Mycobacterium simiae infection in two unrelated patients with different forms of inherited IFN-γR2 deficiency.

Interferon-γ receptor 2 (IFN-γR2) deficiency is a rare primary immunodeficiency characterized by predisposition to infections with weakly virulent mycobacteria, such as environmental mycobacteria and BCG vaccines. We describe here two children with IFN-γR2 deficiency, from unrelated, consanguineous kindreds of Arab and Israeli descent. The first patient was a boy who died at the age of 4.5 years, from recurrent, disseminated disease caused by Mycobacterium simiae. His IFN-γR2 defect was autosomal recessive and complete. The second patient was a girl with multiple disseminated mycobacterial infections, including infection with M. simiae. She died at the age of 5 years, a short time after the transplantation of umbilical cord blood cells from an unrelated donor. Her IFN-γR2 defect was autosomal recessive and partial. Autosomal recessive IFN-γR2 deficiency is life-threatening, even in its partial form, and genetic diagnosis and familial counseling are therefore particularly important for this condition. These two cases are the first of IFN-γR2 deficiency associated with M. simiae infection to be described.

Linking mitochondria metabolism, developmental timing, and human brain evolution.

Changes in developmental timing are an important factor of evolution in organ shape and function. This is particularly striking for human brain development, which, compared with other mammals, is considerably prolonged at the level of the cerebral cortex, resulting in brain neoteny. Here, we review recent findings that indicate that mitochondria and metabolism contribute to species differences in the tempo of cortical neuron development. Mitochondria display species-specific developmental timeline and metabolic activity patterns that are highly correlated with the speed of neuron maturation. Enhancing mitochondrial activity in human cortical neurons results in their accelerated maturation, while its reduction leads to decreased maturation rates in mouse neurons. Together with other global and gene-specific mechanisms, mitochondria thus act as a cellular hourglass of neuronal developmental tempo and may thereby contribute to species-specific features of human brain ontogeny.

Mitochondria metabolism sets the species-specific tempo of neuronal development.

Neuronal development in the human cerebral cortex is considerably prolonged compared with that of other mammals. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny.

Early Venous Filling Following Thrombectomy: Association With Hemorrhagic Transformation and Functional Outcome.

Background and Purpose: Previous studies have noted the angiographic appearance of early venous filling (EVF) following recanalisation in acute ischemic stroke. However, the prognostic implications of EVF as a novel imaging biomarker remain unclear. We aimed to evaluate the correlation between EVF with (i) the risk of subsequent reperfusion hemorrhage (RPH) and (ii) the association of EVF on both the NIHSS score at 24 h and functional outcome as assessed with the Modified Rankin Scale (mRS) score at 90 days. Methods: We conducted a retrospective cohort study of patients presenting with an acute ischemic stroke due to a proximal large-vessel occlusion of the anterior circulation treated by thrombectomy. Post-reperfusion digital subtraction angiography was reviewed to look for EVF as evidenced by the contrast opacification of any cerebral vein before the late arterial phase. Results: EVF occurred in 22.4% of the 147 cases included. The presence of EVF significantly increased the risk of RPH (p = 0.0048), including the risk of symptomatic hemorrhage (p = 0.0052). The presence of EVF (p = 0.0016) and the absence of RPH (p = 0.0021) were independently associated with a better outcome as defined by the NIHSS difference at 24 h, most significantly in the EVF+RPH- group. No significant relationship was however found between either EVF or RPH and a mRS score ≤ 2 at 90 days. Conclusion: Early venous filling on angiographic imaging is a potential predictor of reperfusion hemorrhage. The absence of subsequent RPH in this sub-group is associated with better outcomes at 24 h post-thrombectomy than in those with RPH.

Mitochondrial dynamics in postmitotic cells regulate neurogenesis.

The conversion of neural stem cells into neurons is associated with the remodeling of organelles, but whether and how this is causally linked to fate change is poorly understood. We examined and manipulated mitochondrial dynamics during mouse and human cortical neurogenesis. We reveal that shortly after cortical stem cells have divided, daughter cells destined to self-renew undergo mitochondrial fusion, whereas those that retain high levels of mitochondria fission become neurons. Increased mitochondria fission promotes neuronal fate, whereas induction of mitochondria fusion after mitosis redirects daughter cells toward self-renewal. This occurs during a restricted time window that is doubled in human cells, in line with their increased self-renewal capacity. Our data reveal a postmitotic period of fate plasticity in which mitochondrial dynamics are linked with cell fate.