Different clinical outcomes between cerebral amyloid angiopathy-related inflammation and non-inflammatory form.

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare manifestation related to CAA, thought to be more severe. We aimed to compare the clinical and radiological outcomes of CAA-ri and non-inflammatory CAA. MATERIALS AND METHODS: We retrospectively included all patients with CAA-ri from 13 French centers. We constituted a sex- and age-matched control cohort with non-inflammatory CAA and similar disease duration. Survival, autonomy and cognitive evolution were compared after logistic regression. Cerebral microbleeds (CMB), intracerebral hemorrhage, cortical superficial siderosis and hippocampal atrophy were analyzed as well as CSF biomarker profile and APOE genotype when available. Outcomes were compared using Kaplan-Meier curves and log-rank tests. RESULTS: Data from 48 CAA-ri patients including 28 already reported and 20 new patients were analyzed. Over a mean of 3.1 years, 11 patients died (22.9%) and 18 (37.5%) relapsed. CAA-ri patients were more frequently institutionalized than non-inflammatory CAA patients (30% vs 8.3%, p < 0.001); mortality rates remained similar. MMSE and modified Rankin scale scores showed greater severity in CAA-ri at last follow-up. MRI showed a higher number of CMB at baseline and last follow-up in CAA-ri (p < 0.001 and p = 0.004, respectively). CSF showed lower baseline levels of Aß42 in CAA-ri than non-inflammatory CAA (373.3 pg/ml vs 490.8 pg/ml, p = 0.05). CAA-ri patients more likely carried at least one APOE ε4 allele (76% vs 37.5%, adjusted p = 0.05) particularly as homozygous status (56% vs 6.2%, p < 0.001). INTERPRETATION: CAA-ri appears to be more severe than non-inflammatory CAA with a significant loss of autonomy and global higher amyloid burden, shown by more CMB and a distinct CSF profile. This burden may be partially promoted by ε4 allele.

What contribution can genetics make to predict the risk of Alzheimer's disease?

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Although its etiology remains incompletely understood, genetic variants are important contributors. The prediction of AD risk through individual genetic variants is an important topic of research that may have individual and societal consequences when preventive treatments will become available. However, the genetic substratum of AD is heterogeneous. In addition to the extremely rare and fully penetrant pathogenic variants of the PSEN1, PSEN2 or APP genes causing autosomal dominant AD, a large spectrum of risk factors have been identified in complex forms, including the common risk factor APOEɛ4, which is associated with a moderate-to-high risk, common polymorphisms associated with a modest individual risk, and a plethora of rare variants in genes like SORL1, TREM2 or ABCA7 with moderate to high-magnitude effect. Understanding how these genetic factors contribute to AD risk in a given individual, in additional to non-genetic factors, remains a challenge. Over the last 10 years, age-related penetrance curves have progressively incorporated advances in the knowledge of AD genetics, from APOE to common polygenic components and, currently, SORL1 rare variants, which represents an important step towards precision medicine in AD. In this review, we present the complex genetic architecture of AD and we expose the prediction of AD risk according to its underlying genetic component.

17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.

To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease.

The SORL1 protein plays a protective role against the secretion of the amyloid ß peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

Kinematics of the shoulder joint in tennis players.

OBJECTIVES: Shoulder pain and injury are common in tennis players. The precise causes for such pain remain unclear. Impingement at critical tennis positions and glenohumeral instability have never been dynamically evaluated in vivo. The purpose of this study was to evaluate the different types of impingement and stability during tennis movements. DESIGN: Laboratory study. METHODS: Type and frequency of impingement as well as percentage of subluxation were evaluated in 10 tennis players through a novel dedicated patient-specific measurement technique based on optical motion capture and Magnetic Resonance Imaging (MRI). RESULTS: All volunteers, nine male and one female, had a clinically functional rotator cuff. MRI revealed 11 rotator cuff lesions in six subjects and six labral lesions in five subjects. Lateral subacromial, anterior subacromial, internal anterosuperior, and internal posterosuperior impingements were observed in four, three, two and seven subjects, respectively. No instability could be demonstrated in this population. CONCLUSIONS: Tennis players presented frequent radiographic signs of structural lesions that could mainly be related to posterosuperior impingements due to repetitive abnormal motion contacts. This is the first study demonstrating that a dynamic and precise motion analysis of the entire kinematic chain of the shoulder is possible through a non-invasive method of investigation. This premier kinematic observation offers novel insights into the analysis of shoulder impingement and instability that could, with future studies, be generalized to other shoulder pathologies and sports. This original method may open new horizons leading to improvement in impingement comprehension.

De novo deleterious genetic variations target a biological network centered on Aß peptide in early-onset Alzheimer disease.

We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aß) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aß secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aß-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aß network alteration in AD.

A patient-specific measurement technique to model shoulder joint kinematics.

BACKGROUND: Measuring dynamic in vivo shoulder kinematics is crucial to better understanding numerous pathologies. Motion capture systems using skin-mounted markers offer good solutions for non-invasive assessment of shoulder kinematics during dynamic movement. However, none of the current motion capture techniques have been used to study translation values at the joint, which is crucial to assess shoulder instability. The aim of the present study was to develop a dedicated patient-specific measurement technique based on motion capture and magnetic resonance imaging (MRI) to determine shoulder kinematics accurately. HYPOTHESIS: Estimation of both rotations and translations at the shoulder joint using motion capture is feasible thanks to a patient-specific kinematic chain of the shoulder complex reconstructed from MRI data. MATERIALS AND METHODS: We implemented a patient-specific kinematic chain model of the shoulder complex with loose constraints on joint translation. To assess the effectiveness of the technique, six subjects underwent data acquisition simultaneously with fluoroscopy and motion capture during flexion and empty-can abduction. The reference 3D shoulder kinematics was reconstructed from fluoroscopy and compared to that obtained from the new technique using skin markers. RESULTS: Root mean square errors (RMSE) for shoulder orientation were within 4° (mean range: 2.0°-3.4°) for each anatomical axis and each motion. For glenohumeral translations, maximum RMSE for flexion was 3.7mm and 3.5mm for empty-can abduction (mean range: 1.9-3.3mm). Although the translation errors were significant, the computed patterns of humeral translation showed good agreement with published data. DISCUSSION: To our knowledge, this study is the first attempt to calculate both rotations and translations at the shoulder joint based on skin-mounted markers. Results were encouraging and can serve as reference for future developments. The proposed technique could provide valuable kinematic data for the study of shoulder pathologies. LEVEL OF EVIDENCE: Basic Science Study.

Prevalence of MRI-defined recent silent ischemia and associated bleeding risk with thrombolysis.

BACKGROUND: Uncertainties about the frequency and the associated bleeding risk of recent silent ischemia (RSI), incidentally found on pretreatment MRI, in candidates for thrombolysis require clarification because exclusion from therapy is a serious consequence for patients with such MRI findings. METHODS: We retrospectively analyzed the fluid-attenuated inversion recovery (FLAIR)/diffusion-weighted imaging (DWI) obtained before IV thrombolysis in 115 patients to search for MRI-defined RSI; these corresponded to well-developed FLAIR/DWI brain hyperintensities (RSI+), as distinct from the acute index ischemia, which typically lacked FLAIR changes. Patients without such findings were assigned to the RSI- group. Groups were compared for baseline characteristics and for rates of symptomatic and asymptomatic hemorrhagic transformation (HT) using odds ratios (OR) and their 95%confidence intervals (CI). RESULTS: We observed RSI in 21 patients (18.3%). The mean (SD) volume of RSI was 6.5 (12) mL (interquartile range 0.6-9). None of the baseline parameters differed between groups. There was no significant difference in rates of any type of HT between groups. Parenchymal hemorrhage type 1 or type 2 according to European Cooperative Acute Stroke Study criteria occurred in 2 (10%) RSI+ patients and in 10 (11%) RSI- patients (OR 0.88; 95% CI 0.18-4.37). Symptomatic HT, defined according to National Institute of Neurological Disorders and Stroke criteria, occurred in 1 (5%) RSI+ patient and in 10 (11%) RSI- patients (OR 0.42; 95% CI 0.05-3.47). CONCLUSIONS: We found that 18.3% of patients with acute stroke treated by IV thrombolysis in a stroke unit had RSI on pretreatment MRI. However, the presence of RSI was not associated with an increased risk of asymptomatic or symptomatic HT.

[Psychopathologies encountered on the island of Mayotte between 1998 and 2004]. / Psychopathologies rencontrées sur l'île de Mayotte entre 1998 et 2004.

Before 2001, psychiatric care on the island of Mayotte was ensured by missionaries from the Reunion Island. A mental health system has since been gradually installed, although the culture in Mayotte, mixing practicing Muslim women and traditional animists, still leaves a broad place for traditional healers. This paper presents a retrospective study of 1212 psychiatric case reports, aimed at indexing the various psychopathologies according to the CIM 10, on the island of Mayotte between 1998 and 2004. The files, before and after the opening of the mental health centre, were compared with those of the psychiatric diagnoses of the Comorians. The results show an evolution in the chronic pathologies treated in the Comorians: delirious disorders, and the organic, major, mental disorders in the first psychiatric files have given way to depressive episodes and somatoform disorders. Nevertheless, an underlying prevalence of depression and addiction persist. It is interesting to note the reduced number of suicide attempts, far lower than in western countries: one suicide attempt per annum for 375 inhabitants in metropolitan France, whereas, in this study, one suicide attempt in Mayotte was reported for 2504 inhabitants. The cultural characteristics are also taken into account in the discussion of these results. Thus, if there are more demonstrations with somatic expression in the Comorians, related to a stronger implication of the body in situations of psychological faintness: 1.75% of hysterical conversion in the Comorians versus 0.99% in Mayotte, this does not mean a more histrionic personality in this population: 1.8% of Comorians, against 1.98% in Mayotte. The results of this study consolidate the impressions felt by the experts and show the effects of the mental health policy on the island. Thus, the assumption of responsibility of chronic psychotics made it possible to improve their quality of life, and to decrease the number of medical evacuations that decreased from 17 to three, between 2001 and 2004. However, this study also underlined the possible axes of development in this field, namely the assumption of responsibility of psychiatric emergencies with a crisis centre, and the development of a specialized pedopsychiatric assumption of responsibility. Indeed, in the first six months of 2004, 35% of the patients were 0-20 year-old.

Preparation and antibiotic activity of monobactam analogues of nocardicins.

A series of diverse beta-lactam analogues of nocardicins with interesting antimicrobial properties were prepared. Coupling of glucosamine to these compounds improved their water solubility. Aminoacid derivatives produced a stereoinduction on the quaternary enantiotopic carbon of the starting compound 1. Evaluation of their antimicrobial activity showed that the introduction of alpha-amninoacids to monobactams increased their activity. The importance of asymmetric carbon is exemplified by the higher antibiotic activity of L-alpha-aminoacids than the D-series. No significant difference was observed between fluorinated and non-fluorinated monobactams.

Synthesis of perfluoroalkylated beta-alanine and some peptide derivatives: an access to original surfactants.

The reaction of amines of sodium azide with 3-perfluoroalkyl-3-fluoroprop-2-enoate, followed by hydrogenation, affords perfluoroalkylated beta-alanine analogues in very good yields. These compounds can be linked via an amide bond to produce peptide analogues such as carnosine or carcinine derivatives, which could have surfactive and complexing properties.

Relation between locomotion impairment, functional independence in retirement, and occupational strain resulting from work carried out during working life. Study of a sample population of 350 miners in the Loire valley in France.

STUDY OBJECTIVES: To analyse long term effects of working conditions experienced at an advanced age, and after retirement by quantifying occupational strain, impairment, and disability to establish their interrelation. DESIGN: Retrospective study. PARTICIPANTS: Retired miners from The French Coal Board who had worked in the coal fields of the Loire valley. From a potential population of 507 retired miners, 350 were completely evaluated. MEASUREMENT: The study examines the occupational strain experienced by each subject, measured using both auto-evaluation and evaluation by experts and the locomotion impairment and the functional independence. MAIN RESULTS: A significant relation between the evaluation of occupational strain and functional independence and locomotion impairment of the low back was found and also a significant relation between locomotion impairment of the low back and the length of time spent working at the coal face. CONCLUSIONS: This study confirms other studies as regards the effects of occupation on health status and on the aging process, but it goes further to show the consequences of this relation on functional independence.

Effectiveness and tolerance of pre- and postexposure treatment with purified inactivated rabies vaccine prepared on Vero cell line.

The results are reported of a field trial which was designated to demonstrate the inocuity and efficacy of the purified inactivated rabies vaccine (PVRV), produced on Vero cells by the Institut Mérieux, Lyon, France in pre- and postexposure treatment in man. Four sex and age matched groups of veterinary students and medical personnel received the vaccine. The vaccine was given according to WHO recommendations for pre- and postexposure regimens. The 82 volunteers were divided into four groups and vaccinated as follows. Group IA consisted of 27 individuals, receiving injections on days 0, 7 and 21. Group IB consisted of 29 individuals, injected on days 0, 28 and 56. Group II consisted of 16 individuals, receiving a postexposure schedule of vaccinations on days 0, 3, 7, 14, 28 and 90. Group III consisted of 10 subjects, all of whom had been previously immunized with various antirabies vaccines and received one single booster inoculation of this vaccine. Serum samples were taken on the days of vaccination and 14 days later in all groups and in addition on day 70 in group IA. Neutralizing antibodies against the rabies virus were determined in the rapid fluorescent focus inhibition test (RFFIT). In conclusion it can be stated that, regardless of the schedule of prophylactic immunization, three 0.5 ml inoculations of PVRV result in very high titres of virus neutralizing antibodies and a single vaccination in previously immunized individuals is sufficient to raise the amount of antibodies to a high level. Due to the high purity of the product the vaccine is very well tolerated by the vaccinees.

Clinical characterization of imuthiol.

Imuthiol is a nontoxic agent recruting and regulating T cells. Phase III studies in chronic bronchitis and bronchiectasis showed that immune functions were restored to normal, or near normal values. Cure was obtained in rheumatoid arthritis, tuberculosis and chronic infections in the elderly. Imuthiol is an effective agent for the treatment of syndromes and disease states where the underlying defect is a T-cell deficiency or dysfunction.

Combination of attenuated measles vaccine (Schwarz) with meningococcus A and A + C vaccine.

There is an obvious interest in a combined meningococcus-measles vaccine since the two diseases are widespread and serious in Third World countries among children under five years of age. The purpose of our study was to show the safety and effectiveness of such a combined preparation. The study covered 110 children between 8 months and 4 years of age who were followed systematically in a maternal child health center in the Paris area. Only 93 of them were checked before and after the immunization. The serologic titrations by the hemagglutination assay (IHA) for measles, and by radioimmunological assay (RIA) for meningococcus A and C showed that the Schwarz strain measles vaccine combined with meningococcus A or the association A+C does not interfere with the increase of A or C titers. 100% of the children showed a seroconversion equal to or less than 2 micrograms per ml, in the case of meningococcus A, as well as for C, regardless of age. Furthermore, 88% of the subjects showed a titer greater than or equal to 4 micrograms for the meningococcus A and 79% for C. On the other hand, meningococcus A or the association A+C seem to depress measles vaccine activity. Nevertheless, more than 80% of the children tested showed seroconversion when the measles vaccine was combined with meningococcus A, and only 69% when combined with meningococcus A and C.

[Results of preventive rabies vaccination with a concentrated vaccine of the PM/WI38-1503-3M rabies strain cultured on human diploid cells. Preparation of mixed antirabies-antitetanus hyperimmune immunoglobulin by plasmapheresis of blood taken from vaccinated veterinary students]. / Résultats de la vaccination antirabique préventive par le vaccin inactive concentré souche rabies PM/WI38-1503-3M cultivée sur cellules diploïdes humaines. Obtention d'immunoglobuline hyperimmune mixte antirabique et antitétanique par plasmaphérèse des étudiants vétérinaires vaccinés.

Many thousands of people in France and abroad have already benefited from preventive rabies vaccination by means of a vaccine obtained from culture on human diploid cells, perfected ten years ago by R. Lang, the Institut Mérieux and the Wistar Institute. In addition to being well tolerated, the serological efficacy of this vaccine is such that 100% of the vaccines observed had a seroconversion after only two injections at an interval of one month. However, a booster dose should be given 6 to 12 months after the first injection, and a further booster 3 to 5 years later or on request in case of known contamination. These boosters, combined with an anti-tetanus booster, induce such high antibody titers--between 10-100 and even 1000 I.U./ml--that it is easy to obtain substantial batches of combined anti-rabies and anti-tetanus immunoglobulin from a small number of volunteers. The complete efficacy of this new vaccine reduces the number of systematic post-vaccinal serologic controls and its innocuity is such that an extended preventive vaccination programme may be carried out, for instance in the case of children living in areas known to be dangerous.