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Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a Notch3 mutation-induced cerebral small vessel disease, leading to recurrent ischemic stroke and vascular dementia. There is currently no treatment that can stop or delay CADASIL progression. We have demonstrated the efficacy of treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in reducing cerebral small vessel thrombosis in a TgNotch3R90C mouse model of CADASIL. However, it remains unknown whether SCF+G-CSF treatment protects neurons from microvascular thrombosis-induced ischemic damage. Using bone marrow transplantation to track thrombosis, we observed that capillary thrombosis was widely distributed in the cortex, striatum and hippocampus of 22-month-old TgNotch3R90C mice. However, the capillary thrombosis mainly occurred in the cortex. Neuron loss was seen in the area next to the thrombotic capillaries, and severe neuron loss was found in the areas adjacent to the thrombotic capillaries with bifurcations. SCF+G-CSF repeated treatment significantly attenuated neuron loss in the areas next to the thrombotic capillaries in the cortex of the 22-month-old TgNotch3R90C mice. Neuron loss caused by capillary thrombosis in the cerebral cortex may play a crucial role in the pathogenesis of CADASIL. SCF+G-CSF treatment ameliorates the capillary thrombosis-induced ischemic neuron loss in TgNotch3R90C mice. This study provides new insight into the understanding of CADASIL progression and therapeutic potential of SCF+G-CSF in neuroprotection under microvascular ischemia in CADASIL.

Intravenous immunoglobulin protects against experimental thrombotic microangiopathy. Background. Intravenous immunoglobulin (IVIG) has been utilized in several forms of vasculitis and has many potential mechanisms of action, including the inhibition of C3 activation. We have previously demonstrated that IVIG can reduce glomerular injury in a model of membranous nephropathy mediated by C5b-9 [1]. C5b-9 has also been shown to mediate the thrombotic microangiopathy (TMA) induced by antibody to glomerular endothelial cells leading to a hemolytic uremic syndrome-type lesion [2]. Methods. To test the hypothesis that IVIG might be effective in treating antibody-induced TMA, male uninephrectomized rats underwent right renal artery perfusion with goat anti-rat glomerular endothelial cell (GEN) antibody (20 mg/kg). Sheep IgG (200 mg/kg) was administered either 30 minutes before the renal artery perfusion (group I, N = 6) or 30 minutes postperfusion (group II, N = 9). A third control group received phosphate-buffered saline (PBS; group III, N = 12). A survival biopsy was performed at 15 minutes, and the animals were sacrificed on day 2. Results. There were no significant differences in proteinuria or hematocrit between the groups. Animals pretreated with IVIG had significantly improved survival and renal function, which was associated with a decrease in glomerular C3 deposition. The protective effect of IVIG was abolished if the administration was delayed 30 minutes after perfusion. Conclusions. IVIG is effective in reducing injury in experimental TMA only if given prophylactically. The effect is mediated by inhibition of local intraglomerular complement activation. [ABSTRACT FROM AUTHOR]

When treating patients with soft tissue infections, we sometimes have to deal with an extremely lethal infection: necrotizing fasciitis. This requires immediate surgical intervention with fasciectomy and extensive necrotectomy. The cause is a mixed infection with aerobic and anaerobic organisms, especially with group A Streptococcus. Since 1992, 12 patients who had a clinical and histological diagnosis of necrotizing fasciitis have been treated in our department. Risk factors were found in ten patients (83%). The mean age in the study group was 58.3 years (range 32–93 years). A total of 59 operations were performed. The overall mortality rate was 33% (n=4). Two other patients died due to complications of pre-existing leukemia. In spite of multiple wound cultures taken during the first operation, microorganisms could only be identified in two cultures: group A Streptococcus. All other cultures showed no growth of any microorganism. In view of our results, we believe that necrotizing fasciitis can also develop without an infection with bacteria or fungi due to capillary thrombosis. Urgent surgery is needed. [ABSTRACT FROM AUTHOR]

Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a Notch3 mutation-induced cerebral small vessel disease, leading to recurrent ischemic stroke and vascular dementia. There is currently no treatment that can stop or delay CADASIL progression. We have demonstrated the efficacy of treatment with combined stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in reducing cerebral small vessel thrombosis in a TgNotch3R90C mouse model of CADASIL. However, it remains unknown whether SCF+G-CSF treatment protects neurons from microvascular thrombosis-induced ischemic damage. Using bone marrow transplantation to track thrombosis, we observed that capillary thrombosis was widely distributed in the cortex, striatum and hippocampus of 22-month-old TgNotch3R90C mice. However, the capillary thrombosis mainly occurred in the cortex. Neuron loss was seen in the area next to the thrombotic capillaries, and severe neuron loss was found in the areas adjacent to the thrombotic capillaries with bifurcations. SCF+G-CSF repeated treatment significantly attenuated neuron loss in the areas next to the thrombotic capillaries in the cortex of the 22-month-old TgNotch3R90C mice. Neuron loss caused by capillary thrombosis in the cerebral cortex may play a crucial role in the pathogenesis of CADASIL. SCF+G-CSF treatment ameliorates the capillary thrombosis-induced ischemic neuron loss in TgNotch3R90C mice. This study provides new insight into the understanding of CADASIL progression and therapeutic potential of SCF+G-CSF in neuroprotection under microvascular ischemia in CADASIL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ping, Qiu, Gonzalez-Toledo, Liu and Zhao.)