Governing biological material at the intersection of care and research: the use of dried blood spots for biobanking

A series of governance issues currently surrounds the multiple uses and multiple users of dried blood spots (DBS) for research purposes. Internationally there is a discussion on storing DBS resulting from newborn screening for public health and using them as the basis for large biobank-like collections to facilitate biomedical research. If such a transformation were to be formalized, then DBS would sit at the intersection of care (ie, public health) and research, with the mechanisms through which such a collection could be managed not totally self-evident. What is more, a DBS collection raises questions about the fuzzy boundaries between privacy and anonymity; how to control or define quality control uses of DBS; medical vs nonmedical uses; as well as benefit sharing and stakeholder involvement. Our goal here is to explore some of the key questions relating to DBS governance by way of the bio-objects and bio-objectification concepts. By embracing - rather than resisting to - the blurring of boundaries and problems in categorization that have come to characterize bio-objects and bio-objectification processes recently described in this journal, we attempt to highlight some issues that might not be currently considered, and to point to some possible directions to go (or avoid). Building from our knowledge of the current DBS situation in the Netherlands, we outline questions concerning the uses, management, collection, and storage of DBS.     

Manual derotation of the twisted spermatic cord

OBJECTIVE: To re-emphasize the safety and efficacy of manual derotation in the management of the twisted spermatic cord. PATIENTS AND METHODS: Seventeen patients (mean age 15 years, range 13-28) with acute unilateral torsion of the spermatic cord, initially treated by manual detorsion, were reviewed; all 17 patients were seen by one consulting urologist (H.F.M.K.). RESULTS: In 14 of the 17 patients the attempt resulted in successful manual derotation, i. e. the immediate relief of all symptoms and normal findings at physical examination. No testicular atrophy was detected during the follow-up (mean 22 months, range 9-72). CONCLUSIONS: These results reinforce the efficacy and safety of manual derotation with subsequent elective bilateral orchidopexy as the primary treatment for the twisted spermatic cord.     

Safety and utility of atropine addition during dobutamine stress echocardiography for the assessment of viable myocardium in patients with severe left ventricular dysfunction

Objective To assess the feasibility safety and side effects of the additionof atropine to dobutamine stress echocardio-graphy for the detectionof viable myocardium in patients with left ventricular dysfunction(ejection fraction 35%) prior to coronary revascularization. Background The assessment of viable and/or ischaemic myocardium has highprognostic value as regards improvement of function and survivalafter coronary revasculariz-ation. The addition of atropineto dobutamine during echocardiographic testing for the presenceof viable myocardium is not common practice. Consequently, nodata exist on the safety and additional diagnostic value ofthis practice. Methods Two hundred patients with left ventricular ejection fraction35% were studied. Results Test end-points were: target heart rate in 164 (82%) of thepatients, severe angina in 18 (9%), maximum dobutamine–atropinedose in six (3%), severe ST segment changes in five (2%), cardiacarrhythmias in four (2%), and hypotension in three (1%). Viabilitycould be assessed echocardiogaphically in 105/200 (53%) froma biphasic response (improvement of wall motion with low dosedobutamine and worsening with high dose), in 93 from ischaemiaand in 12 from sustained or late improvements. In 36/105 (34%)patients, ischaemic myocardium could only be assessed afterthe addition of atropine. Cardiac arrhythmias occurred in 11/200(6%) and hypotension (decrease of systolic blood pressure >30mmHg)in 21/200 (11%). Neither the use of atropine nor the inductionof ischaemia were associated with an increased incidence ofcardiac arrhythmias or hypotension. Conclusions In a large group of patients with severe left ventricular dysfunction,dobutamine stress echocardiography is feasible and safe in 186/200(93%); the addition of atropine was necessary in 34% to assessmyocardial viability. Hypotension and cardiac arrhythmias werethe most frequent side effects, but were not related to theinduction of ischaemia or addition of atropine.The EuropeanSociety of Cardiology     

The long pentraxin PTX3 in human endometrium: regulation by steroids and trophoblast products

Human implantation is characterized by blastocyst attachment to endometrial epithelial cells followed by invasion of trophoblast into the maternal decidua. There has been an increasing amount of data linking higher levels of the pentraxin PTX3, a long pentraxin, to embryo implantation. PTX3 levels were found to be higher in patients with preeclampsia and intrauterine growth restriction, both conditions caused by faulty implantation. Furthermore, PTX3 knockout mice have reduced fertility due to cumulus oopherus malformation as well as implantation failure. In a human implantation model, we and others have shown that trophoblast action on endometrial stromal cells induces PTX3 expression. In this study, we analyzed PTX3 expression throughout the menstrual cycle as well as its regulation by hormones involved in the implantation process. We also compared PTX3 expression in stromal cells induced by trophoblast conditioned medium to its induction by trophoblast coculture. PTX3 mRNA expression in human endometrial stromal cells is regulated by progesterone, estrogen, and IL-1 but not human chorionic gonadotropin and is increased by both trophoblast-conditioned medium as well as trophoblast explants. PTX3 protein production and regulation by these factors is shown by Western blot. Based on these findings, we conclude that estradiol and progesterone are involved in PTX3 induction and regulation during implantation. Also, of the factors secreted by trophoblast, IL-1beta induces PTX3 in human endometrial stromal cells.     

The association of ABCB1 polymorphisms and elevated serum digitoxin concentrations in geriatric patients

Objective Digitoxin is a known substrate of the efflux pump P-glycoprotein (gene name: ABCB1). P-glycoprotein expression was shown to be modulated by single nucleotide polymorphisms in the ABCB1 gene, but it remains unclear whether these polymorphisms influence digitoxin blood levels. Our objective was to examine the association of ABCB1 C3435T genotype and elevated serum digitoxin concentrations (SDC) in a cohort of 77 geriatric patients consecutively admitted to a geriatric department over a 12-month period. Methods The impact of ABCB1 3435 CC, CT, and TT genotypes on SDC and SDC normalized for daily digitoxin dosage and body weight was assessed by multivariate regression analysis. Results Among participants, 18 (23%) had the CC, 36 (47%) the CT, and 23 (30%) the TT genotype. Adjusting for relevant covariates, no significant association of ABCB1 C3435T genotype and SDC or normalized SDC was detected. Mean SDC was 22.4 ng/ml (95% CI 18.9–25.9) for the TT, 21.8 ng/ml (95% CI 18.1–25.5) for the CT, and 25.7 ng/ml (95% CI 20.6–30.8) for the CC genotype. The means for normalized SDC were 5.2 kg·l⁻¹ (95% CI 4.3–6.1) for the TT, 6.1 kg·l⁻¹ (95% CI 4.7–7.5) for the CT, and 6.2 kg·l⁻¹ (95% CI 4.6–7.7) for the CC genotype. Conclusion In this sample of frail geriatric patients, the impact of ABCB1 C3435T genotype on serum digitoxin concentration was not of major relevance. Regular monitoring of digitoxin blood levels and surveillance of appropriate drug use remain the best ways to prevent digitoxin intoxications in the elderly.     

Agreement and disagreement between “metabolic viability” and “contractile reserve” in akinetic myocardium

BACKGROUND: In patients with chronic coronary artery disease and depressed left ventricular function, assessment of residual viability in akinetic myocardium is important for therapeutic management. Intact perfusion, preserved metabolism, and presence of contractile reserve are different aspects of cellular viability. However, not all viable cells exhibit all characteristics; it is thought that contractile reserve is less often preserved compared with metabolic activity or intact perfusion. In this study we performed a direct comparison between perfusion imaging with thallium-201 single photon emission computed tomography (SPECT), metabolic imaging with F18-fluorodeoxyglucose SPECT, and assessment of contractile reserve with low-dose dobutamine echocardiography in akinetic myocardium. METHODS AND RESULTS: Forty patients with depressed left ventricular function (mean left ventricular ejection fraction 31% +/- 16%) were studied. Resting echocardiography showed akinesis in 165 (32%) segments. Most (n = 154, 93%) of these segments demonstrated resting hypoperfusion. F18-fluorodeoxyglucose imaging revealed a perfusion-metabolism mismatch in 41 segments and a match in 113 segments. Contractile reserve was present in 33 (80%) of the segments with a perfusion-metabolism mismatch and in 7 (6%) segments with a match (P < .0005). Of the 11 segments with normal perfusion, only 5 (45%) showed contractile reserve. The agreement between SPECT and dobutamine echocardiography was 87%. Although 94% of the segments that were nonviable on scintigraphy did not show contractile reserve, the disagreement between SPECT and dobutamine echocardiography was caused mainly by the absence of contractile reserve in 27% of the segments that were viable on scintigraphy. CONCLUSION: This study shows a good agreement between SPECT and dobutamine echocardiography, although a substantial number of segments with preserved viability on SPECT do not exhibit contractile reserve, indicating underestimation of viability by dobutamine echocardiography compared with F18-fluorodeoxyglucose imaging.     

Dobutamine stress thallium-201 single-photon emission tomography versus echocardiography for evaluation of the extent and location of coronary artery disease late after myocardial infarction

Dobutamine stress echocardiography and thallium-201 myocardial perfusion scintigraphy are clinically useful methods for the evaluation of coronary artery disease (CAD). However, the relative merits of these imaging modalities in the evaluation of the extent of CAD after myocardial infarction have not been well studied. The aim of this study was to compare the accuracy of dobutamine stress echocardiography and simultaneous ²⁰¹Tl single-photon emission tomography (SPET) imaging for the diagnosis and localization of CAD late after acute myocardial infarction. Dobutamine (up to 40 μg kg^–1 min^–1)-atropine (up to 1 mg) stress echocardiography in conjunction with stress-reinjection ²⁰¹Tl SPET was performed for the evaluation of myocardial ischaemia in 90 patients with previous myocardial infarction who underwent coronary angiography. Significant CAD was predicted on bases of myocardial ischemia (new or worsening wall motion abnormalities on echocardiography and reversible perfusion defects on ²⁰¹Tl SPET). Significant CAD (≥ 50% luminal diameter stenosis) was detected in 73 (81%) patients. The sensitivity, specificity and accuracy of echocardiography in detecting remote ischaemia for the diagnosis of remote CAD (present in 53 patients) were, respectively, 79% (CI 70%–88%), 85% (CI 77%–93%) and 81% (CI 73%–90%), while the corresponding figures for ²⁰¹Tl SPET were 75% (CI 66%–85%), 78% (CI 69%–87%) and 76% (CI 67%–86%) respectively (P = NS vs echocardiography). The sensitivity, specificity and accuracy of echocardiography in detecting peri-infarction ischaemia for the diagnosis of infarct-related artery stenosis (present in 70 patients) were, rspectively, 77% (CI 68%–86%), 85% (CI 78%–92%) and 79% (CI 70%–87%) while the corresponding figures for ²⁰¹Tl SPET were 73% (CI 64%–82%), 85% (CI 78%–92%) and 76% (CI 67%–84%) respectively (P = NS vs echocardiography). The agreement between the two methods for the diagnosis of peri-infarction and remote ischaemia was 70% (kappa = 0.37) and 80% (kappa = 0.59) respectively. It is concluded that dobutamine stress echocardiography and ²⁰¹Tl SPET have comparable accuracy for the diagnosis of infarct related and remote CAD in patients with previous myocardial infarction. The agreement between the methods is higher for the diagnosis of remote CAD than for that of peri-infarction ischaemia. Received 17 October 1998 and in revised form 5 January 1999