O2L-001, an innovative thrombolytic to evacuate intracerebral haematoma.

Intracerebral haemorrhage is an unmet medical need affecting more than 3 million people worldwide every year and leading to the formation of an intracerebral haematoma. Updated guidelines (2022) for the management of intracerebral haemorrhage patients recognize that minimally invasive approaches for the evacuation of supratentorial intracerebral haemorrhage have demonstrated reductions in mortality compared with medical management alone. However, improvement of functional outcome with a procedure involving thrombolytic therapy was neutral in the last large phase 3 clinical trial and requires a more effective and safer thrombolytic agent than those currently available. Here, we demonstrate that O2L-001 allows for the extended release of W253R/R275S recombinant tissue-type plasminogen activator (rtPA). A new rtPA variant, called optimized tPA (OptPA), offers improved efficacy for haematoma evacuation as well as improved safety. OptPA was produced in a Chinese hamster ovary cell line before purification, nanoprecipitation using the NANOp2Lysis® technological platform followed by suspension in a solution of 17% poloxamer 407 to obtain O2L-001. Plasmin generation assays were performed to demonstrate O2L-001 safety. Ex vivo haematoma models using human blood were used to demonstrate O2L-001 thrombolysis properties and efficacy. For the best translational significance, a clinical sized haematoma was used to ensure catheter placement and to allow administration of the thrombolytic agent into the core of the haematoma via a minimally invasive procedure. The capacity of OptPA to convert plasminogen into plasmin is strongly decreased compared to rtPA, thereby reducing potential bleeding events. However, a clot lysis assay showed that OptPA had the same fibrinolytic activity as rtPA. We demonstrated that long-term exposure to a thrombolytic agent was essential to achieve high thrombolysis efficacy. Indeed, 24 h continuous exposure to 0.1 µg/ml rtPA had similar efficacy than repeated short exposure to 30 µg/ml rtPA. This finding led to the development of O2L-001, allowing the extended release of OptPA in the first 6 h following injection. An ex vivo model using human blood was used to demonstrate O2L-001 efficacy. Interestingly, unlike rtPA, O2L-001 was able to induce the complete lysis of the 5 ml haematoma. In clinical sized haematomas (obtained from 30 ml of human blood), a single injection of O2L-001 at 1 mg/ml into the core of the haematoma led to a 44% increase in thrombolysis compared to rtPA. Taken together, these results demonstrate that O2L-001 provides new hope for haematoma evacuation and the treatment of patients with intracerebral haemorrhage.

CNS-associated macrophages contribute to intracerebral aneurysm pathophysiology.

Intracerebral aneurysms (IAs) are pathological dilatations of cerebral arteries whose rupture leads to subarachnoid hemorrhage, a significant cause of disability and death. Inflammation is recognized as a critical contributor to the formation, growth, and rupture of IAs; however, its precise actors have not yet been fully elucidated. Here, we report CNS-associated macrophages (CAMs), also known as border-associated macrophages, as one of the key players in IA pathogenesis, acting as critical mediators of inflammatory processes related to IA ruptures. Using a new mouse model of middle cerebral artery (MCA) aneurysms we show that CAMs accumulate in the IA walls. This finding was confirmed in a human MCA aneurysm obtained after surgical clipping, together with other pathological characteristics found in the experimental model including morphological changes and inflammatory cell infiltration. In addition, in vivo longitudinal molecular MRI studies revealed vascular inflammation strongly associated with the aneurysm area, i.e., high expression of VCAM-1 and P-selectin adhesion molecules, which precedes and predicts the bleeding extent in the case of IA rupture. Specific CAM depletion by intracerebroventricular injection of clodronate liposomes prior to IA induction reduced IA formation and rupture rate. Moreover, the absence of CAMs ameliorated the outcome severity of IA ruptures resulting in smaller hemorrhages, accompanied by reduced neutrophil infiltration. Our data shed light on the unexplored role of CAMs as main actors orchestrating the progression of IAs towards a rupture-prone state.

Reproducibility of surface-based deep inspiration breath-hold technique for lung stereotactic body radiotherapy on a closed-bore gantry linac.

Background and purpose: Tumor motion and delivery efficiency are two main challenges of lung stereotactic body radiotherapy (SBRT). The present work implemented the deep inspiration breath hold technique (DIBH) with surface guided radiation therapy (SGRT) on closed-bore linacs and investigated the correlation between SGRT data and internal target position. Materials and methods: Thirteen lung SBRT patients treated in DIBH using a closed-bore gantry linac and a ring-mounted SGRT system were retrospectively analysed. Visual coaching was used to achieve DIBH with a ± 1 mm threshold window in the anterior-posterior direction. Three kV-CBCTs were added to the treatment workflow and examined offline to verify intra-fraction tumor position. Surface-based DIBH was analysed using SGRT treatment reports and an in-house python script. Data from 73 treatment sessions and 175 kV-CBCTs were studied. Correlations between target and surface positions were studied with Linear Mixed Models. Results: Median intra-fraction tumor motion was 0.8 mm (range: 0.7-1.3 mm) in the anterior-posterior direction, 1.2 mm (range: 1-1.7 mm) in the superior-inferior direction, and 1 mm (range: 0.7-1.1 mm) in the left-right direction, with rotations of <1° (range: 0.6°-1.1°) degree in all three directions. Planned target volumes and healthy lung volumes receiving 12.5 Gy and 13.5 Gy were reduced on average by 67% and 54%, respectively. Conclusions: Lung SBRT in DIBH with the ring-mounted SGRT system proved reproducible. The surface monitoring provided by SGRT was found to be a reliable surrogate for internal target motion. Moreover, the implementation of DIBH technique helped reduce target volumes and lung doses.

A Clinical and Psychopathological Approach to Radicalization Among Adolescents.

Recent studies have shown higher rates of radicalization of adolescents than in the 2000s. Since 2015, radicalization prevention units have been implemented in child and adolescent psychiatry departments in France. We aimed to report on the psychopathology of adolescents who were followed up in a university department due to their "radical conduct." Based on the available clinical data (from child psychiatry consultations, long-term family and/or individual therapy, and psychological testing) for 20 adolescents with "radical conduct," we examined the nature of their radical conduct, their psychopathology, their family characteristics, and the existence or absence of traumatic experiences. Among the 20 adolescents, 4 had radical conduct associated with a delusional syndrome (schizophrenia or a psychotic episode after substance abuse). For the other 16, we found no psychotic conditions. The analysis of other data showed that the adolescents shared some characteristics, such as an important prevalence of intrafamilial violence, sexual abuse, imprisonment of family members, traumatic family histories, and significant psychological control or dependence phenomena occurring in divided families. This diversity of psychopathologies appears consistent with previous studies highlighting the relevance of diverse profiles depending on the presence of a delusional syndrome, the individual's gender and the individual's attraction to violence. Finally, we discuss some psychopathological hypotheses and make therapeutic recommendations. We believe that child and adolescent psychotherapy/psychiatry has a role to play in countering violent extremism by offering adolescents a way out of radical commitment.

tPA-NMDAR Signaling Blockade Reduces the Incidence of Intracerebral Aneurysms.

Intracranial aneurysms (IAs) are pathological dilatations affecting cerebral arteries, and their ruptures lead to devasting intracranial hemorrhages. Although the mechanisms underlying the IA formation and rupture are still unclear, some factors have been identified as critical in the control of the vascular remodeling pathways associated with aneurysms. In a preclinical model, we have previously proposed the implication of the vascular serine protease, the tissue-type plasminogen activator (tPA), as one of the key players in this pathology. Here, we provide insights into the mechanism by which tPA is implicated in the formation and rupture of aneurysms. This was addressed using a murine model of IAs combined with (i) hydrodynamic transfections of various tPA mutants based on the potential implications of the different tPA domains in this pathophysiology and (ii) a pharmacological approach using a monoclonal antibody targeting tPA-dependent NMDA receptor (NMDAR) signaling and in vivo magnetic resonance brain imaging (MRI). Our results show that the endovascular tPA-NMDAR axis is implicated in IA formation and possibly their rupture. Accordingly, the use of a monoclonal antibody designed to block tPA-dependent endothelial NMDAR signaling (Glunomab®) decreases the rate of intracranial aneurysm formation and their rupture. The present study gives new insights into the IA pathophysiology by demonstrating the implication of the tPA-dependent endothelial NMDAR signaling. In addition, the present data proposes that a monoclonal antibody injected intravenously to target this process, i.e., Glunomab® could be a useful therapeutic candidate for this devastating disease.

The benefits and tolerance of exercise in myasthenia gravis (MGEX): study protocol for a randomised controlled trial.

BACKGROUND: Research exploring the effects of physical exercise in auto-immune myasthenia gravis (MG) is scarce. The few existing studies present methodological shortcomings limiting the conclusions and generalisability of results. It is hypothesised that exercise could have positive physical, psychological as well as immunomodulatory effects and may be a beneficial addition to current pharmacological management of this chronic disease. The aim of this study is to evaluate the benefits on perceived quality of life (QOL) and physical fitness of a home-based physical exercise program compared to usual care, for patients with stabilised, generalised auto-immune MG. METHODS: MGEX is a multi-centre, interventional, randomised, single-blind, two-arm parallel group, controlled trial. Forty-two patients will be recruited, aged 18-70 years. Following a three-month observation period, patients will be randomised into a control or experimental group. The experimental group will undertake a 40-min home-based physical exercise program using a rowing machine, three times a week for three months, as an add-on to usual care. The control group will receive usual care with no additional treatment. All patients will be followed up for a further three months. The primary outcome is the mean change in MGQOL-15-F score between three and six months (i.e. pre-intervention and immediately post-intervention periods). The MGQOL-15-F is an MG-specific patient-reported QOL questionnaire. Secondary outcomes include the evaluation of deficits and functional limitations via MG-specific clinical scores (Myasthenia Muscle Score and MG-Activities of Daily Living scale), muscle force and fatigue, respiratory function, free-living physical activity as well as evaluations of anxiety, depression, self-esteem and overall QOL with the WHO-QOL BREF questionnaire. Exercise workload will be assessed as well as multiple safety measures (ECG, biological markers, medication type and dosage and any disease exacerbation or crisis). DISCUSSION: This is the largest randomised controlled trial to date evaluating the benefits and tolerance of physical exercise in this patient population. The comprehensive evaluations using standardised outcome measures should provide much awaited information for both patients and the scientific community. This study is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02066519 . Registered on 13 January 2014.

Effects of Strain and Species on the Septo-Temporal Distribution of Adult Neurogenesis in Rodents.

The functional septo-temporal (dorso-ventral) differentiation of the hippocampus is accompanied by gradients of adult hippocampal neurogenesis (AHN) in laboratory rodents. An extensive septal AHN in laboratory mice suggests an emphasis on a relation of AHN to tasks that also depend on the septal hippocampus. Domestication experiments indicate that AHN dynamics along the longitudinal axis are subject to selective pressure, questioning if the septal emphasis of AHN in laboratory mice is a rule applying to rodents in general. In this study, we used C57BL/6 and DBA2/Crl mice, wild-derived F1 house mice and wild-captured wood mice and bank voles to look for evidence of strain and species specific septo-temporal differences in AHN. We confirmed the septal > temporal gradient in C57BL/6 mice, but in the wild species, AHN was low septally and high temporally. Emphasis on the temporal hippocampus was particularly strong for doublecortin positive (DCX+) young neurons and more pronounced in bank voles than in wood mice. The temporal shift was stronger in female wood mice than in males, while we did not see sex differences in bank voles. AHN was overall low in DBA and F1 house mice, but they exhibited the same inversed gradient as wood mice and bank voles. DCX+ young neurons were usually confined to the subgranular zone and deep granule cell layer. This pattern was seen in all animals in the septal and intermediate dentate gyrus. In bank voles and wood mice however, the majority of temporal DCX+ cells were radially dispersed throughout the granule cell layer. Some but not all of the septo-temporal differences were accompanied by changes in the DCX+/Ki67+ cell ratios, suggesting that new neuron numbers can be regulated by both proliferation or the time course of maturation and survival of young neurons. Some of the septo-temporal differences we observe have also been found in laboratory rodents after the experimental manipulation of the molecular mechanisms that control AHN. Adaptations of AHN under natural conditions may operate on these or similar mechanisms, adjusting neurogenesis to the requirements of hippocampal function.

Diagnostic transition towards schizophrenia in adolescents with severe bipolar disorder type I: an 8-year follow-up study.

BACKGROUND: The diagnosis of bipolar disorder-I (BD-I) is currently well-established. However, more studies exploring diagnostic stability and psychosocial adaptation during follow-up in adulthood are needed. OBJECTIVES: We assessed factors at follow-up (FU): (1) the diagnostic stability of manic/mixed episodes from adolescence to adulthood, (2) psychosocial adaptation, and (3) factors associated with psychosocial adaptation. METHODS: A sample of 80 adolescents hospitalized in a university hospital between 1993 and 2004 for a manic or mixed episode were contacted for an FU assessment on average 8 years after the index episode. Assessments included socio-demographic data, mortality, lifetime psychiatric diagnosis, the Social Adaptation Scale, negative life events and insight. RESULTS: Of the 64 patients with available information, one patient died from a heart attack. Of the 55 patients available for an FU assessment, 35 (63.6%) still presented a diagnosis of BD-I at FU, whereas 20 (36.4%) had changed diagnosis towards a schizophrenia spectrum disorder. Psychosocial adaptation was moderate to poor for most patients, and 91% of the patients had at least one relapse. A low socio-economic status, intellectual disability, negative life events, a history of sexual abuse, and treatment with classical antipsychotics at FU were significantly associated with poorer psychosocial adaptation. In contrast, better insight, a family history of depression and a diagnosis of BD-I at FU were associated with better psychosocial adaptation. CONCLUSION: BD-I in adolescent inpatients can lead to important morbidity and mortality during outcome. Diagnostic stability is high, but a high proportion of patients also show a transition towards a schizophrenia spectrum disorder.

Psychodynamic-oriented psychological assessment predicts evolution to schizophrenia at 8-year follow-up in adolescents hospitalized for a manic/mixed episode: interest of an overall subjective rating.

Little is known concerning the prognostic significance of manic/mixed episodes in adolescents. In particular, whether the use of psychodynamic-oriented projective psychological testing predicts evolution to schizophrenia at follow-up has not been established. Eighty subjects, aged 12-20years old, consecutively hospitalized for a manic or mixed episode between 1994 and 2003 were recruited. All patients were contacted in 2005-2006 for a follow-up assessment. For the subgroup of adolescents (N=40) who had psychodynamic-oriented psychological testing (Rorschach and TAT), two scores regarding psychosocial risk and schizophrenia risk were computed using the clinical global impression (CGI) assessment based on an overall subjective rating given by a panel of expert psychologists who reviewed all protocols. At follow-up (average 8years), 25 (62.5%) patients, 16 females and nine males, were assessed: 14 still had a diagnosis of bipolar disorder; eight changed to schizo-affective disorder and three to schizophrenia. Inter-rater reliability of both CGI-risk scores (psychosocial risk and schizophrenia risk) showed good clinical consensus with intraclass correlation and Kappa scores ranging from 0.53 to 0.75. Univariate analysis showed that CGI-psychosocial risk score (p=0.017), type of index episode (p=0.049) and CGI-schizophrenia risk score (p=0.09) were associated with transition to schizophrenia spectrum disorder at follow-up. Age, sex, socioeconomic status, duration of stay and the presence of psychotic features at index episode were not associated with the transition. We conclude that the CGI assessment appears to be valid to score risk of poor outcome using psychodynamic-oriented psychological testing and that these scores may predict, in part, the transition to schizophrenia in adolescents with a history of manic/mixed episode.