The grey mouse lemur: a non-human primate model for ageing studies.

The use of non-human primate models is required to understand the ageing process and evaluate new therapies against age-associated pathologies. The present article summarizes all the contributions of the grey mouse lemur Microcebus murinus, a small nocturnal prosimian primate, to the understanding of the mechanisms of ageing. Results from studies of both healthy and pathological ageing research on the grey mouse lemur demonstrated that this animal is a unique model to study age-dependent changes in endocrine systems, biological rhythms, thermoregulation, sensorial, cerebral and cognitive functions.

Painful medial knee compartment syndrome in over-45 year-olds: I--medical or surgical management: a series of 174 patients.

INTRODUCTION: There is at present no consensus on the management of degenerative medial meniscus lesions in patients aged over 45 years without proven osteoarthritis, especially given that the causal relation between degenerative meniscal lesion and osteoarthritis remains controversial. A prospective multicenter non randomized study was therefore performed. The principal objective was to assess surgeons' practice in the management of degenerative medial meniscus lesions. The secondary objectives were to identify predictive and prognostic factors and to compare medical versus surgical attitudes so as to draw up an adapted treatment strategy. PATIENTS AND METHOD: One hundred and seventy-four patients were included between September 2008 and February 2010, and distributed between a surgical (n=104) and a medical group (n=70). Minimum follow-up was 6 months. Patient satisfaction and health-related quality of life on the SF-36 questionnaire were assessed at 6 months. RESULTS: No difference emerged between the surgical and medical groups. However, predictive factors for poor results were identified: overweight (p=0.005), cartilage lesions (p=0.035) and meniscus extrusion (p=0.006). DISCUSSION: Results clarified the relation between degenerative meniscus lesions and osteoarthritis, in terms of meniscal incompetence. Meniscal extrusion should be seen as an arthrogenic degenerative meniscus lesion. We recommend a management strategy based on terrain and imaging data (X-ray and MRI), with the aim of providing patient relief while conserving cartilage.

A combination of atlas-based and voxel-wise approaches to analyze metabolic changes in autoradiographic data from Alzheimer's mice.

Murine models are commonly used in neuroscience research to improve our knowledge of disease processes and to test drug effects. To accurately study brain glucose metabolism in these animals, ex vivo autoradiography remains the gold standard. The analysis of 3D-reconstructed autoradiographic volumes using a voxel-wise approach allows clusters of voxels representing metabolic differences between groups to be revealed. However, the spatial localization of these clusters requires careful visual identification by a neuroanatomist, a time-consuming task that is often subject to misinterpretation. Moreover, the large number of voxels to be computed in autoradiographic rodent images leads to many false positives. Here, we proposed an original automated indexation of the results of a voxel-wise approach using an MRI-based 3D digital atlas, followed by the restriction of the statistical analysis using atlas-based segmentation, thus taking advantage of the specific and complementary strengths of these two approaches. In a preliminary study of transgenic Alzheimer's mice (APP/PS1), and control littermates (PS1), we were able to achieve prompt and direct anatomical indexation of metabolic changes detected between the two groups, revealing both hypo- and hypermetabolism in the brain of APP/PS1 mice. Furthermore, statistical results were refined using atlas-based segmentation: most interesting results were obtained for the hippocampus. We thus confirmed and extended our previous results by identifying the brain structures affected in this pathological model and demonstrating modified glucose uptake in structures like the olfactory bulb. Our combined approach thus paves the way for a complete and accurate examination of functional data from cerebral structures involved in models of neurodegenerative diseases.

Impaired neurogenesis, neuronal loss, and brain functional deficits in the APPxPS1-Ki mouse model of Alzheimer's disease.

Amyloid-ß peptide species accumulating in the brain of patients with Alzheimer's disease are assumed to have a neurotoxic action and hence to be key actors in the physiopathology of this neurodegenerative disease. We have studied a new mouse mutant (APPxPS1-Ki) line developing both early-onset brain amyloid-ß deposition and, in contrast to most of transgenic models, subsequent neuronal loss. In 6-month-old mice, we observed cell layer atrophies in the hippocampus, together with a dramatic decrease in neurogenesis and a reduced brain blood perfusion as measured in vivo by magnetic resonance imaging. In these mice, neurological impairments and spatial hippocampal dependent memory deficits were also substantiated and worsened with aging. We described here a phenotype of APPxPS1-Ki mice that summarizes several neuroanatomical alterations and functional deficits evocative of the human pathology. Such a transgenic model that displays strong face validity might be highly beneficial to future research on AD physiopathogeny and therapeutics.

Clinical practice guidelines for the surgical management of rotator cuff tears in adults.

CONTEXT: Rotator cuff tears are very common. In 2005, about 45 000 patients in France underwent surgery. Surgical techniques and indications have evolved over recent years with the development of arthroscopic procedures. The lack of visibility on current practice and a request by the French Ministry of Health to assess the fixation devices used in arthroscopic surgery prompted the drafting of these guidelines. OBJECTIVES: To produce guidelines on the indications and limitations of open surgery and arthroscopic surgery. METHODS: A systematic review of the literature (2000-2007) was performed. It was submitted to a multidisciplinary working group of experts in the field (n = 12) who drafted an evidence report and clinical practice guidelines, which were amended in the light of comments from 36 peer reviewers. MAIN RECOMMENDATIONS: (i) Medical treatment (oral medication, injections, physiotherapy) is always the first option in the management of degenerative tears of rotator cuff tendons. Surgery is a later option that depends on clinical and morphological factors, and patient characteristics.(ii) Surgery can be considered for the purpose of functional recovery in cases of a painful, weak or disabling shoulder refractory to medical treatment. (iii) Arthroscopy is indicated for nonreconstructive surgery or debridement, and for partial tear debridement or repair. (iv) Open surgery, mini-open surgery or arthroscopy can be used for a full-thickness tear accessible to direct repair by suture. (v) A humeral prosthesis or total reversed prosthesis is indicated for cuff tear arthropathy. (vi) The fixation devices used for bone reinsertion (anchors, screws, staples,and buttons) are indispensable for fully arthroscopic repair. No studies have determined the number of fixation devices to be used according to tear size.

Validation of MRI-based 3D digital atlas registration with histological and autoradiographic volumes: an anatomofunctional transgenic mouse brain imaging study.

Murine models are commonly used in neuroscience to improve our knowledge of disease processes and to test drug effects. To accurately study neuroanatomy and brain function in small animals, histological staining and ex vivo autoradiography remain the gold standards to date. These analyses are classically performed by manually tracing regions of interest, which is time-consuming. For this reason, only a few 2D tissue sections are usually processed, resulting in a loss of information. We therefore proposed to match a 3D digital atlas with previously 3D-reconstructed post mortem data to automatically evaluate morphology and function in mouse brain structures. We used a freely available MRI-based 3D digital atlas derived from C57Bl/6J mouse brain scans (9.4T). The histological and autoradiographic volumes used were obtained from a preliminary study in APP(SL)/PS1(M146L) transgenic mice, models of Alzheimer's disease, and their control littermates (PS1(M146L)). We first deformed the original 3D MR images to match our experimental volumes. We then applied deformation parameters to warp the 3D digital atlas to match the data to be studied. The reliability of our method was qualitatively and quantitatively assessed by comparing atlas-based and manual segmentations in 3D. Our approach yields faster and more robust results than standard methods in the investigation of post mortem mouse data sets at the level of brain structures. It also constitutes an original method for the validation of an MRI-based atlas using histology and autoradiography as anatomical and functional references, respectively.

Clinical practice guidelines for the management of meniscal lesions and isolated lesions of the anterior cruciate ligament of the knee in adults.

CONTEXT: Meniscal lesions and isolated anterior cruciate ligament (ACL) knee injuries are common. In 2006, about 130,000 patients were admitted to hospital for meniscal surgery and 35,000 for ACL surgery in France. Surgical techniques and indications have evolved over recent years, and interest in meniscus preservation has increased due to the higher risk of femorotibial osteoarthritis following meniscectomy. OBJECTIVES: To encourage good practices in meniscal lesions surgery (particularly meniscus preservation) and to clarify indications and techniques in ACL reconstruction surgery. METHODS: A systematic review of the literature (1996-2007) was performed. It was submitted to a multidisciplinary working group of experts in the field (n=10) who drafted an evidence report and clinical practice guidelines which were subsequently amended in the light of comments from 50 peer reviewers. MAIN RECOMMENDATIONS: (i) Meniscal repair should only be used to heal peripheral meniscal lesions affecting healthy meniscal tissue (injury) in vascularised areas (red-red zone or red-white zone). The current trend is towards use of hybrid implants (fixation material combined with suture wire) and an exclusively arthroscopic technique. (ii) Traumatic meniscal lesions do not always require a meniscectomy; no surgery or meniscal repair should systematically be considered. (iii) The assessment and management of non-traumatic degenerative meniscal lesions depend on the extent of cartilage damage. (iv) All ACL ruptures do not require reconstructive surgery. The indication for reconstruction is based on symptoms, in particular functional instability. As far as acute ACL injuries are considered, reconstruction by arthroscopy should preferably be delayed to reduce the thromboembolic events or joint stiffness. (v) Bone-tendon-bone graft and hamstring tendon reconstruction give similar results. (vi) Lateral tenodesis should be limited to specific cases.

A method based on Monte Carlo simulations and voxelized anatomical atlases to evaluate and correct uncertainties on radiotracer accumulation quantitation in beta microprobe studies in the rat brain.

The beta-microprobe is a simple and versatile technique complementary to small animal positron emission tomography (PET). It relies on local measurements of the concentration of positron-labeled molecules. So far, it has been successfully used in anesthetized rats for pharmacokinetics experiments and for the study of brain energetic metabolism. However, the ability of the technique to provide accurate quantitative measurements using (18)F, (11)C and (15)O tracers is likely to suffer from the contribution of 511 keV gamma rays background to the signal and from the contribution of positrons from brain loci surrounding the locus of interest. The aim of the present paper is to provide a method of evaluating several parameters, which are supposed to affect the quantification of recordings performed in vivo with this methodology. We have developed realistic voxelized phantoms of the rat whole body and brain, and used them as input geometries for Monte Carlo simulations of previous beta-microprobe reports. In the context of realistic experiments (binding of (11)C-Raclopride to D2 dopaminergic receptors in the striatum; local glucose metabolic rate measurement with (18)F-FDG and H(2)O(15) blood flow measurements in the somatosensory cortex), we have calculated the detection efficiencies and corresponding contribution of 511 keV gammas from peripheral organs accumulation. We confirmed that the 511 keV gammas background does not impair quantification. To evaluate the contribution of positrons from adjacent structures, we have developed beta-Assistant, a program based on a rat brain voxelized atlas and matrices of local detection efficiencies calculated by Monte Carlo simulations for several probe geometries. This program was used to calculate the 'apparent sensitivity' of the probe for each brain structure included in the detection volume. For a given localization of a probe within the brain, this allows us to quantify the different sources of beta signal. Finally, since stereotaxic accuracy is crucial for quantification in most microprobe studies, the influence of stereotaxic positioning error was studied for several realistic experiments in favorable and unfavorable experimental situations (binding of (11)C-Raclopride to D2 dopaminergic receptors in the striatum; binding of (18)F-MPPF to 5HT1A receptors in the dorsal raphe nucleus).

HIV seroconversion interval and demographic characteristics: no evidence of selection bias.

OBJECTIVES: To determine if the interval between the last negative and the first positive HIV test is associated with demographic characteristics of HIV seroconverters. METHODS: A prospective cohort of patients with HIV seroconversion enrolled in the Lyons HIV hospital database was analysed. Comparisons of demographic characteristics were performed after stratification on the duration of the interval between the last HIV negative screening test and the first HIV positive screening test, which ranged from 1 day to 24 months. Linear regression methods were used to identify the covariates associated with a negative HIV antibody test followed by a positive test. RESULTS: Age (p = 0.54), sex (p = 0.78), heterosexual route of infection (p = 0.78), other route (p = 0.40) compared with homosexual route, and estimated year of HIV infection (p value ranged from 0.84 to 0.95) were not associated with a shorter seroconversion interval after multivariate analyses. The presence of an acute HIV illness was the only predictor of a short seroconversion interval (p = 0.006) with a reduction of 84 days of the interval when it was reported. CONCLUSIONS: No selection bias for demographic characteristics of HIV seroconverters seems associated with the length of the seroconversion interval, at least for intervals < or = 24 months.

Three-dimensional digital mouse atlas using high-resolution MRI.

We present an archetypal digital atlas of the mouse embryo based on microscopic magnetic resonance imaging. The atlas is composed of three modules: (1) images of fixed embryos 6 to 15.5 days postconception (dpc) [Theiler Stages (TS) 8 to 24]; (2) an annotated atlas of the anterior portion of a 13.5 dpc (TS 22) mouse with anatomical structures delineated and linked to explanatory files; and (3) three-dimensional renderings of the entire 13.5 dpc embryo and specific organ systems. The explanatory files include brief descriptions of the structure at each volume element in the image and links to 3D reconstructions, allowing visualization of the shape of the isolated structures. These files can also contain or be linked to other types of information and data including detailed anatomical and physiological information about structures with pointers to online references, relationships between structures, temporal characteristics (cell lineage patterns, size, and shape changes), and gene expression patterns (both spatial and temporal). As an example, we have "painted" in the expression pattern of Dlx5/Dlx6 genes. This digital atlas provides a means to put specific data within the context of normal specimen anatomy, to analyze the information in 3D, and to examine relationships between different types of information.

MRI description of cerebral atrophy in mouse lemur primates.

We assessed cerebral atrophy in mouse lemur primates (Microcebus murinus) by estimating CSF volume in their brains from 4.7 Tesla T2-weighted magnetic resonance images. Thirty animals aged from 1 to 10.3 years were imaged, 14 of them were followed for up to 2 years. Seven of these animals were examined for neuropathology. In 12 out of 17 animals older than 3.5 years, CSF volumes were increased. A subgroup of six animals had severe atrophy of the temporal lobe. Another subgroup of five animals displayed diffuse atrophy in addition to the temporal atrophy. One animal had a dilation of the external part of the temporal horn of the lateral ventricle in addition to the temporal atrophy. The three animals with diffuse atrophy that could be studied for neuropathology had diffuse cerebral amyloid deposits detected by immunocytochemistry. The other animals did not display amyloid deposits. Relations between the different types of atrophy as well as their causes will have to be assessed in future studies.

[The TT virus: review of the literature]. / Le virus TT: revue de la littérature.

OBJECTIVE: To review the literature on the TT virus. METHODS: The literature review was based on articles identified through MEDLINE between Jan. 1, 1997, and August 15, 1999. RESULTS: In 1997, a new DNA virus, designated TTV, was isolated and seemed to be associated with non A-G post-transfusion hepatitis. The virus was identified using a polymerase chain reaction (PCR) because serology was not routinely available. At least 16 genotypes were identified. Depending on the PCR technique used, the prevalence of infection ranged from 17% to 71% in a group of sera tested. The prevalence rate ranged from 1.2% to 62% among blood donors, from 0.5% to 83% among hemophiliacs and from 1% to 71% in cases of chronic hepatitis. The current hypothesis is that routes of infection were parenteral and orofecal. The pathogenesis of this virus, if it really exists, is not yet clearly established. It has been postulated that some interaction may exist between the TT virus and the hepatitis C virus. The use of interferon seems to decrease the TT viremia, according to results obtained outside the context of clinical trials. CONCLUSION: The pathogenesis of the TT virus needs to be rapidly established for transmission prevention and therapeutic intervention.

Cerebral T2-weighted signal decrease during aging in the mouse lemur primate reflects iron accumulation.

4.7 Tesla T2-weighted magnetic resonance images showed a highly significant signal decrease in the pallidum, substantia nigra, putamen, and a less significant decrease in the thalamus and the caudate of aging mouse lemurs (Microcebus murinus). We evaluated the contribution of iron deposits to the signal decrease comparing Perls' stained histological sections of six mouse lemurs brains aged 1 to 10 years to magnetic resonance images. In young animals, none of the brain structures was stained. A large number of iron deposits were visible in the pallidum and substantia nigra of aged animals and a moderate number in the middle aged ones. In the putamen, few iron deposits were visible in aged and middle-aged animals. The thalamus and the caudate appeared unstained with Perls' technique; iron was too low to be detected. The intensification of the reaction by diaminobenzidine revealed iron deposits in the thalamus of aging animals. This study suggests that in mouse lemurs, iron deposits are responsible for T2-weighted signal decrease in the central gray nuclei.

T2-weighted MRI studies of mouse lemurs: a primate model of brain aging.

Previous histological and behavioral studies of aging mouse lemurs have demonstrated changes similar to those observed in elderly humans and in patients with Alzheimer's disease. We explored 18 animals of ages 6 months to 9 years. Axial T2-weighted images of the brain were performed on a 4.7 Tesla Bruker Biospec 47/30 system. We estimated cerebral atrophy by adding measures of high signal areas characteristic of cerebrospinal fluid (interlobular and sylvian fissures, lateral and third ventricles) of four contiguous cortical slices. We observed a significant increase of cerebral atrophy with aging and one case of an apathetic 8-year-old animal presenting a considerably higher cerebral atrophy. We also observed high correlations between decreased signal intensities and age for the pallidum, the substantia nigra, and the putamen. These results suggest that aging mouse lemurs present similar magnetic resonance images of cerebral alterations to those encountered in aging humans and that high-field T2-weighted magnetic resonance images can help in the early detection, in vivo, of animals suspected of pathological aging.

Age dependence of the T2-weighted MRI signal in brain structures of a prosimian primate (Microcebus murinus).

Mouse lemurs (Microcebus murinus) are prosimian primates described to be convenient models of brain aging. We observed very high correlations between the T2-weighted magnetic resonance imaging (MRI) signal decrease and the natural logarithm of age in the basal ganglia. The correlation coefficient was higher for the pallidum (r = 0.95, P < 0.0001) than for other structures. We suggest that the ratio of the pallidum intensity divided by the amygdala and temporal lobe intensity should be a valuable non-invasive marker of age and of cerebral aging. It should be particularly useful for the non-invasive assessment of interventions and drugs that affect the aging process.