A developmental component to Huntington's disease.

Huntington's disease is a dominantly inherited disorder characterized by the dysfunction and death of cortical and striatal neurons. Striatal degeneration in Huntington's disease is due, at least in part, to defective cortical signalling to the striatum. Although Huntington's disease generally manifests at the adult stage, mouse and neuroimaging studies of presymptomatic mutation carriers suggest that it may affect neurodevelopment. In support of this notion, the development of the cortex is altered in mice with Huntington's disease and the foetuses of human Huntington's disease gene carriers. We will discuss these studies and the contribution of abnormal brain development to the later appearance of the disease.

Pregnancy outcome in patients with a medical history of immunoglobulin A vasculitis: a case-control study.

OBJECTIVE: Data on obstetric outcomes in patients with a history of immunoglobulin A vasculitis (IgA-V) are lacking. The aim of this study was to assess maternal, neonatal, and vasculitis outcomes during pregnancy. METHOD: We conducted a French retrospective case-control study. Pregnancies of patients with a history of IgA-V (cases) were retrospectively studied and compared to pregnancies in women who developed IgA-V after their pregnancies and to pregnancies in healthy women (controls). RESULTS: Twenty-six pregnancies in patients with a history of IgA-V were included and compared to 15 pregnancies in women who later developed IgA-V and 52 pregnancies in healthy women. Both gestational hypertension and pre-eclampsia were more frequent in the case group than in the other groups (23% vs 0% vs 0%, p < 0.01; 12% vs 7% vs 0%, p = 0.04). Hypertensive disorder of pregnancy occurred more frequently in patients with pre-existing kidney disease (78% vs 12%, p < 0.01). Caesarean section was more often performed in the case group than in the other groups (27% vs 0% vs 10%, p = 0.04). No foetal loss or maternal deaths occurred. There were no differences in delivery term or birth weight. No vasculitis flares were observed during pregnancy. CONCLUSION: Women with a history of IgA-V appear to be at higher risk for gestational hypertension and pre-eclampsia, especially in cases with renal involvement; however, both mother and newborn outcomes appear to be favourable.

Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients.

BACKGROUND: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome'). OBJECTIVES: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. METHODS: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded. RESULTS: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. CONCLUSIONS: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.

Does type of immunosupression influence the course of Covid-19 infection?

Coronavirus disease 19 (Covid-19) is a new emerging virus responsible for pandemic and death. High blood pressure, diabetes, obesity have been described as poor prognosis factors. Few data have been reported in patient with immunocompromised status (solid tumor, hematological malignancy, rheumatoid conditions or organ transplant). We evaluated the characteristics of patients, including the outcome, with immunodepression hospitalized in Besancon University hospital (East of France). We wanted to identify if a type of immunosupression influences the course of Covid-19. In a cohort of 80 patients with immunosupression (42 solid tumors, 20 hematological malignancy and 18 non neoplastic immunosupression), poor outcomes (Intensive care unit hospitalization and or deaths) was frequent (38%) and tended to be more frequent in patients with hematological malignancy.

Concomitant association of giant cell arteritis and malignancy: a multicenter retrospective case-control study.

INTRODUCTION: Some studies suggest that there is an increased risk of malignancies in giant cell arteritis (GCA). We aimed to describe the clinical characteristics and outcomes of GCA patients with concomitant malignancy and compare them to a GCA control group. METHOD: Patients with a diagnosis of GCA and malignancy and with a maximal delay of 12 months between both diagnoses were retrospectively included in this study and compared to a control group of age-matched (3:1) patients from a multicenter cohort of GCA patients. RESULTS: Forty-nine observations were collected (median age 76 years). Malignancies comprised 33 (67%) solid neoplasms and 16 (33%) clonal hematologic disorders. No over-representation of a particular type of malignancy was observed. Diagnosis of GCA and malignancy was synchronous in 7 (14%) patients, while malignancy succeeded GCA in 29 (59%) patients. Malignancy was fortuitously diagnosed based on abnormalities observed in laboratory tests in 26 patients, based on imaging in 14 patients, and based on symptoms or clinical examination in the nine remaining patients. Two patients had a concomitant relapse of both conditions. When compared to the control group, patients with concomitant GCA and malignancy were more frequently male (p < 0.001), with an altered general state (p < 0.001), and polymyalgia rheumatica (p < 0.01). CONCLUSIONS: This study does not indicate an over-representation of any particular type of malignancy in GCA patients. Initial follow-up dictated by vasculitis may have led to an early identification of malignancy. Nevertheless, GCA male patients with an altered general state and polymyalgia rheumatica might more frequently show concomitant malignancies.

[Eosinopenia in 2018]. / L'éosinopénie en 2018.

Since 1893, eosinopenia is a biological test to help a diagnosis of bacterial infection. Several publications have confirmed this hypothesis, particularly in the intensive care, pneumology and pediatric units. The value of this marker has been identified in vascular cerebral diseases and coronary bypass. Its contribution seems as relevant as procalcitonin, without extra cost. The diagnostic performance of this test was reinforced by a composite score (CIBLE score) that may improve its value in daily routine. Finally, monitoring eosinopenia appears to be a reliable mortality marker.

[A predictive bacterial infection score according to eosinophil level: An observational study]. / Proposition d'un score prédictif d'infection bactérienne selon le taux d'éosinophiles : étude observationnelle.

INTRODUCTION: Several studies have shown that eosinopenia less than 0.04g/L is a marker of bacterial infection in the presence of unexplained inflammatory syndrome. The aim of our study was to test this hypothesis and to propose a predictive score for bacterial infection (score CIBLE, C reactive protein, bacterial infections, levels of leucocytes and eosinophils). PATIENTS AND METHODS: This was a single-center observational study of patients admitted to an internal medicine department in the year 2015 and presenting with an inflammatory biological syndrome. Patients were divided into 2 groups: bacterial infections (group 1) and nonbacterial inflammatory diseases (group 2). RESULTS: One hundred and ninety patients were included: 92 men (48.4 %) and 98 women (51.6 %). Mean age was 73.5±18.2 years [19-104]. Group 1 consisted of 124 patients (65.2 %) and group 2 of 66 patients (34.8 %). ROC analysis confirmed a cut-off level for eosinophils count at 0.04g/L as discriminant to predict bacterial infection. In a multivariate analysis, the eosinophil/neutrophil ratio, a history of COPD, the C reactive protein concentration, patient age and initial temperature were the most significant variables. They were used to build the CIBLE score. For a score higher than or equal to 87, the probability of a bacterial infection is at least 70 %. CONCLUSION: The CIBLE score appears to be a relevant and inexpensive tool to establish a probability for bacterial infection.

[Use of the Airtraq by inexperienced physicians supervised during a series of tracheal intubation in adult patient with anticipated difficult airway]. / Utilisation de l'Airtraq par des praticiens inexpérimentés supervisés pour une série de patients adultes prévus difficiles à intuber.

INTRODUCTION: The Airtraq optical laryngoscope (Vygon, Écouen, France) is a new intubation device designed to provide a view of the glottis without alignment of the oral, pharyngeal and laryngeal axes. In recent literature, the efficiency of the Airtraq even in difficult intubation and its short learning curve were characterized. The goal of our study is to evaluate Airtraq efficiency when use by inexperienced physicians in anticipated difficult intubation adult patients. METHODS: The patients showing at least one of the four difficult intubation predictors (history of difficult intubation, thyromental distance less than 60mm, mouth opening less than 35 mm and Mallampati class 3 or 4 were included. Before induction of anaesthesia, the inexperienced physicians participating the study received a short oral formation on the use of the Airtraq. For each intubation manoeuvres, the participant were supervised by an expert in Airtraq handling. The Cormack and Lehane grade of direct laryngoscopy view, the duration times to best glottis view and to intubate the trachea, the success or failure of tracheal intubation, the drop in arterial oxygen saturation of below 95%, the need for external manipulation, and the difficulties met by the operators were noted. RESULTS: Twenty patients were included over a month period. Thirteen had a history of difficult intubation, eight a thyromental distance less than 60mm, nine a mouth opening less than 35 mm and 12 patients were classified as Mallampati IV. The success rate of tracheal intubation with the Airtraq laryngoscope was 80%. Times to best glottis view and to complete tracheal intubation were 28 and 47 s, respectively. Four tracheal intubation failures were encountered. The LMA Fastrach and the flexible fiberoscope were used respectively in one and three patients. DISCUSSION: In the majority of the cases, the insertion of the Airtraq, the visualization of the glottis and the subsequent intubation were easy and rapid, without arterial oxygen desaturation. However, the four tracheal intubation failures associated with prolonged tracheal intubation times in some patients highlight the fact that the Airtraq laryngoscope requires a clinical training process particularly in case of anticipated difficult airway management situations.

Brachytherapy: state of the art and possible improvements.

Cancer often remains an incurable disease, despite significant progresses in diagnosis and treatment that have been made. Specifically, the use of nuclear medicine in oncology is greatly contributing to both imaging and therapy aspects. Targeted therapies are a major field of interest since it increases efficiency and reduces side effects. Brachytherapy is among the most valuable of recent developments for treating localized tumours resulting in improvements in improved quality of life. This is primarily because it irradiates cancerous cells most exclusively while barely effecting healthy tissue. The use of radiochemicals implies specific management for production, transport and handling that have limited the development of this technique. This review article describes brachytherapy and their latest developments. Furthermore, alternative activation methods for the production of radioisotopes and a novel delivery system for targeted multi-therapy by using PLA-ferrite nanospheres are described.

Outcomes of children with abdominal compartment syndrome.

INTRODUCTION: Abdominal compartment syndrome (ACS) is a problem across all critical care scenarios and is associated with a high mortality. It has not been well described in pediatric populations. OBJECTIVE: To describe the occurrence of ACS in a subset of critically ill pediatric patients and determine its effects on mortality and length of pediatric intensive care stay (PICU LOS). We also aimed to find predictors of mortality and development of ACS. SETTING: 25 bed tertiary pediatric intensive care unit. PATIENTS: Patients less than 50 kg on mechanical ventilation and a urethral catheter. MEASUREMENTS: Intra-abdominal pressures (IAP) were monitored using the intra-vesical technique. ACS was defined as IAP of >12mmHg associated with new organ dysfunction or failure. Demographics, physiologic measures of organ dysfunction, PICU LOS and mortality were monitored. MAIN RESULTS: 14 (4.7%) of 294 eligible patients had ACS. Mortality was 50% among those with ACS versus 8.2% without (p<.001). PICU LOS stay did not differ between groups. No difference in mortality or PICU LOS was seen in primary versus secondaryACS or in patients who underwent abdominal decompression compared to those without decompression. IAP and ACS were independent predictors of mortality (odds ratio 1.53, 95% CI, 1.17- 1.99 and 9.09, 95% CI, 1.07 - 76.84) respectively. IAP and a PRISM score of >17 were predictive of developing ACS. CONCLUSIONS: ACS is a clinical problem that increases the risk of mortality in critically ill children. IAP and PRISM scores may help identify children likely to develop ACS.

Outcomes of children with abdominal compartment syndrome.

INTRODUCTION: Abdominal compartment syndrome (ACS) is a problem across all critical care scenarios and is associated with a high mortality. It has not been well described in pediatric populations. OBJECTIVE: To describe the occurrence of ACS in a subset of critically ill pediatric patients and determine its effects on mortality and length of pediatric intensive care stay (PICU LOS). We also aimed to find predictors of mortality and development of ACS. SETTING: 25 bed tertiary pediatric intensive care unit. PATIENTS: PATIENTS less than 50 kg on mechanical ventilation and a urethral catheter. MEASUREMENTS: Intra-abdominal pressures (IAP) were monitored using the intra-vesical technique. ACS was defined as IAP of >12mmHg associated with new organ dysfunction or failure. Demographics, physiologic measures of organ dysfunction, PICU LOS and mortality were monitored. MAIN RESULTS: 14 (4.7%) of 294 eligible patients had ACS. Mortality was 50% among those with ACS versus 8.2% without (p<.001). PICU LOS stay did not differ between groups. No difference in mortality or PICU LOS was seen in primary versus secondary ACS or in patients who underwent abdominal decompression compared to those without decompression. IAP and ACS were independent predictors of mortality (odds ratio 1.53, 95% CI, 1.17 - 1.99 and 9.09, 95% CI, 1.07 - 76.84) respectively. IAP and a PRISM score of ≥17 were predictive of developing ACS. CONCLUSIONS: ACS is a clinical problem that increases the risk of mortality in critically ill children. IAP and PRISM scores may help identify children likely to develop ACS.

Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies.

Huntington's disease (HD) is a neurodegenerative disorder that usually starts in middle age and is characterized by involuntary movements (chorea), personality changes and dementia, leading to death within 10-20 years. The defective gene in HD contains a trinucleotide CAG repeat expansion within its coding region that expresses a polyglutamine repeat in the protein huntingtin. Together with the characteristic formation of aggregates in HD, aberrant protein interactions and several post-translational modifications affect huntingtin during disease progression and lead to the dysfunction and death of selective neurons in the brains of patients. The exact molecular mechanisms by which mutant huntingtin induces cell death are not completely understood but may involve the gain of new toxic functions and the loss of the beneficial properties of huntingtin. This review focuses on the cellular functions in which huntingtin is involved and how a better understanding of pathogenic pathways can lead to new therapeutic approaches.

Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic?

Huntington's disease belongs to a class of inherited neurological disorders that are caused by the presence of a polyglutamine expansion in apparently unrelated proteins. In Huntington's disease, expansion occurs in the huntingtin protein. Together with the characteristic formation of aggregates in the diseased state, several post-translational modifications affect huntingtin during the pathological process and lead to the dysfunction and eventual death of selective neurons in the brain of patients. These mechanisms are not completely described but could involve the gain of a new toxic function as well as the loss of the beneficial properties of huntingtin.

p35 and p39 are essential for cyclin-dependent kinase 5 function during neurodevelopment.

Cyclin-dependent kinase 5 (Cdk5) plays a pivotal role in brain development and neuronal migration. Cdk5 is abundant in postmitotic, terminally differentiated neurons. The ability of Cdk5 to phosphorylate substrates is dependent on activation by its neuronal-specific activators p35 and p39. There exist striking differences in the phenotypic severity of Cdk5-deficient mice and p35-deficient mice. Cdk5-null mutants show a more severe disruption of lamination in the cerebral cortex, hippocampus, and cerebellum. In addition, Cdk5-null mice display perinatal lethality, whereas p35-null mice are viable. These discrepancies have been attributed to the function of other Cdk5 activators, such as p39. To understand the roles of p39 and p35, we created p39-null mice and p35/p39 compound-mutant mice. Interestingly, p39-null mice show no obvious detectable abnormalities, whereas p35(-/-)p39(-/-) double-null mutants are perinatal lethal. We show here that the p35(-/-)p39(-/-) mutants exhibit phenotypes identical to those of the Cdk5-null mutant mice. Other compound-mutant mice with intermediate phenotypes allow us to determine the distinct and redundant functions between p35 and p39. Our data strongly suggest that p35 and p39 are essential for Cdk5 activity during the development of the nervous system. Thus, p35 and p39 are likely to be the principal, if not the only, activators of Cdk5.