Quantifying network properties in multi-electrode recordings: spatiotemporal characterization and inter-trial variation of evoked gamma oscillations in mouse somatosensory cortex in vitro.

Linking the structural connectivity of brain circuits to their cooperative dynamics and emergent functions is a central aim of neuroscience research. Graph theory has recently been applied to study the structure-function relationship of networks, where dynamical similarity of different nodes has been turned into a "static" functional connection. However, the capability of the brain to adapt, learn and process external stimuli requires a constant dynamical functional rewiring between circuitries and cell assemblies. Hence, we must capture the changes of network functional connectivity over time. Multi-electrode array data present a unique challenge within this framework. We study the dynamics of gamma oscillations in acute slices of the somatosensory cortex from juvenile mice recorded by planar multi-electrode arrays. Bursts of gamma oscillatory activity lasting a few hundred milliseconds could be initiated only by brief trains of electrical stimulations applied at the deepest cortical layers and simultaneously delivered at multiple locations. Local field potentials were used to study the spatio-temporal properties and the instantaneous synchronization profile of the gamma oscillatory activity, combined with current source density (CSD) analysis. Pair-wise differences in the oscillation phase were used to determine the presence of instantaneous synchronization between the different sites of the circuitry during the oscillatory period. Despite variation in the duration of the oscillatory response over successive trials, they showed a constant average power, suggesting that the rate of expenditure of energy during the gamma bursts is consistent across repeated stimulations. Within each gamma burst, the functional connectivity map reflected the columnar organization of the neocortex. Over successive trials, an apparently random rearrangement of the functional connectivity was observed, with a more stable columnar than horizontal organization. This work reveals new features of evoked gamma oscillations in developing cortex.

Hierarchic species-area relationships and the management of forest habitat islands in intensive farmland

Habitat loss and fragmentation due to land use changes are major threats to biodiversity in forest ecosystems, and they are expected to have important impacts on many taxa and at various spatial scales. Species richness and area relationships (SARs) have been used to assess species diversity patterns and drivers, and thereby in the establishment of conservation and management strategies. Here we propose a hierarchical approach to achieve deeper insights on SARs in small forest islets in intensive farmland and to address the impacts of decreasing naturalness on such relationships. In the intensive dairy landscapes of Northwest Portugal, where small forest stands (dominated by pines, eucalypts or both) represent semi-natural habitat islands, 50 small forest stands were selected and surveyed for vascular plant diversity. A hierarchical analytical framework was devised to determine species richness and inter- and intra-patch SARs for the whole set of forest patches (general patterns) and for each type of forest (specific patterns). Differences in SARs for distinct groups were also tested by considering subsets of species (native, alien, woody, and herbaceous). Overall, values for species richness were confirmed to be different between forest patches exhibiting different levels of naturalness. Whereas higher values of plant diversity were found in pine stands, higher values for alien species were observed in eucalypt stands. Total area of forest (inter-patch SAR) was found not to have a significant impact on species richness for any of the targeted groups of species. However, significant intra-patch SARs were obtained for all groups of species and forest types. A hierarchical approach was successfully applied to scrutinise SARs along a gradient of forest naturalness in intensively managed landscapes. Dominant canopy tree and management intensity were found to reflect differently on distinct species groups as well as to compensate for increasing stand area, buffering SARs among patches, but not within patches. Thus, the maintenance of small semi-natural patches dominated by pines, under extensive practices of forest management, will promote native plant diversity while at the same time contributing to limit the expansion of problematic alien invasive species.

Assessment of myocardial edema and area-at-risk in acute myocardial infarction by CMR: Evaluation of a novel T2-mapping method

Objectives. The goal of this study is to evaluate a T2-mapping sequence by: (i) measuring the reproducibility intra- and inter-observer variability in healthy volunteers in two separate scanning session with a T2 reference phantom; (2) measuring the mean T2 relaxation times by T2-mapping in infarcted myocardium in patients with subacute MI and compare it with patient's the gold standard X-ray coronary angiography and healthy volunteers results. Background. Myocardial edema is a consequence of an inflammation of the tissue, as seen in myocardial infarct (MI). It can be visualized by cardiovascular magnetic resonance (CMR) imaging using the T2 relaxation time. T2-mapping is a quantitative methodology that has the potential to address the limitation of the conventional T2-weighted (T2W) imaging. Methods. The T2-mapping protocol used for all MRI scans consisted in a radial gradient echo acquisition with a lung-liver navigator for free-breathing acquisition and affine image registration. Mid-basal short axis slices were acquired.T2-maps analyses: 2 observers semi- automatically segmented the left ventricle in 6 segments accordingly to the AHA standards. 8 healthy volunteers (age: 27 ± 4 years; 62.5% male) were scanned in 2 separate sessions. 17 patients (age : 61.9 ± 13.9 years; 82.4% male) with subacute STEMI (70.6%) and NSTEMI underwent a T2-mapping scanning session. Results. In healthy volunteers, the mean inter- and intra-observer variability over the entire short axis slice (segment 1 to 6) was 0.1 ms (95% confidence interval (CI): -0.4 to 0.5, p = 0.62) and 0.2 ms (95% CI: -2.8 to 3.2, p = 0.94, respectively. T2 relaxation time measurements with and without the correction of the phantom yielded an average difference of 3.0 ± 1.1 % and 3.1 ± 2.1 % (p = 0.828), respectively. In patients, the inter-observer variability in the entire short axis slice (S1-S6), was 0.3 ms (95% CI: -1.8 to 2.4, p = 0.85). Edema location as determined through the T2-mapping and the coronary artery occlusion as determined on X-ray coronary angiography correlated in 78.6%, but only in 60% in apical infarcts. All except one of the maximal T2 values in infarct patients were greater than the upper limit of the 95% confidence interval for normal myocardium. Conclusions. The T2-mapping methodology is accurate in detecting infarcted, i.e. edematous tissue in patients with subacute infarcts. This study further demonstrated that this T2-mapping technique is reproducible and robust enough to be used on a segmental basis for edema detection without the need of a phantom to yield a T2 correction factor. This new quantitative T2-mapping technique is promising and is likely to allow for serial follow-up studies in patients to improve our knowledge on infarct pathophysiology, on infarct healing, and for the assessment of novel treatment strategies for acute infarctions.

Cell disposition of raltegravir and newer antiretrovirals in HIV-infected patients: high inter-individual variability in raltegravir cellular penetration.

Objectives The site of pharmacological activity of raltegravir is intracellular. Our aim was to determine the extent of raltegravir cellular penetration and whether raltegravir total plasma concentration (C(tot)) predicts cellular concentration (C(cell)). Methods Open-label, prospective, pharmacokinetic study on HIV-infected patients on a stable raltegravir-containing regimen. Plasma and peripheral blood mononuclear cells were simultaneously collected during a 12 h dosing interval after drug intake. C(tot) and C(cell) of raltegravir, darunavir, etravirine, maraviroc and ritonavir were measured by liquid chromatography coupled to tandem mass spectrometry after protein precipitation. Longitudinal mixed effects analysis was applied to the C(cell)/C(tot) ratio. Results Ten HIV-infected patients were included. The geometric mean (GM) raltegravir total plasma maximum concentration (C(max)), minimum concentration (C(min)) and area under the time-concentration curve from 0-12 h (AUC(0-12)) were 1068 ng/mL, 51.1 ng/mL and 4171 ng·h/mL, respectively. GM raltegravir cellular C(max), C(min) and AUC(0-12) were 27.5 ng/mL, 2.9 ng/mL and 165 ng·h/mL, respectively. Raltegravir C(cell) corresponded to 5.3% of C(tot) measured simultaneously. Both concentrations fluctuate in parallel, with C(cell)/C(tot) ratios remaining fairly constant for each patient without a significant time-related trend over the dosing interval. The AUC(cell)/AUC(tot) GM ratios for raltegravir, darunavir and etravirine were 0.039, 0.14 and 1.55, respectively. Conclusions Raltegravir C(cell) correlated with C(tot) (r = 0.86). Raltegravir penetration into cells is low overall (∼5% of plasma levels), with distinct raltegravir cellular penetration varying by as much as 15-fold between patients. The importance of this finding in the context of development of resistance to integrase inhibitors needs to be further investigated.

Interobserver and intraobserver variability of the apparent diffusion coefficient in treated malignant hepatic lesions on a 3.0T machine: measurements in the whole lesion versus in the area with the most restricted diffusion.

PURPOSE: To assess the inter/intraobserver variability of apparent diffusion coefficient (ADC) measurements in treated hepatic lesions and to compare ADC measurements in the whole lesion and in the area with the most restricted diffusion (MRDA). MATERIALS AND METHODS: Twenty-five patients with treated malignant liver lesions were examined on a 3.0T machine. After agreeing on the best ADC image, two readers independently measured the ADC values in the whole lesion and in the MRDA. These measurements were repeated 1 month later. The Bland-Altman method, Spearman correlation coefficients, and the Wilcoxon signed-rank test were used to evaluate the measurements. RESULTS: Interobserver variability for ADC measurements in the whole lesion and in the MRDA was 0.17 x 10(-3) mm(2)/s [-0.17, +0.17] and 0.43 x 10(-3) mm(2)/s [-0.45, +0.41], respectively. Intraobserver limits of agreement could be as low as [-0.10, +0.12] 10(-3) mm(2)/s and [-0.20, +0.33] 10(-3) mm(2)/s for measurements in the whole lesion and in the MRDA, respectively. CONCLUSION: A limited variability in ADC measurements does exist, and it should be considered when interpreting ADC values of hepatic malignancies. This is especially true for the measurements of the minimal ADC.

Interobserver and intraobserver variability of apparent diffusion coefficient measurements in treated malignant hepatic lesions: measurements in the whole lesion versus in the area with the most restricted diffusion

Purpose: The increase of apparent diffusion coefficient (ADC) in treated hepatic malignancies compared to pre-therapeutic values has been interpreted as treatment success; however, the variability of ADC measurements remains unknown. Furthermore, ADC has been usually measured in the whole lesion, while measurements should be probably centered on the area with the most restricted diffusion (MRDA) as it represents potential tumoral residue. Our objective was to compare the inter/intraobserver variability of ADC measurements in the whole lesion and in MRDA. Material and methods: Forty patients previously treated with chemoembolization or radiofrequency were evaluated (20 on 1.5T and 20 on 3.0T). After consensual agreement on the best ADC image, two readers measured the ADC values using separate regions of interest that included the whole lesion and the whole MRDA without exceeding their borders. The same measurements were repeated two weeks later. Spearman test and the Bland-Altman method were used. Results: Interobserver correlation in ADC measurements in the whole lesion and MRDA was as follows: 0.962 and 0.884. Intraobserver correlation was, respectively, 0.992 and 0.979. Interobserver limits of variability (mm2/sec*10-3) were between -0.25/+0.28 in the whole lesion and between -0.51/+0.46 in MRDA. Intraobserver limits of variability were, respectively: -0.25/+0.24 and -0.43/+0.47. Conclusion: We observed a good inter/intraobserver correlation in ADC measurements. Nevertheless, a limited variability does exist, and it should be considered when interpreting ADC values of hepatic malignancies.

Manual reaction times and brain dynamics after 'awake surgery' of slow-growing tumors invading the parietal area. A case report

Primary objectives: Awake surgeries of slow-growing tumours invading the brain and guided by direct electrical stimulation induce major brain reorganizations accompanied with slight impairments post-operatively. In most cases, these deficits are so slight after a few days that they are often not detectable on classical neuropsychological evaluations. Consequently, this study investigated whether simple visuo-manual reaction time paradigms would sign some level of functional asymmetries between both hemispheres. Importantly, the visual stimulus was located in the saggital plane in order to limit attentional biases and to focus mainly on the inter-hemispheric asymmetry. Methods and procedures: Three patients (aged 41, 59 and 59 years) after resections in parietal regions and a control group (age¼44, SD¼6.9) were compared during simple uni- and bimanual reaction times (RTs). Main outcomes and results: Longer RTs were observed for the contralesional compared to the ipsilesional hand in the unimanual condition. This asymmetry was reversed for the bimanual condition despite longer RTs. Conclusion and clinical implications: Reaction time paradigms are useful in these patients to monitor more precisely their functional deficits, especially their level of functional asymmetry, and to understand brain (re)organization following slowgrowing lesions.

Early Tithonian Saturnalidae (Radiolaria) from the Solnhofen area (Southern Franconian Alb, Southern Germany)

In order to complete the study of the very rich early Tithonian (Hybonoticeras hybonotum Zone) radiolarian fauna from the Muhlheim Member of the Mornsheim Formation outcropping in the Solnhofen area, the taxa of the family Saturnalidae are described. Although rather rare, the Saturnalidae of this member contain 14 species, ten of which are new. These species belong to four genera, one of which is new (Moebicircus n. gen.), and two subfamilies (Hexasaturnalinae and Saturnalinae). The taxonomy at generic level of these late Jurassic radiolarians is founded on the basis of the position of the blades along the ring and number and morphology of the spines. Type of spines (simple or forked) has either species level value or none, depending on species. Special attention was given to anomalies, which sometimes are rather frequent, since they can give information of paleobiological and paleoecological orders. Among them frequent cases of open ring and additional spines with Dicerosaturnalis and Siamese twins skeletons with Spongosaturninus and Dicerosaturnalis are to be noted. The authors hope that this new taxonomy will give a better image of the evolution and radiation of the Saturnalidae during the Tithonian.

Garnet growth in the Nufenen Pass area (Swiss Alps)

Abstract : Textural division of a mineral in pyramids, with their apices located at the centre of the mineral and their bases corresponding to the mineral faces is called textural sector zoning. Textural sector zoning is observed in many metamorphic minerals like andalousite and garnet. Garnets found in the graphite rich black shales of the Mesozoic cover of the Gotthard Massif display textural sector zoning. The morphology of this sector zoning is not the same in different types of black shales observed in the Nufenen pass area. Garnets in foliated black shales display a well developed sector zoning while garnets found in cm-scale layered black shales display well developed sectors in the direction of the schistosity plane. This sector zoning is always associated with up to 30μm sized birefringent lamellae emanating radial from the sector boundaries. They alternate with isotrope lamellae. The garnet forming reaction was determined using singular value decomposition approach and results compared to thermodynamic calculations. It is of the form chl + mu + cc + cld = bt + fds + ank + gt + czo and is similar in both layered and foliated black shales. The calculated X(O) is close to 0.36 and does not significantly vary during the metamorphic history of the rock. This corresponds to X CO2, X CH4, and X H2O BSE imaging of garnets on oriented-cuts revealed that the orientation of the lamellae found within the sectors is controlled by crystallography. BSE imaging and electron microprobe analysis revealed that these lamellae are calcium rich compared to the isotropic lamellae. The addition of Ca to an almandine rich garnet causes a small distortion of the X site and potentially, ordering. Ordered and disordered garnet might have very similar free energies for this composition. Hence, two garnets with different composition can be precipitated with minor overstepping of the reaction. It is enough that continued nucleation of a new garnet layer slightly prefers the same structure to assure a fiber-like growth of both garnet compositions side by side. This hypothesis is in agreement with the thermodynamic properties of the garnet solid solution described in the literature and could explain the textures observed in garnets with these compositions. To understand the differences in sector zoning morphology, and crystal growth kinetics, crystal size distribution were determined in several samples using 2D spatial analysis of slab surfaces. The same nucleation rate law was chosen for all cases. Different growth rate law for non-layered black shales and layered black shales were used. Garnet in layered black shales grew according to a growth rate law of the form R=kt ½. The transport of nutrient is the limiting factor. Transport will occur preferentially on the schistosity planes. The shapes of the garnets in such rocks are therefore ovoid with the longest axis parallel to the schistosity planes. Sector zoning is less developed with sectors present only parallel to the schistosity planes. Garnet in non-layered blackshales grew according to a growth rate law of the form R=kt. The limiting factor is the attachment at the surface of the garnet. Garnets in these rocks will display a well developed sector zoning in all directions. The growth rate law is thus influenced by the texture of the rock. It favours or hinders the transport of nutrient to the mineral surface. Résumé : La zonation sectorielle texturale consiste en la division d'un cristal en pyramides dont les sommets sont localisés au centre du minéral. La base de ces pyramides correspond aux faces du minéral. Ce type de zonation est fréquemment observé dans les minéraux métamorphiques tels que l'andalousite ou le grenat. Les grenats présents dans les marnes riches en graphites de la couverture Mésozoïque du Massif du Gotthard présent une zonation sectorielle texturale. La morphologie de cette zonation n'est pas la même dans les marnes litées et dans les marnes foliées. Les grenats des marnes foliées montrent des secteurs bien développés dans 3 directions. Les grenats des marnes litées montrent des secteurs développés uniquement dans la direction des plans de schistosité. Cette zonation sectorielle est toujours associée à des lamelles biréfringentes de quelques microns de large qui partent de la limite des secteurs et qui sont perpendiculaires aux faces du grenat. Ces lamelles alternent avec des lamelles isotropes. La réaction de formation du grenat a été déterminée par calcul matriciel et thermodynamique. La réaction est de la forme chl + mu + cc + cld= bt + fds + ank + gt + czo. Elle est similaire dans les roches litées et dans les roches foliées. L'évaluation des conditions fluides montrent que le X(O) est proche de 0.36 et ne change pas de façon significative durant l'histoire métamorphique de la roche. Des images BSE sur des coupes orientées ont révélé que l'orientation de lamelles biréfringentes est contrôlée parla crystallographie. La comparaison des analyses à la microsonde électronique et des images BSE révèle également que les lamelles biréfringentes sont plus riches en calcium que les lamelles isotropes. L'addition de calcium va déformer légèrement le site X et ainsi créer un ordre sur ce site. L'énergie interne d'un grenat ordré et d'un grenat désordonné sont suffisamment proches pour qu'un léger dépassement de l'énergie de la réaction de formation permette la coexistence des 2 types de grenat dans le même minéral. La formation de lamelles est expliquée par le fait qu'un grenat préférera la même structure. Ces observations sont en accord avec la thermodynamique des solutions solides du grenat et permet d'expliquer les structures similaires observées dans des grenats provenant de lithologies différentes. Une étude de la distribution des tailles des grenats et une modélisation de la croissance a permis de mettre en évidence 2 mécanismes de croissance différents suivant la texture de la roche. Dans les 2 cas, la loi de nucléation est la même. Dans les roches litées, la loi de croissance est de forme R=kt½. Le transport des nutriments est le facteur limitant. Ce transport a lieu préférentiellement dans la direction des niveaux de schistosité. Les grenats ont une forme légèrement allongée car la croissance des secteurs est facilitée sur les niveaux de schistosité. La croissance des grenats dans les roches foliées suit une loi de croissance de la forme R=kt. Les seuls facteurs limitant la croissance sont les processus d'attachement à la surface du grenat. La loi de croissance de ces grenats est donc contrainte par la texture de la roche. Cela se marque par des différences dans la morphologie de la zonation sectorielle.

Increased activation in Broca's area after cognitive remediation in schizophrenia.

Functional magnetic resonance imaging (fMRI) was used to measure changes in cerebral activity in patients with schizophrenia after participation in the Cognitive Remediation Program for Schizophrenia and other related disorders (RECOS). As RECOS therapists make use of problem-solving and verbal mediation techniques, known to be beneficial in the rehabilitation of dysexecutive syndromes, we expected an increased activation of frontal areas after remediation. Executive functioning and cerebral activation during a covert verbal fluency task were measured in eight patients with schizophrenia before (T1) and after (T2) 14 weeks of RECOS therapy. The same measures were recorded in eight patients with schizophrenia who did not participate in RECOS at the same intervals of time (TAU group). Increased activation in Broca's area, as well as improvements in performance of executive/frontal tasks, was observed after cognitive training. Metacognitive techniques of verbalization are hypothesized to be the main factor underlying the brain changes observed in the present study.

Review of therapeutic drug monitoring of anticancer drugs part one - Cytotoxics.

Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1=Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.

A web-based pilot study of inter-pathologist reproducibility using the ISHLT 2004 working formulation for biopsy diagnosis of cardiac allograft rejection: The European experience.

BACKGROUND: The aim of this study was to assess, at the European level and using digital technology, the inter-pathologist reproducibility of the ISHLT 2004 system and to compare it with the 1990 system We also assessed the reproducibility of the morphologic criteria for diagnosis of antibody-mediated rejection detailed in the 2004 grading system. METHODS: The hematoxylin-eosin-stained sections of 20 sets of endomyocardial biopsies were pre-selected and graded by two pathologists (A.A. and M.B.) and digitized using a telepathology digital pathology system (Aperio ImageScope System; for details refer to http://aperio.com/). Their diagnoses were considered the index diagnoses, which covered all grades of acute cellular rejection (ACR), early ischemic lesions, Quilty lesions, late ischemic lesions and (in the 2005 system) antibody-mediated rejection (AMR). Eighteen pathologists from 16 heart transplant centers in 7 European countries participated in the study. Inter-observer reproducibility was assessed using Fleiss's kappa and Krippendorff's alpha statistics. RESULTS: The combined kappa value of all grades diagnosed by all 18 pathologists was 0.31 for the 1990 grading system and 0.39 for the 2005 grading system, with alpha statistics at 0.57 and 0.55, respectively. Kappa values by grade for 1990/2005, respectively, were: 0 = 0.52/0.51; 1A/1R = 0.24/0.36; 1B = 0.15; 2 = 0.13; 3A/2R = 0.29/0.29; 3B/3R = 0.13/0.23; and 4 = 0.18. For the 2 cases of AMR, 6 of 18 pathologists correctly suspected AMR on the hematoxylin-eosin slides, whereas, in each of 17 of the 18 AMR-negative cases a small percentage of pathologists (range 5% to 33%) overinterpreted the findings as suggestive for AMR. CONCLUSIONS: Reproducibility studies of cardiac biopsies by pathologists in different centers at the international level were feasible using digitized slides rather than conventional histology glass slides. There was a small improvement in interobserver agreement between pathologists of different European centers when moving from the 1990 ISHLT classification to the "new" 2005 ISHLT classification. Morphologic suspicion of AMR in the 2004 system on hematoxylin-eosin-stained slides only was poor, highlighting the need for better standardization of morphologic criteria for AMR. Ongoing educational programs are needed to ensure standardization of diagnosis of both acute cellular and antibody-mediated rejection.

Unusual spread of a penicillin-susceptible methicillin-resistant Staphylococcus aureus clone in a geographic area of low incidence.

We describe the unusual spread of a penicillin-susceptible methicillin-resistant Staphylococcus aureus (MRSA) clone in hospitals in western Switzerland, where the incidence of MRSA is usually low. During a 2-year period, this clone had been responsible for several outbreaks and had been isolated from >156 persons in 21 institutions. Molecular typing by pulsed-field gel electrophoresis (PFGE) demonstrated that all of these isolates belonged to the same clone. In 1 of the outbreaks, involving 30 cases, the clone was responsible for at least 17 secondary cases. In contrast, during the period of the latter outbreak, 9 other patients harboring different MRSA strains, as assessed by PFGE, were hospitalized in the same wards, but no secondary cases occurred. These observations suggest that this clone, compared with other MRSA strains, had some intrinsic factor(s) that contributed to its ability to disseminate and could thus be considered epidemic.

Inter-informant agreement and prevalence estimates for substance use disorders: direct interview versus family history method.

OBJECTIVES: Family studies typically use multiple sources of information on each individual including direct interviews and family history information. The aims of the present study were to: (1) assess agreement for diagnoses of specific substance use disorders between direct interviews and the family history method; (2) compare prevalence estimates according to the two methods; (3) test strategies to approximate prevalence estimates according to family history reports to those based on direct interviews; (4) determine covariates of inter-informant agreement; and (5) identify covariates that affect the likelihood of reporting disorders by informants. METHODS: Analyses were based on family study data which included 1621 distinct informant (first-degree relatives and spouses) - index subject pairs. RESULTS: Our main findings were: (1) inter-informant agreement was fair to good for all substance disorders, except for alcohol abuse; (2) the family history method underestimated the prevalence of drug but not alcohol use disorders; (3) lowering diagnostic thresholds for drug disorders and combining multiple family histories increased the accuracy of prevalence estimates for these disorders according to the family history method; (4) female sex of index subjects was associated with higher agreement for nearly all disorders; and (5) informants who themselves had a history of the same substance use disorder were more likely to report this disorder in their relatives, which entails the risk of overestimation of the size of familial aggregation. CONCLUSION: Our findings have important implications for the best-estimate procedure applied in family studies.