Cerebral ischemic small vessel disease (SVD) is the leading cause of vascular dementia and a major contributor to stroke in humans. Dominant mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a genetic archetype of cerebral ischemic SVD. Progress toward understanding the pathogenesis of this disease and developing effective therapies has been hampered by the lack of a good animal model. Here, we report the development of a mouse model for CADASIL via the introduction of a CADASIL-causing Notch3 point mutation into a large P1-derived artificial chromosome (PAC). In vivo expression of the mutated PAC transgene in the mouse reproduced the endogenous Notch3 expression pattern and main pathological features of CADASIL, including Notch3 extracellular domain aggregates and granular osmiophilic material (GOM) deposits in brain vessels, progressive white matter damage, and reduced cerebral blood flow. Mutant mice displayed attenuated myogenic responses and reduced caliber of brain arteries as well as impaired cerebrovascular autoregulation and functional hyperemia. Further, we identified a substantial reduction of white matter capillary density. These neuropathological changes occurred in the absence of either histologically detectable alterations in cerebral artery structure or blood-brain barrier breakdown. These studies provide in vivo evidence for cerebrovascular dysfunction and microcirculatory failure as key contributors to hypoperfusion and white matter damage in this genetic model of ischemic SVD.

The gastrointestinal microbiota of preterm infants in a neonatal intensive care unit differs from that of term infants. In particular, the colonization of preterm infants by bifidobacteria is delayed. A double-blind, placebocontrolled, randomized clinical study was performed on 69 preterm infants to investigate the role of Bifidobacterium lactis Bb12 supplementation in modifying the gut microbiota. Both culture-dependent and cultureindependent approaches were used to study the gut microbiota.

C hronic kidney disease (CKD) affects more than 10% of people worldwide. 1 Renal fibrosis is the common endpoint of most CKD. 2 Therefore, preventing or

The objective of the study was to investigate portal blood flow (PBF) in dairy cows with fatty liver by means of Doppler ultrasonography. Eighty lactating German Holstein cows less than 100 d in milk were used (mean ± standard error of the mean; body weight: 583 ± 9 kg, age: 5 ± 0.2 yr, withers height: 145.4 ± 0.5 cm, milk yield: 9 ± 0.6 kg). All cows had left abomasal displacement and underwent omentopexy via right flank laparotomy. The size of the liver and the thickness over the portal vein were determined ultrasonographically. Doppler ultrasonographic examinations of PBF were carried out transcutaneously and intraoperatively directly via liver surface. The PBF velocities [peak maximum (v(max)), peak minimum (v(min)), and mean maximum (v(mean)) velocity] were recorded. Venous pulsatility index (VPI) was calculated. Because transcutaneous Doppler ultrasonography revealed images of very poor quality in 58 of the 80 cows, only data obtained intraoperatively were presented. Liver biopsies were used for hepatic triacylglycerol (TAG) determination and histological examination. Based on histopathologic and ultrasonographic examinations, none of the cows suffered from hepatic disorders other than hepatic lipidosis. Hepatic TAG content ranged from 5 to 292 mg/g of liver fresh weight (FW). Cows were allocated to 1 of 4 groups according to their hepatic TAG content (very severe: TAG >150 mg/g of FW, n=27; severe: >100-150 mg/g of FW, n=18; moderate: ≥ 50-100mg/g of FW, n=19; mild: <50mg/g of FW, n=16). The VPI decreased with increasing TAG content (r=-0.55). The VPI did not differ between cows with severe and very severe fatty liver but it differed between cows of these 2 groups and cows with mild and moderate fatty liver. Velocities of PBF (v(mean), v(min), v(max)) correlated negatively with hepatic TAG content (r=-0.26 to -0.37). Mean PBF velocity of the cows with very severe fatty liver differed from cows with severe, moderate, and mild fatty liver. Variables of PBF were inversely related to hepatic size and thickness (r=-0.06 to -0.35). In conclusion, the lower VPI and PBF velocities in cows with fatty liver and the negative correlations with the degree of hepatosteatosis may be explained by a reduction of vascular compliance in the liver because of fatty infiltration. These changes, which are believed to result from parenchymal swelling, were particularly pronounced when hepatic TAG content exceeded 150 mg/g FW.

Purpose: Muscle wasting deteriorates life quality after critical illness and increases mortality. Wasting starts upon admission to intensive care unit (ICU). We aimed to determine whether bÀhydroxy-bÀmethylbutyrate (HMB), a metabolite of leucine, can attenuate this process.Methods: Prospective randomized, placebo-controlled double blind trial. Inclusion criteria: ICU patients depending on mechanical ventilation on day 3 having a functional gastrointestinal tract. They were randomized to HMB (3 g/day) or placebo (maltodextrin) from day 4 on for 30 days. Primary outcome: magnitude of loss of skeletal muscle area (SMA) of the quadriceps femoris measured by ultrasound at days 4 and 15. Secondary outcomes: body composition, change in protein metabolism assessed by amino acids tracer pulse, and global health at 60 days. Data are mean [95% CI]. Statistics by ANCOVA with correction for confounders sex, age and/or BMI. Results: Thirty patients completed the trial, aged 65 [59, 71] years, SAPS2 score 48 [43, 52] and SOFA 8.5 [7.4, 9.7]. The loss of total SMA was 11% between days 4 and 15 (p < 0.001), but not different between the groups (p ¼ 0.86). In the HMB group, net protein breakdown (D Estimate HMB-Placebo: À153 [-242, À63]; p ¼ 0.0021) and production of several amino acid was significantly reduced, while phase angle increased more (0.66 [0.09, 1.24]; p ¼ 0.0247), and SF-12 global health improved more 53.19], p ¼ 0.04). Conclusion: HMB treatment did not significantly reduce muscle wasting over 10 days of observation (primary endpoint), but resulted in significantly improved amino acid metabolism, reduced net protein breakdown, a higher phase angle and better global health. Clinicaltrials.gov identifier: NCT03628365.