Targeting Toll-Like Receptors: Promising Therapeutic Strategies for the Management of Sepsis-Associated Pathology and Infectious Diseases.

Toll-like receptors (TLRs) are pattern recognition receptors playing a fundamental role in sensing microbial invasion and initiating innate and adaptive immune responses. TLRs are also triggered by danger signals released by injured or stressed cells during sepsis. Here we focus on studies developing TLR agonists and antagonists for the treatment of infectious diseases and sepsis. Positioned at the cell surface, TLR4 is essential for sensing lipopolysaccharide of Gram-negative bacteria, TLR2 is involved in the recognition of a large panel of microbial ligands, while TLR5 recognizes flagellin. Endosomal TLR3, TLR7, TLR8, TLR9 are specialized in the sensing of nucleic acids produced notably during viral infections. TLR4 and TLR2 are favorite targets for developing anti-sepsis drugs, and antagonistic compounds have shown efficient protection from septic shock in pre-clinical models. Results from clinical trials evaluating anti-TLR4 and anti-TLR2 approaches are presented, discussing the challenges of study design in sepsis and future exploitation of these agents in infectious diseases. We also report results from studies suggesting that the TLR5 agonist flagellin may protect from infections of the gastrointestinal tract and that agonists of endosomal TLRs are very promising for treating chronic viral infections. Altogether, TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis.

Targeted sequence capture and Ultra High Throughput sequencing for gene discovery in inherited diseases

L'introduction des technologies de séquençage de nouvelle génération est en vue de révolutionner la médecine moderne. L'impact de ces nouveaux outils a déjà contribué à la découverte de nouveaux gènes et de voies cellulaires impliqués dans la pathologie de maladies génétiques rares ou communes. En revanche, l'énorme quantité de données générées par ces systèmes ainsi que la complexité des analyses bioinformatiques nécessaires, engendre un goulet d'étranglement pour résoudre les cas les plus difficiles. L'objectif de cette thèse a été d'identifier les causes génétiques de deux maladies héréditaires utilisant ces nouvelles techniques de séquençage, couplées à des technologies d'enrichissement de gènes. Dans ce cadre, nous avons développé notre propre méthode de travail (pipeline) pour l'alignement des fragments de séquence (reads). Suite à l'identification de gènes, nous avons réalisé une analyse fonctionnelle pour élucider leur rôle dans la maladie. Dans un premier temps, nous avons étudié et identifié des mutations impliquées dans une forme récessive de la rétinite pigmentaire qui est à ce jour la dégénérescence rétinienne héréditaire la plus fréquente. En particulier, nous avons constaté que des mutations faux-sens dans le gène FAM161A étaient la cause de la rétinite pigmentaire préalablement associé avec le locus RP28. De plus, nous avons démontré que ce gène avait des fonctions au niveau du cil du photorécepteur, complétant le large spectre des cilliopathies rétiniennes héréditaires. Dans un second temps, nous avons exploré la possibilité qu'un syndrome, relativement fréquent en pédiatrie de fièvre récurrente, appelé PFAPA (acronyme de fièvre périodique avec adénite stomatite, pharyngite et cervical aphteuse) puisse avoir une origine génétique. L'étiologie de cette maladie n'étant pas claire, nous avons tenté d'identifier le spectre génétique de patients PFAPA. Comme nous n'avons pas pu mettre à jour un nouveau gène unique muté et responsable de la maladie chez tous les individus dépistés, il semblerait qu'un modèle génétique plus complexe suggérant l'implication de plusieurs gènes dans la pathologie ait été identifié chez les patients touchés. Ces gènes seraient notamment impliqués dans des processus liés à l'inflammation ce qui élargirait l'impact de ces études à d'autres maladies auto-inflammatoires.

Autoanticorps en neurologie: implications cliniques [Autoantibodies in neurological diseases: clinical implications]

Autoantibodies are defined as antibodies directed against self antigens, i.e., against a normal antigenic endogenous tissue constituent. They can be the immediate cause of the neurological syndrome or be detected as an epiphenomenon of the pathogenic process. Autoantibodies are often considered useful biomarkers for the improvement of diagnostic accuracy, for the staging of disease progression or for the follow up of a biological response to a therapeutic intervention. The purpose of this article is to review the autoantibodies that are available to investigate immune-mediated neurological conditions. The detection of some of these autoantibodies may help the clinician to establish a definite diagnosis which may further facilitate the therapeutic decision.

Management of faecal incontinence and constipation in adults with central neurological diseases.

BACKGROUND: People with neurological disease have a much higher risk of both faecal incontinence and constipation than the general population. There is often a fine dividing line between the two conditions, with any management intended to ameliorate, one risking precipitating the other. Bowel problems are observed to be the cause of much anxiety and may reduce quality of life in these people. Current bowel management is largely empirical with a limited research base. OBJECTIVES: To determine the effects of management strategies for faecal incontinence and constipation in people with neurological diseases affecting the central nervous system. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Trials Register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE and all reference lists of relevant articles. Date of the most recent searches: May 2000. SELECTION CRITERIA: All randomised or quasi-randomised trials evaluating any types of conservative, or surgical measure for the management of faecal incontinence and constipation in people with neurological diseases were selected. Specific therapies for the treatment of neurological diseases that indirectly affect bowel dysfunction have also been considered. DATA COLLECTION AND ANALYSIS: All three reviewers assessed the methodological quality of eligible trials and two reviewers independently extracted data from included trials using a range of pre-specified outcome measures. MAIN RESULTS: Only seven trials were identified by the search strategy and all were small and of poor quality. Oral medications for constipation were the subject of four trials. Cisapride does not seem to have clinically useful effects in people with spinal cord injuries (two trials). Psyllium was associated with increased stool frequency in people with Parkinson's disease but not altered colonic transit time (one trial). Some rectal preparations to initiate defecation produced faster results than others (one trial). Different time schedules for administration of rectal medication may produce different bowel responses (one trial). Mechanical evacuation may be more effective than oral or rectal medication (one trial). The clinical significance of any of these results is difficult to interpret. REVIEWER'S CONCLUSIONS: It is not possible to draw any recommendation for bowel care in people with neurological diseases from the trials included in this review. Bowel management for these people must remain empirical until well-designed controlled trials with adequate numbers and clinically relevant outcome measures become available.

Structural connectomics in brain diseases.

Imaging the connectome in vivo has become feasible through the integration of several rapidly developing fields of science and engineering, namely magnetic resonance imaging and in particular diffusion MRI on one side, image processing and network theory on the other side. This framework brings in vivo brain imaging closer to the real topology of the brain, contributing to narrow the existing gap between our understanding of brain structural organization on one side and of human behavior and cognition on the other side. Given the seminal technical progresses achieved in the last few years, it may be ready to tackle even greater challenges, namely exploring disease mechanisms. In this review we analyze the current situation from the technical and biological perspectives. First, we critically review the technical solutions proposed in the literature to perform clinical studies. We analyze for each step (i.e. MRI acquisition, network building and network statistical analysis) the advantages and potential limitations. In the second part we review the current literature available on a selected subset of diseases, namely, dementia, schizophrenia, multiple sclerosis and others, and try to extract for each disease the common findings and main differences between reports.

Relevance of death receptors in nervous system: role in the pathogenesis of neurodegenerative diseases and targets for therapy

L’apoptosi és un procés fisiològic que controla el nombre de cèl·lules en organismes superiors. L’apoptosi està estrictament regulada i s’ha vist que està implicada en la patogènesi d’algunes malalties del sistema nerviós. En aquest sentit, un excés de mort cel·lular contribueix a les malalties neurodegenerati- ves, mentre que, el seu dèficit és una de les raons del desenvolupament de tumors. El punt principal de regulació del procés apoptòtic és l’activació de les caspases, cisteïna-proteases que tenen especificitat pels residus aspàrtic. Les caspases es poden activar per dos mecanismes principals: (1) alliberament de citocrom C dels mitocondris alterats al citoplasma i (2) l’activació dels receptors de la membrana anomenats receptors de mort (DR, de l’anglès death receptor). Aquests receptors s’han caracteritzat extensament en el sistema immunitari, mentre que en el sistema nerviós les seves funcions són encara desconegudes. El present article se centra en el paper dels DR en la patogènesi de malalties neurodegeneratives i suggereix el seu potencial des del punt de vista terapèutic. També es descriuen diverses molècules intracel·lulars caracteritzades per la seva habilitat en la modulació dels DR. Entre elles, presentem dues noves proteïnes – lifeguard i FAIM – que s’expressen específicament al sistema nerviós.

Involvement of family physicians in structured programs for chronic diseases or multi-morbidity in Switzerland.

The increasing prevalence of chronic diseases and multi-morbidity represents challenges for health systems worldwide. In that perspective, the current organization of healthcare delivery, fragmentation of care, limited use of evidence-based guidelines and patients'insufficient empowerment are some reasons explaining the current limited effectiveness of the management of chronically ill patients. Based on theoretical models such as the Chronic Care Model (CCM), initiatives targeting improvements in the care of patients with chronic diseases have been implemented worldwide since more than a decade. Their development in Switzerland, a health system where more than half of practices are still single handed [6], is only recent and infrequent. Structured programs for patients with chronic diseases or multimorbidity usually propose patient-centered interventions and consider an integrative multidisciplinary approach. Currently, little is known on the existence of such programs and on the role of family physicians (FPs)within these programs, in Switzerland. The objective of this study was to identify and describe current structured programs targeting chronic diseases or multi-morbidity in Switzerland. This may help in examining innovative approaches that are only developed locally but would deserve wider interest for further implementation. We conducted a telephone-based survey between June and November 2013 and contacted systematically key institutions, informants and stakeholders nationwide and in the 26 cantons...

The JAK/STAT3 Pathway Is a Common Inducer of Astrocyte Reactivity in Alzheimer's and Huntington's Diseases.

Astrocyte reactivity is a hallmark of neurodegenerative diseases (ND), but its effects on disease outcomes remain highly debated. Elucidation of the signaling cascades inducing reactivity in astrocytes during ND would help characterize the function of these cells and identify novel molecular targets to modulate disease progression. The Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is associated with reactive astrocytes in models of acute injury, but it is unknown whether this pathway is directly responsible for astrocyte reactivity in progressive pathological conditions such as ND. In this study, we examined whether the JAK/STAT3 pathway promotes astrocyte reactivity in several animal models of ND. The JAK/STAT3 pathway was activated in reactive astrocytes in two transgenic mouse models of Alzheimer's disease and in a mouse and a nonhuman primate lentiviral vector-based model of Huntington's disease (HD). To determine whether this cascade was instrumental for astrocyte reactivity, we used a lentiviral vector that specifically targets astrocytes in vivo to overexpress the endogenous inhibitor of the JAK/STAT3 pathway [suppressor of cytokine signaling 3 (SOCS3)]. SOCS3 significantly inhibited this pathway in astrocytes, prevented astrocyte reactivity, and decreased microglial activation in models of both diseases. Inhibition of the JAK/STAT3 pathway within reactive astrocytes also increased the number of huntingtin aggregates, a neuropathological hallmark of HD, but did not influence neuronal death. Our data demonstrate that the JAK/STAT3 pathway is a common mediator of astrocyte reactivity that is highly conserved between disease states, species, and brain regions. This universal signaling cascade represents a potent target to study the role of reactive astrocytes in ND.

Zoonotic occupational diseases in forestry workers: Lyme borreliosis, tularemia and leptospirosis in Europe

INTRODUCTION: Forestry workers and other people who come into close contact with wild animals, such as hunters, natural science researchers, game managers or mushroom/berry pickers, are at risk of contracting bacterial, parasitological or viral zoonotic diseases. Synthetic data on the incidence and prevalence of zoonotic diseases in both animals and humans in European forests do not exist. It is therefore difficult to promote appropriate preventive measures among workers or people who come into direct or indirect contact with forest animals. OBJECTIVES: The objectives of this review are to synthesise existing knowledge on the prevalence of the three predominant bacterial zoonotic diseases in Europe, i.e. Lyme borreliosis, tularemia and leptospirosis, in order to draw up recommendations for occupational or public health. METHODS: 88 papers published between 1995-2013 (33 on Lyme borreliosis, 30 on tularemia and 25 on leptospirosis) were analyzed. CONCLUSIONS: The prevalences of these three zoonotic diseases are not negligible and information targeting the public is needed. Moreover, the results highlight the lack of standardised surveys among different European countries. It was also noted that epidemiological data on leptospirosis are very scarce.

Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative.

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Excess winter deaths caused by cardiovascular diseases are associated with both mild winter temperature and socio-economic inequalities in the U.S.

Mortality from cardiovascular diseases (CVD) exhibits seasonal variation. For example, 30% more deaths occurred in winter compared to summer in a multicountry study [1]. The effect of cold temperature on several CVD risk factors and on seasonal influenza infection may partially underlie this seasonal variation [2] and [3]. However an unexplained paradox has been observed: seasonality in CVD mortality is larger in temperate mid-latitude countries (e.g. Portugal) than in colder northern countries (e.g. Scandinavian countries) [1]. This paradox has also been previously observed in Europe for overall mortality, and it may relate to uneven proportions between countries of people who are unable to adequately protect themselves against cold due to low socio-economic status (SES), e.g. inadequate clothing, housing insulation and heating systems [4] and [5]. We hypothesized that the seasonal variability in CVD mortality is larger in low socio-economic U.S. states experiencing mild winters compared to high socio-economic states experiencing cold winters.

Diffusion-weighted MR imaging in musculoskeletal diseases: Current concepts.

MR imaging is currently regarded as a pivotal technique for the assessment of a variety of musculoskeletal conditions. Diffusion-weighted MR imaging (DWI) is a relatively recent sequence that provides information on the degree of cellularity of lesions. Apparent diffusion coefficient (ADC) value provides information on the movement of water molecules outside the cells. The literature contains many studies that have evaluated the role of DWI in musculoskeletal diseases. However, to date they yielded conflicting results on the use and the diagnostic capabilities of DWI in the area of musculoskeletal diseases. However, many of them have showed that DWI is a useful technique for the evaluation of the extent of the disease in a subset of musculoskeletal cancers. In terms of tissue characterization, DWI may be an adjunct to the more conventional MR imaging techniques but should be interpreted along with the signal of the lesion as observed on conventional sequences, especially in musculoskeletal cancers. Regarding the monitoring of response to therapy in cancer or inflammatory disease, the use of ADC value may represent a more reliable additional tool but must be compared to the initial ADC value of the lesions along with the knowledge of the actual therapy.

Buccodental health and oral mucositis. Clinical study in patients with hematological diseases

Objectives: The objective of the present study is to assess whether a good buccodental status (evaluated by means of dentogingival indices), is associated with a lower incidence and severity of oral mucositis in patients with hematological diseases who receive treatment with chemotherapy or bone marrow transplant. Study design: The study was carried out on 97 patients admitted to the Hematology Service of the Hospital Duran y Reynals in Barcelona during 2002-2003. These patients received treatment with chemotherapy or conditioning prior to bone marrow transplant. A descriptive study was made, analyzing oral hygiene, one dental index, and two gingivales indices, and evaluating their relationship with the appearance of mucositis. Results: The patients with high plaque (PI) and gingival (GI) indices during chemotherapy presented a higher percentage of mucositis (77.4% and 65.7% respectively) against those who had little or no visible plaque. In the case of the PI, the differences were statistically significant (p=0.015). Likewise, patients who brushed their teeth 3 times/day presented mucositis in only 26.7% of cases, against those who did not brush, or brushed only once a day (65.9% and 68.4%), these differences also being statistically significant (p=0.013). The CAO showed similar results in patients with or without mucositis (7.59 and 7.03 respectively). Conclusions: In our study, a good gingival status as well as good oral hygiene during chemoradiotherapy is associated with a lower incidence and severity of mucositis.

LC-MS/MS based assay and reference intervals in children and adolescents for oxysterols elevated in Niemann-Pick diseases.

BACKGROUND: Niemann-Pick type C (NP-C) is a rare progressive neurodegenerative lipid storage disorder with heterogeneous clinical presentation and challenging diagnostic procedures. Recently oxysterols have been reported to be specific biomarkers for NP-C but knowledge on the intra-individual variation and on reference intervals in children and adolescents are lacking. METHODS: We established a LC-MS/MS assay to measure Cholestane-3β, 5α, 6β-triol (C-triol) and 7-Ketocholesterol (7-KC) following Steglich esterification. To assess reference intervals and intra-individual variation we determined oxysterols in 148 children and adolescents from 0 to 18 years and repeat measurements in 19 of them. RESULTS: The reported method is linear (r>0.99), sensitive (detection limit of 0.03 ng/mL [0.07 nM] for C-triol, and 0.54 ng/mL [1.35 nM] for 7-KC) and precise, with an intra-day imprecision of 4.8% and 4.1%, and an inter-day imprecision of 7.0% and 11.0% for C-triol (28 ng/ml, 67 nM) and 7-KC (32 ng/ml, 80 nM), respectively. Recoveries for 7-KC and C-triol range between 93% and 107%. The upper reference limit obtained for C-triol is 40.4 ng/mL (95% CI: 26.4-61.7 ng/mL, 96.0 nM, 95% CI: 62.8-146.7 nM) and 75.0 ng/mL for 7-KC (95% CI: 55.5-102.5 ng/mL, 187.2 nM, 95% CI: 138.53-255.8 nM), with no age or gender dependency. Both oxysterols have a broad intra-individual variation of 46%±23% for C-triol and 52%±29% for 7-KC. Nevertheless, all Niemann-Pick patients showed increased C-triol levels including Niemann-Pick type A and B patients. CONCLUSIONS: The LC-MS/MS assay is a robust assay to quantify C-triol and 7-KC in plasma with well documented reference intervals in children and adolescents to screen for NP-C in the pediatric population. In addition our results suggest that especially the C-triol is a biomarker for all three Niemann-Pick diseases.