Validation of Existing Clinical Prediction Tools for Primary Aldosteronism Subtyping.

The new clinical prediction score (SCORE) has been recently proposed for primary aldosteronism (PA) subtyping prior to adrenal vein sampling (AVS). This study aimed to compare that SCORE with previously published scores and their validation using a cohort of patients at our center who had had positive SIT confirming PA and had been diagnosed with either bilateral PA according to AVS or unilateral PA if biochemically cured after an adrenalectomy. Final diagnoses were used to evaluate the diagnostic performance of the proposed clinical prediction tools. Only Kamemura's model (with a maximum score of 4 points) and Kobayashi's score (with a maximum score of 12 points) reached 100% reliability for prediction of bilateral PA; however, with sensitivity of only 3%. On the other hand, the values of SCORE = 3 (with sensitivity of 48%), the SPACE score ≥18 (with sensitivity of 35%), the Kobayashi's score ≤2 (with sensitivity of 28%), and the Kocjan's score = 3 (with sensitivity of 28%) were able to predict unilateral PA with 100% probability. Furthermore, Umakoshi's and Young's models both reached 100% reliability for a unilateral PA with score = 4 and both predictive factors together respectively; however, the sensitivity was lower compared with previous models; 4% and 14%, respectively. None of the clinical prediction tools applied to our cohort predicted unilateral and bilateral subtypes together with the expected high diagnostic performance, and therefore can only be used for precisely defined cases.

Hypermetabolism and Substrate Utilization Rates in Pheochromocytoma and Functional Paraganglioma.

The overproduction of catecholamines in pheochromocytoma/paraganglioma (PPGL) induces a hypermetabolic state. The aim of this study was to evaluate the incidence of a hypermetabolic state and differences in substrate metabolism in consecutive PPGL patients divided by catecholamine phenotype. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured in 108 consecutive PPGL patients and 70 controls by indirect calorimetry. Hypermetabolic state was defined according to the Mifflin St. Jeor Equation as a ratio above 110%. Hypermetabolic state was confirmed in 70% of PPGL patients, regardless of phenotype. Older age, prevalence of diabetes mellitus and arterial hypertension were correlated with hypermetabolic PPGL as compared to normometabolic form. Analysis according to overproduced catecholamine showed differences in VCO2 (p < 0.05) and RQ (p < 0.01) and thus different substate metabolism between phenotypes in hypermetabolic form of PPGL. Lipid utilization was higher in the adrenergic phenotype (p = 0.001) and positively associated with the percentage of REE ratio (R = 0.48, p < 0.001), whereas the noradrenergic phenotype preferentially oxidizes carbohydrates (P = 0.001) and is correlated with the percentage of REE ratio (R = 0.60, p < 0.001). Hypermetabolic state in PPGL is a common finding in both catecholamine phenotypes. Hypermetabolic PPGL patients are older and suffer more from diabetes mellitus and arterial hypertension. Under basal conditions, the noradrenergic type preferentially metabolizes carbohydrates, whereas the adrenergic phenotype preferentially metabolizes lipids.

Adrenal Venous Sampling Could Be Omitted before Surgery in Patients with Conn's Adenoma Confirmed by Computed Tomography and Higher Normal Aldosterone Concentration after Saline Infusion Test.

PURPOSE: Adrenal venous sampling (AVS) performed to distinguish unilateral and bilateral primary aldosteronism (PA) is invasive and poorly standardized. This study aimed to identify non-invasive characteristics that can select the patients with unilateral PA who could bypass AVS before surgery. METHODS: A single-center study collected a total of 450 patients with PA. Development and validation cohorts included 242 and 208 patients. The AVS was successful in 150 and 138 patients from the cohorts, and the unilateral PA was found in 96 and 94 patients, respectively. Clinical factors independently associated with lateralized AVS in multivariable logistic regression were used to construct a unilateral PA prediction score (SCORE). RESULTS: The proposed SCORE was calculated as a sum of the prevalence of adrenal nodule on computed tomography (2 points) and plasma/serum aldosterone concentration ≥ 165 ng/L after the saline infusion test (SIT) (1 point). Importantly, the SCORE = 3 points identified 48% of unilateral PA patients with a specificity of 100% in the development cohort. The zero rate of false-positive classifications was preserved with the same cut-off value in the validation cohort. CONCLUSIONS: AVS could be omitted before surgery in patients with typical Conn´s adenoma provided the aldosterone concentration ≥ 165 ng/L after the SIT.

Gene Profile of Adipose Tissue of Patients with Pheochromocytoma/Paraganglioma.

Background: Brown adipose tissue (BAT) is a therapeutic target to combat obesity and related disorders. Pheochromocytoma and functional paraganglioma (PPGL) are associated with activated BAT due to catecholamine excess. Our aim was to evaluate BAT activity by gene profile and assess its relation to clinical characteristics and overproduced catecholamine. Methods: mRNA expression of 15 genes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) was measured via RT-PCR in 25 patients with PPGL and 14 controls undergoing cholecystectomy. Results: We found in VAT of PPGL higher expression of UCP1 (p < 0.001), CEBPB, PPARGC1A (both p < 0.001), PRDM16 (p = 0.069) and DIO2 (p = 0.005). UCP1 expression correlated only with norepinephrine levels and its metabolite. UCP1 expression, among others, correlated negatively with BMI, age and positively with HDLc levels. Dominance of BAT or BeAT markers was not assessed in PPGL. In SAT of PPGL, we found higher expression of ADRB3, CIDEA (both p < 0.05), and PPARGC1A (p = 0.001), but not UCP1. Conclusion: We demonstrate signs of UCP1-dependent norepinephrine-induced thermogenesis connected with higher expression of DIO2, PPARGC1A, CEBPB and PRDM16 in retroperitoneal VAT of PPGL and its relations to circulating HDLc and triglycerides levels. However, no direct relationship with increased basal energy metabolism measured by calorimetry was found.

Effect of adrenalectomy on remission of subclinical left ventricular dysfunction in patients with pheochromocytoma: a speckle-tracking echocardiography study.

BACKGROUND: Pheochromocytomas (PHEO) are tumours with the ability to produce, metabolize and secrete catecholamines. Catecholamines overproduction leads to the decrease of longitudinal function of the left ventricle (LV) measured by speckle-tracking echocardiography. Patients with PHEO have a lower magnitude of global longitudinal strain (GLS) than patients with essential hypertension. GLS normalization is expected after resolution of catecholamine overproduction. METHODS: Twenty-four patients (14 females and 10 males) with a recent diagnosis of PHEO have been examined before and 1 year after adrenalectomy. An echocardiographic examination including speckle-tracking analysis with the evaluation of GLS and regional longitudinal strain (LS) in defined groups of LV segments (basal, mid-ventricular and apical) was performed. RESULTS: One year after adrenalectomy, the magnitude of GLS increased (-14.3 ± 1.8 to -17.7 ± 1.6%; P < 0.001). When evaluating the regional LS, the most significant increase in the differences was evident in the apical segment compared to mid-ventricular and basal segments of LV (-5.4 ± 5.0 vs -1.9 ± 2.7 vs -1.6 ± 3.8; P < 0.01). CONCLUSIONS: In patients with PHEO, adrenalectomy leads to an improvement of subclinical LV dysfunction represented by the increasing magnitude of GLS, which is the most noticeable in apical segments of LV.

FGF21 Levels in Pheochromocytoma/Functional Paraganglioma.

Fibroblast growth factor 21 (FGF21) is a hepatokine with beneficial effects on metabolism. Our aim was to evaluate the relationship between the serum FGF21, and energy and glucose metabolism in 40 patients with pheochromocytoma/functional paraganglioma (PPGL), in comparison with 21 obese patients and 26 lean healthy controls. 27 patients with PPGL were examined one year after tumor removal. Basic anthropometric and biochemical measurements were done. Energy metabolism was measured by indirect calorimetry (Vmax-Encore 29N). FGF21 was measured by ELISA. FGF21 was higher in PPGL than in controls (174.2 (283) pg/mL vs. 107.9 (116) pg/mL; p < 0.001) and comparable with obese (174.2 (283) pg/mL vs. 160.4 (180); p = NS). After tumor removal, FGF21 decreased (176.4 (284) pg/mL vs. 131.3 (225) pg/mL; p < 0.001). Higher levels of FGF21 were expressed, particularly in patients with diabetes. FGF21 positively correlated in PPGL with age (p = 0.005), BMI (p = 0.028), glycemia (p = 0.002), and glycated hemoglobin (p = 0.014). In conclusion, long-term catecholamine overproduction in PPGL leads to the elevation in serum FGF21, especially in patients with secondary diabetes. FGF21 levels were comparable between obese and PPGL patients, despite different anthropometric indices. We did not find a relationship between FGF21 and hypermetabolism in PPGL. Tumor removal led to the normalization of FGF21 and the other metabolic abnormalities.

Blood Pressure Profile, Catecholamine Phenotype, and Target Organ Damage in Pheochromocytoma/Paraganglioma.

CONTEXT: Impaired diurnal blood pressure (BP) variability is related to higher cardiovascular risk. OBJECTIVE: To assess diurnal variability of BP and its relation to target organ damage (TOD) and catecholamine phenotype in a consecutive sample of pheochromocytoma/paraganglioma (PPGL). DESIGN: We included 179 patients with PPGL All patients underwent 24 hours of ambulatory BP monitoring to determine dipping status. Differences in plasma metanephrine or urine adrenaline were used to distinguish catecholamine biochemical phenotype. To evaluate TOD, renal functions, presence of left ventricle hypertrophy (LVH), and the subgroup (n = 111) carotid-femoral pulse wave velocity (PWV) were assessed. Structural equation modeling was used to find the relationship among nocturnal dipping, catecholamine phenotype, and TOD parameters. RESULTS: According to the nocturnal dipping, patients were divided into the three groups: dippers (28%), nondippers (40%), and reverse dippers (32%). Reverse dippers were older (P < 0.05), with a higher proportion of noradrenergic (NA) phenotype (P < 0.05), a higher prevalence of diabetes mellitus (P < 0.05), and sustained arterial hypertension (P < 0.01) and its duration (P < 0.05), as opposed to the other groups. All parameters of TOD were more pronounced only in reverse dippers compared with nondippers and dippers. The presence of NA phenotype (=absence of adrenaline production) was associated with reverse dipping and TOD (LVH and PWV). CONCLUSIONS: Patients with reverse dipping had more substantial TOD compared with other groups. The NA phenotype plays an important role, not only in impaired diurnal BP variability but also independently from dipping status in more pronounced TOD of heart and vessels.

Determination of Circulating Endothelial Cells and Endothelial Progenitor Cells Using Multicolor Flow Cytometry in Patients with Thrombophilia.

BACKGROUND/AIMS: Endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) have been described as markers of endothelial damage and dysfunction in several diseases, including deep venous thrombosis. Their role in patients with known thrombophilia has not yet been evaluated. Both EPCs and CECs represent extremely rare cell populations. Therefore, it is essential to use standardized methods for their identification and quantification. METHODS: In this study, we used multicolor flow cytometry to analyze the number of EPCs and CECs in patients with thrombophilia with or without a history of thrombosis. Patients with hematological malignancies after high-dose chemotherapy and patients with acute myocardial infarction were used as positive controls. RESULTS: EPC and CEC immunophenotypes were determined as CD45dim/-CD34+CD146+CD133+ and CD45dim/-CD34+CD146+CD133-, respectively. Increased levels of endothelial cells were observed in positive control groups. No significant changes in the number of EPCs or CECs were detected in patients with thrombophilia compared to healthy controls. CONCLUSION: Our optimized multicolor flow cytometry method allows unambiguous identification and quantification of endothelial cells in the peripheral blood. Our results support previous studies showing that elevated levels of CECs could serve as an indicator of endothelial injury or dysfunction. Normal levels of CECs or EPCs were found in patients with thrombophilia.

Catecholamines Induce Left Ventricular Subclinical Systolic Dysfunction: A Speckle-Tracking Echocardiography Study.

Background: Pheochromocytomas (PHEO) are tumors arising from chromaffin cells from the adrenal medulla, having the ability to produce, metabolize and secrete catecholamines. The overproduction of catecholamines leads by many mechanisms to the impairment in the left ventricle (LV) function, however, endocardial measurement of systolic function did not find any differences between patients with PHEO and essential hypertension (EH). The aim of the study was to investigate whether global longitudinal strain (GLS) derived from speckle-tracking echocardiography can detect catecholamine-induced subclinical impairments in systolic function. Methods: We analyzed 17 patients (10 females and seven males) with PHEO and 18 patients (nine females and nine males) with EH. The groups did not differ in age or in 24-h blood pressure values. Results: The patients with PHEO did not differ in echocardiographic parameters including LV ejection fraction compared to the EH patients (0.69 ± 0.04 vs. 0.71 ± 0.05; NS), nevertheless, in spackle-tracking analysis, the patients with PHEO displayed significantly lower GLS than the EH patients (-14.8 ± 1.5 vs. -17.8 ± 1.7; p < 0.001). Conclusions: Patients with PHEO have a lower magnitude of GLS than the patients with EH, suggesting that catecholamines induce a subclinical decline in LV systolic function.

Role of Dipyrone in the High On-Treatment Platelet Reactivity amongst Acetylsalicylic Acid-Treated Patients Undergoing Peripheral Artery Revascularisation.

OBJECTIVE: To evaluate the effects of dipyrone on sensitivity to aspirin (acetylsalicylic acid [ASA]) in patients who underwent peripheral artery vascular reconstruction. SUBJECTS AND METHODS: Impedance aggregometry and light transmission aggregometry were used to determine the effects of dipyrone on ASA treatment in 21 patients. Blood samples were drawn in a 7-day period after the surgery. The cut-off value for high on-treatment platelet reactivity (HTPR) was set at < 65% of aggregation inhibition for impedance aggregometry. For light transmission aggregometry the cut-off value for arachidonic acid-induced aggregation was set at > 20% of aggregating platelets, and the cut-off value for epinephrine-induced aggregation was > 44% of aggregating platelets. The cut-off value for each method was derived from a large number of patients treated with a daily dose of 100 mg of ASA. RESULTS: We found HTPR in 14 (67%) of the 21 patients. None had primary resistance to ASA, i.e., after the addition of ASA in vitro all samples showed antiplatelet efficacy. Regression analysis showed a possible correlation between lower efficacy of ASA treatment and higher daily doses of dipyrone (p = 0.005 for impedance aggregometry, p = 0.04 for light transmission aggregometry), higher platelet count (p = 0.005 for impedance aggregometry), and shorter time from surgery (p = 0.03 for impedance aggregometry). CONCLUSION: HTPR occurs in 67% of ASA-treated patients after lower limb vascular surgery. The occurrence of HTPR correlates with the daily dose of dipyrone. Therefore, dipyrone should not be used as a postoperative analgesic in ASA-treated patients after peripheral artery revascularisation due to its influence on the effectiveness of ASA.

28 day post-operative persisted hypercoagulability after surgery for benign diseases: a prospective cohort study.

BACKGROUND: Surgery for benign disease is associated with a low-risk of developing venous thromboembolism (VTE). Despite a relatively low incidence of postoperative VTE in patients after elective cholecystectomy and abdominal hernia repair there are data proving hypercoagulability in the early postoperative period. We focused on assessment of the systemic inflammatory response and coagulation status in these surgical patients after hospital discharge. METHODS: Prospectively, patients who underwent surgery for benign disease were included. Two hundred sixteen patients were enrolled - 90 patients in laparoscopic cholecystectomy (LC) group and 126 patients in hernia surgery (HS) group. Risk assessment of VTE according to the Caprini risk assessment model was performed in all patients. Prevalence of VTE in postoperative period was observed. Markers of systemic inflammatory response (IL-6, CRP, α-1-acid glycoprotein, transferrin) and coagulation markers (PLT, fibrinogen, prothrombin fragment F1 + 2 and D-dimer) were measured before surgery, on 7-10th postoperative day and on 28-30th postoperative day. RESULTS: Clinically apparent deep vein thrombosis was diagnosed in only one patient - 0.46%. Statistically significant elevation of inflammatory markers IL-6, CRP and α-1-acid glycoprotein (p < 0.001; all) were proved in both groups of patients on 7-10th postoperative day. Statistically significant elevation of coagulation markers PLT, fibrinogen, prothrombin fragment F1 + 2 and D-dimer (p < 0.001; all) were proved in LC and HS groups on 7-10th postoperative day. No statistical difference was observed in IL-6, CRP and α-1-acid glycoprotein levels a month after surgery as compared with preoperative levels within each group. Statistically significant elevation of fibrinogen and prothrombin fragment F1 + 2 levels (p < 0.001; both) persisted on 28-30th postoperative day in both groups. Persisted elevation of D-dimer levels was proved only in HS group (p < 0.001), not in LC group (p = 0.138), a month after surgery. CONCLUSIONS: Activated systemic inflammatory response and hypercoagulable condition were verified in patients after laparoscopic cholecystectomy and hernia surgery after their hospital discharge. Hypercoagulability persisted even a month after surgery. Nevertheless, we observed very low prevalence of clinically apparent VTE in patients with in-hospital postoperative VTE prophylaxis. TRIAL REGISTRATION: Trials of the Czech Ministry of Health No. RVO-VFN64165 and NT 13251-4 .

Early and subacute inflammatory response and long-term survival after hip trauma and surgery.

BACKGROUND: Hip fractures represent major source of morbidity in elderly patients. There is little evidence about the impact of inflammatory changes induced by hip trauma and surgery on long term survival. METHODS: We evaluated the prognostic significance of the surgery-related dynamics of white blood cell count (WBC), neutrophil to lymphocyte ratio (NLR), C-reactive protein (CRP), interleukin-6 (IL-6) and soluble adhesion molecules (including P-selectin, E-selectin and VCAM) on survival in 104 consecutive patients with traumatic hip fractures recruited within the 2 years period. RESULTS: In surviving patients, the minimum follow-up length was 48 and maximum 84 months (median 60 months). The mean age of the population was 80 ± 9 years, 72% were women. The survival rates were 69%, 45% and 38% at one, three and five years of the follow-up, respectively. Baseline serum creatinine, older age and subdural anesthesia type were associated with worse survival. The acute inflammatory response failed to predict the long term survival. In contrast, elevated WBC and IL-6 as assessed 21 days after the surgery were associated with a significantly worse outcome. CONCLUSION: The survival of elderly patients undergoing the surgery for acute hip fracture is unfavorable. In contrast to previous reports, we did not confirm that acute inflammatory response to the surgery predicts the long-term survival. On the contrary, persistent elevation of WBC and IL-6 three weeks after the surgery indicates a poor outcome.

[Comparison of the overall stress during large bowel operations in senior patients (laparoscopy versus open surgery)]. / Porovnání stupne záteze pri operacích na tlustém streve u senioru (laparoskopie versus otevrené výkony).

BACKGROUND: Colorectal surgery particularly as a treatment option for colorectal cancer comprises considerable and ever expanding spectrum of surgical procedures. Seniors (over 65 years of age) form the majority of patients operated for benign or malignant colon disease. High age in general poses one of the significant risks of the operation. The study analyses overall stress caused to patients by laparoscopy and laparotomy surgical procedures. METHODS: Literature analysis of surgical stress in patients and prospective study of our patients' data collected over the period of four years. Comparable indicators: objectification of pre-operative stress and risks, per-operative cardiac and circulatory parameters, course of the lesion healing process, laboratory reactions of acute phase proteins, morbidity and lethality related to the surgery treatment. RESULTS: Comparable results of tissue response examinations demonstrated no fundamental difference between laparoscopic and laparotomic operations performed on otherwise healthy younger individuals. Laparoscopic surgery, however, appears to be fully appropriate treatment modality in majority of patients suffering from colorectal disease, even in senior age. In advanced or complicated stages of the disease the open-section surgery still remains more efficient. CONCLUSION: Age itself cannot be generally denoted as a fundamental risk factor. Co-morbid conditions, however, represent considerable risk, especially in high age patients. Laparoscopic surgery may well be applied even in senior age patients with no contra-indications. Yet, its application requires perfectly mastered laparoscopic technique and rational approach. Success of the operation in high-risk patients depends on close interdisciplinary cooperation, especially with anaesthetists.

Influence of long-term thromboprophylaxis with low-molecular-weight heparin (enoxaparin) on changes of bone metabolism markers in pregnant women.

This is a first descriptive, retrospective, observational study aiming to evaluate the changes in bone turnover markers in pregnant women and to assess the effect of a long-term treatment with low-molecular-weight heparin (LMWH), specifically, enoxaparin. Study involved 50 pregnant Caucasian women with thrombophilia. The patients either received prophylactic enoxaparin once daily subcutaneously (N = 35) or were observed without treatment (N = 15). Concentrations of total serum alkaline phosphatase (total AP), bone alkaline phosphatase (bone AP), osteoprotegerin (OPG), and the receptor activator of nuclear factor κB ligand (RANKL) were measured at 15, 25, and 35 weeks of gestation. Total serum AP increased with gestational age. In the group treated with enoxaparin, the percentage of bone AP concentration was lower (P < .05) than in the control group. Serum OPG also increased with gestational age, but no significant difference was found between the groups with- and without treatment. Despite the OPG increased, RANKL did not change.

Factors influencing arterial stiffness in pheochromocytoma and effect of adrenalectomy.

The aim of the study was to evaluate arterial stiffness and its modulating factors measured by carotid-femoral pulse wave velocity (PWV) and central augmentation index (AI) in patients with pheochromocytoma (PHEO) before and after surgery. Forty-five patients with PHEO and 45 healthy controls were investigated using an applanation tonometer (SphygmoCor, AtCor Medical). The gender, age, BMI and lipid profiles were comparable among both groups. The main difference in basic characteristic was as expected for fasting plasma glucose (P<0.001) and all blood pressure modalities. PWV in PHEO was significantly higher than in controls (7.2+/-1.4 vs. 5.8+/-0.5 ms(-1); P<0.001). Between-group difference in PWV remained significant even after the adjustment for age, heart rate, fasting plasma glucose and each of brachial (P<0.001) and 24 h blood pressure parameters (P<0.01). The difference in AI between groups did not reach the statistical significance (19+/-14 vs. 16+/-13%; NS). In multiple regression analysis, age (P<0.001), mean blood pressure (P=0.002), high-sensitive C-reactive protein (hs-CRP) (P=0.007) and 24 h urine norepinephrine (P=0.007) were independently associated with PWV in PHEO. In addition, 27 patients with PHEO were studied 1 year after tumor removal. Successful tumor removal led to a significant decrease in PWV (7.0+/-1.2 vs. 6.0+/-1.1 ms(-1); P<0.001). In conclusion, patients with PHEO have an increase in PWV, which is reversed by the successful tumor removal. Age, mean blood pressure, hs-CRP and norepinephrine levels are independent predictors of PWV.

Older age and type of surgery predict the early inflammatory response to hip trauma mediated by interleukin-6 (IL-6).

Hip trauma and surgery are associated with systemic inflammatory reaction. However, little evidence exists about the role of IL-6. In order to assess the inflammatory response, we evaluated white blood cell (WBC) count, C-reactive protein (CRP) and IL-6 dynamics in sequential pre- and postsurgical samples collected from 125 elderly patients (mean age 78+/-9 years) undergoing osteosynthesis (OS) for extracapsular hip fractures (n=69), hemiarthroplasty (HA) or urgent total hip arthroplasty for intracapsular fractures (UA) (n=35), and elective total hip arthroplasty for osteoarthrosis (OA) (n=21). Both preoperative CRP and IL-6 levels were higher in patients with intracapsular fractures. IL-6 levels reached peak values immediately after the surgery, while CRP peak levels were reached 48 h after the surgery. The overall inflammatory reaction was more intense in HA patients compared to the other subgroups. Independent of each other, older age and the hip fracture type affected the IL-6 response, while the CRP response depended only on the type of surgery. The abrupt increase in IL-6 immediately after the procedure suggests its involvement in the early stages of the postoperative inflammatory reaction after hip surgery. This reaction is particularly pronounced in elderly patients receiving HA.

Favorable coagulation profile with fondaparinux after hip surgery in elderly patients.

Twenty-three patients with fondaparinux prophylaxis over 75 years of age who underwent hip fracture surgery were enrolled in the study. Fondaparinux sodium (2.5 mg) was administered subcutaneously 6 h postoperatively and then every 24 h for 28 days. Coagulation and inflammatory parameters were measured preoperatively, then 10 h, 2, 7, and 28 days postoperatively. Increased D-dimers, positive acute phase proteins, and IL-6, and decreased negative acute phase proteins were observed preoperatively (P < 0.05). Maximum values were reached 10 h postoperatively for IL-6 and D-dimer, and on postoperative days 2 and 7 for positive acute phase proteins (P < 0.05). Transferrin, prealbumin and antithrombin levels were lowest 10 h postoperatively and on postoperative day 2 (P < 0.05). Increased D-dimers, IL-6, and positive acute phase proteins, and decreased negative acute phase proteins persisted until postoperative day 28 (P < 0.05). Prothrombin fragments (F1 + 2) reached peak levels preoperatively and decreased gradually until postoperative day 28. Fondaparinux promoted the inhibition of thrombin generation, as documented by negative correlation between F1 + 2 and FXa inhibition (r = -0.46; P < 0.001). Fondaparinux-induced FXa inhibition increased gradually until postoperative day 28. This increase correlated positively with antithrombin activity (r = 0.4; P < 0.05). Fondaparinux prophylaxis counteracted pro-thrombogenic effect associated with hip fracture and subsequent surgery without severe bleeding complications.

High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism: a genetic substudy of PRAGUE-8 trial.

The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors, enzymes, and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention. The study was performed as a genetic substudy of the PRAGUE-8 trial. Ninety-five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested. Baseline platelet reactivity to ADP was assessed before the drug was administered. Clopidogrel efficacy was tested again at 12 and 28 h after administration. Polymorphisms of platelet receptors, glycoprotein (GP) Ia (807C/T), GPVI (13254C/T), GPIIIa (PlA1/PlA2), PAR-1 (IVSn-14A/T), P2Y12 (32C/T), P2Y12 (H1/H2) haplotype, gene variations of cyclooxygenase-1, Leiden, and factor II mutations were studied. Flow cytometric tests of vasodilator-stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy. None of the gene polymorphisms influenced baseline ADP-induced platelet reactivity significantly. Twenty-eight hours after drug administration, differences in suppression of ADP-induced platelet reactivity were observed between polymorphism-positive and polymorphism-negative patients. Inhibition of platelet reactivity, after 600 mg of clopidogrel, was significantly less in carriers of PlA2 (P=0.009) for mean decrease in platelet reactivity index. The proportion of clopidogrel nonresponders (platelet reactivity index >50%) was apparently higher in PlA2 carriers in comparison with PlA1/PlA1 patients (54 vs. 24%, P=0.082). A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism.

Elevated inflammation markers in pheochromocytoma compared to other forms of hypertension.

OBJECTIVE: To investigate the effect of long-term catecholamine excess in pheochromocytoma on leukocyte and platelet count and on proteins of acute-phase response. METHODS: Fifteen subjects with pheochromocytoma, 16 with primary aldosteronism, 18 with essential hypertension and 17 healthy controls were studied. Sixteen subjects with pheochromocytoma were investigated after tumor removal. Leukocyte, neutrophil and platelet count, as well as C-reactive protein were measured in all subjects, while fibrinogen, alpha(1)-antitrypsin, alpha(2)-macroglobulin, orosomucoid, transferrin and prealbumin were only measured in subjects with pheochromocytoma, primary aldosteronism and essential hypertension. RESULTS: Subjects with pheochromocytoma showed significantly higher leukocyte [7.5 +/- 0.9 10(9)/l, p < 0.001 vs. primary aldosteronism (5.4 +/- 0.9 10(9)/l) and healthy controls (5 +/- 0.9 10(9)/l), p = 0.04 vs. essential hypertension (6.3 +/- 1.6 10(9)/l)], neutrophil (p < 0.001 vs. primary aldosteronism and healthy subjects) and platelet counts (p < 0.001 vs. primary aldosteronism; p = 0.01 vs. essential hypertension) compared to the other groups of subjects. Similar results were obtained for positive proteins of acute-phase response in subjects with pheochromocytoma [C-reactive protein: 0.62 +/- 0.52 mg/dl, p < 0.001 vs. healthy subjects (0.08 +/- 0.08 mg/dl), p = 0.001 vs. primary aldosteronism (0.17 +/- 0.19 mg/dl), p = 0.04 vs. essential hypertension (0.31 +/- 0.26 mg/dl); fibrinogen: p = 0.02 vs. primary aldosteronism; orosomucoid: p = 0.005 vs. primary aldosteronism; alpha(2)-macroglobulin: p = 0.009 vs. primary aldosteronism]. No significant differences were found in plasma levels of alpha(1)-antitrypsin, transferrin and prealbumin. Tumor removal led to a significant decrease in leukocyte (p = 0.004), neutrophil (p = 0.007) and platelet count (p = 0.003) and also to a significant decrease in acute-phase proteins (C-reactive protein: p = 0.03, fibrinogen: p = 0.008, alpha(1)-antitrypsin: p = 0.003, orosomucoid: p = 0.04). CONCLUSIONS: Chronic catecholamine excess in pheochromocytoma is accompanied by an increase in inflammation markers which was reversed by the tumor removal.

Prenatally diagnosable differences in the cellular immunity of fetuses with Down's and Edwards' syndrome.

INTRODUCTION: Lymphocyte subpopulations are identified by the uniform CD classification (Cluster of Differentiation) and can be accurately differentiated with monoclonal antibodies using the method of flow cytometry. With the aid of cordocentesis it is possible to perform studies on the status and development of cellular immunity as early as in the second trimester of pregnancy. OBJECTIVE: To compare lymphocyte subpopulations present in fetuses with chromosomal abnormalities (Down's syndrome (DS), Edwards' syndrome (ES)) and fetuses with normal karyotype. STUDY DESIGN: Prospective observational study. METHODS: We examined a total of 61 pregnant women with an average age of 31.5 years (20- 46 years). RESULTS: In fetuses with DS we found a significant decrease in B lymphocytes (CD19),a decrease in the subpopulations of multi-reactive B-cells (CD5(+)CD19(+), B-CLL),and a decrease in the index of CD4/CD8 and class II HLA-DR. In contrast, the representation of NK cells expressing /CD3-CD (16 + 56)+/ was greatly increased. In ES we found a decrease in T lymphocytes (CD3), a decrease in T-helper lymphocytes (monocytes CD4), a decreased index of CD4/CD8 and a greater representation of NK cells /CD3-CD (16 + 56)+/. CONCLUSION: We determined the normal values of lymphocyte subpopulations in physiological fetuses. We demonstrated that the immunological defect of the affected fetuses is already present antenatally, and can be reliably diagnosed in the second trimester of pregnancy.