Use of tolvaptan in patients hospitalized for worsening chronic heart failure with severe hyponatremia: The initial experience at a single-center in Turkey.

OBJECTIVE: The aim of the present study was to assess the efficacy and safety of tolvaptan for severe hyponatremia (SH) in hypervolemic heart failure (HF) patients within daily clinical practice. METHODS: We restrospectively reviewed our database on tolvaptan as an add-on treatment in hypervolemic patients admitted to our clinic due to deterioration of HF and having hyponatremia resistant to standard therapy. Severe hyponatremia was defined as serum sodium concentration ≤125 mEq/L. The database included demographic, clinical, laboratory, and echocardiographic findings on admission, and numerous outcome measures for oral tolvaptan treatment were used to assess its efficacy and safety. RESULTS: The study group consisted of 56 hypervolemic HF patients with severe hyponatremia (25 female and 31 male) with mean age of 66 years. All patients received a single dose of tolvaptan 15 mg daily for an average of 3.2 days due to severe hyponatremia. Sodium and potassium concentrations, fluid intake, and urine volume increased (p<0.0001, p=0.037, p<0.0001, and p<0.0001, respectively), whereas furosemide dosage, body weight, heart rate, systolic and diastolic blood pressure, and New York Heart Association class decreased significantly in response to tolvaptan treatment, without a rise in serum creatinine or urea concentrations (p<0.0001, p<0.0001, p=0.001, p<0.049, p<0.009 ve p=0.001, respectively). CONCLUSION: In this retrospective, single-centered study conducted in a small group of Turkish patients, short-term treatment with low-dose tolvaptan added to standard therapy of hypervolemic HF patients with severe hyponatremia was well tolerated with a low rate of major side effects and was effective in correcting severe hyponatremia.

Prolonged Tpeak-Tend interval in anti-Ro52 antibody-positive connective tissue diseases.

Patients with connective tissue diseases (CTDs) may have prolonged corrected QT interval which indicates increased risk for ventricular arrhythmias. However, a more sensitive measure of ventricular repolarization, T-peak-to-end (Tpe) interval, has not been studied in CTDs. We aimed to investigate the relationship between ventricular repolarization abnormalities and anti-Ro52-positivity in subjects with connective tissue diseases (CTDs). We enrolled patients with anti-Ro52-positive CTDs, ANA-positive CTDs, and healthy subjects in this cross-sectional study. We excluded conditions potentially affecting the QT interval. We compared the ECG measures between the groups and performed analyses to define factors associated with ventricular repolarization measures. 15 ANA and anti-Ro52-positive, 39 ANA-positive and anti-Ro52-negative, and 22 healthy subjects were enrolled. None of the subjects had rhythm or conduction disturbances. Corrected QT intervals were similar between the groups. Tpe (84, 77.3, and 69.4 msn, respectively) and QT-dispersion (40, 27.2, and 20.1 msn, respectively) were higher in anti-Ro52-positive subjects compared with the ANA-positive and healthy subjects. Anti-Ro52 titers were correlated with Tpe and QT-dispersion (r = 0.52 and p < 0.001 for each). ANA and anti-Ro52-positivity were independently associated with higher Tpe (OR = 7.7, p = 0.001 and OR = 6.9, p = 0.001, respectively), corrected Tpe (OR = 11.3, p = 0.001 and OR = 8.4, p = 0.003, respectively), QT dispersion (OR = 7, p = 0.008 and OR = 13, p < 0.001, respectively), and QTc dispersion (OR = 9.1, p = 0.001 and OR = 14.1, p < 0.001, respectively). This study provides evidence that ANA positivity, especially when concomitant anti-Ro52-positivity is present, significantly deteriorates ventricular repolarization. The aforementioned ventricular repolarization abnormalities may render these subjects susceptible to serious rhythm or conduction disorders in the setting of predisposing conditions.

Catheter-directed ultrasound-accelerated thrombolysis may be life-saving in patients with massive pulmonary embolism after failed systemic thrombolysis.

The treatment options for high risk acute pulmonary embolism (PE) patients with failed systemic thrombolytic treatment (STT) is limited. The clinical use of catheter directed thrombolysis with the EkoSonic Endovascular System (EKOS) in this population has not been evaluated before. Catheter directed thrombolysis is an effective treatment modality for high risk PE patients with failed STT. Thirteen consecutive patients with failed STT were included in the study. EKOS catheters were placed and tissue plasminogen activator (t-PA) in combination with unfractionated heparin were given. Clinical and echocardiographic properties of the patients were collected before EKOS, at the end of EKOS and during the follow-up visit 6 months after discharge. The duration of EKOS treatment was 21.8 ± 3.8 h and the total dose of tPA was 31.2 ± 15.3 mg. One patient who presented with cardiac arrest died and the clinical status of the remaining subjects improved significantly. Any hemorrhagic complication was not observed. EKOS resulted in significant improvement of right ventricular functions and decrease of systolic pulmonary artery pressure. During a follow-up period of 6 months none of the patients died or suffered recurrent PE. In addition, echocardiographic parameters or right ventricular function significantly got better compared to in-hospital measurements. EKOS is an effective treatment modality for high risk PE patients with failed STT and can be applied with very low hemorrhagic complications.

Can infectious endocarditis during pregnancy be cured with only drug treatment?

During pregnancy, infective endocarditis (IE) is quite rare but has a high mortality rate in terms of the mother and the fetus. In this article, a 24-year-old patient with a history of mitral valve prolapse (MVP) who was hospitalized due to IE and treated successfully is presented. On echocardiography, severe mitral valve prolapse, severe mitral regurgitation, and vegetation on the posterior leaflet of mitral valve were observed. Streptococcus mitis was subsequently isolated from four sets of blood cultures. The patient was diagnosed with IE. After 6 weeks of antibiotic therapy, the patient was cured completely without surgical treatment. At 40-weeks of pregnancy, the patient gave birth via a normal vaginal delivery. There were no problems with the 3,800-gram baby born. In current guidelines, there is very limited advice on treatment options for patients who develop IE during pregnancy. Therefore, evaluation of patient-based treatment options would be appropriate. In addition, IE prophylaxis for MVP is not recommended in current guidelines. However, in MVP patients with mitral regurgitation, prior to procedures associated with a high risk of infective endocarditis, IE prophylaxis may be rational.

The utility of inferior vena cava diameter and the degree of inspiratory collapse in patients with systolic heart failure.

INTRODUCTION: Both inferior vena cava (IVC) diameter and the degree of inspiratory collapse are used in the estimation of right atrial pressure. AIM: The purpose of this study is to evaluate the utility of IVC diameter, using echocardiography as a marker of volume overload and the relationship between these parameters and N-terminal pro-B natriuretic peptide (NT-proBNP) in patients with systolic heart failure (HF). METHODS: We included 136 consecutive patients with systolic HF (left ventricular ejection fraction, <50%), including 80 patients with acutely decompensated HF and 56 patients with compensated HF as well as 50 subjects without a diagnosis of HF. All patients underwent transthoracic echocardiography to assess both their IVC diameters and the degree of inspiratory collapse (≥50%, <50%, and no change [absence] groups); NT-proBNP levels were measured, and these data were compared between the 2 groups. RESULTS: Inferior vena cava diameter and NT-proBNP were significantly higher among the patients with HF than among the control subjects (21.7 ± 2.6 vs 14.5 ± 1.6 mm, P < .001 and 4789 [330-35000] vs 171 [21-476], P < .001). The mean IVC diameter was higher among the patients with decompensated HF than among the patients with compensated HF (23.2 ± 2.1 vs 19.7 ± 1.9 mm, P < .001). The values of NT-proBNP were associated with different collapsibility of IVC subgroups among HF patients. The NT-proBNP levels were 2760 (330-27336), 5400 (665-27210), and 16806 (1786-35000), regarding the collapsibility of the IVC subgroups: greater than or equal to 50%, less than 50%, and absence groups, P < .001, respectively, among HF patients. There was a significant positive correlation between IVC diameter and NT-proBNP (r = 0.884, P < .001). A cut off value of an IVC diameter greater than or equal to 20.5 mm predicted a diagnosis of compensated HF with a sensitivity of 90% and a specificity of 73%. CONCLUSIONS: Inferior vena cava diameter correlated significantly with NT-proBNP in patients with HF. Inferior vena cava diameter may be a useful variable in determining a patient's volume status in the setting of HF and may also enable clinicians to distinguish patients with decompensated HF from those with compensated HF.

Serum choline levels in patients with stable angina and acute coronary syndromes: relation to the severity of coronary artery disease.

OBJECTIVE: We sought to investigate whether serum choline levels are increased across the spectrum of coronary artery disease (CAD) manifestations and correlate with the severity of coronary stenosis. METHODS: A total of 36 patients with acute coronary syndrome (ACS) [22 patients with non-ST-segment elevation ACS and 14 patients with ST-segment elevation acute myocardial infarction (STEMI)], 22 patients with stable angina pectoris (SAP), and 18 controls were recruited for the study. In ACS patients, serum choline levels were measured on admission, and at 24 and 48 h thereafter, using high-performance liquid chromatography. The severity of CAD was assessed using the Gensini score. RESULTS: Serum choline levels on admission were significantly higher in the entire group of patients with ACS than in controls. The highest level of choline was observed in the STEMI group, followed by the SAP, and the non-ST-segment elevation ACS groups. Serum choline levels decreased gradually in patients with STEMI over the 48-h period. Serum choline levels on admission, and at 24 or 48 h thereafter, did not correlate with the presence of CAD neither in patients with ACS (P=0.78, 0.98 and 0.98, respectively) nor in those with SAP (P=0.92). CONCLUSION: Our results suggest that serum choline levels are increased in ACS patients. However, there was no clear correlation between levels of choline and the severity and extent of CAD in this patient group.

A rare reason for pulmonary hypertension: primary sarcoma of the pulmonary artery.

Primary sarcoma of the pulmonary artery (PSPA) is an extremely rare tumor of the cardiovascular system. The prognosis is very poor. The clinical symptoms and imaging findings imitate those of pulmonary emboli, causing delays in diagnosis. In this case report, we describe a 73-year-old man with PSPA who initially was admitted with exertional shortness of breath. Transthoracic echocardiographic evaluation revealed 2 masses in the pulmonary artery causing pulmonary hypertension. The patient underwent operation, but he could not be weaned off cardiopulmonary bypass at the end of the operation and died. Pathologic examination of the masses revealed pulmonary sarcoma. Although this patient was admitted to our clinic only 2 weeks after the initial symptoms, he already had distal metastases.

Diffuse involvement of the heart and great vessels in primary cardiac lymphoma.

Primary cardiac lymphoma (PCL) is an extremely rare disorder. In this report, a 57-year-old male with diffuse large B-cell lymphoma involving the heart and great vessels is presented. Trans-thoracic echocardiography was the first modality used to establish the diagnosis. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed diffuse increased metabolic activity of the heart walls and hypermetabolic lesions occupying cardiac chambers in some areas. The patient underwent systemic chemotherapy, and after 13 days, a marked regression of the tumour mass was evident based on echocardiographic examination. After completing six R-CHOP chemotherapy treatments, PET imaging was planned to control the residual mass, but the patient was intubated due to pneumonia that developed after the sixth chemotherapy session and subsequently died due to sepsis.

Effect of rosiglitazone, metformin and medical nutrition treatment on arterial stiffness, serum MMP-9 and MCP-1 levels in drug naive type 2 diabetic patients.

The aim of the study was to evaluate the long-term effect of rosiglitazone and metformin monotherapy with medical nutrition treatment (MNT) and of MNT alone on arterial stiffness, serum monocyte chemoattractant protein (MCP)-1 and matrix metalloproteinase (MMP)-9 in drug naive patients with type 2 diabetes mellitus. Fifty type 2 diabetic patients were randomized to receive rosiglitazone 4 mg/day (n=19) or metformin 850 mg/day (n=16) with MNT or MNT alone (n=15), for 52 weeks. Arterial stiffness was assessed by using large and small artery elasticity index (SAEI and LAEI, respectively). SAEI, LAEI, serum MCP-1 and MMP-9 levels were measured at baseline and following 52 weeks of treatment. SAEI was improved only in the rosiglitazone group, and the difference was still statistically significant when the three groups were compared (p=0.024). There were no differences in LAEI in inter- and intragroup comparisons at the end of the study. Serum MMP-9 levels were decreased in the metformin (-13.5+/-34.8%, p=0.02) and rosiglitazone (-27.2+/-51.0%, p=0.023) groups compared with baseline values, whereas no significant change was seen in serum MCP-1 levels. These results suggest that rosiglitazone monotherapy has favorable effects on arterial stiffness compared with metformin monotherapy independent of glycemic control.

Serum arylesterase activity is negatively correlated with inflammatory markers in patients with acute coronary syndromes.

OBJECTIVES: To examined whether serum paraoxonase (PON1) and arylesterase (ARE) activities are correlated with inflammatory biomarkers (procalcitonin and high sensitivity C-reactive protein (hs-CRP) in patients with acute coronary syndrome (ACS). METHODS: This cross-sectional study was conducted at the Departments of Cardiology and Biochemistry, Uludag University School of Medicine, Bursa, Turkey, from April 2007 to December 2007. Seventy-eight consecutive patients with ACS and 39 healthy controls were investigated. Acute coronary syndrome patients were divided into 3 groups according to their clinical presentation: unstable angina pectoris (UAP) (Braunwald III-B, n=25), non-ST elevation myocardial infarction (NSTEMI) (n=18), and ST-elevation myocardial infarction (STEMI) (n=35). Serum PON1/ARE activities were measured spectrophotometrically. Levels of procalcitonin and hs-CRP were measured by immunoassay. RESULTS: Paraoxonase/ARE activities were significantly lower in all patient groups compared to controls. No correlation between PON1/ARE activities and high-density-cholesterol levels was seen. Among ACS patients, serum ARE activity correlated inversely with baseline and 48-hour procalcitonin (r=-0.577, p=0.009, and r=-0.642, p=0.019) and hs-CRP levels (r=-0.614, p=0.03, and r=-0.719, p=0.044). CONCLUSION: Serum ARE activity is reduced in ACS patients and inversely correlated with inflammatory markers.

Aortic distensibility and coronary artery bypass graft patency.

BACKGROUND: Aortic distensibility is an elasticity index of the aorta, and reflects aortic stiffness. Coronary artery disease has been found to be substantially associated with increased aortic stiffness. In this study we aimed to retrospectively analyze the association of angiographically determined aortic distensibility with the patency rates of coronary bypass grafts METHODS: The study was conducted in the Cardiology department of the Applied Research Centre for Health of Uludag University. The coronary angiograms of 53 consecutive coronary bypass patients were analysed retrospectively. Aortic distensibility was calculated using the formula: 2 x (change in aortic diameter)/(diastolic aortic diameter) x (change in aortic pressure). The number of stenosed and patent bypass grafts and the patient characteristics like age, risk factors were noted. RESULTS: There were 44 male (83%) and 9 female (17%) cases. Eighteen cases had only one saphenous vein grafting. The number of cases with two, three and four saphenous grafting were 18, 11 and 1; respectively. In the control angiograms the number of cases with one, two, three and four saphenous vein graft obstruction were 15 (31.3%), 7 (14.6%), 1 (2.1%) and 1 (2.1%) respectively. The aortic distensibility did not differ in cases with and without saphenous graft occlusion (p > 0.05). Also left internal mammary artery (LIMA) graft patency was not related to the distensibility of the aorta (p > 0.05). We also evaluated the data for cut-off values of 50 and 70 mmHg of pulse pressure and did not see any significant difference between the groups in terms of saphenous or LIMA grafts. CONCLUSION: In this study we failed to show association of angiographically determined aortic distensibility with coronary bypass graft patency in consecutive 53 patients with coronary artery bypass graft surgery (CABG).

Small arterial elasticity predicts the extent of coronary artery disease: Relationship with serum uric acid.

BACKGROUND: Arterial elasticity has been previously linked to atherosclerotic vascular disease states. Serum uric acid level has been recently associated with increased arterial stiffness, but to what extent serum uric acid reflects angiographic coronary artery status and vessel compliance remains to be established. In this study we aimed to evaluate the association of arterial elasticity indexes, serum uric acid and the presence and extent of angiographic coronary artery disease (CAD) in patients with chronic stable angina. METHODS: One hundred and eight consecutive patients attending for elective coronary angiography were investigated. The severity of CAD was expressed using the Gensini score. Quantitative analysis of the arterial elasticity was performed by applanation tonometry. Serum uric acid was measured in all participants. Stepwise multiple linear regression analysis was used to identify the independent correlates of the Gensini score. RESULTS: After adjustment for age, gender, common cardiac risk factors and cardiovascular drugs, small artery elasticity index (SAEI) (p<0.001) and serum uric acid (p<0.001) were independently correlated with the severity of CAD. Stepwise multiple linear regression analysis was also used to identify independent correlates of the SAEI. Serum uric acid emerged as the only independent correlate of SAEI (p<0.001). CONCLUSIONS: SAEI independently reflects the extent of CAD in patients with chronic stable angina. This relationship is chiefly mediated by serum uric acid. Our data add to the growing evidence that serum uric acid may be a marker of arterial stiffness and atherosclerotic burden.

Association between paraoxonase 1 activity and severity of coronary artery disease in patients with acute coronary syndromes.

OBJECTIVE: We sought to investigate serum paraoxonase/arylesterase activities in patients with acute coronary syndromes (ACS) and their correlations with the severity and extent of coronary artery disease (CAD). METHODS AND RESULTS: Three groups of patients were investigated: 89 patients with ACS, 54 patients with normal coronary angiograms (no-CAD group), and 27 healthy comparison subjects. ACS patients were divided into three groups according to their clinical presentation: unstable angina pectoris (UAP, Braunwald III-B, n = 31), non-ST elevation myocardial infarction (NSTEMI) (n = 27), and ST-elevation myocardial infarction (STEMI) (n = 31). Serum paraoxonase/arylesterase activities were measured spectrophotometrically. Angiographic CAD extent was expressed both by the number of vessels diseased and by the Gensini scoring system. Results showed that serum paraoxonase/ arylesterase activities and the paraoxonase/high density lipoprotein-cholesterol (HDL-C) ratio were significantly lower in the STEMI, NSTEMI, UAP groups than in no-CAD and control groups. Serum paraoxonase/arylesterase activities and paraoxonase/HDL-C ratio were reduced in patients with 2-vessel disease (VD) and 3-VD compared to the I-VD and no-CAD group (P < 0.001). In patients with ACS, the Gensini score correlated inversely with serum paraoxonase (r = -0.419, P < 0.001), arylesterase (r = -0.492, P < 0.0001), and the paraoxonase/HDL-C ratio (r = -0.377, P < 0.001). Serum arylesterase (r = 0.161, P = 0.03) and paraoxonase (r = 0.135, P = 0.002) activities were positively correlated with HDL-C levels. Serum arylesterase activity (P < 0.0001), gender (P = 0.0037), diabetes mellitus (P = 0.005) and LDL-C levels (P = 0.03) were independent predictors of CAD presence. CONCLUSIONS: Serum paraoxonase/arylesterase activities are reduced in ACS patients and inversely correlated with the severity of CAD.

Cracking the nut: geographical adjacency of sister taxa supports vicariance in a polytomic salamander clade in the absence of node support.

The urodelan genus Lyciasalamandra, which inhabits a relatively small area along the southern Turkish coast and some Aegean islands, provides an outstanding example of a diverse but phylogenetically unresolved taxon. Molecular trees contain a single basal polytomy that could be either soft or hard. We here use the information of nuclear (allozymes) and mitochondrial (fractions of the 16S rRNA and ATPase genes) datasets in combination with area relationships of lineages to resolve the phylogenetic relationships among Lyciasalamandra species in the absence of sufficient node support. We can show that neither random processes nor introgressive hybridization can be invoked to explain that the majority of pairs of sister taxa form geographically adjacent units and interpret that this pattern has been shaped by vicariant events. Topology discordance between mitochondrial and nuclear trees mainly refers to an affiliation of L. helverseni, a taxon restricted to the Karpathos archipelago, to the western-most and geographically proximate mainland taxon in the nuclear tree, while in the organelle tree it turns out to be the sister lineage to the geographically most distant eastern clade. As this discordance cannot be explained by long-branch attraction in either dataset we suppose that oversea dispersal may have accounted for a second colonization of the Karpathos archipelago. It may have initiated introgression and selection driven manifestation of alien eastern mitochondrial genomes on a western nuclear background. Our approach of testing for area relationships of sister taxa against the null hypothesis of random distribution of these taxa seems to be especially helpful in phylogenetic studies where traditional measures of phylogenetic branch support fail to reject the null hypothesis of a hard polytomy.

Arterial elasticity and plasma levels of adiponectin and leptin in type 2 diabetic patients treated with thiazolidinediones.

BACKGROUND: Thiazolidinediones (TZDs) improve peripheral insulin sensitivity, but the effect on arterial stiffness is less clear. The aim of the present study was to assess the differential effect of pioglitazone or rosiglitazone on arterial stiffness and plasma levels of adiponectin and leptin in patients with type 2 diabetes mellitus. METHODS: Thirty-five type 2 diabetic subjects were randomly assigned to receive pioglitazone (30 mg/day; n = 14), rosiglitazone (4 mg/day; n = 11), or placebo (medical nutrition therapy; n = 10) for 12 weeks. Changes in plasma glucose, glycosylated hemoglobin, insulin resistance (HOMA-IR), total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, adiponectin, and leptin were evaluated at baseline and after 12 weeks. In parallel, large arterial compliance (C1) and small arterial compliance (C2) were measured at baseline and at the end of treatment period. RESULTS: At 12 weeks, the rosiglitazone (P = 0.026) and pioglitazone (P = 0.004) groups had a significant increase from baseline in adiponectin that was not seen in the medical nutrition therapy group. No significant changes in plasma leptin and in C1 and C2 elasticity indexes were observed over the entire study period in any of the treatment groups. CONCLUSIONS: In this study of patients with type 2 diabetes, treatment with TZDs was associated with a significant improvement in adiponectin levels, although no significant effects were seen on leptin levels and arterial elasticity.

Procalcitonin in patients with acute coronary syndrome: correlation with high-sensitive C-reactive protein, prognosis and severity of coronary artery disease.

OBJECTIVES: The aim of this study is to determine the relation of high-sensitive serum C-reactive protein (hsCRP) and procalcitonin with presence and severity of coronary artery disease and early prognosis in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: Procalcitonin and hsCRP levels were measured at admission and after 48 hours in 50 patients (41 men, 9 women) with ACS. The patients were assigned to three groups according to their clinical diagnosis: unstable angina pectoris (UAP) (Braunwald III-B), non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). Incidences of adverse cardiac events were recorded in a 3-month follow-up. Coronary angiography was performed to evaluate presence and severity of coronary artery disease. In the groups of STEMI, NSTEMI and UAP, procalcitonin (P = 0.01 3, P = 0.045 and P = 0.000 1, respectively) and hsCRP (P = 0.000 1, P = 0.01 and P = 0.00 1, respectively) levels were significantly increased. No significant correlation was found between these markers and the presence and severity of coronary artery disease. There was no correlation between procalcitonin and hsCRP levels at admission and after 48 hours and primary end points after 3 months except in the group of UAP with revascularization procedure. In the group of UAP, hsCRP levels at 48 hours were found higher in the patients with a revascularization procedure (P = 0.04). CONCLUSIONS: In conclusion, levels of hsCRP and procalcitonin are increased in patients with ACS but failed to correlate with severity of coronary disease and early prognosis.

Contribution of 99mTc-sestamibi infusion SPECT to the characterization of fixed perfusion defects.

In patients with coronary artery disease, the distinction between scar and viable myocardium by means of myocardial perfusion imaging (MPI) sometimes can be difficult because of the equivocal meaning of fixed perfusion defects. In this study we examined whether addition of a 99mTc-sestamibi infusion study to the standard MPI could provide extra information regarding the fixed defects. Thirty-seven patients underwent standard MPI and an extra SPECT study in which 99mTc-sestamibi was given as a prolonged constant infusion. Of 324 myocardial segments available for analysis, 134 had fixed or resting perfusion abnormalities on standard MPI studies, of which 25% (33/134) in 12 patients showed partial improvement in the perfusion pattern whereas in 6% (8/134) the improvement was very significant in infusion studies. In 19 patients who were also examined with dobutamine echocardiography, 13 showed concordance between echocardiography and infusion MPI. This study suggests that infusion MPI may provide complementary information to the conventional scintigraphy with regard to interpretation of standard myocardial perfusion scans with fixed defects.