Search

The use of metal-on-metal bearing couples in total hip arthroplasty can lead to an increased release of metal ions, particularly cobalt and chromium over time. This can lead to local and systemic metallosis, which has cytotoxic, genotoxic, and immunotoxic effects and can cause a host of secondary disorders. We describe the case of a 37-year-old female patient that was diagnosed with warm-antibody autoimmune hemolytic anemia (WAIHA) one and a half years after bilateral large-diameter head metal-on-metal total hip arthroplasty. For 11 years, it was refractory to all therapy, including splenectomy and rituximab, requiring long-term oral prednisone for disease control. Ultimately, systemic metallosis and periprosthetic joint infection were diagnosed, requiring explantation of the prostheses. By the sixth week postoperatively, she experienced complete spontaneous remission of her WAIHA. In conclusion, WAIHA can be associated with systemic metallosis in patients with metal-on-metal prosthetic joint replacements. Both hematologists and orthopedic surgeons should be aware of this., (© 2024 The Authors.)

Introduction: In France, few centres per region offer genetics consultations. Consequently, each centre covers a large area, often requiring patients to take a day off to travel long distances. In certain situations, genetic counselling in particular, a physical exam is not required. In these cases, teleconsultations between medical professional and patients, at the patient's location of choice, are an interesting offer. The COVID-19 pandemic has accelerated the implementation and the use of this type of consultation. With the aim of developing teleconsultation for certain types of referrals, a study of patient satisfaction, experience and preferences has been set up in our region., Methods: 2307 patients who had a teleconsultation by phone or videoconferencing with professionals from one of five genetic centres in North-eastern France between March and December 2020 were asked by e-mail or by post to answer an online survey., Results: 20% of the patients (n = 465) responded to the survey (80% women, 55% over 40 years old). In 64% of the cases (n = 299), the teleconsultation replaced a physical consultation due to the pandemic. In 56% of cases (n = 217), the consultations were conducted by videoconference. The teleconsultation involved the disclosure of results in 56% of cases (n = 260), a first consultation in 30% of cases (n = 138), and a follow-up consultation in 14% of cases (n = 67). The satisfaction rate was 96% (n = 447), with a rating of "excellent" in 72% of responses (n = 290) and "good" in 24% of responses (n = 157). Only 22% of the patients (n = 103), particularly patients who lived near the hospital or who were older than 70 years, would have preferred a physical consultation. Half of respondents (n = 232) declared that they avoided more than 1.5 h of transport, and 69% (n = 321) avoided taking a work day off. Patients were less often accompanied by a relative than if the consultation had taken place face-to-face (43%; n = 201 vs. 61%; n = 285). There was no change in responses during or after lock-down., Conclusion: This collection of feedback and analysis of patients' preferences has validated the long-term implementation of medical genetics teleconsultations in certain circumstances and indications, for patients who prefer this approach., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Introduction: Fracture of the femoral stem is the cause of ~1 % of revisions after total hip arthroplasty. The risk increases intrinsically with modularity, whereby modularity is particularly useful in revision arthroplasty. We present 7 cases of failure of a specific modular, tapered, fluted, titanium alloy Revitan stem and analyse the different failure modes., Methods: Retrospective review of all Revitan stems revised at our institutions due to implant failure and analysis of clinical presentation, diagnostic workup, and failure mode. The retrieved components were analyzed by optical and scanning electron microscopy., Results: A total of 7 cases were included. There was a significant time lag between symptom onset and correct diagnosis. Conventional radiographs and low-dose CT scans (CT scout imaging) were decisive for diagnosis. All failures occurred at the level of the connection between the proximal component and the distal part of the stem. Three different failure modes were identified: loosening of the proximal component, fatigue fracture of the connection pin, and distal loosening of the connection pin. No alterations of the microstructure or deviation from manufacturing specifications regarding dimensions were observed. Failure was caused by mechanical overload., Conclusion: Conventional radiographs are the mainstay in identifying failed modular stems. Repeated radiographs and low-dose CT scans may be helpful additions. No single modification of the connection will address all possible failure modes. Modularity of revision stems offers advantages up until insertion of the definitive stem. Monoblock definitive stems might overcome the potential mechanical weaknesses of modularity and should be considered in relatively young, heavy and active patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Down syndrome (DS) is a genetic neurodevelopmental disorder. In individuals with DS, a multidisciplinary approach to care is required to prevent multiple medical complications. The aim of this study was to describe the rehabilitation, medical care, and educational and social support provided to school-aged French DS patients with varying neuropsychological profiles. A mixed study was conducted. Quantitative data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Qualitative data were collected by semi-structured face-to-face interviews and focus groups. Ninety-five DS subjects with a mean age of 10.9 years were included. Sixty-six per cent had a moderate intellectual disability (ID) and 18.9% had a severe ID. Medical supervision was generally multidisciplinary but access to medical specialists was often difficult. In terms of education, 94% of children under the age of six were in typical classes. After the age of 15, 75% were in medico-social institutions. Analysis of multidisciplinary rehabilitation conducted in the public and private sectors revealed failure to access physiotherapy, psychomotor therapy and occupational therapy, but not speech therapy. The main barrier encountered by patients was the difficulty accessing appropriate facilities due to a lack of space and long waiting lists. In conclusion, children and adolescents with DS generally received appropriate care. Though the management of children with DS has been improved considerably, access to health facilities remains inadequate., (Copyright © 2021. Published by Elsevier Masson SAS.)

The paper emphasizes the main lessons learned from hydromorphological monitoring following the removal of a medium-sized dam (7.29 m) located on a medium energy gravel bed river over a four year period (2015-2019). The Pierre Glissotte dam was previously located on the upper Yonne river (Morvan massif), where it was an obstacle to sediment continuity and was almost completely filled with sand and silts. The dam was removed in two steps, the first in July 2015 and the second in October 2017. Several methods were used (topographical surveys, SFM photogrammetry, RFID tracking, hydrological monitoring) to characterize river adjustments, i.e. the nature of the morpho-sedimentary dynamics, their rates, their temporal and spatial variations, and their control mechanisms. The results highlight the complex and nonlinear response of the Yonne river and the relevance of a regular prolonged monitoring. The changing patterns in space and over time, underline the vast range of uncertainties surrounding this type of restoration and the difficulty involved in predicting post-removal hydromorphology around the dam (return to pre-dam functioning, no changes, new equilibrium conditions). For instance, up to now, the study shows that intense morpho-sedimentary dynamics in the reservoir and effective restoration of bedload continuity do not necessarily lead to changes in the downstream conditions (bed mobility and morphological configuration) previously shaped under the influence of the dam, thus mitigating the success of the river restoration operation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The Lena, a large river that drains the northern coldest region of the Northern Hemisphere, is deeply influenced by the continuous permafrost and degradation of the frozen ground has been shown to be the main cause of the marked increase in water discharge. The first objective of this study conducted on the middle Lena was to analyze the island dynamics for the last 50 years (1967 to 2017). Several morphological parameters were surveyed using a GIS on seven series of aerial photographs and satellite images of a 100 km-long reach: island size, eroded and deposited areas, position and morphology of the islands. This approach enabled the identification of evolutionary models. Our second objective was to evaluate the potential impact of ongoing climate change. We analyzed morphological parameters with respect to two main factors: efficient discharge (bar-full, bankfull and flood discharges) and water temperature. A potential erosion index (PEI) was calculated by coupling the duration of discharge exceeding the bar-full level and water temperature. The results identified several morphological changes that occurred at the end of the 20th century: an increase in the number of islands, greater eroded surfaces and accelerated migration of islands. Comparing the dynamics of islands with and without permafrost is a good indicator of their sensitivity to climate change. A major change was observed concerning the erosion and migration of islands with and without permafrost. This evolution seems to be linked both with the duration of the discharge that exceeds the bar-full level and with the number of flood peaks. The water temperature in May and August have a major influence on permafrost islands that become increasingly destabilized. Thus, as large rivers are assumed to slowly react to climate change, the recent changes in the Lena River prove that the global change deeply impacts periglacial rivers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: While low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a well-established cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. It remains indeterminate as to whether such transfer is linked to HDL-C and cardiovascular disease., Methods and Results: When TGRL was labelled with fluorescent phospholipid 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), time- and dose-dependent transfer of DiI to HDL was observed upon incubations with lipoprotein lipase (LPL). The capacity of HDL to acquire DiI was decreased by -36% (p<0.001) in low HDL-C patients with acute myocardial infarction (n = 22) and by -95% (p<0.001) in low HDL-C subjects with Tangier disease (n = 7), unchanged in low HDL-C patients with Type 2 diabetes (n = 17) and in subjects with high HDL-C (n = 20), and elevated in subjects with extremely high HDL-C (+11%, p<0.05) relative to healthy normolipidemic controls. Across all the populations combined, HDL capacity to acquire DiI was directly correlated with HDL-C (r = 0.58, p<0.001). No relationship of HDL capacity to acquire DiI with both overall and cardiovascular mortality obtained from epidemiological studies for the mean HDL-C levels observed in the studied populations was obtained., Conclusions: These data indicate that the capacity of HDL to acquire phospholipid from TGRL upon LPL-mediated lipolysis is proportional to HDL-C and does not reflect cardiovascular risk in subjects widely differing in HDL-C levels., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision., (Copyright © 2020. Published by Elsevier Masson SAS.)

Access to active search for actionable secondary findings (SF) in diagnostic practice is a major psychological and ethical issue for genomic medicine. In this study, we analyzed the preferences of patients and their families regarding SF and identified the reporting procedures necessary for informed consent. We interviewed parents of patients with undiagnosed rare diseases potentially eligible for exome sequencing and patients affected by the diseases listed in the ACMG recommendations. Four focus groups (FG) were formed: parents of patients with undiagnosed rare diseases (FG1, n = 5); patients with hereditary cancers (FG2, n = 10); patients with hereditary cardiac conditions (FG3, n = 3); and patients with metabolic diseases (FG4, n = 3). Psychologists presented three broad topics for discussion: 1. Favorable or not to SF access, 2. Reporting procedures, 3. Equity of access. Discussions were recorded and analyzed using simplified Grounded Theory. Overall, 8 participants declared being favorable to SF because of the medical benefit (mainly FG1); 11 were unfavorable because of the psychological consequences (mainly FG2, FG3, FG4); 2 were ambivalent. The possibility of looking for SF in minors was debated. The 4 key information-based issues for participants ranked as follows: explanation of SF issues, autonomy of choice, importance of a reflection period, and quality of interactions between patients and professionals. Examining equity of access to SF led to philosophical discussions on quality of life. In conclusion, individual experience and life context (circumstances) were decisive in participants' expectations and fears regarding access to SF. Additional longitudinal studies based on actual SF disclosure announcements are needed to establish future guidelines., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

With the development of next generation sequencing, beyond identifying the cause of manifestations that justified prescription of the test, other information with potential interest for patients and their families, defined as secondary findings (SF), can be provided once patients have given informed consent, in particular when therapeutic and preventive options are available. The disclosure of such findings has caused much debate. The aim of this work was to summarize all opinion-based studies focusing on SF, so as to shed light on the concerns that this question generate. A review of the literature was performed, focusing on all PubMed articles reporting qualitative, quantitative or mixed studies that interviewed healthcare providers, participants, or society regarding this subject. The methodology was carefully analysed, in particular whether or not studies made the distinction between actionable and non-actionable SF, in a clinical or research context. From 2010 to 2016, 39 articles were compiled. A total of 14,868 people were interviewed (1259 participants, 6104 healthcare providers, 7505 representatives of society). When actionable and non-actionable SF were distinguished (20 articles), 92% of respondents were keen to have results regarding actionable SF (participants: 88%, healthcare providers: 86%, society: 97%), against 70% (participants: 83%, healthcare providers: 62%, society: 73%) for non-actionable SF. These percentages were slightly lower in the specific situation of children probands. For respondents, the notion of the «patient's choice» is crucial. For healthcare providers, the importance of defining policies for SF among diagnostic lab, learning societies and/or countries is outlined, in particular regarding the content and extension of the list of actionable genes to propose, the modalities of information, and the access to information about adult-onset diseases in minors. However, the existing literature should be taken with caution, since most articles lack a clear definition of SF and actionability, and referred to hypothetical scenarios with limited information to respondents. Studies conducted by multidisciplinary teams involving patients with access to results are sadly lacking, in particular in the medium term after the results have been given. Such studies would feed the debate and make it possible to measure the impact of such findings and their benefit-risk ratio., (Copyright © 2018. Published by Elsevier Masson SAS.)

Purpose: PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth., Methods: Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy., Results: Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of -7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently., Conclusion: This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk-benefit evaluations for sirolimus treatment in PROS.

Background: The capillary zone electrophoresis method of albumin measurement is frequently used in monoclonal gammopathy patients but some studies suggest poor performances of the method in this population. The aim of this study was to analyse the impact of serum monoclonal immunoglobulins on human serum albumin determination by capillary zone electrophoresis method compared to other available methods., Method: We prospectively measured albumin in 100 freshly collected non-frozen serum samples in a monoclonal gammopathy patients population, by using four different methods: the capillary zone electrophoresis method, the bromocresol purple dye method, the nephelometric method and the turbidimetric method. Differences in albumin values between the different methods were analysed with respect to serum monoclonal immunoglobulin concentration. These differences were further investigated by measuring albumin levels in human serum samples spiked with exogenous monoclonal immunoglobulins., Results: Human serum albumin difference values between capillary zone electrophoresis compared to immunonephelometry method are significantly correlated with increasing monoclonal immunoglobulins concentrations: regression analyses revealed a correlation coefficient r 2  = 0.60 and a slope of 0.14 (0.12-0.17, 95% confidence interval). The capillary zone electrophoresis method overestimated serum albumin levels by up to 67% (12 g/L) when monoclonal immunoglobulin level was 63 g/L. The determination of albumin levels in human serum samples spiked with exogenous monoclonal immunoglobulins showed an overestimation of human serum albumin measurement by the capillary zone electrophoresis method proportional to the amount of monoclonal immunoglobulin added in the serum with a slope of 0.19 (0.18-0.20, 95% confidence interval)., Conclusion: Monoclonal immunoglobulins directly interfere with serum albumin measurement by the capillary zone electrophoresis method leading to a systematic overestimation of serum albumin concentrations proportional to the serum monoclonal immunoglobulin level., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The capillary zone electrophoresis method of albumin measurement is frequently used for oncologic and haematologic patients but few data exist about the agreement between the albumin measurements performed by capillary zone electrophoresis and other methods. The aim of this study was to analyse the agreement between human serum albumin measurements by capillary zone electrophoresis and by the nephelometry, bromocresol purple and turbidimetry methods., Method: We prospectively measured 100 freshly collected non-frozen patient serum samples, by using four different methods: the capillary zone electrophoresis method performed with a CAPILLARYS 2 instrument, the bromocresol purple dye method performed with an Advia XPT analyser, the nephelometric method performed with a BN ProSpec analyser and the turbidimetric method with reagents from DiAgam and performed with the Advia XPT analyser., Results: A bias towards higher values in the lower range of albumin concentrations was observed with capillary zone electrophoresis compared to immunonephelometry: correlation coefficient r 2  = 0.925; slope of 0.86 (0.82-0.89, 95% confidence interval), which is significantly different from 1; and an intercept of 4.94 g/L (3.67-6.16, 95% confidence interval). Similar results were observed when comparing capillary zone electrophoresis to the bromocresol purple and immunoturbidimetry methods. The capillary electrophoresis method overestimated low albumin levels by up to 25% (5 g/L)., Conclusion: Compared to the nephelometry, turbidimetry and bromocresol purple methods, the capillary zone electrophoresis method tends to overestimate human serum albumin concentrations for levels below 30 g/L. This discrepancy could lead to an overestimation of the nutritional status, an inappropriate scoring of the disease and a delay in nutritional treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: The arrival of high-throughput sequencing (HTS) has led to a sweeping change in the diagnosis of developmental abnormalities (DA) with or without intellectual deficiency (ID). With the prospect of deploying these new technologies, two questions have been raised: the representations of HTS among geneticists and the costs incurred due to these analyses., Methods: Geneticists attending a clinical genetics seminar were invited to complete a questionnaire. The statistical analysis was essentially descriptive and an analysis of costs was undertaken., Results: Of those responding to the questionnaire, 48% had already prescribed exome analysis and 25% had already had the occasion to disclose the results of such analyses. Ninety-six percent were aware that whole-exome sequencing (WES) had certain limits and 74% expressed misgivings concerning its use in medical practice. In parallel, the evaluation of costs showed that WES was less expensive than conventional procedures., Discussion: The survey revealed that geneticists had already come to terms with HTS as early as 2015. Among the major concerns expressed were the complexity of interpreting these tests and the many ethical implications. Geneticists seemed to be aware of the advantages but also the limits of these new technologies. The cost analysis raises questions about the place of HTS and in particular WES in the diagnostic work-up: should it be used early to obtain an etiological diagnosis rather than as the last resort?, Conclusion: It is essential for future generations of doctors and for the families concerned to learn about the concepts of HTS, which is set to become a major feature of new genomic medicine., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background and Aims: Statins are prescribed for their preventative effects within atherosclerosis development. To our knowledge, no study focusing on very low-dose (non-hypolipidemic effect) and long-term atorvastatin treatment in vivo was available. Our aim was to assess the effect of such atorvastatin treatment on the mechanical and functional characteristics of arteries in the context of primary prevention., Methods: An atorvastatin treatment (2.5 mg/kg/day) was tested against controls on 34 male 3 to 12 month-old WHHL rabbits. No effect on total cholesterol, triglycerides, HDL or LDL was observed. The arterial stiffness was evaluated on vigil animals by pulse wave velocity (PWV) measurement. Then, in vitro measurements were made to evaluate (1) the endothelial and vascular smooth muscle function, (2) the elasticity of the arterial wall and (3) the composition in collagen and elastin in the aorta., Results: The PWV increasing observed with age in control group was canceled by treatment, creating a significance difference between groups at 12 months (5.17 ± 0.50 vs 2.14 ± 0.34 m s(-1) in control and treated groups respectively). Vasoreactivity modifications can't explain this result but maintain of elasticity with treatment in large arteries was confirm by a static tensile test. A first possible explanation is the change of wall composition with treatment, validated by the percentage of elastin at 12 months, 4.4% lower in the control group compared to the treated group (p < 0.05)., Conclusions: This study shows that a non-hypocholesterolemic statin treatment could improve vessel elasticity in the atherosclerotic WHHL model. The great novelty of this work is the vessel wall composition changing associated. This first approach in animal opens the reflection on the use of these low doses in humans. This could be interesting in the context of arterial stiffening with aging, non-hyperlipidemic atherosclerosis or with cholesterol reduce by another therapy or lifestyle modification., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To evaluate de performances of noninvasive prenatal testing using cell free circulating fetal DNA (cffDNA) for the detection of fetal trisomy 21, 18 and 13 in a French population., Materials and Methods: cffDNA analysis was performed by massive parallel sequencing during a multicenter, non interventional, prospective study and the results were compared with a standard fetal karyotype., Results: Results were available for 886 patients who have been classified as high- or moderate-risk depending on the presence of fetal abnormalities on ultrasound examination. For the high-risk group (n=376), the sensitivity and specificity of the test were 100% and 99.9% for trisomy 21, 88% and 99.9% for trisomy 18 and 100% and 99.9% for trisomy 13. The rate of other pathogenic chromosomal abnormalities with a negative NIPT was 7.9%. In the low-risk group (n=510), the sensitivity was 100% and the specificity 99.8% for trisomy 21, and only 0.4% of pathogenic chromosomal abnormalities were revealed by fetal karyotyping but not detected by cffDNA analysis., Conclusion: Noninvasive prenatal testing using cffDNA for high risk patients without fetal anomalies at ultrasound could be recommended in France after counseling on the possible risk of undiagnosed anomalies., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objective: Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a post-transcriptional inhibitor of LDL-receptor. In non-diabetic men, plasma PCSK9 levels were found to be inversely correlated with low-density lipoprotein (LDL) apolipoprotein B100 (apoB) fractional catabolic rate (FCR). Here, we aimed to determine the effect of type 2 diabetes on the association between plasma PCSK9 and FCR of LDL., Methods: A kinetic study of LDL-apoB100, using stable isotopes, was performed in 38 individuals (20 men, 18 women) including 23 non-diabetic normolipidemic subjects and 15 patients with type 2 diabetes., Results: In the non-diabetic group, plasma PCSK9 was positively correlated with LDL-C (r=0.64, p=0.001), apoB (r=0.67, p<0.001), and inversely correlated with LDL-apoB FCR (r=-0.61, p=0.002). In contrast, in type 2 diabetic patients, plasma PCSK9 was not associated with LDL-C, apoB and LDL-apoB FCR. However, the lack of association between PCSK9 and LDL-apoB FCR seemed to be limited to the patients with "uncontrolled" diabetes (HbA1c>7%) since a borderline significant negative correlation between PCSK9 and LDL FCR (r=-0.70, p=0.08) was retrieved in patients with HbA1c≤7%. In multivariate analysis, LDL-apoB FCR was independently associated with PCSK9 (p=0.001) and fasting glycaemia (log) (p=0.030) in the non-diabetic population and with PCSK9 (p=0.040) and HbA1c (p=0.029) in diabetic patients., Conclusion: Our data indicate that both PCSK9 and glycaemia are independent factors influencing LDL catabolism. Plasma PCSK9 influences significantly the catabolism of LDL-apoB100 in individuals without diabetes, but not in patients with uncontrolled type 2 diabetes. Thus, the influence of diabetes on LDL-apoB FCR catabolism may overwhelm the influence of PCSK9., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Since their introduction, genetic tests have been carefully considered, with special attention to the release of information about the test and test results, the confidentiality of genetic information, the request and its motivation, and the psychological impact of the test. Careful consideration is needed when family members at risk are asymptomatic children or adolescents. Cautious reflection is warranted on whether and under which conditions genetic testing should be performed. Here, we report on the results of a survey conducted in France among 50 geneticists questioned on their opinions and practices concerning presymptomatic testing in three groups of diseases: those for which a medical benefit exists during childhood (e.g., retinoblastoma), diseases with onset during childhood for which there are no immediate medical consequences (e.g., type II/III spinal muscular atrophy), and those with onset during adulthood for which there is no medical benefit during childhood (e.g., Huntington disease). Guidelines are proposed: presymptomatic testing should not be performed in a minor without individual and direct information, all requests for presymptomatic genetic testing concerning a disease with onset in adulthood should be postponed, and all presymptomatic test requests for a minor should be addressed to a multidisciplinary team., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

Human CYP450 omega-hydroxylases of the CYP4 family are known to convert arachidonic acid (AA) to its metabolite 20-hydroxyeicosatetraenoic acid (20-HETE). This study deals with hydroxylations of four PUFAs, eicosatrienoic acid (ETA), AA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) by either human recombinant CYP4s enzymes or human liver microsomal preparations. CYP4F3A and CYP4F3B were the most efficient omega-hydroxylases of these PUFAs. Moreover, the differences in the number of unsaturations of ETA, AA, and EPA allowed us to demonstrate a rise in the metabolic rate of hydroxylation when the double bond in 14-15 or 17-18 was missing. With the CYP4F enzymes, the main pathway was always the omega-hydroxylation of PUFAs, whereas it was the (omega-1)-hydroxylation with CYP1A1, CYP2C19, and CYP2E1. Finally, we demonstrated that the omega9 and omega3 PUFAs (ETA, EPA, and DHA) could all be used as alternative substrates in AA metabolism by human CYP4F2 and -4F3B. Thus, they decreased the ability of these enzymes to convert AA to 20-HETE. However, although ETA was the most hydroxylated substrate, EPA and DHA were the most potent inhibitors of the conversion of AA to 20-HETE. These findings suggest that some physiological effects of omega3 FAs could partly result from a shift in the generation of active hydroxylated metabolites of AA through a CYP-mediated catalysis.

The regulation of the human liver-specific cytochrome P450 4F3B (CYP4F3B) isoform, a splice variant of the CYP4F3 gene with strong substrate specificity for long chain fatty acids, is yet an unsolved question. This report provides the first evidence that CYP4F3B is uniquely induced by prostaglandin A1 (PGA1) in human hepatocyte-like HepaRG cells and leads to the synthesis of 20-hydroxy-eicosatetraenoic acids (HETEs). Real time PCR, immunoblot analysis with a specific antipeptide antibody, and determination of fatty acid omega-hydroxylase activity demonstrate that PGA1 treatment strongly increases expression of CYP4F3B. This induction drives the production of 20-HETE (19-fold increase). SiRNA-mediated-silencing of CYP4F3 suppresses both 20-HETE synthesis and PGA1 induced 20-HETE production. Taken together, these results provide evidence that CYP4F3B is the key enzyme to produce 20-HETE by omega-hydroxylation of arachidonic acid in liver cells. Since 20-HETE is a potent activator of PPARalpha and an important inflammatory mediator, CYP4F3B may exert important functions in lipid homeostasis and in inflammatory diseases.

Objective: The purpose of this study was to determine the accuracy of the none-invasive prenatal determination of polymerase chain reaction (PCR)-based fetal RhD genotyping., Study Design: A prospective case series was undertaken on all RhD-negative pregnant women presenting for genetic counseling in our prenatal diagnosis center from January 2001 until December 2002. Results were compared with serologic RhD typing of the newborns., Results: Among the 285 pregnant women who participated in the study, fetal RhD status could be determined for 283 patients. In 2 cases, the RhD-negative phenotype of the mother was not the result of a complete RHD gene deletion, and therefore, the status of the fetus could not be determined. Neither false-negative nor false-positive results were observed., Conclusion: The present report demonstrates that a reliable fetal RHD genotype determination can be achieved with 100% accuracy. It is therefore possible to consider that such an assay could be systematically proposed to all RhD-negative pregnant women in order to more effectively utilize RhD prophylaxis.

CYP4F isoforms are involved in the oxidation of important cellular mediators such as leukotriene B4 (LTB4) and prostaglandins. The proinflammatory agent LTB4 and cytotoxic leukotoxins have been associated with several inflammatory diseases. We present evidence that the hydroxylation of Z 9(10)-epoxyoctadecanoic, Z 9(10)-epoxyoctadec-Z 12-enoic, and Z 12(13)-epoxyoctadec-Z 9-enoic acids and that of monoepoxides from arachidonic acid [epoxyeicosatrienoic acid (EET)] is important in the regulation of leukotoxin and EET activity. These three epoxidized derivatives from the C18 family (C18-epoxides) were converted to 18-hydroxy-C18-epoxides by human hepatic microsomes with apparent Km values of between 27.6 and 175 microM. Among recombinant P450 enzymes, CYP4F2 and CYP4F3B catalyzed mainly the omega-hydroxylation of C18-epoxides with an apparent Vmax of between 0.84 and 15.0 min(-1), whereas the apparent Vmax displayed by CYP4F3A, the isoform found in leukocytes, ranged from 3.0 to 21.2 min(-1). The rate of omega-hydroxylation by CYP4A11 was experimentally found to be between 0.3 and 2.7 min(-1). CYP4F2 and CYP4F3 exhibited preferences for omega-hydroxylation of Z 8(9)-EET, whereas human liver microsomes preferred Z 11(12)-EET and, to a lesser extent, Z 8(9)-EET. Moreover, vicinal diol from both C18-epoxides and EETs were omega-hydroxylated by liver microsomes and by CYP4F2 and CYP4F3. These data support the hypothesis that the human CYP4F subfamily is involved in the omega-hydroxylation of fatty acid epoxides. These findings demonstrate that another pathway besides conversion to vicinal diol or chain shortening by beta-oxidation exists for fatty acid epoxide inactivation., (Copyright 2004 American Society for Biochemistry and Molecular Biology, Inc.)

Circulating fetal DNA in maternal plasma and serum was first demonstrated by Lo et al. in 1997 and has become a useful tool for prenatal diagnosis less than five years later. There is more and more evidence that the trophoblastic cells act as the major source of this circulating fetal DNA. Contrary to fetal cells analysis in maternal blood which requires isolation and enrichment procedures, fetal DNA analysis is relatively easy to perform with the use of real-time PCR. Non-invasive fetal sex and fetal RHD genotype determination are, to date, the two main clinical indications. Those newly offered possibilities have changed the management of pregnant women who are carriers for X-linked genetic disorders; prenatal diagnosis by choriovillous sampling could only be performed for male fetuses avoiding an unnecessary risk of fetal loss for female fetuses. Moreover, fetal RHD genotyping by maternal blood analysis could be useful in RhD-negative women at risk of immunization in order to adapt prophylactic anti-D injection.

The Locking Compression Plate (LCP) is a new screw-plate system that offers the possibility of inserting conventional and locking head screws into the specially designed combination holes. It represents a further development of the PC-Fix and the LISS and was released for clinical application in March 2000. In a prospective multicentre study, the new system was used to treat 144 patients (f: 67, m: 77; average age: 51.4 years) with 169 fractures: of these, 57 were tibial fractures, 45 humerus, 19 radius and 18 femoral. After one year, clinical and radiological follow-up assessment was carried out on 127 patients with 151 fractures (88%). In 130 fractures (86%), healing took place within the expected period and without complication or secondary dislocation ("uneventful healing"). In 19 patients, a total of 27 unexpected complications occurred ("adverse events"), in which 18 revision operations were necessary in 13 patients: five for implant loosening/pull-out, four for plate failure, one for non-union, five for secondary fractures immediately adjacent to the implant after a subsequent injury and two for infection. Analysis by a committee of experts indicated that mechanical complications arose entirely from technical errors of application (incorrect fixation technique, incorrect choice of plate). No purely implant-related complications were observed. The new system can be regarded as technically mature. It offers numerous fixation possibilities and has proven its worth in complex fractures situations and in revision operations after the failure of other implants. A good knowledge of biomechanics is essential as well as precise preoperative planning.

The Locking Compression Plate (LCP), in combination with the LISS and the PHILOS, is part of a new plate generation requiring an adapted surgical technique and new thinking about commonly used concepts of internal fixation using plates. The following guidelines are needed to avoid failures and possible complications in the hands of surgeons not yet confident with the new implant philosophy. The importance of the reduction technique and minimal-invasive plate insertion and fixation is addressed to keep bone viability undisturbed. Understanding of mechanical background for choosing the proper implant length and the type and number of screws is essential to obtain a sound fixation with a high plate span ratio and a low plate screw density. A high plate span ration decreases the load onto the plate. A high working length of the plate in turn reduces the screw loading, thus fewer screws need to be inserted and the plate screw density can be kept low. Knowledge of the working length of the screw is helpful for the proper choice of monocortical or bicortical screws. Selection is done according to the quality of the bone structure and is important to avoid problems at the screw thread bone interface with potential pullout of screws and secondary displacement. Conclusive rules are given at the end of this chapter.

Objective: Fetal sex prediction can be achieved using PCR targeted at the SRY gene by analyzing cell-free fetal DNA in maternal serum. Unfortunately, the results reported to date, show lack of sensitivity, especially in the first trimester of pregnancy. Therefore, determination of fetal sex by maternal serum analysis can not replace caryotype analysis following chorionic villus sampling., Patients and Methods: A new highly sensitive real-time PCR was developed to detect a SRY gene sequence in maternal serum. Analysis was performed on 121 pregnant women during their first trimester of pregnancy (mean gestational age: 11.8 weeks). Among them, 61 had at least one previous male-bearing pregnancy. Results were compared to fetal sex., Results: SRY PCR analysis of maternal serum was in complete concordance with fetal sex. Among the 121 pregnant women, 61 were bearing a male fetus and 60 a female fetus No false negative results were observed. Furthermore, no false positive results results occurred although 27 women carried female fetus during the current pregnancy, had at least one previous male-bearing pregnancy., Discussion and Conclusion: This study demonstrates that a reliable, non-invasive sex determination can be achieved by PCR analysis of maternal serum during the first trimester of pregnancy. This non-invasive approach for fetal sex prediction should have great implications in the management of pregnant women carriers of an X-linked genetic disorder. Prenatal diagnosis is thus performed for male fetuses only, avoiding invasive procedures and the risk of fetal loss for female fetuses.

Alcohol and xenobiotics share the same oxidative microsomal pathway, which is mainly located in the endoplasmic reticulum of hepatocytes. This pathway involves enzymes that belong to the super family of cytochrome P450 and allows to explain a lot of pharmacokinetic or toxic interactions between alcohol and xenobiotics. Cytochrome P450 2E1 (CYP2E1) is the key enzyme of the microsomal pathway of ethanol oxidation. It is inducible by chronic ethanol consumption and its activity is increased by three to five fold in liver from alcoholics subjects. This induction involves to a lesser extent cytochromes P450 3A4 and 1A2 and contributes to the metabolic tolerance of alcohol and drugs observed in alcoholics. The metabolic tolerance persits several days after ethanol withdrawal. Furthermore, CYP2E1 has a high capacity to activate numerous xenobiotics into toxic or carcinogenic compounds. Drugs currently used such as paracetamol, anesthetics (enflurane, halothane), industrial solvents (benzene or its derivatives), halogenated solvents (CCl4, trichlorethylene) and nitrosamines which are present in food or tobacco smoke are included. Therefore, heavy consumption of alcohol, which results in CYP2E1 induction, increases individual susceptibility to the toxic or carcinogenic effects of these xenobiotics.

Mechanical unloading of the plated bone segment is observed after plate osteosynthesis because the implant takes over a part of the physiological loading. Strain reduction in the bony tissue depends on the rigidity of the plate (cross-sectional area, geometrical form, and modulus of elasticity). The aim of the present study was to calculate theoretically the effect of plate position relative to bending direction on the overall bending stiffness of the composite system plate-bone. To calculate the rigidity, a cylindrical bone model with mechanical characteristics similar to a sheep tibia and a rectangular plate cross-section corresponding to a DC-plate with either a modulus of elasticity of steel or titanium was used. Calculations under different bending directions were performed according to the laws of the linear bending theory and the composite beam theory. The bending stiffness of a plate osteosynthesis reaches a minimum and a maximum respectively, in cases in which the bending moment acts in the direction of the main axis of the area moment of inertia of the plate. The minimum is present with the plate bent vertically, the maximum with the plate bent horizontally, e.g. on the tension side of the composite system--on the assumption that the bone structure opposite the plate is capable of withstanding compressive loading. For steel and titanium plates, factors of 2 and 2.25 respectively were calculated between the minimum and the maximum bending stiffnesses of the osteosynthesis. The bending rigidity of the plate alone has only a minimal effect on the total stiffness of the osteosynthesis. With a plate bent vertically, the difference between steel and titanium plates was 18%, with the plate bent horizontally (situated on the tension side), it was only 7%. The bending stiffness of a plate osteosynthesis depends on the cross-section, the geometrical form, and the modulus of elasticity of the plate, as well as on the plate position relative to the bending direction of the composite system. The modulus of elasticity of the plate is relatively unimportant, while with a given plate the individual plate position relative to the bending direction is of crucial importance. Thus, changing the modulus of elasticity of the plate cannot solve the problem of implant induced unloading of the bone cortex because the bending stiffness of the composite system depends much more on the plate position relative to the bending direction.

After plate osteosynthesis changes in bone biology and bone mechanics are observed in the plated bone segment. Compromise of the vascular supply in the plate bed leads to a remodelling process and to a temporary porosity in the bone cortex underneath the plate. In addition, the plate takes over some of the physiological loading of the bone, which in turn alters the normal strain distribution of the cortical bone tissue. The aim of the present study is to determine the tissue deformation of the sheep tibia in vivo and the changes in tissue strain due to plating with plates of different rigidities. Measurements were performed on the intact bone at the mid diaphysis using the strain gauge technique. With different connections on the tension bridge (Wheatstone bridge), the strain was measured separately for pure axial loading, bending, and torsion before and after plating with a 4.5 mm stainless steel or titanium DCP. Under physiological load the sheep tibia is mainly deformed in torsion (62%) and bending (33%), and much less in axial loading (5%). Plating with a steel plate reduces the overall tissue strain by 18%, with a titanium plate by 13%. This reduction is mainly due to a reduction in axial tissue strain due to axial loading and bending and less to the reduction of tissue strain under torsion. In our in vivo model, plating with steel or titanium plates leads to a reduction of the physiological tissue strains. The difference between the different plates is small due to the fact that the high tissue strain under torsion is only slightly affected by plating. Thus, from the purely mechanical point of view and with regard to preserving normal tissue strains as much as possible, titanium plates offer little advantage compared with stainless steel plates. But, titanium as an implant material may offer advantages with respect to tissue compatibility and infection resistance.

The development of an analytical methodology for the specific determination of arsenite, arsenate and the organic species monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), is described. The method is based on an ion chromatographic separation, coupled on-line to post-column generation of the gaseous hydrides by reaction with sodium tetrahydroborate in acidic medium. Detection and measurement were performed by inductively coupled plasma spectrometry operated in the atomic emission mode. Arsenic emission was monitored at 193.7 nm. Different types and sizes of anion-exchange columns, silica and polymeric, were tested using EDTA as eluent. Composition, acidity and flow-rate of the mobile phase were optimized in order to obtain the required resolution. Complete elution and resolution of the four species was achieved in about 6 min. Linear calibration curves were obtained in the 0.05-2 microg ml(-1) range for As(III), As(V) and MMA, and between 0.1 and 2.0 microg ml(-1) for DMA. The absolute limits of detection for 200-microl sample injections were in the ng range, with DMA the compound measured with less sensitivity. Results of the analyses of natural samples, such as river and ground waters spiked with the studied species, suggested that analyte recoveries might be dependent on the sample composition.

The use of Eriochrome Black T in an alkaline, 40% methanol solution was found to be appropriate as post-column reagent for the determination of rare earths by ion chromatography. Detection of individual lanthanides and lanthanum was carried out at 512 nm and 650 nm after separation by dynamic cation exchange chromatography with gradient elution on C18 column and employing a solution containing alpha-hydroxyisobutiric acid/sodium octanesulfonate at pH 3.8 as eluent. The effect of the presence of micelles in the post-column reagent was studied. Sensitivities obtained by the addition of the cationic surfactants cetylpyridinium chloride (CPC) and hexadecyltrimethylammonium bromide (CTAB) were lower than those measured without surfactant addition. In some cases, the signal was totally suppressed. No change in sensitivity was observed with non-ionic (Triton X-100) or anionic (sodium dodecylsulphate, SDS) surfactants but a slight improvement in the baseline noise was observed with the SDS. An evaluation of the influence of chemical and operational variables on the post column reaction (PCR) reagent was carried out either by spectrophotometric tests or by chromatographic experiments. A comparison was performed between three PCR reagents: Eriochrome Black T and xylenol orange in the presence of a cationic surfactant and arsenazo III. Calibration response was linear up to an analyte concentration of 5.0 micrograms ml-1. Absolute detection limits lower than 7 and 17 ng were obtained at the detection wavelengths of 650 nm and 512 nm respectively, for all the natural lanthanides and lanthanum.

Background: Although schizophrenic and control subjects differ on a variety of neuroanatomical measures, the specificity and sensitivity of any one measure for differentiating between groups are low. This study investigated the cumulative effect of deviant brain structure on diagnosis., Methods: Hemisphere and third ventricle volume and the normalized (Talairach) location of three association cortex sulcal landmarks were measured on high-resolution MRI scans in 37 male patients with schizophrenia and 33 male control subjects matched on age, handedness, and parental socioeconomic status., Results: While there were few group differences on individual anatomical measures, the 10 variables reliably discriminated between the two groups when used in concert in a discriminant function analysis (F[10.59] = 3.6, p < .0009) with 77% of the subjects correctly classified. Five of the measures (left posterior cingulate, left inferior frontal sulcus, right sylvian fissure, and left and right halves of the third ventricle) correlated significantly with the discriminant function (p < .005)., Conclusions: This is the first study to demonstrate that schizophrenics can be distinguished from matched controls on the basis of brain anatomy alone. The risk of schizophrenia may depend on the total amount of neural deviance, rather than on anomalies in a single structure or circuit.

The internal restructuring of bone as a reaction to physiological load described by Wolff's law is related to both stress and strain in the bone. Bone is a rather brittle material, with nearly equal properties in tension and in compression: Elastic modulus E = 20 Gpa, tensile strength sigma tens = 200 Mpa (cortical bone). In biomechanics, it is very easy to assess strain using strain gauges. The theoretical and technical aspects specific to the use of strain gauges on bones are presented in this paper including how the measurements are taken and how the data is analyzed.

How to choose and prepare the strain gauges for bonding on bones "in vitro" and "in vivo"? This communication aims to elucidate technical details and some applications: direct assessment of the axial load, the bending moment, and the torque applied to long bones by the physiological loads. As a typical example of application, we will show the assessment of stress protection due to plates on the bones in the sheep tibia.

The problem addressed in this part is the analysis of the strain pattern within the bone, when the strain has been measured using strain gauges along the long axis of the diaphysis of a bone subjected to axial load, bending, or eccentric axial load. It is first necessary to obtain the position of the strain gauges using, for instance, computed tomography. The linear bending theory is then used to determine graphically the position of the neutral axis in a cross section and the strain field within the bone. An example of application is taken from the literature: Rybicky et al. (1) measured the reduction of strain within a plated horse metatarsus, relative to that of the intact bone. They made an analytical strain analysis. A comparison is made between the analytical results and the graphic ones, validating the graphic method.

Pelvic malunions or nonunions are the result of inappropriate treatment of rotationally or linearly unstable injuries of the pelvic ring. Long-term sequelae such as chronic pain in the posterior pelvic ring, gait abnormalities, leg length discrepancy, sitting discomfort, neurological problems or impingement on the visceral organs may be secondary to the disturbed integrity of the pelvic ring. The late correction of the deformity is technically much more demanding than the treatment of acute pelvic ring injuries. Depending on the specific problem, osteotomies at the site of the deformity, excision of scar tissue and callus, release of ligaments, bone grafting, and an adapted technique of reduction and fixation may be required. Possible complications include nerve or vascular injuries, incomplete reduction of the deformity, failure to unite, incomplete pain relief, and infection. Prior to surgery, a careful clinical and radiological examination is mandatory to assess the relationship between the presenting anatomical deformity and the complaints of the patient. The final decision for surgery has to be made by the patient taking into account reasonable expectation and the potential complications associated with the corrective procedure.

Objective: Fetal hyperchogenic bowel is associated with a variety of conditions, the incidence of which has yet to be studied., Study Design: The outcomes of 182 cases of fetal hyperechogenic bowel were reviewed. Screening for maternal toxoplasmosis, fetal karyotyping, and amniotic fluid digestive enzyme assays were performed in all cases. Eight mutations associated with cystic fibrosis were analyzed in 116 cases., Results: Of 135 newborns, 121 were normal, but nine underwent surgery for gastrointestinal obstruction, three had cytomegalovirus or parvovirus infection, one had a triple X chromosome, and one died from sudden infant death syndrome. In utero fetal death was observed in 24 cases. Elective termination of pregnancy was performed in 23 cases for associated anomalies., Conclusions: Hyperechogenic fetal bowel was associated with increased risk for adverse outcome. Prenatal management should include ultrasonographic surveillance, fetal karyotyping, amniotic digestive enzyme assays, and screening for cystic fibrosis and infectious disease.

A modification of the standard setup of the small external fixator is presented for use mainly on the wrist. The setup used since 1988 offers further possibilities as compared with conventional application: Completely free positioning of the wrist joint for all possible six degrees of freedom, therefore: Better possibility to postpone manual reduction until the frame is applied ("modular" fixator frame, comparable to the tube-to-tube configuration of the standard external fixator), Easy correction of axial, flexural and rotational malalignment during surgery with the external fixator in situ and without changing the pin position, Easy relaxation of overdistraction postoperatively, Temporary postoperative mobilization of the wrist joint possible. Better preoperative distraction due to higher force and longer distance of the compression/distraction device. Rigid construction by using comparably short threaded K-wires and large diameter connecting bar. Less interference with peri- and postoperative imaging techniques.

Two micro enzyme immunoassays (microEIA) for circulating immune complexes (CICs) are described. The Raji cell microEIA was similar in sensitivity, reproducibility and specificity to the Raji radioimmunoassay. The F(ab')2 anti-C3 microEIA was comparable to the 2 Raji cell assays. The 2 microEIAs for CICs were used to analyze sera from patients with systemic lupus erythematosus (SLE), the acquired immune deficiency syndrome (AIDS) and from hemophiliacs with AIDS-like symptoms. The microEIAs were very sensitive in detecting CICs in pathologic sera. In contrast, only 3% of normals (n = 30) were positive in the Raji microEIA while none were positive in the F(ab')2 anti-C3 microEIA. The initial high positivity of some normals (9/30) in the F(ab')2 microEIA was due to bovine serum albumin (BSA)-anti-BSA immune complex formation in vitro and was corrected when human albumin was used in buffer preparation instead of BSA. The reagents required for the microEIAs are more stable and less expensive than those required for the RIAs and the need for facilities to deal with 125-labeling and disposal is avoided.