The coupling between healthspan and lifespan in Caenorhabditis depends on complex interactions between compound intervention and genetic background.

Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the Caenorhabditis Intervention Testing Program and thought to promote longevity in different ways - NP1 (nitrophenyl piperazine-containing compound 1), propyl gallate, and resveratrol. Overall, we find the relationships among median lifespan, oxidative stress resistance, thermotolerance, and mobility vigor to be complex. We show that oxidative stress resistance and thermotolerance vary with compound intervention, genetic background, and age. The effects of tested compounds on swimming locomotion, in contrast, are largely species-specific. In this study, thermotolerance, but not oxidative stress or swimming ability, correlates with lifespan. Notably, some compounds exert strong impact on some health measures without an equally strong impact on lifespan. Our results demonstrate the importance of assessing health and lifespan across genetic backgrounds in the effort to identify reproducible anti-aging interventions, with data underscoring how personalized treatments might be required to optimize health benefits.

Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes.

The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies-for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.

Influencing factors and prognostic value of left ventricular systolic dysfunction in patients with complete occlusion of the left anterior descending artery reperfused by primary percutaneous coronary intervention.

BACKGROUND: The aim of this study was to perform a retrospective analysis of patients with acute anterior wall ST-segment elevation myocardial infarction (AAW-STEMI) whose left anterior descending (LAD) artery was completely occluded and reperfused by primary percutaneous coronary intervention (PPCI) and to determine the influencing factors and prognostic value of left ventricular systolic dysfunction (LVSD) in the acute phase of acute myocardial infarction (AMI). METHODS: A total of 304 patients with AAW-STEMI were selected. The selected patients were divided into two groups: the preserved left ventricular ejection fraction (pLVEF) group (LVEF ≥ 50%, n = 185) and the reduced left ventricular ejection fraction (rLVEF) group (LVEF < 50%, n = 119). The influencing factors of LVSD and their predictive value for LVSD were analyzed. Patients were followed up by examining outpatient records and via telephone. The predictive value of LVSD for the cardiovascular mortality of patients with AAW-STEMI was analyzed. RESULTS: Age, heart rate (HR) at admission, number of ST-segment elevation leads (STELs), peak creatine kinase (CK) and symptom to wire-crossing (STW) time were independent risk factors for LVSD (P < 0.05). The receiver operating characteristic (ROC) analysis showed that the peak CK had the strongest predictive value for LVSD, with an area under the curve (AUC) of 0.742 (CI, 0.687 to 0.797) as the outcome. At a median follow-up of 47 months (interquartile range, 27 to 64 months), the Kaplan‒Meier survival curves up to 6-year follow-up revealed a total of 8 patients succumbed to cardiovascular disease, with 7 (6.54%) in the rLVEF group and 1 (0.56%) in the pLVEF group, respectively (hazard ratio: 12.11, [P = 0.02]). Univariate and multivariate Cox proportional hazards regression analysis demonstrated that rLVEF was an independent risk predictor of cardiovascular death in patients with AAW-STEMI discharged after PPCI (P < 0.01). CONCLUSIONS: Age, HR at admission, number of STELs, peak CK, and STW time may be used to identify patients with a high risk of heart failure (HF) in a timely manner and initiate early standard therapy for incident LVSD in the acute phase of AAW-STEMI reperfused by PPCI. A trend toward increased cardiovascular mortality at follow-up was significantly linked to LVSD.

Enhanced stent visualization system for percutaneous coronary intervention in patients with chronic kidney disease: effects on contrast media volume and radiation exposure.

OBJECTIVE: We aimed to assess the impact of using enhanced stent visualization (ESV) systems on contrast media volume and radiation dose in percutaneous coronary intervention (PCI), especially for patients with chronic kidney disease (CKD). BACKGROUND: Coronary heart disease (CHD) is associated with chronic kidney disease (CKD), as they share a similar pathological pathway. In addition, the iodinated contrast media used for angiography is a risk factor for contrast-associated acute kidney injury (CA-AKI), which could aggravate the progression of CKD. We hypothesized that ESV systems have the potential to reduce the use of contrast media as well as the radiation dose; however, few studies have reported the impact on contrast media with the use of ESV systems. METHODS: We retrospectively collected 124 patients with acute coronary syndrome who underwent PCI from May 2020 to July 2021. The patients were divided into the ESV-guided group (n = 64) and angiography-guided group (n = 60). Procedural parameters, including contrast media volume, radiation exposure (in Air Kerma-AK and Dose Area Product-DAP), number of cines, cine frames, fluoroscopy and procedure time, were recorded and analysed. RESULTS: The groups were comparable regarding the patient characteristics. There was a significant reduction in contrast media volume (174.7 ± 29.6 ml vs.132.6 ± 22.3 ml, p = 0.0001), radiation exposure (776 (499 - 1200) mGy vs. 1065 (791 - 1603) mGy, p = 0.002 in AK; 43 (37 - 73) Gycm2 vs. 80 (64 - 133) Gycm2, p = 0.030 in DAP) and procedure time (53.06 ± 21.20 min vs. 72.00 ± 30.55 min, p = 0.01) with the use of ESV systems. Similar results were observed in the subgroup analysis for the patients with CKD. CONCLUSION: This study suggested that the use of ESV is associated with reduced contrast media usage, radiation dose and procedure time during PCI. The same results were observed in a subgroup analysis in patients with CKD, and this shows that ESV-guided PCI has the potential to reduce renal impairment and mitigate the progression of CKD for those CHD patients with CKD.

Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes.

Metformin, the most commonly prescribed anti-diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti-aging drug-the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose-dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.

Automated lifespan determination across Caenorhabditis strains and species reveals assay-specific effects of chemical interventions.

The goal of the Caenorhabditis Intervention Testing Program is to identify robust and reproducible pro-longevity interventions that are efficacious across genetically diverse cohorts in the Caenorhabditis genus. The project design features multiple experimental replicates collected by three different laboratories. Our initial effort employed fully manual survival assays. With an interest in increasing throughput, we explored automation with flatbed scanner-based Automated Lifespan Machines (ALMs). We used ALMs to measure survivorship of 22 Caenorhabditis strains spanning three species. Additionally, we tested five chemicals that we previously found extended lifespan in manual assays. Overall, we found similar sources of variation among trials for the ALM and our previous manual assays, verifying reproducibility of outcome. Survival assessment was generally consistent between the manual and the ALM assays, although we did observe radically contrasting results for certain compound interventions. We found that particular lifespan outcome differences could be attributed to protocol elements such as enhanced light exposure of specific compounds in the ALM, underscoring that differences in technical details can influence outcomes and therefore interpretation. Overall, we demonstrate that the ALMs effectively reproduce a large, conventionally scored dataset from a diverse test set, independently validating ALMs as a robust and reproducible approach toward aging-intervention screening.

Early Renal-Protective Effects of Remote Ischemic Preconditioning in Elderly Patients with Non-ST-Elevation Myocardial Infarction (NSTEMI).

BACKGROUND With the wide clinical application of angiography, contrast-enhanced nephropathy (CIN) has become the third-leading cause of acute kidney injury (AKI). Remote ischemic preconditioning (RIPC) is a non-fatal ischemia-reperfusion injury that can provide protection against lethal ischemia-reperfusion. This study aimed to assess the effect of RIPC on CIN in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). MATERIAL AND METHODS Patients were randomly divided into 2 groups with 119 patients in each group treated with interventional therapy. Patients in the RIPC group received distal ischemic preconditioning 2 h before contrast exposure, while patients in the control group received a sham RIPC procedure. Incidence of CIN was the primary outcome. Changes in creatinine, NGAL, and KIM-1 after contrast administration were secondary outcomes. RESULTS CIN occurred in a total of 27 (12.3%) patients, including 12 (10.1%) in the RIPC group and 15 (15.1%) in the control group (P=0.329). RIPC treatment significantly reduced the levels of NGAL (P=0.024) and KIM-1 (P=0.007) at 12 h after contrast administration, suggesting RIPC treatment reduces sub-clinical renal damage. Subgroup analysis revealed that significant reduction of KIM-1 and NGAL by RIPC, mainly occurring in patients with a Mehran risk score of 6-10. CONCLUSIONS Although RIPC did not significantly reduce CIN incidence in elderly patients with NSTEMI, the application of more sensitive biomarkers - NGAL and KIM-1 - indicated a reduction of sub-clinical renal damage by RIPC, especially in the early stage of injury. As a simple and well-tolerated method, RIPC may be a potentially feasible option to prevent CIN.

Constructing differential co-expression network to predict key pathways for myocardial infarction.

New thoughts are warranted to develop efficient diagnosis and optimal therapeutics to combat unstable angina (UA)/myocardial infarction (MI). Therefore, the gene data of patients with UA or MI were used in this study to identify the optimal pathways which can provide comprehensive information for UA/MI development. Differentially expressed genes (DEGs) between UA and MI were detected using LIMMA package, and pathway enrichment analysis was conducted for the DEGs, based on the DAVID tool, to detect the significant pathways. Then, differential co-expression network (DCN) and sub-DCN for the DEGs were constructed. Subsequently, informative pathways were extracted using guilt-by-association (GBA) principle relying on the area under the curve (AUC), and the pathway categories with AUC >0.8 were defined as the informative pathways. Finally, we selected the optimal pathways based on the traditional pathway analysis and the sub-DCN-based-GBA pathway prediction method. A total of 203 and 266 DEGs were identified from the expression profile of blood of MI samples comparing with UAs in the time-point 1 and time-point 2 groups. Moreover, 7 and 10 informative pathway terms were identified based on AUC>0.8. Significantly, cytokine-cytokine receptor interaction, as well as MAPK signaling pathway were the common optimal pathways in the two groups. Calcium signaling pathway was unique to the whole blood of patients with acute coronary syndrome (ACS) taken at 30 days post-ACS. In conclusion, the optimal pathways (MAPK signaling pathway, cytokine-cytokine receptor interaction, and calcium signaling pathway) might play important roles in the progression of UA/MI.

Impact of genetic background and experimental reproducibility on identifying chemical compounds with robust longevity effects.

Limiting the debilitating consequences of ageing is a major medical challenge of our time. Robust pharmacological interventions that promote healthy ageing across diverse genetic backgrounds may engage conserved longevity pathways. Here we report results from the Caenorhabditis Intervention Testing Program in assessing longevity variation across 22 Caenorhabditis strains spanning 3 species, using multiple replicates collected across three independent laboratories. Reproducibility between test sites is high, whereas individual trial reproducibility is relatively low. Of ten pro-longevity chemicals tested, six significantly extend lifespan in at least one strain. Three reported dietary restriction mimetics are mainly effective across C. elegans strains, indicating species and strain-specific responses. In contrast, the amyloid dye ThioflavinT is both potent and robust across the strains. Our results highlight promising pharmacological leads and demonstrate the importance of assessing lifespans of discrete cohorts across repeat studies to capture biological variation in the search for reproducible ageing interventions.

CeleST: computer vision software for quantitative analysis of C. elegans swim behavior reveals novel features of locomotion.

In the effort to define genes and specific neuronal circuits that control behavior and plasticity, the capacity for high-precision automated analysis of behavior is essential. We report on comprehensive computer vision software for analysis of swimming locomotion of C. elegans, a simple animal model initially developed to facilitate elaboration of genetic influences on behavior. C. elegans swim test software CeleST tracks swimming of multiple animals, measures 10 novel parameters of swim behavior that can fully report dynamic changes in posture and speed, and generates data in several analysis formats, complete with statistics. Our measures of swim locomotion utilize a deformable model approach and a novel mathematical analysis of curvature maps that enable even irregular patterns and dynamic changes to be scored without need for thresholding or dropping outlier swimmers from study. Operation of CeleST is mostly automated and only requires minimal investigator interventions, such as the selection of videotaped swim trials and choice of data output format. Data can be analyzed from the level of the single animal to populations of thousands. We document how the CeleST program reveals unexpected preferences for specific swim "gaits" in wild-type C. elegans, uncovers previously unknown mutant phenotypes, efficiently tracks changes in aging populations, and distinguishes "graceful" from poor aging. The sensitivity, dynamic range, and comprehensive nature of CeleST measures elevate swim locomotion analysis to a new level of ease, economy, and detail that enables behavioral plasticity resulting from genetic, cellular, or experience manipulation to be analyzed in ways not previously possible.

Effects of tributyltin on metamorphosis and gonadal differentiation of Xenopus laevis at environmentally relevant concentrations.

Tributyltin (TBT), a well known endocrine disruptor, has high teratogenicity to embryos of amphibian (Xenopus tropicalis). An amphibian metamorphosis assay (AMA) and a complete AMA (CAMA) were conducted for TBT. In AMA, the body weight, the snout-to-vent length and the hind limb length of X. laevis tadpoles were decreased in tributyltin chloride (TBTCl; 12.5-200 ng/L) treatment groups after 7 days exposure. TBT greatly retarded the development of tadpoles, decreased the number of follicle and induced thyroid follicle cell hyperplasia after 19 days exposure. In CAMA, 10 and 100 ng/L TBTCl led to various malformations of gonad, including intersex, segmental aplasia and multiple ovary cavities of X. laevis following exposure from stages 46 to stage 66. The sex ratio was male-biased in TBT treatment groups. These results suggest that TBT delayed the metamorphosis, inhibited the growth of tadpoles and disrupted the gonadal differentiation of X. laevis at environmentally relevant concentrations.

Teratogenic effects of tetrabromobisphenol A on Xenopus tropicalis embryos.

Tetrabromobisphenol A (TBBPA) is the most widely used brominated flame retardant and a known thyroid disruptor. We reported exposing Xenopus tropicalis embryos (NF10) to 0.01, 0.1 or 1 mg/L of TBBPA with or without 70 microg/L triiodothyronine (T(3)). Compared with the controls, 1 mg/L of TBBPA significantly reduced the body length of embryos after 24, 36 and 48 h of exposure. Embryos treated with TBBPA showed multiple malformations, including: abnormal eyes, skin hypopigmentation, enlarged proctodaeum, narrow fins and pericardial edemas. The effect of abnormal eyes manifested itself in the loss of pigmentation, reduction in size, or absence of external eyes. The degree of eye malformations was quantified with the index of eye malformations (IEM) with 0 being normal and 3 being severe. In the 1 mg/L TBBPA treatment groups, the incidence of total malformations (ITM) was 68-93%, and IEM was 0.8-0.9. T(3) showed no teratogenic effects on embryos, but it significantly enhanced TBBPA-induced teratogenic effects. In the T(3)+1 mg/L TBBPA treatment groups, ITM was 91-99%, and IEM was 1.8-1.9. Histological observations showed that the retinas were generally smaller, and the lenses were underdeveloped or even absent. These results indicate that TBBPA at relatively high concentration has teratogenic effects on X. tropicalis embryos. The results also suggest that thyroid hormone signaling might be involved in TBBPA induced-teratogenicity.

Effects of tributyltin (TBT) on Xenopus tropicalis embryos at environmentally relevant concentrations.

Tributyltin (TBT) has been widely used as a biocide in antifouling paints and is a known endocrine disrupting chemical. In this paper, we exposed embryos of Xenopus tropicalis to 50-400ngL(-1) tributyltin chloride. TBT significantly decreased the survival rate, reduced the body length and retarded the development of embryos after 24, 36 and 48h of exposure. These effects of TBT were concentration- and time-dependent. Embryos treated with TBT showed multiple malformations. The most obvious alterations were abnormal eyes, enlarged proctodaeum, narrow fins, and skin hypopigmentation. Enlarged proctodaeum and narrow fins were mainly observed after 36 and 48h of exposure. The loss of eye pigmentation or the absence of external eyes occurred after 24 and 36h of exposure, while extended lenses or edemas of eyes were more commonly observed after 48h of exposure. Additional malformations included: small anterior region of heads, pericardial edemas, enlarged trunks, and bent tails. These results suggested that TBT is very toxic to X. tropicalis embryos at environmentally relevant concentrations.

[Oral candidal carriage and biotyping of Candida species in HIV positive patients].

OBJECTIVE: To investigate the candidal carriage and the Candida species in HIV positive patients and to explore the relationship between oral candidal carriage and oral candidiasis. METHODS: Sixty-four HIV positive patients and 42 healthy controls were included in this study. Oral rinse technique was used to detect the candidal carriage. The isolates were identified using multiple measures, including Gram staining reaction, chlamydospore, pseudo-hyphal and hyphal production test, CHROMagar Candida test and API 20 C AUX yeast identification system. RESULTS: Thirty-nine of 64 HIV positive cases were diagnosed as oral candidiasis. Seventy-four Candida strains were isolated from 52 of 64 HIV positive cases, only 7 strains were isolated from 42 healthy controls (P < 0.001). Of the 74 Candida strains isolated from HIV positive cases, 39 were Candida albicans, 15 Candida tropicalis, and 20 other 6 species. CONCLUSIONS: A high prevalence of oral candidiasis and high candidal carriage were found in HIV positive patients compared with those in controls. Candida albicans and Candida tropicalis were the major species. The biotyping of the species isolated from HIV positive patients showed more diversified compared to healthy people, which may suggest the decreased immune ability of the HIV positive patients.

Modulated microRNA expression during adult lifespan in Caenorhabditis elegans.

MicroRNAs (miRNAs) are small, abundant transcripts that can bind partially homologous target messages to inhibit their translation in animal cells. miRNAs have been shown to affect a broad spectrum of biological activities, including developmental fate determination, cell signaling and oncogenesis. Little is known, however, of miRNA contributions to aging. We examined the expression of 114 identified Caenorhabditis elegans miRNAs during the adult lifespan and find that 34 miRNAs exhibit changes in expression during adulthood (P

[Investigation on oral lesions in 64 Chinese HIV/AIDS patients in Guangxi province].

OBJECTIVE: To investigate the prevalence, age and gender distribution and clinical features of HIV/AIDS oral lesions in patients in Guangxi province, and to provide the epidemiological information for prevention and treatment of these diseases in the certain population. METHODS: A total of 64 HIV/AIDS patients were included in this study. All patients HIV serum-status was confirmed in Guangxi Center of Disease Control (GXCDC). Oral examination was carried out by standardized specialists. HIV/AIDS orofacial lesions were recorded and diagnosed using the EC Clearing House Criteria on Oral Problems related to HIV Infection (1992). RESULTS: Among the total of 64 HIV/AIDS patients included in this study, there were 53 males and 11 females, with mean age of 36.1 years. Candidiasis was the most common lesion with the pseudomembranous type predominating. High prevalences of xerostomia, 11 oral ulceration and 7 HIV related periodontitis were noted. 6 Herpetic stomatitis and 3 herpes zoster, 2 oral hairy leukoplakia and 1 Kaposi's sarcoma and 1 lymphadentitis also were found. CONCLUSION: This study shows a high prevalence of candidiasis, salivary gland disease. Maybe oral ulceration prevalence is not increased, but lesion severity is increased with more severe heperiform or major RAU. It suggested that HIV/AIDS usually shows oral lesion and partly can appear in early phase.