Surface Structure Characterization of Aspergillus fumigatus Conidia Mutated in the Melanin Synthesis Pathway and Their Human Cellular Immune Response

In Aspergillus fumigatus, the conidial surface contains dihydroxynaphthalene (DHN)-melanin. Six-clustered gene products have been identified that mediate sequential catalysis of DHN-melanin biosynthesis. Melanin thus produced is known to be a virulence factor, protecting the fungus from the host defense mechanisms. In the present study, individual deletion of the genes involved in the initial three steps of melanin biosynthesis resulted in an altered conidial surface with masked surface rodlet layer, leaky cell wall allowing the deposition of proteins on the cell surface and exposing the otherwise-masked cell wall polysaccharides at the surface. Melanin as such was immunologically inert; however, deletion mutant conidia with modified surfaces could activate human dendritic cells and the subsequent cytokine production in contrast to the wild-type conidia. Cell surface defects were rectified in the conidia mutated in downstream melanin biosynthetic pathway, and maximum immune inertness was observed upon synthesis of vermelone onward. These observations suggest that although melanin as such is an immunologically inert material, it confers virulence by facilitating proper formation of the A. fumigatus conidial surface.     

Douleur chronique : la place du psychiatre

Objectives

Chronic pain affects nineteen percent of the European adult population and its impact on morbidity is major. Considering psychosocial factors allows improving functional re-establishment. Psychiatric comorbidities are under-diagnosed and worsen the prognosis. The psychiatrist has an important role to play in the assessment and treatment of these subjects.

Methods

We will detail the relationship between chronic pain and some psychiatric diseases as well as their psychological and biological correlation. Then, we will discuss the therapeutic implements available to the psychiatrist.

Results

We have to distinguish the psychosomatic disorders, which is a somatic disorder closely intertwined with a psychic disorder, from the somatoform disorder which is a body complaint to indicate a psychosocial distress. These disorders induce huge medico-economic costs: high prevalence and wrong care pathways, rarely using the psychiatrist expertise. The subjects with post-traumatic disorder combined with chronic pain have more severe post-traumatic symptoms with greater functional impairment. Twenty to fifty percent of subjects suffering of chronic pain have a depressive syndrome and fifty percent of the depressed subjects complain about chronic pain. Their symptoms are more numerous, more intense and longer lasting. Regardless of the used assessment tools, there are more pathological personality traits in chronic pain subjects with heterogeneous profiles than in general population which is useful for offering more targeted therapeutic strategies. Neurobiological integration of painful experience is based on two components : A somatosensory component (S1 and S2 areas) and an affective component with a central role of the anterior cingulate cortex. Functional dysfunctions involved in chronic pain affects the affective component of the pain experience and this component can be modulated. The psychiatrist should definitely avoid psychological explanation for the pain. He should focus on a multidisciplinary approach with partnership and complementarity. Its assessment identifies involved psychosocial factors, not for disqualifying the complaint but for considering all its aspects. Among drug treatments, antidepressants have a specific analgesic action particularly for IRS and MAOIs. Among non-drug treatments, reconditioning through physical activity combined or not with behavioral experiments can be associated with psycho education. Mindfulness, therapy of acceptance and commitment are used to promote voluntary consciousness of the body, of the pain and of thoughts. In some situations, transcranial magnetic stimulation can provide a useful aid. Analytical inspired therapies allow the subjects who are questioning about the meaning of the pain, better understanding a broader suffering.

Conclusion

Chronic pain is closely linked to some psychiatric disorders. We should propose specific therapeutic strategies to each patient and the psychiatrist should be involved in assessment and treatment of chronic pain. In particular, the fear related to pain should be always assessed and supported. There are drug and non-drug strategies available for the psychiatrist to help taking care of these patients.     

Investigating the role of FUS exonic variants in Essential Tremor

Essential Tremor is the most common form of movement disorder. Aggregation in families suggests a strong genetic component to disease. Linkage and association studies have identified several risk loci but the specific causal variants are still unknown. A recent study using whole exome sequencing identified a rare nonsense variant in the FUS gene (p.Q290X) that segregated with Essential Tremor in a large French Canadian family. In addition, two other rare FUS variants were identified (p.R216C and p.P431L) in Essential Tremor patients however co-segregation analysis with disease was not possible. In the present study, we sequenced all 15 exons of FUS in 152 familial probands with Essential Tremor and genotyped three reported FUS variants in 112 sporadic Essential Tremor patients and 716 control subjects recruited at Mayo Clinic Florida. Only known synonymous SNPs unlikely to be pathogenic were detected in our sequencing and not any of the recently identified mutations or novel ones. We conclude that the FUS mutations associated with risk of Essential Tremor are probably a rare occurrence.     

The Minimum Clinically Important Difference in the Repeatable Battery for the Assessment of Neuropsychological Status

Objective: There is no established minimum clinically important difference (MCID) for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) index and total scale scores. This study aimed to estimate the MCID for the RBANS index scores and total scale score. Method: Participants included 1,856 ethnic Chinese, older adults. Distribution- and anchor-based methods were used to estimate values for the MCID. Distribution-based estimates were calculated as the standard error of measurement (SEM) and .5 standard deviations (SD). For anchor-based estimates, we compared RBANS scores between the clinical dementia rating (CDR) scale no dementia and very mild dementia groups and between the clinical assessment of dementia (CAD) cognitively normal and mild cognitive impairment groups using regression models adjusting for demographic characteristics. Results: Estimates from the CDR anchor were 7.79, 8.63, 10.74, 9.74, 5.61, and 3.77 for the total scale score, language, immediate memory, delayed memory, visuospatial/constructional, and the attention index, respectively. Estimates from the distribution-based methods were similar to the estimates based on the CDR, except for the language and attention indexes. Estimates from the CAD anchor were larger. Conclusions: We estimated the MCID for the total scale score, language, immediate memory, delayed memory, visuospatial/constructional, and attention indexes of the RBANS as 8, 9, 10, 10, 6, and 4 points, respectively. These estimates are best suited to discriminate between patient groups, for example, in a clinical trial setting. Further research is needed using longitudinal data to assess their applicability to assess within patient differences.     

Neuropathological features in a female fetus with OPHN1 deletion and cerebellar hypoplasia

We report the case of a 33-year-old pregnant woman. The third-trimester ultrasound scan during pregnancy revealed fetal bilateral ventricular dilatation, macrosomia and a transverse diameter of the cerebellum at the 30th centile. A brain MRI scan at 31 weeks of gestation led to a diagnosis of hypoplasia of the cerebellar vermis without hemisphere abnormalities and a non compressive expansion of the cisterna magna. The fetal karyotype was 46,XX. The pregnancy was terminated and array-CGH analysis of the fetus identified a 238 kb de novo deletion on chromosome Xp12, encompassing part of OPHN1 gene. Further studies revealed a completely skewed pattern of X inactivation. OPHN1 is involved in X-linked mental retardation (XLMR) with cerebellar hypoplasia and encodes a Rho-GTPase-activating protein called oligophrenin-1, which is produced throughout the developing mouse brain and in the hippocampus and Purkinje cells of the cerebellum in adult mice. Neuropathological examination of the female fetus revealed cerebellar hypoplasia and the heterotopia of Purkinje cells at multiple sites in the white matter of the cerebellum. This condition mostly affects male fetuses in humans. We report here the first case of a de novo partial deletion of OPHN1, with radiological and neuropathological examination, in a female fetus.     

The psychological impact of cryptic chromosomal abnormalities diagnosis announcement

This qualitative study aims to describe the psychological impact of the diagnosis announcement of pathogenic Copy Number Variations (pCNVs). We performed semi-structured interviews of 60 parents of 41 affected children and 5 geneticists who announced the diagnoses. The diagnosis of the best characterized microdeletion syndromes, often defined by patronymic names (e.g. Williams syndrome), is generally made on a clinical basis by geneticists and confirmed by fluorescence in situ hybridization analysis. Chromosomal microarray, on the contrary, can allow the disclosure of rare pCNVs named after cytogenetic formulas, with poorly known clinical consequences: this makes doctors feel less confident with these diagnosis announcements. The disclosure of pCNVs named after cytogenetic formulas does not facilitate the parental mental representation of the disease, leading some parents to call into question the genotype-phenotype correlation or the very notion of a diagnosis. The announcement of inherited pCNVs can increase the feeling of parental guilt; the disclosure of de novo pCNVs can induce a feeling of “breakage” in the mental representation of the parent-child vertical transmission. In conclusion, our study shows that the disclosure of pCNVs has a significant psychological impact: a multidisciplinary approach to the diagnosis announcement, including a psychological support, should be systematically warranted.