90Y TOF-PET based EUD reunifies patient survival prediction in resin and glass microspheres radioembolization of HCC tumours.

Clinical studies reported a twofold ratio between the efficacies per Gy of resin versus glass spheres. Our aim is to investigate whether this difference could result from the different degrees of heterogeneity in sphere distribution between the two medical devices. The 90Y TOF-PET based equivalent uniform doses (EUD) was used for this purpose. 58 consecutive HCC radioembolizations were retrospectively analyzed. Absorbed doses D and Jones-Hoban EUD in lesions were computed. Radioembolization efficacy was assessed using Kaplan-Meier survival curves. In order to match together the glass and resin spheres survival curves using a 40 Gy-threshold, an efficacy factor of 0.73 and 0.36 has to be applied on their absorbed dose, respectively. Using EUD, a nice matching between glass and resin survival curves was obtained with a better separation of the responding and not responding survival curves. The results clearly support the fact that the activity heterogeneity observed in 90Y TOF-PET post radioembolization does not only result from statistical noise, but also reflects the actual heterogeneity of the spheres distribution. Use of EUD reunifies the efficacy of the two medical devices.

Posterior shoulder instability: Prospective non-randomised comparison of operative and non-operative treatment in 51 patients.

BACKGROUND: The management of posterior shoulder instability remains controversial. Consequently, for a symposium on this topic, the French Arthroscopy Society (SFA) conducted a prospective multicentre study comparing outcomes of operative and non-operative treatment. OBJECTIVE: To compare outcomes after operative versus non-operative treatment of posterior shoulder instability. HYPOTHESIS: The surgical treatment of posterior shoulder instability may achieve better clinical outcomes than non-operative treatment in selected patients. MATERIAL AND METHODS: Fifty-one patients were included prospectively then followed-up for 12months. Three groups were defined based on the clinical presentation: recurrent dislocation or subluxation, involuntary instability or voluntary instability that had become involuntary, and shoulder pain with instability. Of the 51 patients, 19 received non-operative therapy involving a three-step rehabilitation programme and 32 underwent surgery with a posterior bone block, labral repair and/orcapsule tightening, or bone defect filling. At inclusion and at last follow-up, the Subjective Shoulder Value (SSV), Rowe score, Walch-Duplay score, and Constant score were determined. RESULTS: The preliminary results after the first 12 months are reported here. In the non-operative and operative groups, the Constant score was 78 versus 87, the Rowe score 64 versus 88, and the Walch-Duplay score 69 versus 82, respectively. These differences were statistically significant (P<0.05). DISCUSSION: To our knowledge, this study is the first comparison of non-operative versus operative treatment in a cohort of patients with documented posterior shoulder instability. Outcomes were better with operative treatment. However, this finding remains preliminary given the short follow-up of only 1 year. LEVEL OF EVIDENCE: III, case-control study.

MRI in patients with chronic pubalgia: Is precise useful information provided to the surgeon? A case-control study.

BACKGROUND: Recent studies described that MRI is a good examination to assess damage in chronic athletic pubalgia (AP). However, to our knowledge, no studies focus on systematic correlation of precise tendon or parietal lesion in MRI with surgery and histological assessment. Therefore, we performed a case-control study to determine if MRI can precisely assess Adductor longus (AL) tendinopathy and parietal lesion, compared with surgery and histology. HYPOTHESIS: MRI can determine if AP comes from pubis symphysis, musculotendinous or inguinal orifice structures. MATERIALS/METHODS: Eighteen consecutive patients were enrolled from November 2011 to April 2013 for chronic AP. To constitute a control group, we also enrolled 18 asymptomatic men. All MRI were reviewed in consensus by 2 skeletal radiologists for pubic symphysis, musculotendinous, abdominal wall assessment and compared to surgery and histology findings. RESULTS: Regarding pubis symphysis, we found 4 symmetric bone marrow oedema (14%), 2 secondary cleft (7%) and 2 superior ligaments lesions (7%). For AL tendon, we mainly found 13 asymmetric bone marrow oedema (46%), 15 hyperaemia (54%). Regarding abdominal wall, the deep inguinal orifice size in the group of symptomatic athletes and the control group was respectively 27.3±6.4mm and 23.8±6.3mm. The correlation between MRI and surgery/histology was low: 20% for the AL tendon and 9% for the abdominal wall. If we chose the criteria "affected versus unaffected", this correlation became higher: 100% for AL tendon and 73% for the abdominal wall. CONCLUSION: MRI chronic athletic pubalgia concerns preferentially AL tendinopathy and deep inguinal canal dehiscence with high correlation to surgery/histology when only considering the item "affected versus unaffected" despite low correlation when we try to precisely grade these lesions. LEVEL OF EVIDENCE: III: case-control study.

Rotator cuff tears after 70 years of age: a prospective, randomized, comparative study between decompression and arthroscopic repair in 154 patients.

INTRODUCTION: Arthroscopic repair of rotator cuff tears leads to better clinical outcomes than subacromial decompression alone; however the former is rarely proposed to patients above 70 years of age. Our hypothesis was that arthroscopic repair would be superior to decompression in patient 70 years or older. The primary goal was to compare the clinical results obtained with each technique. The secondary goal was to analyze the effects of age, tendon retraction and fatty infiltration on the outcome. METHODS: This was a prospective, comparative, randomized, multicenter study where 154 patients were included who were at least 70 years of age. Of the included patients, 143 (70 repair and 73 decompression) were seen at one-year follow-up; these patients had an average age of 74.6 years. Shoulders had a complete supraspinatus tear with extension limited to the upper-third of the infraspinatus and Patte stage 1 or 2 retraction. Clinical outcomes were evaluated with the Constant, ASES and SST scores. RESULTS: All scores improved significantly with both techniques: Constant +33.81 (P<0.001), ASES +52.1 (P<0.001), SST +5.86 (P<0.001). However, repair led to even better results than decompression: Constant (+35.85 vs. +31.8, P<0.05), ASES (+56.09 vs. +48.17, P=0.01), SST (+6.33 vs. +5.38, P=0.02). The difference between repair and decompression was not correlated with age; arthroscopic repair was also better in patients above 75 years of age (Constant, ASES and SST scores P<0.01). There was no significant correlation between the final outcomes and initial retraction: Constant (P=0.14), ASES (P=0.92), SST (P=0.47). The difference between repair and decompression was greater in patients with stages 0 and 1 fatty infiltration (Constant P<0.02) than in patients with stages 2 and 3 fatty infiltration (Constant P<0.05). CONCLUSION: There was a significant improvement in all-clinical scores for both techniques 1 year after surgery. Repair was significantly better than decompression for all clinical outcomes, even in patients above 75 years of age. The difference observed between repair and decompression was greater in patients with more retracted tears and lesser in patients with more severe fatty infiltration.

Arthroscopic repair of the rotator cuff: prospective study of tendon healing after 70 years of age in 145 patients.

INTRODUCTION: The level of activity of patients older than 70 years is tending to increase, as are their expectations in terms of joint function recuperation. It has not been proven that rotator cuff repair healing is satisfactory in the elderly. The main hypothesis of this study was: repair of supraspinous lesions in patients older than 70 years is reliable in terms of both clinical results and healing. The secondary hypothesis was: tendon healing is significantly correlated with the Constant, ASES, and SST scores as well as with age, tendon retraction, and fatty infiltration. MATERIAL AND METHODS: Multicenter prospective study on 145 patients older than 70 years, with 135 patients reviewed at 1 year (93%). The mean age was 73.9 years. Full-thickness tears of the supraspinatus extended at most to the upper third of the infraspinatus and retraction limited to Patte stages 1 and 2 were included. Clinical assessment was carried out in accordance with the Constant, ASES, and SST scores. Healing was evaluated with ultrasound. RESULTS: A significant improvement was noted in the Constant (44/76)+31.5 (P<0.0001), ASES (35/90)+54.4 (P<0.0001), and SST (3.5/10)+6.6 (P>0.0001) scores at 1 year of follow-up. The healing rate was 89% with 15 re-tears, nine of which were stage 1 and six stage 2. The clinical result was not correlated with patient age (Constant, P=0.24; ASES, P=0.38; SST, P=0.83) nor with the retraction stage (Constant, P=0.71; ASES, P=0.35; SST, P=0.69) or the stage of fatty infiltration (P>0.7). Healing was correlated with the quality of the clinical result (Constant, P=0.02; ASES, P=0.03) and age (P=0.01) but was not correlated with retraction or the fatty infiltration stage (P>0.3). DISCUSSION/CONCLUSION: Arthroscopic repair significantly improves the clinical results, even in patients older than 70 years. The clinical results are not correlated with age (but deterioration of the result was not noted after 75 years) or frontal retraction (but the study only included retractions limited to stages 1 and 2). The healing rate is satisfactory, but this study is limited to small ruptures of the supraspinatus, and the postoperative ultrasound analysis probably inferior to CT imaging with contrast agent injection, often used as the reference. Healing proves to be correlated with the quality of the clinical result and patient age.

Strength, diversity and plasticity of postmating reproductive barriers between two hybridizing oak species (Quercus robur L. and Quercus petraea (Matt) Liebl.).

Very little is known about the nature and strength of reproductive isolation (RI) in Quercus species, despite extensive research on the estimation and evolutionary significance of hybridization rates. We characterized postmating pre- and postzygotic RI between two hybridizing oak species, Quercus robur and Quercus petraea, using a large set of controlled crosses between different genotypes. Various traits potentially associated with reproductive barriers were quantified at several life history stages, from pollen-pistil interactions to seed set and progeny fitness-related traits. Results indicate strong intrinsic postmating prezygotic barriers, with significant barriers also at the postzygotic level, but relatively weaker extrinsic barriers on early hybrid fitness measures assessed in controlled conditions. Using general linear modelling of common garden data with clonal replicates, we showed that most traits exhibited important genotypic differences, as well as different levels of sensitivity to micro-environmental heterogeneity. These new findings suggest a large potential genetic diversity and plasticity of reproductive barriers and are confronted with hybridization evidence in these oak species.

Cemented total hip stem design influence on adaptative cortical thickness and femoral morphology.

INTRODUCTION: Five-year following total hip implantation femur adaptive morphology was compared between two groups differing only in their femoral stem design. MATERIAL AND METHODS: Group 1, recruited prospectively, included 51 Dédicace stems(Stryker-Howmedica) and group 2, retrospectively matched to group 1, comprised 51 Kerboull MK3 stems (Stryker-Howmedica). While MK3 prosthetic system increases in size homogeneously (widening along the whole length as the implant dimension increases), the Dédicace prosthetic system provides various metaphyseal widths for a given diaphyseal size. We opted for primary fixation (press fit according to the "French paradox") prior to cementing in both cases, despite the risk of discontinuity in the cement mantle. The homogeneous dimensioning of the MK3 stem enables distal primary fixation, whereas the Dédicace range allows differentiated adaptation to diaphyseal length and metaphyseal caliber. The following parameters were measured and calculated: Noble index, femoral cortical thickness score of Barnett and Nordindiaphyseal filling and stress-shielding at three levels around the stem. RESULTS: Bone-remodeling, assessed on X-ray, was without clinical impact, whether it took the form of spongialization or stress-shielding. The sole factor tending to induce stress-shielding was a high degree of canal filling by the distal third of the stem, more frequently encountered with the MK3 model. Metaphyseal filling was equivalent with all stems. In the matched series on the contralateral healthy side, femoral spongialization was comparable. LEVEL OF PROOF: Level III; case/control study.

Distal femur rotational alignment and patellar subluxation: a CT scan in vivo assessment.

BACKGROUND: Patellofemoral instability following total knee arthroplasty is a very common complication which may result from a defective rotational positioning of the femoral component. However, rotational landmarks for optimal orientation are not unequivocal. Moreover, no proven correlation has yet been established between preexisting rotational malposition and patellofemoral instability occurrence. HYPOTHESIS: Any preexisting distal femoral rotational misalignment is associated with a preop patellofemoral instability in arthritic knees prior to undergoing arthroplasty. A prospective diagnostic study was conducted to test this hypothesis on the basis of morphometric data. MATERIAL AND METHODS: One hundred and eighteen patients were prospectively enrolled in this study. Patellar lateralization was measured on 30 flexion patellofemoral views. Three positionings were arbitrarily defined (less than 3 mm of lateralization, between 3 and 5 mm, over 5 mm). Three angles were preoperatively measured using CT scans: (1) the posterior condylar angle between posterior bicondylar axis and transepiphyseal axis, (2) the anterior trochlear angle between transepicondylar axis and trochlear opening plane, (3) the sum of anterior trochlear and posterior condylar angles finally formed the global trochlear opening angle. RESULTS: The patella was centered in 86 cases and lateralized in 32 cases (less than 5 mm in 25 cases and over 5 mm in seven cases). Independently from the degree of patellar lateralization, the global trochlear opening angle was constant (p=0.41). The value of the posterior condylar angle was statistically inferior when patella was centered (p=0.01; r=0.44). The value of the anterior trochlear angle varied opposite to the posterior condylar angle. Femoral anteversion, position of the anterior tibial tuberosity and tibiofemoral index could not be correlated with patellar positioning. No relationship could be established between patellar lateralization and overall torsional deformities of the lower extremity. CONCLUSION: The centering of the patella in arthritic knees depends on distal femoral osseous factors which determines the posterior condylar angle and anterior trochlear angle on either side of the transepicondylar axis. Since the trochlear opening angle is constant, the obliquity of the transepicondylar axis appears crucial in patellar lateralization. A better understanding of the influence of distal femoral morphology on patellar positioning will ensure improved positioning of femoral components in total knee arthroplasties or in isolated femoropatellar joint replacements. LEVEL OF EVIDENCE III: Prospective diagnostic study.

[Distal femoral torsion: comparison of CT scan and intra operative navigation measurements during total knee arthroplasty. A report of 70 cases]. / Torsion distale fémorale du genou : comparaison de la mesure par tomodensitométrie et par navigation peropératoire au cours des arthroplasties totales de genou. A propos de 70 cas.

INTRODUCTION: Proper positioning of the prosthesis components in total knee arthroplasty is an important factor for satisfactory outcomes such as mobility, pain and wear. If an independent cutting technique is performed, rotational alignment of the femoral component should adapt patient's specific anatomy. The distal epiphyseal femoral torsion (DEFT) is adjusted in order to align the prosthetic posterior condylar axis along the bone transepicondylar axis. The DEFT presents a high rate of interindividual variations. Computed tomography scanning produces reliable and reproducible measurement of the epiphyseal torsion, but this requires additional procedure. We therefore used intraoperative computed navigation for DEFT measurement, thus accurately adapting each patient's epiphyseal torsion during the procedure, without resorting to the preoperative CT scan. MATERIAL AND METHODS: This prospective study included 70 patients with arthritic knees who underwent TKA. Mean patient age was 74 years old. There were 52 women, 35 right knees, 33 genu varum, 19 genu valgum, 18 normal knees. DEFT was determined by preoperative CT scan, using the Yoshioka angle referencing. Distal epiphyseal femoral torsion measurement was carried out using the Navitrack system (Orthosoft). The DEFT was the navigated measured angle between the transepicondylar axis and the posterior condylar axis manually located and digitized with an optically tracked stylus. The navigation system was therefore used as a simple digital measurement device to evaluate the distal epiphyseal femoral torsion. We had established the reference transepicondylar axis as the line connecting the prominence of the medial and lateral epicondyles. During the procedure, we also carried out computer-assisted measurement of HKA axis in full extension and at 90 degrees of knee flexion. Correlation between the navigated HKA in full extension and HKA measured on the preoperative pangonogram (R(2)=0.621) demonstrated a high reliability of the navigation system in the frontal plane. RESULTS: There was no correlation between the mean epiphyseal torsion determined with computer navigation and the epiphyseal torsion measured on the CT scan (R(2)=0.09). Significant interindividual variations were reported. Navigated HKA at 90 degrees of knee flexion was not correlated with navigated HKA in full extension (R(2)=0.398) nor with epiphyseal torsion measured on the CT scan (R(2)=0.063). Results demonstrated a major interindividual variation. DISCUSSION: Our results report a large variability in distal epiphyseal femoral torsion measured with CT scan. Moreover, computed navigation does not provide a reliable and reproducible evaluation of the epiphyseal torsion. Due to inaccurate identification of femoral epicondyles, the related navigated measurement is not considered to be reliable and reproducible. Navigated HKA at 90 degrees of knee flexion is not a fair indirect reflection of epiphyseal torsion. Computer-assisted navigation fails to provide direct or indirect, reliable and reproducible intraoperative measurement of distal epiphyseal femoral torsion. Preoperative CT scan is the only reliable method to produce accurate measurement of distal epiphyseal femoral torsion.

[Rotational alignment of femoral component with computed-assisted surgery (CAS) during total knee arthroplasty]. / Rotation fémorale par navigation sur la base d'un scanner préopératoire dans l'arthroplastie totale de genou : à propos de 70 cas.

INTRODUCTION: Accurate implantation of the prosthesis components is a prognostic factor for long-term total knee arthroplasty survival as it reduces wear and loosening failure. Computer-assisted navigation systems have proved to produce accurate bone cuts orthogonal to the mechanical axis. Proper rotational alignment of the femoral component is one of the requirements for optimal positioning of the femoral prosthesis. The posterior bicondylar axis of the femoral prosthesis should therefore be parallel to the transepicondylar axis. The purpose of the present study was to determine whether computer-assisted navigation provides an accurate rotational alignment of the femoral implant, when preoperatively defined with CT scan. MATERIAL AND METHODS: This prospective study, carried out between December 2003 and June 2005, included 70 patients of average age 74 years old (range 57-85) who underwent primary total knee arthroplasty, with a SAL prosthesis (Zimmer). Preoperative investigations with computed tomography scanning produced accurate measurements of distal epiphyseal femoral torsion (DEFT). The posterior bicondylar axis was found to be a reliable landmark for the rotational orientation of the femoral cutting-guide during bone-cuts. The rotational orientation of the cutting-guide was based on the preoperative CT data. A three-month follow-up CT scan was carried out to evaluate final rotational position of the femoral component. RESULTS: The mean DEFT evaluated on the preoperative CT scan was 6.9+/-2.9 degrees . The mean rotational orientation of the cutting guide was 4.8+/-2 degrees . The mean postoperative measurement of DEFT was 1.56+/-2.7 degrees . The mean adjustment of DEFT was 5.34 degrees . Adopting a +/- 2 degrees cutoff, 77 % of patients achieved acceptable alignment within +/- 2 degrees compared with our objectives. These findings were compared to a previous series of 34 cases using an arbitrary 3 degrees standardized rotation of the femoral component and following an identical radiological protocol. Among the knees, 44% reported alignment within +/- 2 degrees . DISCUSSION: When femoral and tibial bone cuts are performed independently, conventional instrumentation techniques seem insufficient to adapt patient's specific anatomy and prove inadequate to provide precise rotational alignment of the femoral component. Computed tomography scan is a reliable mean to produce precise preoperative measurements for proper DEFT. Moreover, it allows accurate postoperative control of the implant positioning. Other studies have documented a higher degree of precision in the rotational alignment of the femoral component with computed navigation systems in comparison to conventional instrumentation. However, in such studies, rotational alignment was always determined by computer navigation, and based on a controversial intraoperative identification (epicondyles and Whiteside's line referencing). We believe that preoperative CT scanning is a more favourable method. Actually, 77% of the cases reported satisfactory rotational alignment of the femoral component using this technique.

[Hip dysplasia and misalignment in patients aged 20-50 years]. / Dysplasie et conflits de hanche de 20 à 50 ans.

Anterior hip pain in young adult (20 to 50) has two main causes: secondary osteo-arthritis on development dysplasia of the hip, and femoro-acetabular impigement (FAI). This symposium had two parts: the first one analyses long-term results of non-prosthetic surgery (283 osteotomies and shelfs at 15 years FU). The second part concerned the different syndromes with acute anterior hip pain, especially due to FAI and to labral tears.In hip dysplasia, 56 shelf operations, 100 proximal femoral varus osteotomies associated or not with a shelf arthroplasty,and 127 Chiari osteotomies were examined with 10 years minimum follow-up. Only 15% of patients were lost at follow-up before 10 years and average follow-up was 15 years. Results were considered as satisfactory when the Merle d'Aubigne rating was 15/18 or more. The 3 main factors of good prognosis were: a complete correction of both femoral and acetabular dysplasia; age at operation under 40; a moderate arthritis (grade I or II according to De Mourgues and Patte). In single acetabular dysplasia with 3 favorable prognosis factors(no coxa valga, age under 40, arthritis 1 or 2), 85% good results were achieved at 15 years. When patients were over 40 at operation, or in arthritis grade over 2, only 55% of good results were observed. Varus osteotomies, associated or not with shelf arthroplasties, achieved also 85% goods results at 15 years when the 3 favorable prognosis factors were present. Similar good results were also obtained by Chiari osteotomy, but this operation was associated with 12% complications, and more that 25% of lasting limping. Therefore, with 85% good results at 15 years (and often over 20 years), non prosthetic surgery performed at 30-35 years, achieved better functional results than total hip arthroplasty, longer lasting, and not jeopardizing any further possibility of prosthetic surgery.As concerns acute anterior pain of the hip, the clinical and imaging patterns of the different syndromes have been precised: femoro-acetabular impigement by cam (or by pincer), labral tears in hip dysplasia. There were distinguished from the other secondary impigements, for example by acetabular malposition due to pelvis anteflexion or by other hip diseases: overuse arthritis, coxa retrorsa, etc. Several examples of typical syndromes were presented to support the recommended imaging techniques. The results of the speakers with different surgical treatments were reported as well as concerns open surgery than arthroscopic treatment (60 cases).

Identification of multiple differentially expressed messenger RNAs in normal and pathological trophoblast.

In an attempt to assess the molecular basis of phenotypic alterations present in the gestational trophoblastic diseases (GTDs) and to identify genes whose expression is specifically associated to these placental proliferative disorders we performed differential display techniques. Initially 19 candidate gene fragments were identified and differential expression was confirmed in eight of these fragments by Northern blot analysis. At the mRNA level ribosomal L26 (rL26), ribosomal L27 (rL27), a new Krüppel type zinc finger protein and TIS11d were preferentially expressed in normal early placenta (NEP) relative to complete hydatidiform mole (CHM), persistent gestational trophoblastic disease (PGTD) and choriocarcinoma JEG-3 cell line. In contrast, heterogeneous ribonucleoprotein A1 (hnRNPA1), the ferritin light chain mRNA, and the uncharacterized protein KIAA0992 were predominantly expressed in JEG-3 cell line. Finally, decorin, a prototype member of an expanding family of small leucine-rich proteoglycans, showed high expression in CHM. In addition we demonstrated by immunohistochemistry analysis that increased decorin mRNA in CHM reflected a genuine augmentation in average steady state mRNA levels within cells. Taken together, these findings provide several interesting candidates for regulation of tumorigenic expression as well as early placentation development, including those involved in protein synthesis (rL26 and rL27), metabolism (ferritin light chain), intercellular communication (decorin) and regulation of gene expression (Krüppel-like zinc finger, TIS11d and hnRNPA1). Information about such alterations in gene expression could be useful for elucidating the genetic events associated to gestational trophoblastic pathogenesis, developing new diagnostic markers, or determining novel therapeutic targets.

Altered mitochondrial gene expression in human gestational trophoblastic diseases.

To assess the molecular basis of phenotypic alterations present in the gestational trophoblastic diseases (GTDs) and to identify genes whose expression is specifically associated with these placental proliferative disorders we performed differential display (DD) techniques. This strategy resulted in the isolation of four mitochondrial transcripts downregulated in benign, as well as in malignant, trophoblastic diseases encoding the cytochrome oxidase subunit I (COX I), the ATPase subunit 6, the 12S ribosomal RNA (12S rRNA) and the transfer RNA for phenylalanine (tRNA(Phe)). This expression pattern was confirmed by Northern blot in normal early placenta (NEP), complete hydatidiform mole (CHM), persistent gestational trophoblastic disease (PGTD) and the human choriocarcinoma derived cell line JEG-3. Quantification of mitochondrial DNA by dot blot indicated that these changes in expression were not associated with a significant alteration in the number of mitochondrial genome. In addition, a reduction in the mitochondrial transcription factor A (mtTFA) mRNA level was observed in benign as well as in malignant trophoblastic diseases in correlation with the decrease in the mitochondrial transcript levels. Furthermore, Western blot analysis for COX-I showed a close parallelism with the expression level of the cognate RNA. Taken together, these data demonstrate that a significant change in mitochondrial transcription is associated with the phenotypic alteration present in GTDs.

[Eye tracking disorders in schizophrenic patients and their parents]. / La poursuite oculaire lente chez les patients schizophrènes et leurs parents.

UNLABELLED: Several studies have confirmed the existence of genetic factors in schizophrenia. However, the genotype predisposing for the disease is not known yet. Nevertheless, those genetic factors in the families of schizophrenic patients urge us to search for genetic vulnerability markers of schizophrenia. Ocular pursuit disorders, in particular, could be one of those vulnerability markers. Eye movements have been often tested in schizophrenia. Most of the schizophrenic patients have eye-tracking disorders and their biological relatives demonstrate an increased prevalence of eye-tracking impairments. The aim of the study was to research if smooth pursuit eye movements could be a vulnerability marker of schizophrenia. In order to have an indication about this hypothesis, impairments of smooth pursuit eye movements were researched in both schizophrenics and their parents. METHODS: Fifteen DSM IV schizophrenic patients stabilized at the time of the inclusion and not treated with lithium, benzodiazepines, barbiturates, or chloral hydrate; 19 parents without history of schizophrenic spectrum disorders (SADSLA and IPDE), and 2 groups of healthy subjects matched in age and sex with probands and with the parents, were included in the study. Parents only were included (fathers or mothers) in order to have an homogeneous population for the genetic risk and age. The eye-tracking paradigm used was a smooth pursuit task. The stimulus was a sinusoidal wave form moving on a horizontal line, with a frequency of 0.4 Hz and an amplitude of 30 degrees. Different parameters were measured: gain (ratio between the eye velocity and the target velocity) and saccades frequencies (catch-up saccades, back-up saccades, anticipatory saccades and square-wave-jerks). For each parameter, analysis of covariance (ANCOVA) with age as covariable was carried out. For the results reaching the significance of 0.05, the Bonferroni correction was applied (level of significance 0.016). The effect size of the parameter was calculated ((the mean of the subjects minus the mean of the matched controls) divided by standard deviation of the two groups). According to Cohen, 0.20 indicates a small effect size, 0.50 indicates a medium effect size and 0.80 indicates a large effect size. RESULTS: Comparison between patients and matched controls: the means of global gain, of gain for the movements to the left and of gain for the movements to the right did not differ significantly between patients and their matched controls. The size effects are 0.31 for the global gain, 0.20 for the movements to the left and 0.41 for the movements to the right. The frequencies of total saccades, catch-up saccades, back-up saccades, anticipatory saccades and square-wave-jerks did not differ significantly between patients and their controls. The size effects for those parameters were 0.09, 0.03, 0.00, 0.39 and 0.63 respectively. Comparison between parents and matched controls: the means of global gain, of gain for the movements to the left and of gain for the movements to the right did not differ significantly between the two groups. The size effects for those parameters were 0.00, 0.05 and 0.17 respectively. The frequency of total saccades did not differ significantly between the groups whereas the size effect was 0.63. The frequency of catch-up saccades was significantly more important in parents than in controls (p = 0.006) and the size effect was 0.80. The other saccadic parameters did not differ significantly between groups, their size effects were 0.24 for the back-up saccades, 0.21 for the anticipatory saccades and 0.00 for the square-wave-jerks. Whereas the gain of the patients had a tendency to be lower than the gain of their controls, no significant difference was observed between patients and their controls. Only a size effect of 0.63 for the frequency of square-wave-jerks was obtained. This large effect size suggests that the difference between patients and controls might be significant in a larger sample. The catch-up saccades frequency between parents and controls was significant. The differences between our study and the previous studies could be due to several factors. The paradigms used were different between the studies and our sample was small (only 15 patients and 19 relatives). Moreover, some patients in the previous studies were treated by lithium, drug well known to modify ocular pursuit and, finally the relatives in the other studies were 10 years older than ours and age is known to alter ocular pursuit. Since an impairment of the smooth pursuit was observed in the relatives of schizophrenic patients but not in the probands, this study does not support the hypothesis that eye-tracking disorders could be considered as a marker of vulnerability of schizophrenia.

Proton magnetic resonance spectroscopy of the medial prefrontal cortex in patients with deficit schizophrenia: preliminary report.

OBJECTIVE: Proton magnetic resonance spectroscopy (1H-MRS) was used to study medial prefrontal metabolic impairments in schizophrenic patients with the deficit syndrome. METHOD: The subjects were 22 schizophrenic patients categorized as deficit (N=5) or nondeficit (N=17) and 21 healthy subjects. (1)H-MRS was performed for the right and the left medial prefrontal cortex. RESULTS: The patients with the deficit syndrome had significantly lower ratios of N-acetylaspartate to creatine plus phosphocreatine than did the healthy subjects or nondeficit patients. CONCLUSIONS: As N-acetylaspartate levels could reflect neuronal density and/or viability, this finding suggests a neuronal loss in the medial prefrontal cortex of deficit patients.

Relationships between trait and state anxiety and the central benzodiazepine receptor: a PET study.

The central benzodiazepine receptor (cBZr) has long been implicated in anxiety disorders on the basis of: (i) the well-known anxiolytic and anxiogenic properties of cBZr agonists and inverse agonists, respectively; (ii) a possibly reduced sensitivity to benzodiazepines in anxious subjects; and (iii) a putative endogenous ligand. Thus, two main hypothesis have been advanced, namely changes in the concentration or properties of the latter, and changes in the GABAA complex conformation, which contains the cBZr. Neither postmortem studies nor appropriate animal models are available to investigate these ideas. We have used positron emission tomography (PET) to measure both the density and affinity of the cBZr in multiple brain regions in unmedicated patients and age- and sex-matched healthy volunteers, and have looked for differences between groups as well as correlations between cBZr parameters and state and trait anxiety scores. We studied 10 unmedicated patients (sex ratio 1 : 1; mean age: 39 years), prospectively recruited using DSM III-R criteria, and 10 age- and gender-matched healthy unmedicated volunteers. Thanks to a PET procedure using two successive administrations of 11C-flumazenil (at high and low specific radioactivity) and previously validated by us, we estimated the Bmax, Kd and bound : free (B/F) ratios in 11 neocortical areas and in the cerebellum. Before and after the PET session, anxiety scores from Spielberger's and Covi's scales were obtained. There was no statistically significant difference in Bmax, Kd or B/F-values between the two groups for any region. Across the two groups, there were only a few marginally significant anxiety-score-PET correlations, suggesting chance findings. This is the first fully quantitative study to report on the relationships between cBZr parameters and anxiety. Using two independent approaches (i.e. group comparison and across-group correlations), we found no evidence for a link between anxiety trait or state and the cBZr in neocortex or cerebellum in this sample. These findings, if confirmed by studies on larger samples, have implications for the pharmacotherapy of anxiety disorders, and will need to be considered when designing new neurobiological models of anxiety.

Central benzodiazepine receptor occupancy by zolpidem in the human brain as assessed by positron emission tomography.

The central benzodiazepine receptor occupancy by zolpidem in man is unknown. The present study used positron emission tomography (PET) and [11C]flumazenil to assess in five healthy volunteers, central benzodiazepine receptor occupancy in brain regions with high receptor densities 1 h following an acute oral administration of twice the usual hypnotic dose of zolpidem (20 mg). Receptor occupancy was measured in five discrete structures (middle frontal gyrus, middle temporal gyrus, posterior occipital cortex, lateral parietal cortex, and cerebellar cortex) and in a large neocortical area as the fractional change in the [11C]flumazenil bound/free ratio for the interval 15-40 min post-administration of the radiotracer. The free-radioligand concentration was estimated from the pons, a reference structure virtually devoid of central benzodiazepine receptor. With individual pons values, mean occupancy was about 21% but with spurious inter-subject variability. With pons values averaged across the five subjects and separately for control and treated condition, the occupancy was (mean +/- S.D.) 27 +/- 11% for the whole neocortex, and ranged from 26 to 29% in the five discrete structures (P < 0.01). By showing hypnotic effect at moderate occupancies, this study directly provides evidence for the full-agonist properties of zolpidem in human.

Central benzodiazepine receptors in human brain: estimation of regional Bmax and KD values with positron emission tomography.

Studies of central benzodiazepine receptors in the human brain in vivo are now possible using positron emission tomography (PET) and [11C]flumazenil. With the aim of measuring Bmax and Kd in brain regions, we used a two-injection [11C]flumazenil (at high and low specific radioactivity, respectively) pseudo-equilibrium paradigm to evaluate, in seven unmedicated healthy volunteers, the relative merits of three 'reference' structures (pons, hemispheric white matter and corpus callosum) in which the free radioligand concentration in brain tissue was estimated 15-40 min after i.v. injection of the radioligand. By means of high-resolution PET, the Bmax and Kd were calculated for each subject in 18 gray matter structures, based on a two-point Scatchard plot. We found that the use of the corpus callosum as reference often resulted in spurious Bmax and Kd values. The pons was the best reference structure because it provided satisfactory Bmax values (closest to in vitro data) and most consistent Kd values, and was the region easiest to sample on PET images. The pattern of regional Bmax was consistent with that expected from in vitro studies, with values highest in the cerebral cortex, intermediate in the cerebellum, and lowest in the striatum and the thalamus. The Kd values were uniform among regions and were consistent with earlier in vitro and in vivo data. This work documents the feasibility of estimating Bmax and Kd of central benzodiazepine receptors in multiple brain regions for clinical research.