Longitudinal relationship between grip strength and cognitive function in a European population older than 50 years: A cross-lagged panel model.

OBJECTIVES: The aim of this study was to investigate the dynamic longitudinal relationship between grip strength and cognitive function. METHODS: 6175 participants aged ≥50 years were included in the study using three waves of follow-up data from the Survey of Health, Ageing, and Retirement in Europe in 2015 (T1), 2017 (T2) and 2019 (T3). Cognitive function was assessed using numeracy, verbal fluency, immediate recall, delayed recall and total. The cross-lagged panel model was used for analysis. RESULTS: There was a correlation between grip strength and cognitive function. Standardized path coefficient from numeracy T1 to grip strength T2 was 0.017 (p = 0.003), and from numeracy T2 to grip strength T3 was 0.014 (p = 0.012). Standardized path coefficient from grip strength T1 to numeracy T2 was 0.096 (p < 0.001), and from grip strength T2 to numeracy T3 was 0.113 (p < 0.001). Other indicators of cognitive function had similar relationships with grip strength. CONCLUSIONS: The study found a statistically significant longitudinal and bidirectional relationship between grip strength and cognitive function in a sample of people aged ≥50 years from several European countries.

Role of Proviral HIV-1 DNA Genotyping for People Living with HIV (PLWH) Who Had Low-Level Viremia While Receiving Antiretroviral Therapy.

Objective: To analyze the antiretroviral resistance in people living with HIV (PLWH) who developed low-level viremia (LLV) during antiretroviral therapy (ART) via sequencing of their HIV-1 proviral DNA and RNA and comparisons of their proviral DNA genotyping data with their past and synchronous RNA genotyping data. Patients and Methods: PLWH with LLV while receiving ART for 6 months or longer from January 2020 to September 2021 were included. HIV-1 proviral DNA and RNA were extracted from white-blood cells and concentrated plasma by ultracentrifugation, respectively, and HIV-1 pol gene fragments were amplified and sequenced. The concordance in the detection of resistance-associated mutations (RAMs) were examined between proviral DNA vs past RNA genotyping and proviral DNA vs synchronous RNA genotyping. Results: Of the 150 PLWH with LLV, 117 proviral DNA pol sequences detected in 105 PLWH were successfully amplified and RAMs were present in 27.6% and the rate of RAMs conferring low-level or greater resistance to antiretrovirals examined was 17.1%. Fifty-six and 57 PLWH had results of past and synchronous RNA genotyping, respectively, for comparisons with those of proviral DNA genotyping; and the concordance rates were 76.8% and 75.4%, respectively. However, proviral DNA genotyping lost than gained partial information on antiretroviral resistance compared with past or synchronous RNA genotyping. Conclusion: We found that the concordance between proviral DNA and past and synchronous RNA genotyping was moderate. Proviral DNA genotyping lost than gained more information on antiretroviral resistance compared with past or synchronous RNA genotyping. To optimize ART in PLWH with LLV, antiretroviral resistance profile should be interpreted in combination with proviral DNA and RNA genotyping and a comprehensive review of previous treatment history.

Trends in total cholesterol control among American adults with hypercholesterolemia, 1988-2018.

BACKGROUND AND AIMS: Cholesterol control and management in patients with hypercholesterolemia are significant for the primary and secondary prevention of atherosclerotic cardiovascular disease. This study analyzed the trend of serum total cholesterol (TC) control (<240 mg/dL and <200 mg/dL) in American adults with hypercholesterolemia and thereby make some effective recommendations for the public health measures. METHODS AND RESULTS: Basing on the National Health and Nutrition Examination Survey (NHANES) data from 1988 to 2018 (12 cycles), we calculated the weighted and representative rate of patients with hypercholesterolemia who had controlled TC, and then described the trend. Among the adults with hypercholesterolemia, the age-adjusted rate of those whose TC was less than 240 mg/dL increased from 7.67% (95%CI: 5.94%-9.40%) in 1988-1991 to 58.52% (95%CI: 55.89%-61.15%) in 2013-2014 and then remained stable; and the age-adjusted rate of those whose TC was less than 200 mg/dL increased from 2.49% (95%CI: 1.48%-3.50%) in 1988-1991 to 44.58% (95%CI: 40.00%-49.16%) in 2017-2018. CONCLUSION: We concluded that the rate of controlling TC below 200 mg/dL among all patients had shown an increasing trend from 1988 to 2018 in America, while the rate of controlling TC below 240 mg/dL remained stable in recent years after an increasing.

Competing risks analysis of external versus internal radiation in patients with hepatocellular carcinoma after controlling for immortal time bias.

PURPOSE: In cohort studies on liver cancer, there are often immortal time bias and interference of competing risk events. This study proposes to explore the role of internal and external radiotherapy for hepatocellular carcinoma using SEER data, using a competing risk model and controlling immortal time bias. METHODS: Data of SEER from 2004 till 2015 was included. To analyze whether there was a difference in survival between HCC (hepatocellular carcinoma) patients receiving external radiation and internal radiation, we used a competing risk analysis after excluding immortal time bias, and created a nomogram to assess the risk of cancer-specific death (CSD) in hepatocellular carcinoma patients receiving radiotherapy. RESULTS: Potential confounding factors adjusted, there was no significant difference in CSD between external and internal radiation therapy [HR and its 95% CI = 1.098 (0.874-1.380)]. The constructed nomogram performed better than the traditional AJCC model. The AUC and calibration curve results showed that this well-calibrated nomogram could be used to make clinical decisions regarding the prognosis and personalized treatment of hepatocellular carcinoma treated. There was no difference in the cumulative risk of death between patients with liver cancer treated with external radiation therapy and internal radiation therapy. CONCLUSION: There is no difference in the cumulative risk of death between patients with liver cancer treated with external radiation therapy and internal radiation therapy. The nomogram predicts the results more accurately. These results can be used to guide the choice of treatment options for patients with HCC and to predict their survival prognosis.

Parabacteroides distasonis ameliorates hepatic fibrosis potentially via modulating intestinal bile acid metabolism and hepatocyte pyroptosis in male mice.

Parabacteroides distasonis (P. distasonis) plays an important role in human health, including diabetes, colorectal cancer and inflammatory bowel disease. Here, we show that P. distasonis is decreased in patients with hepatic fibrosis, and that administration of P. distasonis to male mice improves thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis. Administration of P. distasonis also leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal farnesoid X receptor (FXR) signaling and decreased taurochenodeoxycholic acid (TCDCA) levels in liver. TCDCA produces toxicity in mouse primary hepatic cells (HSCs) and induces mitochondrial permeability transition (MPT) and Caspase-11 pyroptosis in mice. The decrease of TCDCA by P. distasonis improves activation of HSCs through decreasing MPT-Caspase-11 pyroptosis in hepatocytes. Celastrol, a compound reported to increase P. distasonis abundance in mice, promotes the growth of P. distasonis with concomitant enhancement of bile acid excretion and improvement of hepatic fibrosis in male mice. These data suggest that supplementation of P. distasonis may be a promising means to ameliorate hepatic fibrosis.

Genetic characteristics of a novel HIV-1 recombinant lineage (CRF103_01B) and its prevalence in northern China.

During the routine surveillance of HIV-1 pretreatment drug resistance in Beijing, five men who have sex with men (MSM) and a woman were observed to get infected by newly identified CRF103_01B strain. To elucidate the genetic characteristics, the near full-length genome (NFLG) was obtained. Phylogenetic inference indicated that CRF103_01B NFLG was composed of six mosaic segments. Segments IV and V of CRF103_01B were located among the clusters subtype B and CRF01_AE (group 5), respectively. The CRF103_01B strain was deduced to originate from Beijing MSM population around 2002.3-2006.4 and continued to spread among MSM population at a low level, then to the general population via heterosexual contact in northern China. Molecular epidemiology surveillance of CRF103_01B should be reinforced.

Genetic Characteristics of Two Unique Recombinant Forms of HIV-1 CRF01_AE/CRF07_BC by Near Full-Length Genome from Men Who Have Sex with Men in Beijing, China.

Two HIV-1 infections with unassigned genotypes were identified during HIV-1 pretreatment drug resistance surveillance. The near full-length genome sequences of BL5040-00 and BL5085-00 were obtained and were classified as unique recombinant forms (URFs) between CRF01_AE and CRF07_BC. Simplot (version 3.5) analyses showed that the two URFs shared similar recombinant forms, and in the backbone belonging to CRF01_AE, the gag-pol, vpu, env, and nef gene fragments were genetically substituted by CRF07_BC. BL5040-00, with 10 breakpoints, had 6 CRF07_BC fragments and 5 CRF01_AE fragments, whereas BL5085-00, with 6 breakpoints, had 4 CRF07_BC fragments and 3 CRF01_AE fragments. BL5040-00 strain had two additional recombination breakpoints in pol-vif gene. The presence of URFs suggests that the men who have sex with men population in Beijing has an active HIV epidemic and the genetic diversity of HIV-1 is complex, emphasizing molecular epidemiology and disease progression monitoring should be strengthened.

Waist Circumference-Years Construct Analysis and the Incidence of Type 2 Diabetes: China Health and Nutrition Survey, 1997-2015.

Background: Few studies have combined the degree and duration of abdominal obesity into a waist circumference-years construct for analysis. The purpose of this study was to investigate the effect of waist circumference-years on the incidence of type 2 diabetes. Methods: A total of 6616 adults from the China Health and Nutrition Survey (CHNS) were enrolled in this study from 1997. The waist circumference-years construct was represented as the sum of the upper and lower area between the waist circumference baseline (men: ≥90 cm, women: ≥85 cm) and the waist circumference line. The correlations in the study were analyzed using logistic regression. Results: The incidence of type 2 diabetes increased with increasing waist circumference-years, with an adjusted risk increase of 38% (95% CI: 31−47%) for each additional 50 waist circumference-years, and this rate was similar across gender and age groups. The area under the curve of waist circumference-years (0.743) was greatest in the receiver operating characteristic curve (ROC) analysis compared to baseline waist circumference (0.731) and the waist-height ratio (0.728) (p < 0.05). Conclusion: The waist circumference-years construct is closely associated with an increased risk of type 2 diabetes and may be a stronger predictor of type 2 diabetes risk than baseline waist circumference or the waist-height ratio.

Polyamine metabolism links gut microbiota and testicular dysfunction.

BACKGROUND: Male fertility impaired by exogenous toxins is a serious worldwide issue threatening the health of the new-born and causing infertility. However, the metabolic connection between toxic exposures and testicular dysfunction remains unclear. RESULTS: In the present study, the metabolic disorder of testicular dysfunction was investigated using triptolide-induced testicular injury in mice. We found that triptolide induced spermine deficiency resulting from disruption of polyamine biosynthesis and uptake in testis, and perturbation of the gut microbiota. Supplementation with exogenous spermine reversed triptolide-induced testicular dysfunction through increasing the expression of genes related to early and late spermatogenic events, as well as increasing the reduced number of offspring. Loss of gut microbiota by antibiotic treatment resulted in depletion of spermine levels in the intestine and potentiation of testicular injury. Testicular dysfunction in triptolide-treated mice was reversed by gut microbial transplantation from untreated mice and supplementation with polyamine-producing Parabacteroides distasonis. The protective effect of spermine during testicular injury was largely dependent on upregulation of heat shock protein 70s (HSP70s) both in vivo and in vitro. CONCLUSIONS: The present study linked alterations in the gut microbiota to testicular dysfunction through disruption of polyamine metabolism. The diversity and dynamics of the gut microbiota may be considered as a therapeutic option to prevent male infertility. Video Abstract.

Discovery of quality markers in Rubus Chingii Hu using UPLC-ESI-QTOF-MS.

Raspberry, the fruit of Rubus Chingii Hu, has been used as a traditional Chinese medicine (TCM) to nourish kidney and strengthen Yang-qi. In order to determine the quality of raspberry, the quality markers (Q-markers) of raspberry that can improve renal function were investigated using UPLC-ESI-QTOF-MS in this study. The results of serum pharmacochemistry indicated that six components rutin, ellagic acid, kaempferol-3-rutinoside, astragalin, tiliroside, and goshonoside F5 in raspberry were absorbed into rat blood. The HEK293 cells treated with cisplatin were used to evaluate the kidney-protecting activity of these absorbed components. All these components could markedly inhibit cell damage induced by cisplatin and restore the levels of malondialdehyde (MDA) and catalase (CAT) in the cells, suggesting that these components may be the Q-markers of raspberry. More importantly, except for ellagic acid, other five Q-markers in raspberries from Dexing of Jiangxi province were higher than those from most of other areas. It is well known that Dexing raspberry is the Dao-di herbs raspberry used in the clinic of Chinese Medicine, demonstrating that these components could be used as Q-markers of raspberry. This study provides a reliable and valuable method for quality evaluation of raspberry.

FXR activation prevents liver injury induced by Tripterygium wilfordii preparations.

Tripterygium glycosides tablets (TGT) and Tripterygium wilfordii tablets (TWT) are the preparations of Tripterygium wilfordii used to treat rheumatoid arthritis (RA) in the clinic, but the hepatotoxicity was reported frequently. This study aimed to determine the potential toxicity mechanism of liver injury induced by the preparations of Tripterygium wilfordii in mice.Here, we performed metabolomic analysis, pathological analysis and biochemical analysis of samples from mice with liver injury induced by TGT and TWT, which revealed that liver injury was associated with bile acid metabolism disorder. Quantitative real-time PCR (QPCR) and western blot indicated that the above changes were accompanied by inhibition of farnesoid X receptor (FXR) signalling.Liver injury from TWT could be alleviated by treatment of the FXR agonist obeticholic acid (OCA) via activation of the FXR to inhibit the c-Jun N-terminal kinase (JNK) pathway and improve bile acid metabolism disorder by activating bile salt export pump (BSEP) and organic solute-transporter-ß (OSTB). The data demonstrate that FXR signalling pathway plays a key role in T. wilfordii-induced liver injury, which could be alleviated by activated FXR.These results indicate that FXR activation by OCA may offer a promising therapeutic opportunity against hepatotoxicity from the preparations of T. wilfordii.

Discovery and validation of quality markers of Fructus Aurantii against acetylcholinesterase using metabolomics and bioactivity assays.

Fructus Aurantii is a traditional medicated diet in East Asia. To determine the underlying chemical markers responsible for the quality and efficacy of Fructus Aurantii, a sensitive metabolomic method was applied to distinguish Fructus Aurantii in Jiangxi Province from other two geographical locations (Hunan Province and Chongqing City) in China. In the present study, multivariate analyses were adopted to compare chemical compositions in 21 batches of Fructus Aurantii samples. Among three geographical origins, 23 differential compounds were structurally identified. Serum pharmacochemistry exhibited that 22 components could be detected in rat serum. Six differential and absorbed components were selected as six potential markers. Statistical analysis revealed that the content of six markers varied widely in three origins of Fructus Aurantii. Six differential and absorbed components were evaluated further by biological activity. Neohesperidin, naringin, and meranzin showed inhibitory effect on acetylcholinesterase that regulates gastrointestinal motility in vitro and in silico, suggesting that these three components may be determined as the active biomarkers of Fructus Aurantii. These findings demonstrate the potential of biomarkers for identification and quality control of Fructus Aurantii.

Acute Administration of Methyleugenol Impairs Hippocampus-Dependent Contextual Fear Memory and Increases Anxiety-like Behavior in Mice.

Methyleugenol (ME) as a natural essential oil in many plant species is widely used in human food and beverage for its fragrance and possible beneficial health effects. Previous chronic or subacute studies in rodents show that ME mainly causes liver toxicity. However, whether and how acute ME affects the central nervous system still remain elusive. Here, we found that ME administrated into the hippocampus impaired the acquisition of hippocampus-dependent contextual fear memory in mice (ME vs control: repeated-measures two-way ANOVA, F(5,70) = 2.937, p < 0.05; Fisher test, p < 0.05, respectively, 53 ± 5.2% vs 73 ± 7.6% during trial 4 and 46.8 ± 6% vs 74.5 ± 9.3% during trial 5). Meanwhile, acute ME impaired hippocampal CA1 long-term potentiation (LTP; ME vs control: independent t-test, p < 0.01, 110.6 ± 1.8% vs 133.3 ± 5.6%) while facilitated long-term depression (LTD; p < 0.01, 75.7 ± 3.4% vs 88.6 ± 1.7%) in mice brain slices and inducing a decrease in learning-dependent phosphorylation of Ser831 (ME vs control: independent t-test, p < 0.001, 0.87 ± 0.03 vs 1.23 ± 0.03) and Ser845 (p < 0.01, 0.42 ± 0.07 vs 0.97 ± 0.14) sites of excitatory glutamate AMPA receptor subunit 1 (GluA1) in the hippocampus, which may be the underlying mechanisms of impairment of hippocampus-dependent learning. In addition, intrahippocampal infusion of ME also increased anxiety-like behaviors in mice. These results suggested that acute ME impaired the hippocampus function at behavioral, cellular, and molecular levels, indicating the potential risks of ME on the central nervous system.

Gut microbiota protects from triptolide-induced hepatotoxicity: Key role of propionate and its downstream signalling events.

As a potential drug for treating inflammatory, autoimmune diseases and cancers, triptolide (TP) is greatly limited in clinical practice due to its severe toxicity, particularly for liver injury. Recently, metabolic homeostasis was vitally linked to drug-induced liver injury and gut microbiota was established to play an important role. In this study, we aimed to investigate the functions of gut microbiota on TP-induced hepatotoxicity using metabolomics in mice. Here, predepletion of gut microbiota by antibiotic treatment strikingly aggravated liver injury and caused mortality after treated with a relatively safe dosage of TP at 0.5 mg/kg, which could be reversed by gut microbial transplantation. The loss of gut microbiota prior to TP treatment dramatically elevated long chain fatty acids and bile acids in plasma and liver. Further study suggested that gut microbiota-derived propionate contributed to the protective effect of gut microbiota against TP evidenced by ameliorative inflammatory level (Tnfa, Il6 and Cox2), ATP, malondialdehyde and hepatic histology. Supplementing with propionate significantly decreased the mRNA levels of genes involved in fatty acid biosynthesis (Srebp1c, Fasn and Elovl6), resulting in the decreased long chain fatty acids in liver. Moreover, TP restricted the growth of Firmicutes and led to the deficiency of short chain fatty acids in cecum content. In conclusion, our study warns the risk for TP and its preparations when antibiotics are co-administrated. Intervening by foods, prebiotics and probiotics toward gut microbiota or supplementing with propionate may be a clinical strategy to improve toxicity induced by TP.

Metabolic Activation of Elemicin Leads to the Inhibition of Stearoyl-CoA Desaturase 1.

Elemicin is a constituent of natural aromatic phenylpropanoids present in many herbs and spices. However, its potential to cause toxicity remains unclear. To examine the potential toxicity and associated mechanism, elemicin was administered to mice for 3 weeks and serum metabolites were examined. Enlarged livers were observed in elemicin-treated mice, which were accompanied by lower ratios of unsaturated- and saturated-lysophosphatidylcholines in plasma, and inhibition of stearoyl-CoA desaturase 1 (Scd1) mRNA expression in liver. Administration of the unsaturated fatty acid oleic acid reduced the toxicity of 1'-hydroxylelemicin, the primary oxidative metabolite of elemicin, while treatment with the SCD1 inhibitor A939572 potentiated its toxicity. Furthermore, the in vitro use of recombinant human CYPs and chemical inhibition of CYPs in human liver microsomes revealed that CYP1A1 and CYP1A2 were the primary CYPs responsible for elemicin bioactivation. Notably, the CYP1A2 inhibitor α-naphthoflavone could attenuate the susceptibility of mice to elemicin-induced hepatomegaly. This study revealed that metabolic activation of elemicin leads to SCD1 inhibition in liver, suggesting that upregulation of SCD1 may serve as potential intervention strategy for elemicin-induced toxicity.

[Pharmacokinetics of Nimodipine after Intraocular Administration in Rats].

Objective To explore the pharmacokinetics of nimodipine in plasma of rats after intraocular administration.Methods Totally 135 SD rats were randomly divided into three groups according to drug administration routes:intraocular(io group),intravenous (iv group),and intragastric (ig group). The doses were 5.0 mg/kg for IO and IV groups and 10.0 mg/kg for IG group. The serum nimodipine level was analyzed by high performance liquid chromatography. The main pharmacokinetic parameters were calculated and compared.Results The pharmacokinetic parameters in io group were as follows:Cmax:0.52 mg/ml;tmax:5.0 min;and AUC0-t:21.10 mg/(ml·min). The main pharmacokinetic parameters in iv group were as follows:Cmax:3.62 mg/ml;and AUC0-t:52.58 mg/(ml·min). The main pharmacokinetic parameters in ig group were as follows:Cmax:0.20 mg/ml;tmax:5.0 min;and AUC0-t:5.98 mg/(ml·min).Conclusions Nimodipine is rapidly absorbed after io administration,and the ophthalmic formulation has a higher bioavailability than the oral solution. Therefore,the io route may help to improve the treatment effectiveness of cardiovascular diseases.

[Analysis of the cause and clinical characteristics of maternal cardiac arrest].

OBJECTIVE: To analyze the cause and clinical characteristics of maternal cardiac arrest. METHODS: The data of all cases of maternal cardiac arrest from January 2005 to December 2009 in Third Affiliated Hospital of Guangzhou Medical College was retrospectively studied. RESULTS: (1) A total of 41 maternal cardiac arrests (6 in prenatal period, 2 in the first stage of labor, 7 in the third stage of labor, 26 in postpartum period) were included. All patients regained spontaneous circulation after basic life support. Twelve (29%) mothers survived. Twelve cardiac arrests occurred in the hospital, and the total delivery number from January 2005 to December 2009 was 17 101, with occurrence rate of 1:1425. (2) The causes of arrest were hemorrhagic shock (12, 29%), amniotic fluid embolism (7, 17%), severe preeclampsia/eclampsia (7, 17%), septic shock (6, 15%), cardiac disease (2, 5%), unidentified cause (2, 5%) and other occasional causes. (3) Thirty-seven (90%) in-hospital maternal cardiac arrest occurred in operation room (16, 39%), ICU (7, 17%), maternity wards (6, 15%), delivery room (5, 12%) and the emergency room (3, 7%). Three (7%) arrest occurred out of hospital and one in the ambulance. Maternal survival rate was 2/3 in the emergency room, 8/16 in the operation room, 1/5 in the maternity wards, and 1/6 in the delivery room. No mother survived in ICU, ambulance or out of hospital. (4) Five of the 12 survived women showed ischemic encephalopathy after cardiac arrest and one of them developed cerebral infarction in the right corona radiate. (5) In 4 of the 8 cases of cardiac arrest in pregnancy, perimortem caesarean section (PMCS) was performed. In the four PMCS, 2 mothers and 2 children survived. In the 4 cases that PMCS was not carried out, no infant survived. CONCLUSIONS: Hemorrhagic shock, severe preeclampsia and eclampsia, amniotic fluid embolism are the major obstetric causes of maternal cardiac arrest. Septic shock and cardiac diseases are the major non-obstetric causes. Cardiac arrests occurred in emergency room and operation room has a higher maternal survival rate than those occurred in the delivery room and maternity wards. Timely PMCS may ensure the optimal outcome for mothers and fetuses.