Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology.

According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations. A crucial element in this theory is the presence of binding proteins, which function as gatekeepers for steroid action. For testosterone, tissue exposure is governed by a delicate equilibrium between free and total testosterone which is determined through interaction with the binding proteins sex hormone-binding globulin and albumin. Ageing, genetics and various pathological conditions influence this equilibrium, hereby possibly modulating hormonal exposure to the target tissues. Despite ongoing controversy on the subject, strong evidence from recent in vitro, in vivo and human experiments emphasizes the relevance of free testosterone. Currently, however, clinical possibilities for free hormone diagnostics are limited. Direct immunoassays are inaccurate, while gold standard liquid chromatography with tandem mass spectrometry (LC-MS/MS) coupled equilibrium dialysis is not available for clinical routine. Calculation models for free testosterone, despite intrinsic limitations, provide a suitable alternative, of which the Vermeulen calculator is currently the preferred method. Calculated free testosterone is indeed associated with bone health, frailty and other clinical endpoints. Moreover, the added value of free testosterone in the clinical diagnosis of male hypogonadism is clearly evident. In suspected hypogonadal men in whom borderline low total testosterone and/or altered sex hormone-binding globulin levels are detected, the determination of free testosterone avoids under- and overdiagnosis, facilitating adequate prescription of hormonal replacement therapy. As such, free testosterone should be integrated as a standard biochemical parameter, on top of total testosterone, in the diagnostic workflow of male hypogonadism.

Comparison between the STENTYS self-apposing bare metal and paclitaxel-eluting coronary stents for the treatment of saphenous vein grafts (ADEPT trial).

AIMS: To describe the safety and performance of STENTYS self-expandable bare metal stents (BMS) versus paclitaxel-eluting stents (PES) in saphenous vein grafts (SVGs). METHODS AND RESULTS: A randomised controlled trial was performed in four hospitals in three European countries between December 2011 and December 2013. Patients with de novo lesions (>50% stenosis) in an SVG with a diameter between 2.5-6 mm were included. Primary endpoint was late lumen loss at 6 months. Secondary endpoints included procedural success and the occurrence of major adverse cardiac events (MACE) at 12 months. A total of 57 patients were randomised to STENTYS self-apposing BMS (n = 27) or PES (n = 30). Procedural success was obtained in 89.5%. No significant differences in late lumen loss were found between BMS and PES at 6 months (0.53 mm vs 0.47; p = 0.86). MACE rates at 12 months were comparable in both groups (BMS 22.2% vs. PES 26.7%; p = 0.70). CONCLUSIONS: Treatment of SVGs with STENTYS self-expandable stents is safe and effective. No significant differences were found in late lumen loss and MACE between BMS and PES.

Cefazolin plasma protein binding and its covariates in neonates.

Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830-4,200) g and a postmenstrual age (PMA) of 39 (25-45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10-0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration (R (2) = 0.39) had a slope significantly different from zero (p < 0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R (2) value of 0.496. The median unbound CFZ fraction at the peak concentration (0.46, range 0.28-0.69) was significantly higher compared to the trough level (0.36, range 0.17-0.73) (p < 0.001). The between- and within-patient saturability of CFZ plasma protein binding were documented in neonates. The median unbound CFZ fraction in neonates is higher than in adults and depends partly on albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA. Integration of CFZ protein binding in future pharmacokinetic/pharmacodynamic research is warranted in order to optimise neonatal CFZ dosing. We recommend protein binding assessment in the neonatal pharmacokinetic evaluation of highly protein-bound or clinically relevant drugs.

Left atrial appendage occlusion in recurrent ischaemic stroke, a multicentre experience.

BACKGROUND: Oral anticoagulation therapy (OAC) remains the gold standard for ischaemic stroke prevention in patients with non-valvular atrial fibrillation (NVAF) and elevated stroke risk. Percutaneous left atrial appendage occlusion (LAAO) has emerged as a potential alternative for stroke prevention in patients who cannot tolerate OAC. Although no randomized data is available, recurrent stroke in NVAF-patients, while on adequate OAC, is regarded as a treatment failure and therefore is considered as a potential indication for LAAO, based upon expert opinion. METHODS/OBJECTIVES: A multicentre retrospective cohort study evaluating efficacy, safety and mortality of LAAO in NVAF-patients presenting with recurrent ischaemic stroke, after excluding other plausible causes. RESULTS: Fifteen LAAO have been performed in NVAF-patients with recurrent stroke despite ongoing OAC, after exclusion of other plausible causes. Mean age was 78.1 ± 5.8 years, mean CHA2DS2-VASc-score = 6 ± 1.2 and mean HAS-BLED-score = 5 ± 1.2. Successful implantation was achieved in all patients (73% Amplatzer device and 27% Watchman device), without any access-related complications and only one procedure/device-related complication (device embolization) was reported. In all but four patients, OAC was continued at long term after LAAO. No haemorrhagic strokes and only two ischaemic strokes were observed. During follow-up three patients died, all due to non-atrial fibrillation or non-device-related causes. CONCLUSIONS: In NVAF-patients at high risk for stroke presenting with recurrent stroke despite adequate OAC, LAAO may be considered an adjunctive, but not alternative treatment to OAC with high feasibility and safety.Abbreviations: AF: atrial fibrillation; ESC: European Society of Cardiology; INR: international normalized ratio; LAA: left atrial appendage; LAAO: left atrial appendage occlusion; NOAC: non-vitamin K oral anticoagulants; NVAF: non-valvular atrial fibrillation; OAC: oral anticoagulation; RS: recurrent (ischaemic) stroke; SD: standard deviation; TIA: transient ischaemic attack; TOE: transoesophageal echocardiography; TTE: transthoracic echocardiography; VKA: vitamin K antagonists.

Diagnostic performance of seven rapid IgG/IgM antibody tests and the Euroimmun IgA/IgG ELISA in COVID-19 patients.

OBJECTIVES: To evaluate the diagnostic performance of seven rapid IgG/IgM tests and the Euroimmun IgA/IgG ELISA for antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in COVID-19 patients. METHODS: Specificity was evaluated in 103 samples collected before January 2020. Sensitivity and time to seropositivity was evaluated in 167 samples from 94 patients with COVID-19 confirmed with RT-PCR on nasopharyngeal swab. RESULTS: Specificity (confidence interval) of lateral flow assays (LFAs) was ≥91.3% (84.0-95.5) for IgM, ≥90.3% (82.9-94.8) for IgG, and ≥85.4% (77.2-91.1) for the combination IgM OR IgG. Specificity of the ELISA was 96.1% (90.1-98.8) for IgG and only 73.8% (64.5-81.4) for IgA. Sensitivity 14-25 days after the onset of symptoms was between ≥92.1% (78.5-98.0) and 100% (95.7-100) for IgG LFA compared to 89.5% (75.3-96.4) for IgG ELISA. Positivity of IgM OR IgG for LFA resulted in a decrease in specificity compared to IgG alone without a gain in diagnostic performance, except for VivaDiag. The results for IgM varied significantly between the LFAs with an average overall agreement of only 70% compared to 89% for IgG. The average dynamic trend to seropositivity for IgM was not shorter than for IgG. At the time of hospital admission the sensitivity of LFA was <60%. CONCLUSIONS: Sensitivity for the detection of IgG antibodies 14-25 days after the onset of symptoms was ≥92.1% for all seven LFAs compared to 89.5% for the IgG ELISA. The results for IgM varied significantly, and including IgM antibodies in addition to IgG for the interpretation of LFAs did not improve the diagnostic performance.

Localization, etiology and impact of calcium phosphate deposits in renal allografts.

Hypercalcemia, hypophosphatemia and renal phosphate wasting are common after kidney transplantation. Animal data suggest that these alterations in mineral metabolism may contribute to calcium phosphate (CaPhos) deposition in the kidney and renal dysfunction. We tested the hypothesis that CaPhos deposition is highly prevalent in the early posttransplant period and is related to a disturbed mineral metabolism. For this purpose, biomarkers of mineral metabolism and renal calcium and phosphorus handling were prospectively assessed in 201 renal transplant recipients. CaPhos deposits were observed in 4.6, 30.4 and 24.7% of protocol biopsies obtained at the time of engraftment, and 3 and 12 months thereafter, respectively. In multivariate logistic regression analysis, high calcium and low serum phosphorus levels were independently associated with renal CaPhos deposition at month 3. The extent of CaPhos deposition correlated significantly with the severity of mineral metabolism disturbances. Renal function after a mean follow-up of 33 months was similar in patients with and without CaPhos deposition at month 3. In conclusion, our data demonstrate that CaPhos deposition is highly prevalent in the early posttransplant period and suggest that a disordered mineral metabolism is implicated in its pathogenesis. The clinical relevance of CaPhos deposition remains to be established.

Blade technology in the egyptian-nile valley: some new evidence.

An Upper Paleolithic site with blade technology was excavated at Nazlet Khater, Egypt. Radiocarbon dates center around 31,500 years ago, indicating that the Egyptian Nile Valley was not an isolated enclave where blade technology appeared late in comparison with other eastern Mediterranean areas. This site fills a gap in the record of human history in Egypt between 40,000 and 20,000 years ago.

Free Testosterone Reflects Metabolic as well as Ovarian Disturbances in Subfertile Oligomenorrheic Women.

BACKGROUND: Diagnosing polycystic ovary syndrome (PCOS) is based on ovulatory dysfunction, ovarian ultrasound data, and androgen excess. Total testosterone is frequently used to identify androgen excess, but testosterone is mainly bound to sex hormone-binding globulin (SHBG) and albumin. Only 1-2% of nonprotein-bound testosterone (so-called free testosterone) is biologically active and responsible for androgen action. Moreover, automated immunoassays which are frequently used for female testosterone measurements are inaccurate. OBJECTIVE: To assess the clinical usefulness of liquid chromatography-tandem mass spectrometry measured testosterone and calculated free testosterone in subfertile women attending a fertility clinic with oligomenorrhea and suspected PCOS. METHODS: Hormonal and metabolic parameters were evaluated, and ovarian ultrasound was performed. Total testosterone was measured by liquid chromatography-tandem mass spectrometry. Free testosterone was calculated from total testosterone and SHBG. RESULTS: Sixty-six women were included in the study. Total testosterone was associated with ovarian volume and antral follicle count but not with metabolic parameters. However, SHBG and calculated free testosterone were associated with both ovarian ultrasound and metabolic parameters, such as BMI and insulin resistance. CONCLUSIONS: Assessing SHBG and free testosterone is important in evaluating androgen excess in subfertile women with ovulatory dysfunction and suspected PCOS, as it reflects both ovarian and metabolic disturbances.

Percutaneous treatment of diseased saphenous vein grafts: current state-of-the-art and future directions.

The percutaneous treatment of patients with obstructive atherosclerotic disease in diseased coronary saphenous vein bypass grafts still remains a challenge in interventional cardiology. We discuss the actual evidence-based knowledge for the percutaneous management of this lesion subset, focusing on the devices that are actually considered the gold standard for this treatment: bare-metal stents and distal protection devices. We also comment the negative results of the trials regarding the promising covered stent-grafts. We finally offer insights into the currently available evidence for the use of drug-eluting stents in saphenous vein grafts. These devices are potentially a promise for the successful sealing of vein graft disease, however, available long-term safety and effectiveness data are conflicting and give reason for caution.

L-arginine administration reduces neointima formation after stent injury in rats by a nitric oxide-mediated mechanism.

The clinical outcome of vascular stenting is limited by in-stent stenosis. Increased nitric oxide (NO)/cGMP signaling by L-arginine (L-Arg) supplementation, the substrate for NO synthase (NOS), or NOS gene transfer may reduce in-stent neointima formation. After stenting, vascular cell proliferation in rat carotid arteries, as measured by 5'-bromodeoxyuridine (5'-BrdU) incorporation, indicated 15+/-8%, 28+/-5%, and 33+/-7% 5'-BrdU-positive vascular cells at 4, 7, and 14 days, respectively. Reporter beta-galactosidase gene transfer efficacy was evidenced by 30% beta-galactosidase-expressing medial smooth muscle cells at 14 days. The intima-to-media ratio (I/M) progressively increased to 2.32+/-0.24 at 14 days. To target in-stent neointima formation, animals were infected with adenoviral vectors (4x10(10) plaque-forming units per mL) expressing NOS2 (AdNOS2) or no transgene (AdRR5), or they received daily doses of L-Arg (500 mg. kg(-1). (d-1) IP). The neointima at 14 days was smaller in L-Arg-treated than in untreated rats (I/M 1.25+/-0.35 vs 2.32+/-0.24, P<0.05, n=7 each) or in AdRR5- and AdNOS2-infected rats (I/M 2.57+/-0.43, n=7 and 1.82+/-0.75, n=8, respectively; P<0.05 for both). The effect of L-Arg was abolished by simultaneous administration of N(G)-nitro L-arginine methyl ester, an NOS inhibitor (2.03+/-0.39, P<0.05, vs L-Arg). Inflammation was markedly less in L-Arg- and AdNOS2-treated than in AdRR5-infected rats. Supplemental L-Arg reduces neointima formation after stenting by way of an NOS-dependent mechanism and may be a valuable strategy to target in-stent stenosis.

Evaluation of the Sebia Minicap Flex Piercing capillary electrophoresis for hemoglobinopathy testing.

INTRODUCTION: Capillary zone electrophoresis (CZE) at alkaline pH is one of the techniques used for hemoglobinopathy screening. In this study, an evaluation of the performance of a lower throughput CZE instrument, the Sebia Minicap Flex Piercing system, for this purpose is reported for the first time. METHODS: The analytical performance of the Sebia Minicap Flex Piercing system was evaluated. Furthermore, a method comparison between the Sebia Minicap Flex Piercing and two HPLC methods, that is, the Bio-Rad Variant Classic(™) and the Bio-Rad D-10(™) systems was performed by measuring samples with and without clinically relevant hemoglobin disorders. RESULTS: The analytical performance was acceptable for the determination of HbA, HbA2, HbS, and HbF, with an imprecision ≤2.0%. Method comparison showed a linear correlation for HbA2, HbF, and HbS measurements. Clinical concordance was acceptable when comparing CZE and HPLC. CONCLUSIONS: Lower throughput CZE using the Sebia Minicap Flex Piercing can be used for precise and accurate first line screening and follow-up of hemoglobinopathies.

Inadequate exercise leads to suboptimal imaging. Thallium-201 myocardial perfusion imaging after dipyridamole combined with low-level exercise unmasks ischemia in symptomatic patients with non-diagnostic thallium-201 scans who exercise submaximally.

This study was undertaken to establish the additional value of 201TI imaging after dipyridamole in combination with low-level exercise in 15 symptomatic patients with non-diagnostic 201TI scans, who exercised submaximally. Most patients had angina, ST-segment depression and even exertional hypotension and were referred for stress 201TI testing for determining the functional significance of known coronary artery disease. Six patients with a normal exercise 201TI test and one patient with an apical defect only were found to have 37 segments (of 105 segments) with reversible perfusion defects after dipyridamole infusion. One patient showing two reversible defects after exercise had five reversible segments after dipyridamole. Seven patients with fixed defects in 28 segments after exercise and two with small areas of border zone ischemia in seven additional (sub)segments, demonstrated fixed in defects in only nine segments but reversible defects in 40 segments after dipyridamole. Quantitative analysis resulted in 24.8 +/- 28.5 (mean value) sample points below -2 s.d. of the mean normal uptake after exercise, which increased to 72 +/- 26.5 after dipyridamole infusion (p less than 0.005). The washout analysis resulted in a mean value of 5.5 +/- 8.1 sample points below -2 s.d. after exercise, increasing to 33.3 +/- 22.1 after dipyridamole (p less than 0.005). Thallium-201 myocardial perfusion imaging after dipyridamole combined with low-level upright bicycle exercise may unmask scintigraphic evidence for ischemia in symptomatic patients who would otherwise have non-diagnostic imaging studies during submaximal exercise.

Usefulness of low-dose dobutamine stress echocardiography in predicting recovery of poor left ventricular function in atrial fibrillation dilated cardiomyopathy.

Assessment of contractile reserve was performed in 16 patients with dilated cardiomyopathy and chronic atrial fibrillation. In this prospective study, low-dose dobutamine echocardiography could predict recovery of left ventricular dysfunction and could identify tachycardiomyopathy before restoration of sinus rhythm.

Saphenous vein graft disease treated with the Wiktor Hepamed stent: procedural outcome, in-hospital complications and six-month angiographic follow-up.

OBJECTIVES: To evaluate the effectiveness of electively placed heparin-coated stents in the treatment of coronary saphenous vein bypass grafts with de novo lesions less than 15 mm in diameter in a prospective study with all eligible consecutive patients presenting to Middelheim Hospital, Antwerp, Belgium between September 1997 and August 1998. PATIENTS AND METHODS: Fifty patients with 53 lesions were studied. Anginal class, risk factors, quantitative coronary angiographic measurements pre- and postprocedure, procedural outcome, in-hospital events, clinical status on discharge, and six-month clinical and angiographic follow-up (in 48 patients) were recorded. All patients received acetylsalicylic acid and ticlopidine, unless known intolerance was present. RESULTS: On average, 1.1 stents/patient were placed in very old saphenous vein grafts (11. 7+/-3.9 years). Procedural success was 98%. Only two non-Q wave myocardial infarctions (MIs) occurred, with no Q-wave MIs and no deaths during hospital stay. Length of hospital stay was short (2. 4+/-1.7 days), and 96% of patients were free of angina on discharge. At six-months' follow-up, two patients had died, one of whom died of a noncardiac cause. One patient suffered a non-Q wave MI. At six months, 86% of patients were free from angina. Minimal luminal diameter decreased from 1.14 mm before to 3.33 mm after stenting and to 2.52 mm at six months. Restenosis was present in 22% of patients (21.6% of lesions). CONCLUSIONS: In a selected population with coronary saphenous vein bypass graft disease, Wiktor heparin-coated stents can be delivered with an excellent periprocedural outcome. Six-month outcome appears favourable with a low recurrence of angina (18%) and a low rate of angiographic restenosis (21.6%).

Elective Wiktor GX stenting for symptomatic stenosis in old aortocoronary saphenous vein bypass grafts: the Antwerp experience.

PURPOSE: We compared initial outcome, peri-procedural complications and long-term clinical follow-up of elective Wiktor GX stent implantation in severely narrowed vein grafts to a historic register of elective angioplasties in saphenous vein grafts in the same center. METHODS: Eighty-one consecutive patients with angina and a history of coronary artery bypass grafting (CABG), all received elective angioplasty (PTCA) of the diseased graft; we described them as group P. The next 38 consecutive patients were treated with elective angioplasty and Wiktor Stent implantation, followed by one month ticlopidine; they were called group S. CONCLUSION: This retrospective study suggests that elective Wiktor stenting in old saphenous vein graft stenosis, in combination with one month ticlopidine, leads to: 1) a better angiographic result, with reduction of peri-procedural complications; and 2) a lower incidence of recurrent angina, need for invasive or surgical re-intervention, myocardial infarction and death during follow-up.

Comparison of adenosine and high-dose dipyridamole both combined with low-level exercise stress for 99Tcm-MIBI SPET myocardial perfusion imaging.

Intravenously administered adenosine and high-dose dipyridamole, both combined with low-level exercise stress, were compared in a head-to-head fashion using 99Tcm-methoxyisobutyl isonitrile (99Tcm-MIBI) single photo emission tomography (SPET) myocardial perfusion imaging. Thirty-nine consecutive patients who had undergone coronary arteriography underwent 99Tcm-MIBI (740 Mbq) SPET after dipyridamole (0.84 mg kg-1) and after adenosine (0.84 mg kg-1), both combined with low-level exercise (30 W load), and under resting conditions. Our results demonstrate that adenosine and dipyridamole combined with exercise have comparable haemodynamic effects, with a low incidence of side-effects. The time of recovery from the stress protocol was not significantly different: adenosine, 5.7 +/- 3.9 min; dipyridamole, 6.6 +/- 4.9 min. However, aminophylline was significantly (P < 0.05) more often administered to reverse side-effects using the dipyridamole protocol (36% of patients) compared with the adenosine protocol (8% of patients). The results of 99Tcm-MIBI SPET imaging were highly concordant and demonstrated a high diagnostic accuracy for identifying coronary artery disease (CAD). The sensitivity was 90% (95% confidence intervals 79-100%) with adenosine SPET and 93% (95% confidence intervals 84-100%) with dipyridamole SPET for identifying patients with CAD (i.e. luminal stenosis > 50%); their specificities were both 100% (95% confidence intervals 66-100%). The sensitivity of identifying angiographically diseased vessels was 81% (95% confidence intervals 70-92%) using adenosine SPET and 85% (95% confidence intervals 75-95%) using dipyridamole; the specificity for both stress modalities was 94% (95% confidence intervals 89-100%). The combination of exercise with adenosine and high-dose dipyridamole appears to be a feasible and safe method to alleviate some of the undesirable A1-receptor-mediated side-effects of adenosine. The choice of the pharmacological stress will depend on local expertise and availability.

Fatal acute liver failure associated with pirprofen. Report of a case and a review of the literature.

This report is about a 71-yr-old woman who suffered from acute liver failure, induced by the nonsteroidal antiinflammatory drug, pirprofen. She presented with jaundice 6 weeks after starting treatment with 800 mg pirprofen daily. She is the fifth patient described in the literature to die from pirprofen-induced hepatotoxicity.