Elevated TGFß signaling contributes to cerebral small vessel disease in mouse models of Gould syndrome.

Cerebral small vessel disease (CSVD) is a leading cause of stroke and vascular cognitive impairment and dementia. Studying monogenic CSVD can reveal pathways that are dysregulated in common sporadic forms of the disease and may represent therapeutic targets. Mutations in collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) cause highly penetrant CSVD as part of a multisystem disorder referred to as Gould syndrome. COL4A1 and COL4A2 form heterotrimers [a1α1α2(IV)] that are fundamental constituents of basement membranes. However, their functions are poorly understood and the mechanism(s) by which COL4A1 and COL4A2 mutations cause CSVD are unknown. We used histological, molecular, genetic, pharmacological, and in vivo imaging approaches to characterize central nervous system (CNS) vascular pathologies in Col4a1 mutant mouse models of monogenic CSVD to provide insight into underlying pathogenic mechanisms. We describe developmental CNS angiogenesis abnormalities characterized by impaired retinal vascular outgrowth and patterning, increased numbers of mural cells with abnormal morphologies, altered contractile protein expression in vascular smooth muscle cells (VSMCs) and age-related loss of arteriolar VSMCs in Col4a1 mutant mice. Importantly, we identified elevated TGFß signaling as a pathogenic consequence of Col4a1 mutations and show that genetically suppressing TGFß signaling ameliorated CNS vascular pathologies, including partial rescue of retinal vascular patterning defects, prevention of VSMC loss, and significant reduction of intracerebral hemorrhages in Col4a1 mutant mice aged up to 8 months. This study identifies a novel biological role for collagen α1α1α2(IV) as a regulator of TGFß signaling and demonstrates that elevated TGFß signaling contributes to CNS vascular pathologies caused by Col4a1 mutations. Our findings suggest that pharmacologically suppressing TGFß signaling could reduce the severity of CSVD, and potentially other manifestations associated with Gould syndrome and have important translational implications that could extend to idiopathic forms of CSVD.

[Monthly deworming in dogs for echinococcosis control in two counties of Xinjiang Uygur Autonomous Region].

OBJECTIVE: To verify the application and effectiveness of monthly deworming for all dogs in the control of Echinococcus granulosus infection. METHODS: Baited praziquantel was used to treat all registered dogs monthly by hydatid disease control officers at village level and all stray (unowned) dogs were eliminated in the counties of Hutubi and Wensu in 1987-1990 and 1990-1994 respectively. Prevalence of echinococcosis in dogs and sheep was recorded yearly. RESULTS: The infection rate in dogs decreased from 18.5% and 14.7% before implementation of the control measure to zero in 3-4 years in Hutubi and Wensu Counties respectively. Prevalence of hydatid disease in new born sheep was reduced by more than 85% in comparison to the same age sheep before the control program in both counties. CONCLUSION: "Monthly drug administration to all dogs" is an effective way to the control of echinococcosis in dogs and of hydatid disease in sheep.