with type 2 diabetes mellitus.

BACKGROUND: Adequate persistence of oral antidiabetic treatment is highly important to achieve proper glycemic control in patients with type 2 diabetes. The aim of this study was to evaluate the persistence of initial treatment with metformin and/or sulphonylureas in patients with type 2 diabetes. MATERIAL/METHODS: The study was performed among diabetic patients (n=256,384) who were with newly prescribed oral antidiabetic drugs (metformin and/or sulphonylureas) between 2007 and 2009. For making comparison, patients with newly prescribed statin or clopidogrel therapy (with and without percutaneous coronary intervention) were investigated. The database of the Hungarian National Health Insurance Fund Administration was used. RESULTS: The 1-year persistence of initial treatment with metformin, sulphonylureas or metformin/sulphonylurea combination was 47.7%, 45.4% and 55.8%, respectively, which was significantly better than the persistence of statin therapy (26.3%) but worse than that of clopidogrel therapy in patients undergoing coronary intervention (73.2%). Within the sulphonylurea group there was a tendency of better persistence of treatment with the "modified-release" tablets at 12 months compared to the conventional sulphonylureas (47.8 vs. 42.2%). The persistence of therapy using metformin 1000 mg - 60 tablets was significantly better (60.4%) at 12 months than that of other forms of metformin therapy with lower doses and smaller boxes (with fewer tablets) analyzed together (47.7%). CONCLUSIONS: The persistence of initial treatment with metformin and/or sulphonylureas is far from optimal. Better diabetic care and continuous patient education should be encouraged to achieve higher persistence of oral antidiabetic treatment in patients with type 2 diabetes.

Serum leptin levels in relation to circulating cytokines, chemokines, adhesion molecules and angiogenic factors in normal pregnancy and preeclampsia.

OBJECTIVE: In this study, we determined circulating levels of C-reactive protein, several cytokines, chemokines, adhesion molecules and angiogenic factors along with those of leptin in healthy non-pregnant and pregnant women and preeclamptic patients, and investigated whether serum leptin levels were related to the clinical characteristics and measured laboratory parameters of the study participants. METHODS: Sixty preeclamptic patients, 60 healthy pregnant women and 59 healthy non-pregnant women were involved in this case-control study. Levels of leptin and transforming growth factor (TGF)-beta1 in maternal sera were assessed by ELISA. Serum levels of interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-18, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interferon-gamma-inducible protein (IP)-10, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 were determined by multiplex suspension array. Serum C-reactive protein (CRP) concentrations were measured by an autoanalyzer. Serum total soluble fms-like tyrosine kinase-1 (sFlt-1) and biologically active placental growth factor (PlGF) levels were determined by electrochemiluminescence immunoassay. For statistical analyses, non-parametric methods were applied. RESULTS: There were significant differences in most of the measured laboratory parameters among the three study groups except for serum IL-1beta and TGF-beta1 levels. Serum leptin levels were significantly higher in preeclamptic patients and healthy pregnant women than in healthy non-pregnant women. Additionally, preeclamptic patients had significantly higher leptin levels as compared to healthy pregnant women. Serum leptin levels were independently associated with BMI in healthy non-pregnant women. In healthy pregnant women, both BMI and serum CRP concentrations showed significant positive linear association with leptin levels. There were significant positive correlations between serum leptin concentrations of healthy pregnant women and systolic blood pressure, as well as serum levels of IP-10, while their serum leptin levels correlated inversely with fetal birth weight. In preeclamptic patients, a significant positive correlation was observed between serum concentrations of leptin and IP-10. Furthermore, elevated serum leptin level and sFlt-1/PlGF ratio had an additive (joint) effect in the risk of preeclampsia, as shown by the substantially higher odds ratios of their combination than of either alone. CONCLUSIONS: Simultaneous measurement of leptin with several inflammatory molecules and angiogenic factors in this study enabled us to investigate their relationship, which can help to understand the role of circulating leptin in normal pregnancy and preeclampsia.

Severe mitral regurgitation and heart failure due to caseous calcification of the mitral annulus.

Caseous calcification is a rare form of mitral annular calcification. Echocardiography reveals an echodense mass in the inferior mitral annulus with smooth borders and an echolucent inner core. We present a case where caseous calcification of the mitral annulus caused severe mitral regurgitation, atrial fibrillation and heart failure. Transthoracic echocardiography, transesophageal echocardiography, cardiac magnetic resonance and computed tomography were performed and ensured the diagnosis. The mass was surgically removed and a prosthetic valve was implanted. We conclude that caseous calcification of the mitral annulus should be considered not only in the differential diagnosis of cardiac masses but also in the background of mitral regurgitation, atrial fibrillation and heart failure. This case also represents the usefulness of multimodal imaging in identifying cardiac masses.

A pharmacokinetics-based approach to the monitoring of patient adherence to atorvastatin therapy.

The inadequate adherence of patients whose hyperlipidemia is treated with atorvastatin (ATR) to medical instructions presents a serious health risk. Our aim was to develop a flexible approach based on therapeutic drug monitoring (TDM), nonparametric population pharmacokinetic modeling, and Monte Carlo simulation to differentiate adherent patients from partially and nonadherent individuals in a nonrandomized, unicentric, observational study. Sixty-five subjects were enrolled. Nonparametric, mixed-effect population pharmacokinetic models of the sums of atorvastatin and atorvastatin lactone concentrations (ATR+ATRL) and of the concentrations of the acid and lactone forms of ATR and its 2- and 4-hydroxylated pharmacologically active metabolites (ATR+MET) were elaborated by including the TDM results obtained in 128 samples collected from thirty-nine subjects. Monte Carlo simulation was performed based on the elaborated models to establish the probabilities of attaining a specific ATR+ATRL or ATR+MET concentration in the range of 0.002-10 nmol (mg dose)-1 L-1 at 1-24 h postdose by adherent, partially adherent, and nonadherent patients. The results of the simulations were processed to allow the estimation of the adherence of further 26 subjects who were phlebotomized at sampling times of 2-20 h postdose by calculating the probabilities of attaining the ATR+ATRL and ATR+MET concentrations measured in these subjects in adherent, partially adherent, and nonadherent individuals. The best predictive values of the estimates of adherence could be obtained with sampling at early sampling times. 61.54% and 38.46% of subjects in the adherence testing set were estimated to be fully and partially adherent, respectively, while in all cases the probability of nonadherence was extremely low. The evaluation of patient adherence to ATR therapy based on pharmacokinetic modeling and Monte Carlo simulation has important advantages over the collection of trough samples and the use of therapeutic ranges.

Plasma osteopontin concentrations in preeclampsia - is there an association with endothelial injury?

UNLABELLED: Abstract Background: It has been previously reported that plasma osteopontin (OPN) concentrations are increased in cardiovascular disorders. The goal of the present study was to determine plasma OPN concentrations in healthy pregnant women and preeclamptic patients, and to investigate their relationship to the clinical characteristics of the study subjects and to markers of inflammation [C-reactive protein (CRP)], endothelial activation [von Willebrand factor antigen (VWF:Ag)] or endothelial injury (fibronectin), oxidative stress [malondialdehyde (MDA)] and trophoblast debris (cell-free fetal DNA). METHODS: Forty-four patients with preeclampsia and 44 healthy pregnant women matched for age and gestational age were involved in this case-control study. Plasma OPN concentrations were measured with ELISA. Serum CRP concentrations were determined with an autoanalyzer using the manufacturer's reagents. Plasma VWF:Ag was quantified by ELISA, while plasma fibronectin concentrations were measured by nephelometry. Plasma MDA concentrations were estimated by the thiobarbituric acid-based colorimetric assay. The amount of cell-free fetal DNA in maternal plasma was determined by quantitative real-time PCR analysis of the sex-determining region Y (SRY) gene. For statistical analyses, non-parametric methods were applied. RESULTS: Serum levels of CRP, as well as plasma concentrations of VWF:Ag, fibronectin, MDA and cell-free fetal DNA were significantly higher in preeclamptic patients than in healthy pregnant women. There was no significant difference in plasma OPN concentrations between controls and the preeclamptic group. However, preeclamptic patients with plasma fibronectin concentrations in the upper quartile had significantly higher plasma OPN concentrations than those below the 75th percentile, as well as healthy pregnant women [median (interquartile range): 9.38 (8.10-11.99) vs. 7.54 (6.31-9.40) and 7.40 (6.51-8.80) ng/mL, respectively, p<0.05 for both]. Furthermore, in preeclamptic patients, plasma OPN concentrations showed a significant positive linear association with plasma fibronectin (Spearman R=0.38, standardized regression coefficient (beta)=0.41, p<0.05 for both). CONCLUSIONS: Plasma OPN concentrations are increased in preeclamptic patients with extensive endothelial injury. However, further studies are warranted to explore the relationship between OPN and endothelial damage. Clin Chem Lab Med 2010;48:181-7.

The effect of long-term danazol prophylaxis on liver function in hereditary angioedema-a longitudinal study.

BACKGROUND: Danazol is a drug most widely used for the prophylaxis of hereditary angioedema resulting from the deficiency of the C1-inhibitor. Potential hepatotoxic or liver tumor-inducing side effects of long-term danazol prophylaxis have been investigated during the follow-up of hereditary angioedema patients. METHODS: Characteristic parameters of liver function (including bilirubin, GOT, GPT, gammaGT, total protein, ALP, LDH), as well as findings of viral serology screens and abdominal ultrasonography-determined during years 0 and 5 of follow-up of patient groups taking/not taking danazol-have been reviewed and analyzed comparatively. RESULTS: From a population of 126 hereditary angioedema patients, 46 subjects taking danazol and another 46 not taking danazol fulfilled the inclusion criteria. Longitudinal follow-up did not reveal any clinically relevant difference between the liver function parameters determined in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations of the liver parenchyma. There were no discontinuations of treatment during the study. CONCLUSIONS: Our results clearly suggest that, administered at the lowest effective dose, danazol does not induce liver injury in hereditary angioedema patients.

A detailed investigation of maternally inherited diabetes and deafness (MIDD) including clinical characteristics, C-peptide secretion, HLA-DR and -DQ status and autoantibody pattern.

BACKGROUND: This article presents a clinically characterization of the mitochondrial DNA mutation (A3243G) associated with maternally inherited diabetes and deafness (MIDD) syndrome in two families. METHODS: Six patients with MIDD and one mutation-positive relative with normal glucose tolerance (NGT) were examined. Fasting serum C-peptide was measured in all subjects and compared with controls having NGT (n = 14). C-peptide response to an intravenous glucose tolerance test (IVGTT) was investigated in the diabetic patients not treated with insulin (n = 3) and in the mutation-positive healthy individual and compared with the controls. RESULTS: The A3243G heteroplasmy value varied between 5 and 30%. All A3243G carriers had HLA-DR1-DQ5 haplotype, and either the -DQ5 or the -DQ6 allele. The fasting and the serum C-peptide levels at 120 min during the IVGTT did not differ between the A3243G carriers and the controls. A missing first phase and a decreased total C-peptide response was detected in the mutation-positive diabetics compared with controls (p < 0.0001). The same abnormality was found in the A3243G carrier with NGT. Circulating islet cell antibody (ICA) was present in three patients with MIDD. Glutamic acid decarboxylase (GAD), tyrosine phosphatase-like protein IA-2 (IA-2) and mitochondrial antibodies were missing. The diagnosis of MIDD was delayed in each case. CONCLUSIONS: A missing first phase and a decreased total C-peptide response during an IVGTT was characteristic for the A3243G mutation. The fasting C-peptide level of the carriers did not differ from the controls. Circulating ICA was present in some patients, but GAD, IA-2 and mitochondrial antibodies were absent. All subjects had HLA-DR1-DQ5 haplotype, and either -DQ5 or -DQ6 alleles.

Early complement activation follows eversion carotid endarterectomy and correlates with the time of clamping of the carotid artery.

BACKGROUND: Complement activation plays an important role in ischemia/reperfusion (I/R) injury. The objective of the present study was to detect the presence and mechanism of complement activation in patients who underwent carotid endarterectomy (CEA). METHODS: Complement activation products C1rsC1-inhibitor, C4d, C3a and SC5b-9 and concentrations of C-reactive protein (CRP) were measured in samples serially taken from 16 patients with eversion CEA and 10 with carotid artery stenting (CAS) in the first 24h post-surgery/intervention. MBL2 genotypes were also determined. RESULTS: In patients with CEA an intense increase in C3a levels were observed immediately after surgery (p<0.001), accompanied by a slight elevation in SC5b-9 levels (p<0.05). C3a levels remained elevated until 4h post-surgery, compared with the baseline values and with CAS patients. Peak C3a levels correlated with the time of carotid clamping (r=0.5921, p=0.02). No significant changes were detected in C1rsC1-inhibitor or C4d levels following CEA, and we found no association between the generation of C3a and MBL2 genotypes or CRP levels. Complement activation was not present in patients with CAS. CONCLUSIONS: Early complement activation follows CEA and correlates with the time of I/R injury. The lack of C4d generation suggests the role of the alternative and not the lectin pathway in the process.

[Community-acquired bacterial infections among type 2 diabetic and non-diabetic patients hospitalized on a general medical ward: a clinical comparison]. / 2-es típusú diabetesesek és nem cukorbetegek területen szerzett, belgyógyászati osztályos felvételt igénylo bakteriális infekcióinak klinikai összehasonlítása.

Introduction: Previous data showed bacterial infections among diabetic patients to be more serious and frequent, with higher mortality rates in comparison with non-diabetics. Recent investigations, however, are contradictory. Aim: The goal of our prospective, observational study was to compare patients hospitalized on a general medical ward due to community-acquired bacterial infections with type 2 diabetes mellitus (T2DM) to those of non-diabetics (K) by 1) infection localization, 2) spectrum of pathogens, 3) three-month mortality rates. Method: Patients were consecutively involved (T2DM: n = 205, K: n = 202). We characterized the infections, clinical parameters, mortalities of the two groups, and matched them to international data. Results: No difference regarding clinical details of the groups were found except for glycemic parameters and BMI. In the T2DM group the skin- and soft tissue- (37.1%), in the K patients respiratory infections (37.1%) were the most common, followed by urinary ones (31.2% and 31.7%, respectively). Skin- and soft tissue infection incidence among T2DM subjects were higher compared to international results (37.1% vs. 16%). Co-presence of Gram positive and Gram negative bacteria in the skin- and soft tissue infections (23/76 vs. 5/46, p = 0.0149), and polymicrobial origin in the urinary tract infections (34.0% vs. 15.1%, p = 0.0335) were found to be more frequent in T2DM than in K. No difference regarding mortality rates were detected. In T2DM the skin- and soft tissue while in the K group the respiratory infections had the most death counts. Conclusions: We found higher rates of skin- and soft tissue infections among T2DM patients hospitalized on a general medical ward compared to international data. In total we did not find difference regarding three-month mortality between the groups. Our results highlight the importance of primary prevention and shows its inadequacy concerning skin and soft tissue infections among type 2 diabetics in Hungary. Orv Hetil. 2019; 160(41): 1623-1632.

Polymorphisms of TNF-alpha and LT-alpha genes in multiple myeloma.

Allelic distribution of -308 G>A (TNF 1/2) polymorphism of the TNF-alpha, and the +252 A>G promoter polymorphism of the LT-alpha gene, the 1267 A>G polymorphism of the HSP70-2 gene as well as the -429 T>C promoter polymorphism of the RAGE gene were tested in 94 MM cases and 141 controls. Significantly less MM patients than controls carried the TNF2 allele (p=0.018) and the TNF2-LTA 252G haplotype (p=0.025). The difference was, however, restricted to the females, as well as the relatively young (<69 years) subjects. By contrast, we did not find differences with the other SNPs tested.

Acquired angioedema associated with primary antiphospholipid syndrome in a patient with antithrombin III deficiency.

Acquired angioedema (AAE) due to the functional deficiency of the C1 inhibitor (C1-INH) is a rare disease characterized by recurrent bouts of edema that involve subcutaneous tissues, the larynx or the gastrointestinal tract. In the present paper, we report the case of a male patient with symptoms of AAE and recurrent deep venous and arterial thrombosis. As a trigger of AAE in the present patient, we revealed primary antiphospholipid syndrome accompanied by antithrombin III deficiency, along with malignancy in the history, and angiotensin-converting enzyme inhibitor therapy. Although anti-C1-INH titers (type I AAE) were normal initially, we observed a sharp increase in anti-C1-INH titers (suggestive of type II AAE) during follow-up. It seems that thrombosis might worsen angioedematous attacks in functional C1-INH deficiency. Thrombophilia should be considered a provoking factor of AAE and should be carefully sought for in these patients, as the key to successful management of AAE is the effective treatment of the underlying disease.

Low c1-inhibitor levels predict early restenosis after eversion carotid endarterectomy.

OBJECTIVE: Homozygotes for the normal (A) allele of mannose-binding lectin (MBL2) gene have higher risks to develop an early restenosis after eversion carotid endarterectomy (CEA). Activation of the lectin pathway is regulated by C1-inhibitor (C1-INH). The objective of the present study was to determine the predictive value of C1-INH in restenosis after CEA. METHODS AND RESULTS: C1-INH and MBL-associated serine protease-2 (MASP-2) were determined in samples serially taken from 64 patients with CEA, who were followed-up with carotid duplex scan (CDS) examinations for 14 months. MBL2 genotypes were also determined. Patients with >50% restenosis had lower C1-INH levels at 6 weeks (P=0.0052) and at 4 days (P=0.0277) postsurgery. C1-INH levels at 6 weeks correlated inversely with the CDS values at 14 months (r=-0.3415, P=0.0058), but only in MBL2 A/A homozygotes (r=-0.5044, P=0.0015). Patients with low C1-INH levels (C1-INH <115%) had higher CDS values already at 7 months postsurgery. Patients with MBL2 A/A and low C1-INH levels at 6 weeks postsurgery had 13.97 (95% CI:1.95 to 100.21, P=0.0087) times higher risk to develop an early restenosis. Differences in the MASP-2 concentration were not associated with restenosis. CONCLUSIONS: Determining C1-INH levels at 6 weeks postsurgery-together with genotyping of MBL2-might be a useful marker in the identification of patients with high risk for early carotid restenosis.