Psychological impact of COVID-19 containment on CADASIL patients.

INTRODUCTION: COVID-19 restrictive containment was responsible for major psychological distress and alteration of quality of life (QoL) in the general population. Their impact in a group of patients having cerebral small vessel disease (SVD) and at high risk of stroke and disability was unknown. OBJECTIVE: We aimed to determine the potential psychological impact of strict containment during the COVID-19 pandemic in a sample of CADASIL patients, a rare SVD caused by NOTCH3 gene mutations. METHODS: Interviews of 135 CADASIL patients were obtained just after the end of the strict containment in France. Depression, QoL and negative subjective experience of the containment were analysed, as well as predictors of posttraumatic and stressor-related manifestations, defined as an Impact Event Scale-Revised score ≥ 24, using multivariable logistic analysis. RESULTS: Only 9% of patients showed a depressive episode. A similar proportion had significant posttraumatic and stressor-related disorder manifestations independently associated only with socio-environment factors, rather than clinical ones: living alone outside a couple (OR 7.86 (1.87-38.32), unemployment (OR 4.73 (1.17-18.70)) and the presence of 2 or more children at home (OR 6.34 (1.35-38.34). CONCLUSION: Psychological impact of the containment was limited in CADASIL patients and did not appear related to the disease status. About 9% of patients presented with significant posttraumatic and stressor-related disorder manifestations which were predicted by living alone, unemployment, or exhaustion related to parental burden.

Two new flavone glycosides from the leaves of Ochna afzelii Oliv. (Ochnaceae).

Two new glycosylflavones, 6''-O-acetyl-8-C-ß-D-galactopyranosylchrysoeriol (1) and 8-C-ß-D-galactopyranosylchrysoeriol (2) were isolated from the methanol extract of the leaves of Ochna afzelii Oliv., along with four known compounds namely 8-C-ß-D-galactopyranosylapigenin (3), ochnaflavone (4), sitosterol-3-O-ß-D-glucopyranoside (5) and D-mannitol (6). Isolation was performed chromatographically and the structures of the purified compounds were elucidated by analyzing their spectroscopic and mass spectrometric data. The antibacterial activity of extract, fractions, and compounds 1 - 4 was evaluated using broth microdilution method against Gram-positive and Gram-negative bacteria while the antioxidant capacity was performed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the ferric reducing antioxidant power (FRAP) methods. The new flavones (1 and 2) displayed moderate antibacterial activities (MIC = 32 - 64 µg/mL) and weak antioxidant properties.

The Epidermal Growth Factor Domain of the Mutation Does Not Appear to Influence Disease Progression in CADASIL When Brain Volume and Sex Are Taken into Account.

BACKGROUND AND PURPOSE: By studying the evolution of brain volume across the life span in male and female patients, we aimed to understand how sex, brain volume, and the epidermal growth factor repeat domain of the mutation, the 3 major determinants of disability in CADASIL, interact in driving disease evolution. MATERIALS AND METHODS: We used validated methods to model the evolution of normalized brain volume with age in male and female patients using nonparametric regression in a large, monocentric cohort with prospectively collected clinical and high-resolution MR imaging data. We used k-means clustering to test for the presence of different clinical course profiles. RESULTS: We included 229 patients (mean age, 53 [SD, 12] years; 130 women). Brain volume was larger in women (mean size, 1024 [SD, 62] cm3 versus 979 [SD, 50] cm3; P < .001) and decreased regularly. In men, the relationship between brain volume and age unexpectedly suggested an increase in brain volume around midlife. Cluster analyses showed that this finding was related to the presence of a group of older male patients with milder symptoms and larger brain volumes, similar to findings of age-matched women. This group did not show specific epidermal growth factor repeat domain distribution. CONCLUSIONS: Our results demonstrate a detrimental effect of male sex on brain volume throughout life in CADASIL. We identified a subgroup of male patients whose brain volume and clinical outcomes were similar to those of age-matched women. They did not have a specific distribution of the epidermal growth factor repeat domain, suggesting that yet-unidentified predictors may interact with sex and brain volume in driving disease evolution.

Entomopathogenic Fungi as Endophytes for Biological Control of Subterranean Termite Pests Attacking Cocoa Seedlings.

This study was conducted in the scope of developing a sustainable effective approach against subterranean termite pests using entomopathogenic and endophytic fungus-based biopesticides. Termites, Odontotermes spp. workers, were tested for their susceptibility to 15 entomopathogenic fungal isolates through the direct spraying of conidia suspensions at 1 × 108 conidia/mL. In general, all the isolates screened were pathogenic, with 100% mortality 4-7 days post-inoculation. However, the most virulent isolates were Metarhizium brunneum Cb15-III; the M. anisopliae isolates ICIPE 30 and ICIPE 60; Hypocrea lixii F3ST1; and the Beauveria bassiana isolates ICIPE 279, ICIPE 706 and ICIPE 662. These isolates were further tested for their endophytic colonization of cocoa seedlings using seed soaking, soil drench and foliar spray at 1 × 108 conidia/mL. The colonization of the plant tissues by the fungi was determined using a culture-based technique. Only the B. bassiana isolates ICIPE 706 and ICIPE 279, and H. lixii F3ST1 colonized the cocoa seedlings, with varied colonization rates among isolates and inoculation methods. Three naturally occurring endophytes-Trichoderma asperellum, Fusarium solani and F. redolens-were also isolated from the cocoa seedling tissues. These findings suggest that cocoa seedlings are conducive to endophytic fungal growth either occurring naturally or from artificial inoculation Our findings could possibly lead to an innovative approach to the management of herbivory and subterranean termite pests in cocoa agroforests.

[Coronary artery spasm revealed by an out-of-hospital cardiac arrest associated with a moyamoya disease. A case report of multimodality imaging]. / Arrêt cardiaque par spasme coronaire associé à une maladie de Moyamoya. Apport de l'imagerie cardiaque multimodale.

Moyamoya disease is a rare angiopathy characterized by a progressive distal occlusion of the internal carotid arteries and their branches. Extracerebral involvement, including coronary arteries, has been described. We report the case of a patient with moyamoya disease who suffered an out-of-hospital cardiac arrest associated with coronary spasm. We discussed the possible links between coronary spasm and moyamoya, as well as the contribution of multimodal cardiac imaging, combining conventional and intracoronary imaging, cardiac MRI, provocative tests for spasm, in the exploration of out-of-hospital cardiac arrest without obvious electrocardiographic and angiographic cause.

Impact of a sports project centered on scuba diving for adolescents with type 1 diabetes mellitus: New guidelines for adolescent recreational diving, a modification of the French regulations.

BACKGROUND: Recreational scuba diving has been authorized for type 1 diabetics over 18 years old - the age of majority in France - since 2004, but it remained forbidden for younger diabetics by the French underwater federation (FFESSM). Here, we present a study to evaluate: - the conditions under which diving could be authorized for 14- to 18 year olds with type 1 diabetes; - the value of continuous glucose monitoring (CGM) while diving. A secondary objective was to monitor the impact of diving on the teenagers' quality of life. SUBJECT AND METHODS: Sixteen adolescents (14-17.5 years old) were included. Diabetes was known for 6 years (range, 1-14) and Hb1Ac was 9.0% (range, 7.7-11.9). The study was conducted in Mayotte with both capillary glycemia (CG) and CGM measurements taken during five dives. RESULTS: The average CG prior to diving was 283mg/dL and decreased by 75±76mg/dL during the dive. No hypoglycemia occurred during the dives and four episodes occurred after. Glycemia variations during dives and for the overall duration of the study were greater than for adults, most likely due to the general adolescent behavior, notably regarding diet and diabetes management. CGM was greatly appreciated by the adolescents. They had an overall satisfactory quality of life. No significant variations were observed during the entire course of the study. CONCLUSIONS: Although in need of further studies, these preliminary results show that CGM can be used while diving. CGM records show a continuous decrease of glycemia during dives. Based on these results, the French underwater federation has now authorized diving for adolescent type 1 diabetics following a specific diving protocol that includes HbA1c<8.5%, autonomous management of diabetes by the adolescent, reduction of insulin doses, and target glycemia prior to the dive>250mg/dL.

Cryptogenic mechanism in ischaemic stroke patients is a predictor of 5-year survival: A population-based study.

INTRODUCTION: The present study sought to identify factors affecting mortality beyond 28 days in ischaemic stroke patients with whatever ischaemic mechanism. PATIENTS AND METHODS: A prospective population-based registry was set up in Brest County, Brittany, France. Demographic data, clinical presentation, vascular risk factors and mortality were collected from January 2008 to December 2012. At "home without help" was used as a surrogate marker for low Rankin (0-1) at discharge from the hospital. IS was classified on the TOAST classification. Overall mortality was calculated using the Kaplan-Meier method. Multivariate analysis of mortality beyond 28 days was implemented, using a Cox model, on significant risk factors identified on univariate analysis. RESULTS: About 3024 IS cases were followed up beyond 28 days. Overall mortality beyond 28 days was 38.49% at 60 months. On multivariate analysis, age (10 years: HR = 1.84; [1.66-2.02]), coronary artery disease (HR = 1.28; [1.05-1.56]), cardiac arrhythmia (HR = 1.36; [1.11-1.67]), peripheral artery disease (HR = 1.66 [1.29-2.13]) and incomplete assessment (HR = 1.39; [1.12-1.74]) were associated with higher mortality risk, whereas female gender (HR = 0.80; [0.68-0.94]), high Glasgow Coma Scale score (GCS > 12) (HR = 0.58; [0.45-0.76]), lacunar syndrome (HR = 0.82; [0.68-0.99], being 'at home without help' (HR = 0.50; [0.41-0.59]) and negative assessment (HR = 0.75; [0.58-0.97], compared to cardioembolism) were associated with better survival probability. DISCUSSION: Initial clinical status, prior cardiovascular diseases and age was associated with more risk of death: an increment of 10 years almost doubled mortality. Women had more survival probability than men, controlling for age. Ischaemic stroke mechanisms were predictors of late 5-year mortality. CONCLUSION: Patients with negative assessment, i.e. representing truly cryptogenic ischaemic stroke, had the best survival probability probably due to fewer atherosclerotic markers.

Functional outcome of prolonged refractory status epilepticus.

INTRODUCTION: To characterize etiology, clinical course and outcomes of patients in prolonged refractory status epilepticus (PRSE) and looking for prognostic factors. METHODS: Retrospective study conducted in patients hospitalized from January 1, 2001 to December 31, 2011 in 19 polyvalent intensive care units in French university and general hospitals. Patients were adults with a generalized convulsive refractory status epilepticus that lasted more than seven days, despite treatment including an anesthetic drug and mechanical ventilation. Patients with anoxic encephalopathy were excluded. Follow-up phone call was used to determine functional outcome using modified Rankin Scale (mRS) with mRS 0-3 defining good and mRS 4-6 poor outcome. RESULTS: 78 patients (35 female) were included. Median age was 57 years. Causes of status epilepticus were various, mainly including prior epilepsy (14.1%), CNS infection (12.8%), and stroke (12.8%). No etiology was found in 27 (34.6%) patients. PRSE was considered controlled in only 53 (67.9%) patients after a median duration of 17 (IQR 12-26) days. The median length of ICU stay was 28 (19-48) days. Forty-one (52.5%) patients died in the ICU, 26 from multiple organ failure, 8 from care withdrawal, 2 from sudden cardiac arrest, 1 from brain death and 4 from unknown causes. PRSE was previously resolved in 20 patients who died in the ICU. At one-year follow-up, there were 12 patients with good outcome and 58 with poor outcome and 8 lost of follow-up. On multivariate analysis, only vasopressor use was a predictor of poor outcome (OR 6.54; 95%CI 1.09-39.29; p = 0.04). CONCLUSION: Poor outcome was observed in about 80% of this population of PRSE. Most patients died from systemic complications linked to their ICU stay. Some patients can recover satisfactorily over time though we did not identify any robust factor of good outcome.

Dopaminergic regulation of olfactory type G-protein α subunit expression in the striatum.

BACKGROUND: In rodents, the olfactory type G-protein α subunit (Gαolf) couples the dopamine D1 receptor (D1R) to adenylyl cyclase, triggering intracellular signaling and neuronal activation. In the striatum, Gαolf is enriched in the striosomes. Changes in Gαolf protein levels have been observed after dopamine depletion. However, the regulation of Gαolf expression by dopamine and dopamine receptors is not fully understood. METHODS: To address this, Striatal Gαolf expression pattern was studied in wild-type and genetically engineered mice lacking D1R, D2R (D2 receptor), and downstream regulatory element antagonist modulator (DREAM) protein whose dopamine levels were manipulated. Dopamine depletion was accomplished by 6-hydroxydopamine (6-OHDA) or by Pitx3 ablation, and dopamine replacement by chronic levodopa (l-dopa). The Gαolf levels were analyzed by immunohistochemistry, Western blot, and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Our results demostrate that Dopamine depletion or inactivation of D1R abolished the striosomal pattern of Gαolf expression and increased Gαolf protein levels. Dopamine replacement in wild-type lesioned mice reestablished both the expression pattern and protein levels, but paradoxically increased Gαolf messenger RNA (mRNA). In D1R(-/-) mice, dopamine depletion decreased striatal Gαolf expression, whereas l-dopa did not restore either Gαolf levels or its expression pattern. Inactivation of D2R or changes in the cAMP/PKA signaling pathway downstream of Gαolf did not modify its expression. CONCLUSION: Our results show a homeostatic, negative regulation of Gαolf by dopamine and by D1R stimulation, which are also required for the striosomal Gαolf pattern. These results shed light on the regulation of Gαolf by dopamine signaling that could be involved in the pathophysiology of the maladaptive response to chronic l-dopa treatment in Parkinson's disease.

Presymptomatic genetic testing in CADASIL.

Genetic counselling has been poorly investigated in cerebrovascular diseases. Characteristics, motivations and long-term outcome of presymptomatic tests (PT) in subjects at risk of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) were investigated at the National Centre for Rare Vascular Diseases of the Brain and/or Retina (CERVCO). Sociodemographic, motivational and psychological variables were collected between 2003 and 2010 for PT applicants. Multidisciplinary consultations (with a geneticist, neurologist and psychologist) were proposed over a 6 month period. When PT showed a deleterious mutation of the NOTCH3 gene, cognitive performances, mood, autonomy and quality of life were also assessed. Over 7 years, only 33 subjects asked for a PT of CADASIL. They were predominantly women, lived as a couple, had children and were of high sociocultural level. The dropout rate after the first step of the procedure was 63%. The characteristics of the 11 subjects who reached the end of the procedure did not differ from the 22 who dropped out. Six were carriers of the deleterious mutation and were still asymptomatic after a mean follow-up of 19 months. They did not experience any particular negative event and all of them indicated a high score of overall quality of life. Indeed, two carriers gave birth to their first child. These initial data in CADASIL show that PT is rarely requested and that there is a high dropout rate. Our study also highlights that a multidisciplinary and multistep procedure in genetic counselling testing appears useful to obtain minimal harmful consequences of genetic testing.

Paediatric moyamoya in mainland France: a comprehensive survey of academic neuropaediatric centres.

BACKGROUND: Epidemiological data of paediatric moyamoya disease/syndrome (MMD/MMS) in non-Asian populations are scarce. METHODS: A questionnaire was sent to every French neuropaediatric academic centre to estimate the prevalence, incidence, familial form rate and location of paediatric MMD/MMS cases. Specific paediatric data were also retrieved from the most recent nationwide Japanese study. RESULTS: A 100% response rate was obtained. The prevalence of paediatric MMD/MMS was estimated at 0.39/100,000 children (95% CI: 0.28-0.49), and the incidence was estimated at 0.065/100,000 children/year (95% CI: 0.025-0.12), with 7.5% familial cases. The prevalence was homogenous within the different administrative areas. CONCLUSIONS: This comprehensive survey of MMD/MMS in academic neuropaediatric centres suggests that the prevalence of the disease in children in France is approximately 1/20th of that estimated in Asia.

Diagnosis of fetal urinary tract malformations: prenatal management and postnatal outcome.

OBJECTIVE: To evaluate prenatal management and to define the criteria of gravity for accurate assessment of the renal and overall prognosis of fetuses presenting malformations of the urinary tract. METHODS: We carried out a retrospective study of 127 cases of urinary tract malformation. We carried out descriptive statistical and univariate analyses as a function of severity criteria and the outcome of pregnancy. RESULTS: One-third of fetuses presented associated extrarenal malformations and 10% of the karyotypes were abnormal. There were more abortions in case of decrease in amniotic fluid volume (p < 0.001), extent of renal damage (p < 0.05), presence of associated extrarenal malformations (p < 0.05), early diagnosis of the malformation (p < 0.001) and presence of chromosomal syndrome (p = 0.01). In our study, there was an excellent correlation between prenatal data and pathological findings for the fetus following abortions for medical reasons or obtained during the surveillance of live-born children. Fetal biochemistry made very little contribution. CONCLUSION: In cases of urinary tract malformation, this work confirms the need for regular and frequent ultrasound scans, checking for the echographic factors indicative of gravity and for adapted karyotyping. It also demonstrates that pluridisciplinary management is necessary for the prenatal evaluation of renal and overall fetal prognosis.

Apathy is related to cortex morphology in CADASIL. A sulcal-based morphometry study.

OBJECTIVES: Apathy is a debilitating symptom in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the pathophysiology of which remains poorly understood. The aim of this study was to evaluate the neuroanatomic correlates of apathy, using new MRI postprocessing methods based on the identification of cortical sulci, in a large cohort of patients with CADASIL. METHODS: A total of 132 patients with genetically confirmed diagnosis were included in this prospective cohort study. Global cognitive performances were assessed by the Mattis Dementia Rating Scale (MDRS) and disability by the modified Rankin score (mRS). Apathy was defined according to standard criteria. Depth, width, and cortical thickness of 10 large sulci of the frontal lobe in each hemisphere were measured. Logistic regression modeling was used to evaluate the links between apathy and cortical thickness, depth, or width of the different sulci. All models were adjusted for age, gender, level of education, MDRS, mRS, depression, and global brain volume. RESULTS: Complete MRI datasets of high quality were available in 119 patients. Depth of the posterior cingulate sulcus exhibited the strongest association with apathy in fully adjusted models (right: p value = 0.0006; left: p value = 0.004). Depth and width of cortical sulci in mediofrontal and orbitofrontal areas were independently associated with apathy. By contrast, cortical thickness was not. CONCLUSIONS: Cortical morphology in mediofrontal and orbitofrontal areas, by contrast to cortical thickness, is strongly and independently associated with apathy. These results suggest that apathy is related to a reduction of cortical surface rather than of cortical thickness secondary to lesion accumulation in CADASIL.

Verbal memory impairment in subcortical ischemic vascular disease: a descriptive analysis in CADASIL.

In the elderly, the high prevalence of Alzheimer's disease neuropathology presents a major challenge to the investigation of memory decline in common diseases such as small vessel disease. CADASIL represents a unique clinical model to determine the spectrum of memory impairment in subcortical ischemic vascular dementia (SIVD). One hundred and forty CADASIL patients underwent detailed clinical, neuropsychological and imaging analyses. The Free and Cued Selective Reminding Test was used as a measure of verbal memory. Forty-four out of 140 CADASIL patients (31.4%) presented with memory impairment according to this test. Eight out of 44 (18.2%) subjects with memory impairment matched the definition of the amnestic syndrome of hippocampal type. While alterations in spontaneous recall were related to the severity of subcortical ischemic lesions, the profile of memory impairment, particularly the sensitivity to cueing was found related to other factors such as hippocampal atrophy.

CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a dominantly inherited small artery disease that leads to dementia and disability in mid-life. The clinical presentation of CADASIL is variable between and within affected families and is characterized by symptoms including migraine with aura, subcortical ischemic events, mood disturbances, apathy, and cognitive impairment. The mean age at onset of symptoms is 45 years, with variable duration of the disease ranging from 10 to 40 years. In 1996, linkage studies mapped and identified mutations in the NOTCH3 gene on chromosome 19 as causative in CADASIL. Head magnetic resonance imaging (MRI) is always abnormal in participants with NOTCH3 mutations after age 35. Magnetic resonance imaging shows on T2-weighted images or fluid attenuation inversion recovery (FLAIR) sequence, widespread areas of increased signal in the white matter associated with focal hyperintensities in basal ganglia, thalamus, and brainstem. The pathologic hallmark of CADASIL is the presence of electron-dense granules in the media of arterioles that can be identified by electron microscopic evaluation of skin biopsies.

A hereditary moyamoya syndrome with multisystemic manifestations.

OBJECTIVE: We report a detailed description of a family affected by a hereditary multisystem disorder associated with moyamoya syndrome. METHODS: In this family case report, we evaluated 9 members of the same family originating from Algeria. Investigations included neuroimaging, cardiologic and ophthalmologic evaluation, hormonal testing, hemoglobin electrophoresis, chromosomal karyotyping, muscle biopsy for morphology, immunohistochemistry and enzyme assays, mtDNA mutation screening, and haplotype analysis of 2 loci previously linked to moyamoya, on chromosomes 10 (ACTA2) and 17. RESULTS: Five males related through a maternal lineage were affected, suggesting an X-linked inheritance. Four of them had symptomatic moyamoya syndrome with an onset of acute neurologic manifestations between 4 and 32 years. Hypergonadotropic hypogonadism, azoospermia, short stature of postnatal onset (-2 to -4 SD in adulthood), premature graying of hair, and dysmorphism were present in all patients. The other features of the disease included early cataract in 4, dilated cardiomyopathy in 3, and partial growth hormone deficiency in 2 members. Muscle biopsy data did not reveal signs of a mitochondrial disorder. All conditions known to be associated with moyamoya syndrome such as Down syndrome, neurofibromatosis, and sickle cell disease were excluded. We also excluded linkage to the 2 loci previously reported to be involved in autosomal dominant syndromic and nonsyndromic moyamoya. Carrier females had normal phenotype and clinical history. CONCLUSIONS: These data strongly suggest that this family is affected by a hereditary moyamoya multisystem disorder with X-linked recessive pattern of inheritance.

Zygomycosis: an uncommon cause for peripheral facial palsy in diabetes.

Mucormycosis is an emerging fungal infection with a high rate of mortality. Diabetic and immuno-compromised patients are the most frequent hosts. We report a case of rhino-orbito-cerebral mucormycosis revealed by facial palsy in a diabetic, immuno-compromised patient with difficult life conditions. He received intravenous antifungal treatment (amphotericin B) and early surgical debridement and completely recovered with no recurrence after 3 months of follow-up. Physicians should be aware of such atypical clinical presentations due to the need for early appropriate combined medical and surgical management to improve disease recovery and prognosis.

[Role and regulation of dopamine D1 receptors in the striatum: implications for the genesis of dyskinesia in Parkinson's disease]. / Rôle et régulation du récepteur D1 de la dopamine dans le striatum: implications dans les dyskinésies de la maladie de Parkinson.

L-dopa treatment of Parkinson's disease is complicated in the long term by the appearance of dyskinesia. Hypersensitivity of D1 dopamine receptor has been suggested to play a role in these delayed adverse effects. Hypersensitivity of dopamine D1 receptor in Parkinson's disease can be accounted for by increased levels of Galphaolf, the stimulatory G protein which couples D1 receptor to adenylyl cyclase in the striatum. We here discuss the possible role of D1 receptor signal transduction in the genesis of L-dopa-induced dyskinesia in the light of Galphaolf regulation.