Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis.

BACKGROUND & AIMS: Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro. METHODS: FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2-/-). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics. RESULTS: FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP. CONCLUSIONS: Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.

Suicide rate and social environment characteristics in South Korea: the roles of socioeconomic, demographic, urbanicity, general health behaviors, and other environmental factors on suicide rate.

BACKGROUND: Suicide is a serious worldwide public health concern, and South Korea has shown the highest suicide rate among Organisation for Economic Co-operation and Development (OECD) countries since 2003. Nevertheless, most previous Korean studies on suicide had limitations in investigating various social environment factors using long-term nationwide data. Thus, this study examined how various social environment characteristics are related to the suicide rate at the district-level, using nationwide longitudinal data over 11 years. METHODS: We used the district-level age-standardized suicide rate and a total of 12 annual social environment characteristics that represented socioeconomic, demographic, urbanicity, general health behaviors, and other environmental characteristics from 229 administrative districts in South Korea. A Bayesian hierarchical model with integrated Laplace approximations (INLA) was used to examine the spatiotemporal association between the rate of suicide and the social environment indicators selected for the study. RESULTS: In the total population, the indicators "% of population aged 65 and older eligible for the basic pension", "% vacant houses in the area", "% divorce", "% single elderly households", "% detached houses", "% current smokers", and "% of population with obesity" showed positive associations with the suicide rate. In contrast, "% of people who regularly participated in religious activities" showed negative associations with suicide rate. The associations between these social environment characteristics and suicide rate were generally more statistically significant in males and more urbanized areas, than in females and less urbanized areas; however, associations differed amongst age groups, depending on the social environment characteristic variable under study. CONCLUSIONS: This study investigated the complex role of social environments on suicide rate in South Korea and revealed that higher suicide rates were associated with lower values of socioeconomic status, physical exercise, and religious activities, and with higher social isolation and smoking practice. Our results can be used in the development of targeted suicide prevention policies.

Effects of urbanization on vulnerability to heat-related mortality in urban and rural areas in South Korea: a nationwide district-level time-series study.

BACKGROUND: Although urbanization is often an important topic in climate change studies, the complex effect of urbanization on heat vulnerability in urban and rural areas has rarely been studied. We investigated the disparate effects of urbanization on heat vulnerability in urban and rural areas, using nationwide data. METHODS: We collected daily weather data for all 229 administrative districts in South Korea (2011-17). Population density was applied as an urbanization indicator. We calculated the heat-mortality risk using a distributed lag nonlinear model and analysed the relationship with population density. We also examined district characteristics that can be related to the spatial heterogeneity in heat-mortality risk. RESULTS: We found a U-shaped association between population density and heat-mortality risk, with the highest risk for rural populations; in urban areas, risk increases with increasing population density. Higher heat-mortality risk was associated with a lower number of hospital beds per person and higher percentage of people requiring recuperation. The association between hospital beds and heat-mortality risk was prominent in high-density urban areas, whereas the association between the percentage of people requiring recuperation and heat-mortality risk was pronounced in rural areas. CONCLUSIONS: Our findings indicate that the association between population density and heat-mortality risk is different in urban and rural areas, and that district characteristics related to heat-mortality risk also differ by urbanicity. These results can contribute to understanding the complex role of urbanization on heat vulnerability and can provide evidence to policy makers for prioritizing resources.

Social isolation and vulnerability to heatwave-related mortality in the urban elderly population: A time-series multi-community study in Korea.

Although several studies have reported that social isolation is one of the important health risk factors in the elderly population living in urban areas, its effects on vulnerability to heatwaves have been studied relatively less than climatic and other socio-economic factors. Thus, we investigated the association between social isolation levels and heatwave-related mortality risk in the elderly population in 119 urban administrative districts in Korea, using a time-series multi-city dataset (2008-2017). We used a two-stage analysis. In the first stage, we estimated the heatwave-related mortality risk in the elderly population (age ≥ 65) for each district using a time-series regression with a distributed lag model. Subsequently, in the second stage, we applied meta-regressions to pool the estimates across all the districts and estimate the association between social isolation variables and heatwave-related mortality risk. Our findings showed that higher social gathering and mutual aid levels were associated with lower heatwave-related mortality risk. Further, the lower percentage of single elderly households living in detached houses was also related to higher heatwave-related mortality risk. The associations were generally more evident in males compared to females. Our findings suggest that vulnerability to heatwave-related mortality among the urban, city-dwelling, elderly population may be amplified by higher isolation indicators.

Extramarginal excision is preferable for hypertrophic scars.

BACKGROUND: Recently, higher proliferative activity and collagen production in the peripheral parts of keloids have been reported. Therefore, we hypothesized that insufficient removal of active proliferating and collagen-producing fibroblasts at the scar margin might cause a high recurrence rate of hypertrophic scars and keloids. To address this hypothesis, we evaluated the influence of surgical margins on the recurrence of hypertrophic scars and compared the recurrence rates between intramarginal excision and extramarginal excision. METHODS: A retrospective review was performed of patients with car tire injury-induced hypertrophic scars treated by surgical excision from 2004 to 2010. To evaluate the influence of surgical margins on the recurrence of hypertrophic scars, we divided these patients into two groups, the intramarginal excision group and the extramarginal excision group, and compared the recurrence rate. RESULTS: A total of 15 patients with car tire injury-induced hypertrophic scars were treated with surgical excision and skin grafting. The recurrence rate in those with intramarginal excision was significantly higher than in those with extramarginal excision. All patients treated with intramarginal excision experienced hypertrophic scar recurrence within six months. Three of nine patients exhibited recurrence when the hypertrophic scars were excised with a 3-5 mm margin. CONCLUSION: Extramarginal excision with complete removal of the abnormal collagen bundles followed by skin grafting is a viable alternative to reconstruction of the foot after hypertrophic scar excision, and this treatment can effectively decrease issues related to recurrence.

Cloning, expression, and characterization of a new deoxyribose 5-phosphate aldolase from Yersinia sp. EA015.

A new deoC gene encoding deoxyribose 5-phosphate aldolase (DERA) was identified in Yersinia sp. EA015 isolated from soil. The DERA gene had an open reading frame (ORF) of 672 base pairs encoding 223 amino acids to yield a protein of molecular mass 24.8 kDa. The amino acid sequence was 94% identical to that of DERA from Yersinia intermedia ATCC 29909. DERA was over-expressed in Escherichia coli and purified using Ni-NTA affinity chromatography. The specific activity was 137 micromol/min/mg. The Michaelis constant (k(m) value) of DERA was 9.1 mM. DERA was optimally active at pH 6.0 and 50 degrees C. DERA was tolerant to a high concentration (300 mM) of acetaldehyde.