Impact of follow-up visits on disease outcome in Chinese systemic lupus erythematosus

The objective of this study is to determine whether the frequency of visits would affect disease activity and disease damage in patients with systemic lupus erythematosus (SLE). We recruited 147 patients who met the 1997 American College of Rheumatology (ACR) criteria for SLE. Patients were divided into three groups based on follow-up frequency: ≤ 6 visits/year (group 1), 6–12 visits/year (group 2), and > 12 visits/year (group 3). Disease activity and organ damage were evaluated using the SLE disease activity index (SLEDAI) and Systemic Lupus International Collaborative Clinics (SLICC)/ACR criteria, respectively. Data on disease features, patient characteristics, and treatment were retrospectively reviewed. We found that the SLICC score was significantly lower in patients with > 12 visits/year (P = 0.008), while the SLEDAI score showed no significant difference. The age at symptom onset (32.68 ± 13.53) and the age at SLE diagnosis (33.32 ± 13.81) in group 3 were significantly older than those in the other two groups. In univariate regression analysis, the frequency of visits, the age at symptom onset, and the age at SLE diagnosis were found to be associated with the SLICC scores. Visit frequency has no impact on SLE disease activity, but may be associated with less disease damage, an important outcome.     

Association between sleep disorders and morning blood pressure in hypertensive patients

Sleep disorders are known to increase the risk of hypertension, yet few studies have investigated the relation between sleep disorders and morning blood pressure (BP). This study aimed to determine, whether the morning BP is associated with sleep quality and sleep-disordered breathing. A total of 144 hypertensive patients were included in this cross-sectional study. Each subject underwent anthropometric measurements, biochemical testing, 24-h ambulatory BP monitoring, and polysomnography (PSG). Sleep quality and sleep-disordered breathing were determined by PSG parameters of sleep architecture and sleep respiratory. There were no significant differences between subjects with and without morning hypertension in the parameters of sleep architecture and sleep respiratory. In multiple regression analysis, morning BP was independently associated with night-time BP and morning BP surge, but not with the parameters of sleep architecture and sleep respiratory. Further analysis showed that both night-time BP and morning BP surge were independently associated with the sleep respiratory parameters. In conclusion, sleep-disordered breathing might indirectly affect the morning BP by elevated night-time BP, yet neither poor sleep quality nor sleep-disordered breathing was major determinants of elevated morning BP in hypertensive patients.     

Different patterns of tibial plateau fractures associated with hyperextension injuries of the knee with or without varus/valgus component

This study aims to introduce a morphological classification of hyperextension tibial plateau fractures based on CT scans and to reveal the correlation between the anterior compression and posterior tension fractures.From January 2015 to January 2019, 37 patients with hyperextension tibial plateau fractures were studied retrospectively. Based on this classification, the fractures were divided into 2 groups: group A had anterolateral or anteromedial compression fractures while group B had both. Three observers classified the fractures and recorded the morphology and incidences of posterior plateau fractures and proximal fibular fractures.All 37 fractures were allocated to group A (n = 15; 40%) and B (n = 22; 60%). Of the posterior tibial plateau fractures, 10 (27%) fractures were defined as partial and 27 (73%) as total. Of the 37 fractures, 18 (49%) proximal fibular avulsion fractures were observed. There was a significant difference between groups A and B regarding the incidence of total posterior tibial plateau fractures (P < .05). However, there was no significant difference between the incidence of proximal fibular avulsion fractures in the 2 groups or the combined and non-combined type fractures in group B (P > .05).Hyperextension tibial plateau fractures with a decreased posterior slope angle always involve both the anteromedial and anterolateral plateaus. This CT-based classification may improve the understanding of fracture features and is helpful for planning treatment.     

The biosynthesis of thymol,carvacrol, and thymohydroquinone in Lamiaceae proceeds via cytochrome P450s and a short-chain dehydrogenase

Thymol and carvacrol are phenolic monoterpenes found in thyme, oregano, and several other species of the Lamiaceae. Long valued for their smell and taste, these substances also have antibacterial and anti-spasmolytic properties. They are also suggested to be precursors of thymohydroquinone and thymoquinone, monoterpenes with anti-inflammatory, antioxidant, and antitumor activities. Thymol and carvacrol biosynthesis has been proposed to proceed by the cyclization of geranyl diphosphate to γ-terpinene, followed by a series of oxidations via p-cymene. Here, we show that γ-terpinene is oxidized by cytochrome P450 monooxygenases (P450s) of the CYP71D subfamily to produce unstable cyclohexadienol intermediates, which are then dehydrogenated by a short-chain dehydrogenase/reductase (SDR) to the corresponding ketones. The subsequent formation of the aromatic compounds occurs via keto–enol tautomerisms. Combining these enzymes with γ-terpinene in in vitro assays or in vivo in Nicotiana benthamiana yielded thymol and carvacrol as products. In the absence of the SDRs, only p-cymene was formed by rearrangement of the cyclohexadienol intermediates. The nature of these unstable intermediates was inferred from reactions with the γ-terpinene isomer limonene and by analogy to reactions catalyzed by related enzymes. We also identified and characterized two P450s of the CYP76S and CYP736A subfamilies that catalyze the hydroxylation of thymol and carvacrol to thymohydroquinone when heterologously expressed in yeast and N. benthamiana. Our findings alter previous views of thymol and carvacrol formation, identify the enzymes involved in the biosynthesis of these phenolic monoterpenes and thymohydroquinone in the Lamiaceae, and provide targets for metabolic engineering of high-value terpenes in plants.

The phenolic monoterpenes of the Lamiaceae are widely used constituents of pharmaceuticals, cosmetics, and food products (1). Extracts of plants containing thymol or carvacrol are employed in medicine for their antibacterial, anti-spasmodic, antioxidant, and anti-cancer properties. Because of their pungent, warm, and aromatic odors, they also serve as additives to cosmetics and are used in aromatherapy. Thymol and carvacrol are best known as the aroma compounds of oregano and thyme, in which they provide the herbal, pizza-like tastes that are traditionally used in Mediterranean cuisine and food preservation (2). The occurrence of phenolic monoterpenes is restricted to a few genera in the Lamiaceae (Thymus, Origanum, Satureja, and Thymbra), Apiaceae (Trachyspermum), and Verbenaceae (Lippia). Of these, the essential oils of Thymus are the most important commercial source of phenolic monoterpenes (3). Thymus vulgaris L. and Origanum species also produce the structurally related monoterpenes thymohydroquinone and thymoquinone, which were first described in the essential oil of Nigella sativa L. black seed (4). Thymohydroquinone was shown to exhibit anti-cancer activity (5), and thymoquinone displays anti-inflammatory, hepatoprotective, antioxidant, cytotoxic, and anti-cancer activities (6).To date, only a few biosynthetic pathways to pharmaceutically valuable, oxidized terpenes have been completely elucidated, such as those leading to artemisinin, paclitaxel, and the phenolic, labdane-type diterpenes of sage and rosemary (7–9). For monoterpenes, a complex biosynthetic pathway has only been described for menthol and its derivatives in Mentha (10). However, the biosynthetic pathways for phenolic monoterpenes like thymol or carvacrol remain uncharacterized. Most monoterpenes are biosynthesized by fusion of the ubiquitous C₅ intermediates, isopentenyl diphosphate, and its isomer dimethylallyl diphosphate, resulting in the formation of a C₁₀ compound, geranyl diphosphate (GDP). This acyclic intermediate is the substrate for the large enzyme family of monoterpene synthases that form cyclic or acyclic products with an enormous variety of carbon skeletons (11, 12). In previous studies in thyme and oregano, the cyclic monoterpene olefin γ-terpinene was proposed as a precursor of thymol and carvacrol (Fig. 1A). Studies with ³H-labeled γ-terpinene showed that this compound was converted into thymol and carvacrol after incubation with young thyme leaves (13). Furthermore, the essential oils of plant species rich in either thymol or carvacrol have always been reported to contain substantial amounts of γ-terpinene (3). Terpene synthases forming γ-terpinene have been identified and characterized from various Lamiaceae species (14–19). In oregano, the expression of the γ-terpinene synthase OvTPS2 was found to correlate with thymol and carvacrol content in leaves (14). Beyond γ-terpinene, however, no further precursors of phenolic monoterpenes have been identified. The aromatic hydrocarbon p-cymene was suggested to be an intermediate in thymol and carvacrol formation from γ-terpinene (20), but its participation in the phenolic monoterpene pathway and the nature of the enzymes involved in formation of the aromatic ring still remain unknown. Moreover, there is little information about the conversion of the thymol and carvacrol to thymohydroquinone.Open in a separate windowFig. 1.T. vulgaris is composed of different monoterpene chemotypes. (A) Proposed biosynthetic pathway to the phenolic monoterpenes thymol and carvacrol as well as thymohydroquinone and thymoquinone. γ-terpinene and p-cymene were suggested as intermediates in the formation of thymol and carvacrol (17). (B) Essential oil composition of the T. vulgaris chemotypes dominated by carvacrol (C type), thymol (T type), and geraniol (G type). Terpenes were extracted with hexane and analyzed by GC-MS. The following terpenes were identified: 1, α-thujene; 2, α-pinene; 3, myrcene; 4, α-terpinene; 5, p-cymene; 6, γ-terpinene; 7, cis-sabinene hydrate; 8, linalool; 9, nerol; 10, neral; 11, thymoquinone; 12, geraniol; 13, geranial; 14, thymol; 15, carvacrol; 16, geranyl acetate; 17, (E)-β-caryophyllene; 18, thymohydroquinone; and 19, germacrene D. Nonyl acetate (10 µl/mL) was added as internal standard (IS) for quantification.In this study, we investigated the biosynthetic pathway leading to the formation of thymol, carvacrol, and thymohydroquinone in thyme and oregano. We isolated and characterized six cytochrome P450 monooxygenases (P450s) of the CYP71D subfamily from thyme and oregano accessions producing high levels of thymol and carvacrol. When these CYP genes were heterologously expressed and combined with a short-chain dehydrogenase from thyme in vitro or coexpressed in vivo in Nicotiana benthamiana, thymol or carvacrol were formed. Based on the characteristics of the expressed enzymes and their reaction with other substrates, we constructed the biosynthetic pathway leading to thymol and inferred the nature of unstable intermediates. Furthermore, we identified and characterized two P450s of the CYP76S and CYP736A subfamilies that hydroxylate thymol and carvacrol to thymohydroquinone when expressed in vivo in yeast and in N. benthamiana.     

胶原纤维在小鼠酒精性肝损伤过程中的表达变化

目的:探究胶原纤维在酒精性肝损伤发展过程中各个阶段的变化规律及其与酒精性肝损伤的关系.方法:饲养清洁健康BALB/c♂小鼠40只,随机分为对照组(n=3)与模型组(n=37).将对照组3只小鼠处死,取肝;模型组小鼠每日给予0.15 m L/10 kg 56°红星二锅头白酒灌胃,持续4 wk,于开始灌胃后1、2、3、4 w k各取3只小鼠进行肝脏取材.天狼星红染色法观察小鼠肝组织胶原纤维病理变化情况,蛋白印迹法检测小鼠肝脏增殖细胞核抗原(proliferating cell nuclear antigen,P C N A)蛋白表达及变化趋势.运用ImageProPlus6.0对病理切片样本进行积分光密度(IOD)定量分析,Gel Pro4.0软件对目标蛋白条带灰度值进行测定.运用SPSS16.0对数据进行处理,用ANOVE法和非参数秩和检验法进行显著性分析.结果:第1、2周组小鼠肝组织胶原纤维含量持续显著增高(852.21±10.65 vs 345.24±65.94,1054.15±10.80 vs 852.21±10.65,P0.01),第2周达到最高,随后第3、4周小鼠肝组织胶原纤维含量依次降低(588.75±17.18 vs 1054.15±10.80,559.40±14.17,P0.01);小鼠肝组织中PCNA蛋白含量前2 wk明显下降,第2周时达到最小值,第3周较第2周增加显著,差异有统计学意义(P0.05).第4周与第3周变化无明显差异.结论:在酒精诱导小鼠肝脏损伤的过程中,肝脏胶原纤维的变化规律是先增加后减少,变化明显;PCNA的表达出现显著动态变化,二者均可能与肝脏的损伤修复机制密切相关.     

Interaction of poor sleep quality,family history of type 2 diabetes,and abdominal obesity on impaired fasting glucose: a population-based cross-sectional survey in China

This study aims to explore the interaction of sleep quality, family history of type 2 diabetes, and obesity in relation to impaired fasting glucose in a Chinese population. A representative population-based cross-sectional study was conducted, and 15,145 residents aged between 18 and 75 years were selected from 11 districts of Xuzhou City, Jiangsu Province. The Pittsburgh Sleep Quality Index was used to evaluate sleep conditions, with categories of good and poor. Impaired fasting glucose (IFG) was assessed by fasting blood glucose. Interaction of sleep quality, obesity, and family history of diabetes (FHD) on IFG was analyzed by logistic regression. Relative excess risk due to interaction (RERI) and the synergy index (SI) were applied to evaluate the additive interaction between the two factors. Either poor sleep or positive FHD was independently associated with an increased odds ratio (OR) for IFG. Those with both poor sleep and positive FHD had a significantly increased risk compared with those without poor sleep and FHD (OR 20.6, 95 % confidence interval (CI) 16.4–29.0, P?<?0.001). The corresponding RERI and SI was 14.6 (8.6–20.6) and 3.7 (1.4–5.1), respectively. Both abdominal obesity and FHD significantly increased the risk of being IFG. The synergistic effect of abdominal obesity and FHD on IFG was statistically significant (OR 40.1, 95 % CI 28.8–61.5). The results suggest that additive interactions exist between poor sleep quality, abdominal obesity, and family history of diabetes in relation to impaired fasting glucose.     

Adipose-derived lipocalin 14 alleviates hyperglycaemia by suppressing both adipocyte glycerol efflux and hepatic gluconeogenesis in mice

Aims/hypothesis

Growing evidence supports that dysregulation of adipose tissue-derived factors contributes to the pathogenesis of diabetes and its complications. Since our global gene profiling analysis has identified lipocalin-14 (LCN14)—a secretory protein with lipid-binding properties—as a potential adipokine highly expressed in white adipose tissue (WAT), this study aims to explore the metabolic roles of LCN14 in obese mice, and to investigate the functional mechanisms involved.

Methods

Immunoassays and western blotting were performed to determine the circulating level and tissue distribution of LCN14, respectively. Recombinant adeno-associated virus (rAAV)-mediated gene delivery was used to overexpress LCN14 in diet-induced obese (DIO) mice and the effects on glucose and lipid metabolism were examined.

Results

LCN14 is expressed predominantly in WAT. Both circulating levels of LCN14 and its expression in adipose tissues are repressed in DIO and genetically inherited diabetic (db/db) mice. Overexpression of LCN14 by rAAV-mediated gene delivery in DIO mice significantly increased insulin sensitivity in major metabolic tissues and ameliorated hyperglycaemia by inhibiting hepatic gluconeogenesis. The reduced hepatic glucose production is attributed to the suppressive effects of LCN14 on the expression of gluconeogenic genes and on glycerol efflux in adipocytes, possibly by reducing the expression of aquaporin-7.

Conclusions/interpretation

Reduced LCN14 expression is involved in the pathogenesis of obesity-related metabolic dysregulation. LCN14 exerts its beneficial effects on glucose homeostasis and insulin sensitivity via its actions in both adipocytes and hepatocytes.