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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.

Background Patients with acrocyanosis are known to display a capillaroscopic pattern characterised by normal/mild reduction of capillary density, microhemorrhages, asymmetrical capillary ectasias with greater width of venular loop and capillary thrombosis (1). At the best of our knowledge, one small series study only as so far reported the occurrence of megacapillaries (i.e. giant capillary: homogeneously enlarged loops with a diameter >50µm) in patients with acrocyanosis (2). Objectives To investigate the presence of megacapillaries in a cohort of patients with acrocyanosis Methods We enrolled 71 consecutive patients attending the Videocapillaroscopy Outpatient clinicof the Second University of Naples from 1st January 2011 to 1st June 2012 (median age 45 years, range 18-70) diagnosed to have acrocyanosis (i.e. persistent, symmetrical and painful cyanosis of extremities, triggered by cold, often associated to hyperhidrosis) and 35 control patients affected by osteoarthritis. Nailfold videocapillaroscopy was carried out with optical probes of 200X (VideoCap 2.5). Results Megacapillaries (maximal loop width 80 µm) were detected in 14 out of 71 patients (19%). In 12 and 2 patients a mean score of 1 (less than 4 megacapillaries / mm) and of 2 (≥4 megacapillaries ≤ 6 / mm) was registered, respectively. In all patients the capillaroscopic alterations already described in patients with acrocyanosis were found : mild reduction of capillary density (mean capillary number 7±1/mm), asymmetrical capillary ectasias with greater width of venular loop, microhemorrhages, capillary thrombosis. In controls rare ectasias were the only capillaroscopic alterations detected. Conclusions Our study confirms the possible occurrence of megacapillaries in a larger cohort of patients with acrocyanosis. It suggests the need of a careful clinical approach in order to make differential diagnosis between acrocyanosis and Raynaud’s Phenomenon. The patients enrolled will be prospectically followed-up to assess the changes of capillaroscopic scores overtime. References Kurklinsky et al. Vasc Med 2011 16(4):288-301 Monticone et a J Am Acad Dermatol 2000; 42:787-90 Davis E. Adv Microcirc 1982 ;10:101-119 Disclosure of Interest None Declared

Excerpt Capillary thrombosis is observed in a number of conditions. Extensive involvement has been reported in a variety of diseases, such as rickettsial infections,1disseminated lupus erythematosu...

Pappenheimer and Goettsch1 described the symptoms of chick encephalomalacia produced by vitamin E deficiency and indicated that capillary thrombosis may be the primary cause of the observed ischaemic necrosis. Muscular dystrophy of vitamin E-deficient rabbits may be considered the counterpart of experimental encephalomalacia in chicks since both diseases can be produced by lack of dietary vitamin E.