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Objectives: The F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD)., Methods: Eight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination., Results: The female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38-57 years and had imaging and biomarker profiles similar to hers., Discussion: The results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Knockoff-based methods have become increasingly popular due to their enhanced power for locus discovery and their ability to prioritize putative causal variants in a genome-wide analysis. However, because of the substantial computational cost for generating knockoffs, existing knockoff approaches cannot analyze millions of rare genetic variants in biobank-scale whole-genome sequencing and whole-genome imputed datasets. We propose a scalable knockoff-based method for the analysis of common and rare variants across the genome, KnockoffScreen-AL, that is applicable to biobank-scale studies with hundreds of thousands of samples and millions of genetic variants. The application of KnockoffScreen-AL to the analysis of Alzheimer disease (AD) in 388,051 WG-imputed samples from the UK Biobank resulted in 31 significant loci, including 14 loci that are missed by conventional association tests on these data. We perform replication studies in an independent meta-analysis of clinically diagnosed AD with 94,437 samples, and additionally leverage single-cell RNA-sequencing data with 143,793 single-nucleus transcriptomes from 17 control subjects and AD-affected individuals, and proteomics data from 735 control subjects and affected indviduals with AD and related disorders to validate the genes at these significant loci. These multi-omics analyses show that 79.1% of the proximal genes at these loci and 76.2% of the genes at loci identified only by KnockoffScreen-AL exhibit at least suggestive signal (p < 0.05) in the scRNA-seq or proteomics analyses. We highlight a potentially causal gene in AD progression, EGFR, that shows significant differences in expression and protein levels between AD-affected individuals and healthy control subjects., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuroimaging-genetics cohorts gather two types of data: brain imaging and genetic data. They allow the discovery of associations between genetic variants and brain imaging features. They are invaluable resources to study the influence of genetics and environment in the brain features variance observed in normal and pathological populations. This study presents a genome-wide haplotype analysis for 123 brain sulcus opening value (a measure of sulcal width) across the whole brain that include 16,304 subjects from UK Biobank. Using genetic maps, we defined 119,548 blocks of low recombination rate distributed along the 22 autosomal chromosomes and analyzed 1,051,316 haplotypes. To test associations between haplotypes and complex traits, we designed three statistical approaches. Two of them use a model that includes all the haplotypes for a single block, while the last approach considers each haplotype independently. All the statistics produced were assessed as rigorously as possible. Thanks to the rich imaging dataset at hand, we used resampling techniques to assess False Positive Rate for each statistical approach in a genome-wide and brain-wide context. The results on real data show that genome-wide haplotype analyses are more sensitive than single-SNP approach and account for local complex Linkage Disequilibrium (LD) structure, which makes genome-wide haplotype analysis an interesting and statistically sound alternative to the single-SNP counterpart., (© 2021. The Author(s).)

Objective: The objective of this study was to identify genetic variants on the X-chromosome associated with Parkinson disease (PD) risk., Methods: We performed an X-chromosome-wide association study (XWAS) of PD risk by meta-analyzing results from sex-stratified analyses. To avoid spurious associations, we designed a specific harmonization pipeline for the X-chromosome and focused on a European ancestry sample. We included 11,142 cases, 280,164 controls, and 5,379 proxy cases, based on parental history of PD. Additionally, we tested the association of significant variants with (1) PD risk in an independent replication with 1,561 cases and 2,465 controls and (2) putamen volume in 33,360 individuals from the UK Biobank., Results: In the discovery meta-analysis, we identified rs7066890 (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, p = 2.2 × 10 -9 ), intron of GPM6B, and rs28602900 (OR = 1.10, 95% CI = 1.07-1.14, p = 1.6 × 10 -8 ) in a high gene density region including RPL10, ATP6A1, FAM50A, and PLXNA3. The rs28602900 association with PD was replicated (OR = 1.16, 95% CI = 1.03-1.30, p = 0.016) and shown to colocalize with a significant expression quantitative locus (eQTL) regulating RPL10 expression in the putamen and other brain tissues in the Genotype-Tissue Expression Project. Additionally, the rs28602900 locus was found to be associated with reduced brain putamen volume. No results reached genome-wide significance in the sex-stratified analyses., Interpretation: We report the first XWAS of PD and identify 2 genome-wide significant loci. The rs28602900 association was replicated in an independent PD dataset and showed concordant effects in its association with putamen volume. Critically, rs26802900 is a significant eQTL of RPL10. These results support a role for ribosomal proteins in PD pathogenesis and show that the X-chromosome contributes to PD genetic risk. ANN NEUROL 2021;90:22-34., (© 2021 American Neurological Association.)

The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability, and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

KLOTHO∗VS heterozygosity (KL∗VS HET+ ) was recently shown to be associated with reduced risk of Alzheimer's disease (AD) in APOE∗4 carriers. Additional studies suggest that KL∗VS HET+ protects against amyloid burden in cognitively normal older subjects, but sample sizes were too small to draw definitive conclusions. We performed a well-powered meta-analysis across 5 independent studies, comprising 3581 pre-clinical participants ages 60-80, to investigate whether KL∗VS HET+ reduces the risk of having an amyloid-positive positron emission tomography scan. Analyses were stratified by APOE∗4 status. KL∗VS HET+ reduced the risk of amyloid positivity in APOE∗4 carriers (odds ratio = 0.67 [0.52-0.88]; p = 3.5 × 10 -3 ), but not in APOE∗4 non-carriers (odds ratio = 0.94 [0.73-1.21]; p = 0.63). The combination of APOE∗4 and KL∗VS genotypes should help enrich AD clinical trials for pre-symptomatic subjects at increased risk of developing amyloid aggregation and AD. KL-related pathways may help elucidate protective mechanisms against amyloid accumulation and merit exploration for novel AD drug targets. Future investigation of the biological mechanisms by which KL interacts with APOE∗4 and AD are warranted., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Many Alzheimer's disease (AD) genetic association studies disregard age or incorrectly account for it, hampering variant discovery., Methods: Using simulated data, we compared the statistical power of several models: logistic regression on AD diagnosis adjusted and not adjusted for age; linear regression on a score integrating case-control status and age; and multivariate Cox regression on age-at-onset. We applied these models to real exome-wide data of 11,127 sequenced individuals (54% cases) and replicated suggestive associations in 21,631 genotype-imputed individuals (51% cases)., Results: Modeling variable AD risk across age results in 5-10% statistical power gain compared to logistic regression without age adjustment, while incorrect age adjustment leads to critical power loss. Applying our novel AD-age score and/or Cox regression, we discovered and replicated novel variants associated with AD on KIF21B, USH2A, RAB10, RIN3, and TAOK2 genes., Conclusion: Our AD-age score provides a simple means for statistical power gain and is recommended for future AD studies.

Progress in glycoscience is strongly dependent on the availability of broadly diverse tailor-made, well-defined, and often complex oligosaccharides. Herein, going beyond natural resources and aiming to circumvent chemical boundaries in glycochemistry, we tackle the development of an in vitro chemoenzymatic strategy holding great potential to answer the need for molecular diversity characterizing microbial cell-surface carbohydrates. The concept is exemplified in the context of Shigella flexneri , a major cause of diarrhoeal disease. Aiming at a broad serotype coverage S. flexneri glycoconjugate vaccine, a non-natural lightly protected tetrasaccharide was designed for compatibility with (i) serotype-specific glucosylations and O -acetylations defining S. flexneri O-antigens, (ii) recognition by suitable α-transglucosylases, and (iii) programmed oligomerization following enzymatic α-d-glucosylation. The tetrasaccharide core was chemically synthesized from two crystalline monosaccharide precursors. Six α-transglucosylases found in the glycoside hydrolase family 70 were shown to transfer glucosyl residues on the non-natural acceptor. The successful proof of concept is achieved for a pentasaccharide featuring the glucosylation pattern from the S. flexneri type IV O-antigen. It demonstrates the potential of appropriately planned chemoenzymatic pathways involving non-natural acceptors and low-cost donor/transglucosylase systems to achieve the demanding regioselective α-d-glucosylation of large substrates, paving the way to microbial oligosaccharides of vaccinal interest.

Identifying the genes that contribute to the variability in brain regions involved in language processing may shed light on the evolution of brain structures essential to the emergence of language in Homo sapiens. The superior temporal asymmetrical pit (STAP), which is not observed in chimpanzees, represents an ideal phenotype to investigate the genetic variations that support human communication. The left STAP depth was significantly associated with a predicted enhancer annotation located in the 14q23.1 locus, between DACT1 and KIAA0586, in the UK Biobank British discovery sample (N = 16 515). This association was replicated in the IMAGEN cohort (N = 1726) and the UK Biobank non-British validation sample (N = 2161). This genomic region was also associated to a lesser extent with the right STAP depth and the formation of sulcal interruptions, "plis de passage," in the bilateral STAP but not with other structural brain MRI phenotypes, highlighting its notable association with the superior temporal regions. Diffusion MRI emphasized an association with the fractional anisotropy of the left auditory fibers of the corpus callosum and with networks involved in linguistic processing in resting-state functional MRI. Overall, this evidence demonstrates a specific relationship between this locus and the establishment of the superior temporal regions that support human communication., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Importance: Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets. Klotho-VS heterozygosity (KL-VSHET+ status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carry APOE4 from AD remains unclear., Objectives: To determine if KL-VSHET+ status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carry APOE4., Design, Setting, and Participants: This study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified by APOE4 status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019., Main Outcomes and Measures: The risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling., Results: Of 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84]; P = 7.4 × 10-7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79]; P = 3.6 × 10-8). Additionally, control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94]; P = .02). Finally, in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10]; P = .03) and lower Aβ on PET scans (β, -0.04 [95% CI, -0.07 to -0.00]; P = .04)., Conclusions and Relevance: The genotype KL-VSHET+ is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carrying APOE4. Molecular pathways associated with KL merit exploration for novel AD drug targets. The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.

Cortical folding is a hallmark of brain topography whose variability across individuals remains a puzzle. In this paper, we call for an effort to improve our understanding of the pli de passage phenomenon, namely annectant gyri buried in the depth of the main sulci. We suggest that plis de passage could become an interesting benchmark for models of the cortical folding process. As an illustration, we speculate on the link between modern biological models of cortical folding and the development of the Pli de Passage Frontal Moyen (PPFM) in the middle of the central sulcus. For this purpose, we have detected nine interrupted central sulci in the Human Connectome Project dataset, which are used to explore the organization of the hand sensorimotor areas in this rare configuration of the PPFM.

Cationic amphiphiles featuring two thioether functions in each lipid chain of bicatenar cationic amphiphiles are reported here for the first time. The physicochemical properties and transfection abilities of these new amphiphiles were compared with those of already reported analogues featuring either (i) saturated, (ii) unsaturated or (iii) mono-thioether containing lipid chains. The homogeneity of the series of new compounds allowed to clearly underscore the effect of bis-thioether containing lipid chains. This study shows that besides previous strategies based on unsaturation or ramification, the incorporation of two thioether functions per lipid chain constitutes an original complementary alternative to tune the supramolecular properties of amphiphilic compounds. The potential of this strategy was evaluated in the context of gene delivery and report that two cationic amphiphiles (i. e. 4 a and 4 b) can be proposed as new efficient transfection reagents., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The grey and white matter volumes are known to reduce with age. This cortical shrinkage is visible on magnetic resonance images and is conveniently identified by the increased volume of cerebrospinal fluid in the sulci between two gyri. Here, we replicated this finding using the UK Biobank dataset and studied the genetic influence on these cortical features of aging. We divided all individuals genetically confirmed of British ancestry into two sub-cohorts (12,162 and 3435 subjects for discovery and replication samples, respectively). We found that the heritability of the sulcal opening ranges from 15 to 45% (SE = 4.8%). We identified 4 new loci that contribute to this opening, including one that also affects the sulci grey matter thickness. We identified the most significant variant (rs864736) on this locus as being an expression quantitative trait locus (eQTL) for the KCNK2 gene. This gene regulates the immune-cell into the central nervous system (CNS) and controls the CNS inflammation, which is implicated in cortical atrophy and cognitive decline. These results expand our knowledge of the genetic contribution to cortical shrinking and promote further investigation into these variants and genes in pathological context such as Alzheimer's disease in which brain shrinkage is a key biomarker.

Bioelectronic Medicines that modulate the activity patterns on peripheral nerves have promise as a new way of treating diverse medical conditions from epilepsy to rheumatism. Progress in the field builds upon time consuming and expensive experiments in living organisms. To reduce experimentation load and allow for a faster, more detailed analysis of peripheral nerve stimulation and recording, computational models incorporating experimental insights will be of great help. We present a peripheral nerve simulator that combines biophysical axon models and numerically solved and idealised extracellular space models in one environment. We modelled the extracellular space as a three-dimensional resistive continuum governed by the electro-quasistatic approximation of the Maxwell equations. Potential distributions were precomputed in finite element models for different media (homogeneous, nerve in saline, nerve in cuff) and imported into our simulator. Axons, on the other hand, were modelled more abstractly as one-dimensional chains of compartments. Unmyelinated fibres were based on the Hodgkin-Huxley model; for myelinated fibres, we adapted the model proposed by McIntyre et al. in 2002 to smaller diameters. To obtain realistic axon shapes, an iterative algorithm positioned fibres along the nerve with a variable tortuosity fit to imaged trajectories. We validated our model with data from the stimulated rat vagus nerve. Simulation results predicted that tortuosity alters recorded signal shapes and increases stimulation thresholds. The model we developed can easily be adapted to different nerves, and may be of use for Bioelectronic Medicine research in the future.

Cognitive performance is highly heritable. However, little is known about common genetic influences on cognitive ability and brain activation when engaged in a cognitive task. The Human Connectome Project (HCP) offers a unique opportunity to study this shared genetic etiology with an extended pedigree of 785 individuals. To investigate this common genetic origin, we took advantage of the HCP dataset, which includes both language and mathematics activation tasks. Using the HCP multimodal parcellation, we identified areals in which inter-individual functional MRI (fMRI) activation variance was significantly explained by genetics. Then, we performed bivariate genetic analyses between the neural activations and behavioral scores, corresponding to the fMRI task accuracies, fluid intelligence, working memory and language performance. We observed that several parts of the language network along the superior temporal sulcus, as well as the angular gyrus belonging to the math processing network, are significantly genetically correlated with these indicators of cognitive performance. This shared genetic etiology provides insights into the brain areas where the human-specific genetic repertoire is expressed. Studying the association of polygenic risk scores, using variants associated with human cognitive ability and brain activation, would provide an opportunity to better understand where these variants are influential.

The asymmetry of the superior temporal sulcus (STS) has been identified as a species-specific feature of the human brain. The so-called superior temporal asymmetrical pit (STAP) area is observed from the last trimester of gestation onwards and is far less pronounced in the chimpanzee brain. This asymmetry is associated with more frequent sulcal interruptions, named plis de passage (PPs), leading to the irregular morphology of the left sulcus. In this paper, we aimed to characterize the variability, asymmetry, and heritability of these interruptions in the STS in comparison with the other main sulci. We developed an automated method to extract PPs across the cortex based on a highly reproducible grid of sulcal pits across individuals, which we applied to a subset of Human Connectome Project (HCP) subjects (N = 820). We report that only a few PPs across the cortex are genetically constrained, namely in the collateral, postcentral and superior temporal sulci and the calcarine fissure. Moreover, some PPs occur more often in one hemisphere than the other, namely in the precentral, postcentral, intraparietal sulci, as well as in both inferior and superior temporal sulci. Most importantly, we found that only the interruptions within the STAP region are both asymmetric and genetically constrained. Because this morphological pattern is located in an area of the left hemisphere related to speech, our results suggest structural constraints on the architecture of the linguistic network., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The influence of genes on cortical structures has been assessed through various phenotypes. The sulcal pits, which are the putative first cortical folds, have for long been assumed to be under tight genetic control, but this was never quantified. We estimated the pit depth heritability in various brain regions using the high quality and large sample size of the Human Connectome Project pedigree cohort. Analysis of additive genetic variance indicated that their heritability ranges between 0.2 and 0.5 and displays a regional genetic control with an overall symmetric pattern between hemispheres. However, a noticeable asymmetry of heritability estimates is observed in the superior temporal sulcus and could thus be related to language lateralization. The heritability range estimated in this study reinforces the idea that cortical shape is determined primarily by nongenetic factors, which is consistent with the important increase of cortical folding from birth to adult life and thus predominantly constrained by environmental factors. Nevertheless, the genetic cues, implicated with various local levels of heritability in the formation of sulcal pits, play a fundamental role in the normal gyral pattern development. Quantifying their influence and identifying the underlying genetic variants would provide insight into neurodevelopmental disorders.

The concept of asthma has changed substantially in recent years. Asthma is now recognised as a heterogeneous entity that is complex to treat. The subdivision of asthma, provided by "cluster" analyses, has revealed various groups of asthma patients who share phenotypic features. These phenotypes underlie the need for personalised asthma therapy because, in contrast to the previous approach, treatment must be tailored to the individual patient. Determination of the patient's asthma phenotype is therefore essential but sometimes challenging, particularly in elderly patients with a multitude of comorbidities and a complex exposure history. This review first describes the various asthma phenotypes, some of which were defined empirically and others through cluster analysis, and then discusses personalisation of the patient's diagnosis and therapy, addressing in particular biological therapies and patient education. This personalised approach to curative medicine should make way in the coming years for personalised preventive and predictive medicine, focused on subjects at risk who are not yet ill, with the aim of preventing asthma before it occurs. The concept of personalised preventive medicine may seem a long way off, but is it really?, (Copyright ©ERS 2017.)

Shigella flexneri serotypes 1b and 1a are Gram-negative enteroinvasive bacteria causing shigellosis in humans. The O-antigen from S. flexneri 1b is a { → 2)-[3Ac/4Ac]-α-L-RHAP-(1 → 2)-α-L-Rhap-(1 → 3)-[2Ac]-α-L-Rhap-(1 → 3)-[α-D-Glcp-(1 → 4)]-β-D-GlcpNAc-(1 → }n branched polysaccharide ({(Ac)AB(Ac)C(E)D}n). It is identical to that from S. flexneri 1a, except for the 2C-acetate. A concise synthesis of the disaccharide ED, trisaccharides (Ac)C(E)D and C(E)D, tetrasaccharides B(Ac)C(E)D and BC(E)D, and pentasaccharides AB(Ac)C(E)D and ABC(E)D is described starting from a 2-N-acetyl-D-glucosaminide acceptor and using the imidate glycosylation chemistry. The E residue was efficiently introduced via a potent stereoselective [E + D] coupling. In contrast, harsh conditions and appropriate tuning of the donor were required for a high yielding [C + ED] glycosylation. Irrespective of the level of steric bulk at residue C, glycosylation at O-3D of the ED acceptor generated a major change of conformation of the D residue within the obtained C(E)D trisaccharide, as attested by NMR data. Proper manipulation of the constrained C(E)D trisaccharide was necessary to proceed with the stepwise chain elongation at O-3C of an acceptor having the 2C-O-acetyl already in place. The protected intermediates went through a one- to three-step deprotection sequence to give the propyl glycoside targets, as portions of the O-antigens from both S. flexneri 1a and 1b. Protecting group removal was clearly associated with conformational relief, yielding oligosaccharides, for which NMR data were consistent with a (4)C1 conformation for the 3,4-di-O-glycosylated residue D, as in the native bacterial polymers.

Background: Clinical experience suggests that lung cancer (LC) is associated with sleep disturbances that may contribute to impaired daytime functioning and quality of life. Using questionnaires and home actigraphic recordings, we tried to determine whether sleep quality and daytime alertness are impaired in patients with newly diagnosed LC., Patients and Methods: Twenty-nine outpatients with newly diagnosed LC and an Eastern Cooperative Oncology Group performance status

Background: There is no standard second-line treatment for small cell lung cancer (SCLC). The prognosis of these patients is poor and special attention should be paid to both quality of life and economic factors., Methods: The aim of this phase II randomised trial (GFPC0501) is to compare, in patients with progressive SCLC after first-line platinum based chemotherapy, oral multi drug chemotherapy (CCNU, cyclophosphamide, etoposide) and classical intravenous chemotherapy with cyclophosphamide, doxorubicin and vincristine (CAV) in terms of tolerability, efficacy (response rate, median one year survival and overall survival), quality of life and consumption of health care resources. Based on a two-stage Bryant and Day approach, this study will require a total of 138 patients with an interim analysis of the first 38., Expected Results: This trial will provide information on several aspects of second-line chemotherapy for patients with SCLC. Thirty six patients have been enrolled in 16 centres by December 2006 and the results of the interim analysis will be available in June 2007.

Introduction: Bronchogenic cysts are benign tumours of the posterior or middle mediastinum. Treatment usually consists of complete surgical resection. We report the case of an elderly woman presenting with an inoperable bronchogenic cyst causing tracheal compression which was treated successfully using computed-tomography (CT)-guided needle aspiration., Case Report: A 92 years old woman was admitted for inspiratory dyspnoea associated with stridor. She reported the incidental discovery of a right paratracheal mass, 2 years previously. Thoracic CT scan and bronchoscopy revealed a large mediastinal bronchogenic cyst causing tracheal compression. Surgery was contraindicated because of the patient's age and cardiac disease. CT-guided needle aspiration of 250 ml of viscous fluid was performed, followed by rapid clinical improvement. The patient remained symptom free for several months. The procedure was repeated successfully one year later because of a recurrence of compression., Conclusion: This observation supports the potential use of CT guided transthoracic needle aspiration as an alternative to surgical treatment in cases of inoperable symptomatic bronchogenic cyst.

The term chronic obstructive pulmonary disease (COPD) is mainly characterised by an irreversible obstructive airway obstruction, that in most cases, is secondary to tobacco exposure. Management of the disease includes an assessment of severity, and measures to decrease FEV decline, to treat bronchial obstruction, to improve exercise tolerance and to correct abnormal gas exchange. Treatment not only requires drug therapy, but also respiratory rehabilitation, surgery of emphysema, and psychosocial support. In this way, a global strategy, adapted to the severity of COPD, can be proposed.

Docetaxel (Taxotere) is a taxoid used in various tumoral diseases. Its role in metastatic or locally advanced non small cell lung cancer treatment is undeniable. In pretreated patients with metastatic NSCLC, two recent phase III trials have shown an improvement of survival and quality of life for patients receiving docetaxel. In front line treatment, docetaxel administered alone every three weeks or in combination with a platine compound has became a gold standard treatment. Activity of the associations cisplatinium/docetaxel and carboplatin/docetaxel is similar to those reported with previous combinations containing a platine derivative. The weekly schedule of docetaxel and its combination with other well known active drugs in NSCLC such as gemcitabin or vinorelbin deserve further evaluations. Therapeutic options with docetaxel in adjuvant situation in resected NSCLC or in combination with radiation therapy in operable locally advanced NSCLC should be developed in the next future.

Molecular targeted therapies offer great hope in lung cancer because they are supposed to act upon biologic abnormalities specific to cancer cells. In the present review, we will describe the major pathways of tumor cell growth, apoptosis, angiogenesis and invasion as well as the targeted therapies interacting with these pathways. We will provide an overview of the trials involving targeted therapies in lung cancer, along with the specific problems related to the development of these new therapies., (Copyright John Libbey Eurotext 2003.)

Purpose: The purpose of this work was to assess results obtained with the MIP (mitomycin 6 mg/m(2) day 1, ifosfamide 1500 mg/m(2) days 1,2, 3, cisplatin 30 mg/m(2) days 1,2, 3) chemotherapy protocol combined with cisplatin-sensitized chest radiotherapy as developed in the French multicentric trial on perioperative chemotherapy., Patients and Methods: Thirty-five patients with grade III non-small-cell lung cancer (NSCLC) were given two or three starter MIP cycles every 4 weeks then underwent radiation therapy for six weeks for a total dose of 60 Gy with injection of 8 mg/m(2) cisplatin every day for the first two weeks and the last two weeks of treatment. In case of objective response (OR) to MIP before radiotherapy, the MIP protocol was repeated for one to four supplementary cycles according to tolerance., Results: The rate of OR after MIP was 51% and after chemoradiotherapy it was 69%. Toxic effects were limited to one death due to aplasia and 18 cases of grade 3-4 toxicity, mainly due to hematology disorders. Moderate esophagitis was observed in ten cases. Median survival was 13.5 months. Survival rates were 57% and 29% at one and two years., Discussion: This novel scheme, which can be improved, has demonstrated its efficacy. Tolerance is satisfactory and the cost is low compared with associations using "new" drugs.

Dyspnea is the principal clinical feature of pulmonary leukostasis, a syndrome called "poumon hyperleucocytaire" in French. It is a common complication of chronic myeloid leukemia. In the course of pulmonary carcinoma, leukocytosis is frequently noted. One of the etiologies is a paraneoplastic syndrome with production of colony stimulating factor. We report a case of pulmonary hyperleukostasis following antineoplastic chemotherapy for pulmonary carcinoma.

Purpose: The pathogenesis of the sensory retinal detachment of the macula associated with congenital pit of the optic nerve remains controversal. Based on our cases and the cases reported in literature, we propose a management plan for macular retinal detachment associated with optic nerve pit., Methods: In this retrospective study ten eyes were treated for progressive visual loss. Treatment modalities were different depending on the time period: laser photocoagulation (to the juxtapapillary region) alone, laser combined with intraocular gas injection (C3 F8), laser combined with vitrectomy and intraocular gas tamponnade (S F6, C3 F8), laser combined with vitrectomy and temporary silicone oil tamponade., Results: The follow-up period ranged between one and five years (mean follow-up thirty three months). We had eight successes and two definitive failures (an old macular detachment treated only by one laser session, and a young girl who had not kept the prone position after gas injection). In the group of six eyes treated by laser alone, only two retinal treatments were directly successfully treated; in three other eyes, the detachment recurred and was treated with success in a second step by a gas injection; the sixth eye is the first definitive failure (old detachment). In the five eyes treated by laser combined gas injection with or without pars plana vitrectomy (including three failures of laser alone), the retina remained attached in four eyes during the follow-up period; the sixth eye was the second definitive failure (the young girl). In the both eyes treated by vitrectomy and silicon oil injection, the retina has flattened., Conclusion: The results suggest that laser photocoagulation alone is not so efficient and that vitrectomy is not necessary with gas injection. Complete resorption of subretinal fluid occurred in eight eyes: two with laser photocoagulation alone, and six with a long term tamponnade combined with a peripapillary laser photocoagulation. In first treatment, this technique (laser with tamponade) is a valuable approach to manage serous macular detachment associated with optic nerve pit.

The derivatives in question are prepared by reaction of substituted anilines with 1,4-ketones in an acidic medium. The diketones are themselves obtained either using Friedel and Crafts reaction with levulinic acid chloride, or by Stetter's method reacting Mannich bases with aryl aldehydes in the presence of sodium cyanide. The results of test of acute toxicity and of analgesic and anti-inflammatory activity are reported.

In order to increase the pharmacological activities of the molecules described in the first part of the paper, an acetic or a 2-propionic group was introduced in to the fundamental structure, either on the aromatic ring, on the pyrrole nitrogen or on carbon 3 of the heterocycle. Moreover, a 4-chlorobenzoyl group was fixed on carbon 3 of the pyrrole via condensation of 4-chloroaniline with 4-chlorobenzoyl triketones. The structure of the adducts was demonstrated both by N.M.R. spectra and by using another unambiguous synthetic route. Finally, derivatives with the salicylic substructure on the nitrogen of the pyrrole are described. Their analgesic and anti-inflammatory properties are reported as well as some effects on the central nervous system.