Second Affiliated Hospital of Kunming Medical College

Short tandem repeats (STRs) are short tandemly repeated DNA sequences that involve a repetitive unit of 1-6 bp. Because of their polymorphisms and high mutation rates, STRs are widely used in biological research. Strand-slippage replication is the predominant mutation mechanism of STRs, and the stepwise mutation model is regarded as the main mutation model. STR mutation rates can be influenced by many factors. Moreover, some trinucleotide repeats are associated with human neurodegenerative diseases. In order to deepen our knowledge of these diseases and broaden STR application, it is essential to understand the STR mutation process in detail. In this review, we focus on the current known information about STR mutation.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

It has been established that reactive oxygen species (ROS) such as H2O2 or superoxide anion is involved in bone loss-related diseases by stimulating osteoclast differentiation and bone resorption and that receptor activator of NF-kappaB ligand (RANKL) is a critical osteoclastogenic factor expressed on stromal/osteoblastic cells. However, the roles of ROS in RANKL expression and signaling mechanisms through which ROS regulates RANKL genes are not known. Here we report that increased intracellular ROS levels by H2O2 or xanthine/xanthine oxidase-generated superoxide anion stimulated RANKL mRNA and protein expression in human osteoblast-like MG63 cell line and primary mouse bone marrow stromal cells and calvarial osteoblasts. Further analysis revealed that ROS promoted phosphorylation of cAMP response element-binding protein (CREB)/ATF2 and its binding to CRE-domain in the murine RANKL promoter region. Moreover, the results of protein kinase A (PKA) inhibitor KT5720 and CREB1 RNA interference transfection clearly showed that PKA-CREB signaling pathway was necessary for ROS stimulation of RANKL in mouse osteoblasts. In human MG63 cells, however, we found that ROS promoted heat shock factor 2 (HSF2) binding to heat shock element in human RANKL promoter region and that HSF2, but not PKA, was required for ROS up-regulation of RANKL as revealed by KT5720 and HSF2 RNA interference transfection. We also found that ROS stimulated phosphorylation of extracellular signal-regulated kinases (ERKs) and that PD98059, the inhibitor for ERKs suppressed ROS-induced RANKL expression either in mouse osteoblasts or in MG63 cells. These results demonstrate that ROS stimulates RANKL expression via ERKs and PKA-CREB pathway in mouse osteoblasts and via ERKs and HSF2 in human MG63 cells.

Two cationic iridium(III) complexes with bright green and red emissions were demonstrated as phosphorescent dyes for living cell imaging. In particular, their exclusive staining in cytoplasm, low cytotoxicity and reduced photobleaching, as well as cell membrane permeability, make the two complexes promising candidates for the design of specific bioimaging agents.

Phosphorescent heavy-metal complexes exhibit relatively long lifetimes and significant Stokes shifts for easy separation of excitation and emission and could be used as promising candidates for fluorescence probes. To date, however, very limited examples of the use of phosphorescent heavy-metal complexes in bioimaging have been reported. Herein, a series of cationic iridium(III) complexes, [Ir(dfpy)2L]+PF6− (dfpy = 2-(2,4-difluorophenyl)pyridine; L denotes a series of N∧N ligands with different conjugated lengths), have been synthesized. By variation of the N∧N ligands, the emission colors of these complexes can be tuned from blue to red, while high quantum efficiencies are retained. Further investigation reveals that these complexes exhibit different excited-state properties, which are responsible for the significant emission color tuning. Moreover, the exclusive staining of cytoplasm and low cytotoxicity were observed for these cationic iridium(III) complexes, as well as good cell membrane permeability, which makes them promising candidates as fluorescent probes for living cell imaging. Furthermore, in order to tune the excitation wavelength to the longer region, another cationic iridium(III) complex with lower singlet and triplet energy levels was also investigated to be used as living cell imaging material, achieving a longer excitation wavelength of 488 nm.

Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis, are the most common causes of bone tissue destruction. Recently, human periodontal ligament tissue-derived mesenchymal stem cells (PDLSCs), a population of multipotent stem cells, have been used to reconstruct tissues destroyed by chronic inflammation. However, the impact of the local inflammatory microenvironment on tissue-specific stem cells and the mechanisms controlling the effects of the local inflammatory environment remain poorly understood. In this study, we found that the multidifferentiation potential of mesenchymal stem cells (MSCs) isolated from periodontitis-affected periodontal ligament tissue (P-PDLSCs) was significantly lower than that of MSCs isolated from healthy human periodontal ligament tissue (H-PDLSCs). Inflammation in the microenvironment resulted in an inhibition of miR-17 levels, and a perturbation in the expression of miR-17 partly reversed the differentiation potential of PDLSCs in this microenvironment. Furthermore, inflammation in the microenvironment promoted the expression of Smad ubiquitin regulatory factor one (Smurf1), an important negative regulator of MSC osteogenic differentiation. Western blotting and 3' untranslated regions (3'-UTR) reporter assays confirmed that Smurf1 is a direct target of miR-17 in PDLSCs. Our data demonstrate that excessive inflammatory cytokine levels, miR-17, and Smurf1 were all involved in a coherent feed-forward loop. In this circuit, inflammatory cytokines led to direct activation of Smurf1 and downregulation of miR-17, thereby increasing degradation of Smurf1-mediated osteoblast-specific factors. The elucidation of the molecular mechanisms governing MSC osteogenic differentiation in a chronic inflammatory microenvironment could provide us with a better knowledge of chronic inflammatory disorder and improve stem cell-mediated inflammatory bone disease therapy.

Background/objectives The assessment of nutritional status and the quality of life in patients with gastric cancer has become one of the important goals of current clinical treatment. The purpose of this study was to assess the nutritional status in hospitalized gastric cancer patients by using patient-generated subjective global assessment (PG-SGA) and to analyze the influence of nutritional status on the patients' quality of life (QOL). Methods We reviewed the pathological diagnosis of gastric cancer for 2322 hospitalized patients using PG-SGA to assess their nutritional status and collected data on clinical symptoms, the anthropometric parameters (height, weight, body mass index (BMI), mid-arm circumference (MAC), triceps skin-fold thickness (TSF), and hand-grip strength (HGS). We also collected laboratory data (prealbumin, albumin, hemoglobin) within 48 h after the patient was admitted to the hospital. The 30-item European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) was used for QOL assessment in all patients.

The association of Fcgamma receptor (FcgammaR) polymorphisms with systemic lupus erythematosus (SLE) has been demonstrated in various populations; however, the results have been inconsistent. We recently identified a single-nucleotide polymorphism encoding a non-synonymous substitution, Ile232Thr (I232T), of FCGR2B and its association with SLE in Japanese and in Thais. Multiple functional FcgammaR genes with polymorphisms (FCGR2A, FCGR2B, FCGR3A, and FCGR3B) cluster in 1q23, and some of them are in linkage disequilibrium (LD). To differentiate contributions from multiple-linked loci, comparison of different populations may provide useful information. In this study, we analyzed the above four FCGR polymorphisms of the Chinese patients and controls for the association with SLE. FCGR2A-H131R, FCGR2B-I232T, FCGR3A-F176V, and FCGR3B genotypes were determined in 167 Chinese patients with SLE and 129 healthy controls. Association was examined using case-control analysis. Allele frequencies of FCGR2B-232T and FCGR3A-176F were significantly increased in SLE [odds ratio (OR) = 1.67 and OR = 1.41, respectively]. Interestingly, while these alleles had a tendency of positive LD in the controls, FCGR2B-232T was in positive association with FCGR3A-176V in SLE, suggesting that these two alleles were associated with SLE in an independent manner. Comparison between SLE with and without nephritis indicated significant association of FCGR2B-232T with nephritis (OR = 2.65). When the present results were combined with our previous data on the Japanese and the Thais using meta-analytic methods, highly significant and independent association was observed for FCGR2B and FCGR3A genotypes. These results strongly suggested that FCGR2B is a common susceptibility factor to SLE in the Asians.

Melatonin is a potent antioxidant with neuroprotective activity in animal models of ischemic stroke, which based on its lack of serious toxicity has raised hopes that it might be used for human stroke treatment in the future. This study investigated how subacute delivery of melatonin, starting at 24 hr after stroke onset, and continuing for 29 days (4 mg/kg/day; via drinking water), influences neuronal survival, endogenous neurogenesis, motor recovery and locomotor activity in C57Bl6/j mice submitted to 30-min middle cerebral artery occlusion. Histologic studies showed that melatonin improved neuronal survival and enhanced neurogenesis, even when applied 1 day after stroke. Cell survival was associated with a long-lasting improvement of motor and coordination deficits, evaluated by the grip strength and RotaRod tests, as well as with attenuation of hyperactivity and anxiety of the animals as revealed in open field tests. The robust functional neurologic improvements encourage proof-of-concept studies with melatonin in human stroke patients.

OBJECTIVES: This study was designed to investigate the role of circ_0078767/miR-330-3p/RASSF1A in non-small-cell lung cancer (NSCLC). Bioinformatic analysis was performed to screen for the differentially expressed genes in NSCLC tissues from adjacent lung tissues. MATERIALS AND METHODS: qRT-PCR was used to detect the RNA expression of genes in cells and tissues, and Western blot was conducted to determine the protein levels of RASSF1A in tissues and cells. A miRanda algorithm was used to predict the targeted relationship among RNAs. A dual-luciferase reporter gene assay was conducted to verify the targeted relationship. Flow cytometry was performed to investigate the effects of circ_0078767/miR-330-3p/RASSF1A on cell cycle progression and apoptosis. A CCK-8 assay was conducted to explore the effects of circ_0078767/miR-330-3p/RASSF1A on cell proliferation. A transwell invasion assay was completed to study the effects of circ_0078767/miR-330-3p/RASSF1A on cell invasion. Lastly, an in vivo assay was conducted to investigate the effects of circ_0078767/miR-330-3p/RASSF1A on tumour development. RESULTS: Circ_0078767 and RASSF1A were downregulated, while miR-330-3p was upregulated in NSCLC tissues than that in adjacent tissues. miR-330-3p had a binding relationship with circ_0078767 and RASSF1A. The overexpression of circ_0078767 and RASSF1A or the underexpression of miR-330-3p significantly suppressed NSCLC cell viability, cell cycle progression and invasion while also significantly promoting cell apoptosis. Additionally, these modulations significantly suppressed in vivo tumour growth. CONCLUSIONS: Circ_0078767 could suppress NSCLC progression by inhibiting miR-330-3p, which thereby increased RASSF1 levels.

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.

To evaluate the psychometric properties of the Chinese (mainland) version of Job Content Questionnaire (JCQ), this validation study was conducted in university hospitals among 193 men and 581 women health care workers. The Cronbach's alpha coefficients for decision latitude, psychological job demands and social support ranged from 0.56 to 0.82, which indicated that psychological job demands had lower internal consistency. The decision latitude displayed a negative correlation with psychological job demands and a positive correlation with social support. Exploratory factor analysis showed 3 meaningful factors that could explain the 3 theoretical dimensions of job strain model. Apart from some uncertainty over psychological job demands particularly, it is concluded that the Chinese (mainland) version of JCQ is a reliable and valid instrument for measuring job stressors, and is applicable to Chinese working population.

OBJECTIVE: To identify the in vitro characteristics and functional properties of fibrocytes and investigate the in vivo mechanism of action of fibrocytes injection in accelerating the cutaneous healing process in diabetic mice. BACKGROUND: Fibrocytes are hematopoietic derived stem cells that may have a role in tissue repair, perhaps as the precursors of fibroblast- or myofibroblast-like cells. METHODS: In vitro, the time-dependent phenotypic expression of peripheral blood (PB) fibrocytes was stained with anti-CD11b, anti-CD45, anti-Col-I, and anti-α-SMA antibodies. The functional properties of fibrocytes and dermal fibroblasts were tested by using reverse-transcriptase polymerase chain reaction. In vivo, full thickness wounds in diabetic mice were treated either with fibrocytes, dermal fibroblasts, or phosphate buffered saline (PBS) through tail vein injection. Wound healing kinetics, including wound contraction, re-epithelialization, and microscopic metrics such as cell proliferation, angiogenesis, and granulation growth were investigated. Expression of proinflammatory factors, profibrotic factors, growth factors, and extracellular matrix components were measured in wound tissues. RESULTS: Fibrocytes gradually lose their hematopoietic cell markers and increase mesenchymal cell markers during differentiation in vitro. Fibrocytes stimulate wound healing by dermal cell proliferation, keratinocyte proliferation with re-epithelialization, and angiogenesis compared with dermal fibroblast and PBS treated wounds. Expression of angiogenesis markers (VEGF and b-FGF), growth factors (TGF-β, PDGF-A, and FGF-7), chemokines (MCP-1 and MIP-1α), and extracellular matrix (collagen-I and α-SMA) were upregulated in fibrocyte-treated wounds. CONCLUSION: Peripheral blood fibrocytes can accelerate wound healing by stimulating cell proliferation, re-epithelialization, and angiogenesis in a diabetic mice experimental model. The application of fibrocytes may represent a potential clinical solution for the treatment of chronic wounds across all fields of surgery.

OBJECTIVE: Acinetobacter baumannii is considered the prototypical example of a multi- or pan- drug-resistant bacterium. It has been increasingly implicated as a major cause of nosocomial and community-associated infections. This study proposed to evaluate the efficacy of immunological approaches to prevent and treat A. baumannii infections. METHODS: Mice were immunized with outer membrane vesicles (OMVs) prepared from a clinically isolated multidrug-resistant strain of A. baumannii. Pneumonia and sepsis models were used to evaluate the efficacy of active and passive immunization with OMVs. The probable effective mechanisms and the protective potential of clonally distinct clinical isolates were investigated in vitro using an opsonophagocytic assay. RESULTS: Intramuscular immunization with OMVs rapidly produced high levels of OMV-specific IgG antibodies, and subsequent intranasal challenge with A. baumannii elicited mucosal IgA and IgG responses. Both active and passive immunization protected the mice from challenges with homologue bacteria in a sepsis model. Bacterial burden in bronchoalveolar lavage fluids (BALF), lung, and spleen, inflammatory cell infiltration in BALF and lung, and inflammatory cytokine accumulation in BALF was significantly suppressed in the pneumonia model by both active and passive immunization strategies. The antisera from immunized mice presented with significant opsonophagocytic activities in a dose-dependent manner against not only homologous strains but also five of the other six clonally distinct clinical isolates. CONCLUSIONS: Utilizing immunological characteristics of outer membrane proteins to elevate protective immunity and circumvent complex multidrug-resistance mechanisms might be a viable approach to effectively control A. baumannii infections.

BACKGROUND: It has been hypothesized that alterations of the serotonergic system contribute to neuropsychiatric symptoms in Alzheimer disease (AD). Cellular expressions of the two serotonergic receptors 5-HT2A and 5-HT6 have therefore been determined by immunohistochemistry in the prefrontal cortex of patients with AD (n=6) and normal age-matched controls (n = 7). RESULTS: In normal aging patients, 5-HT2A label was mainly observed in large pyramidal cells, but to a lesser extent also in small pyramidal cells and in stellate cells of cortical layers II-VI. In AD, a similar distribution was observed, but density of positive cells was significantly reduced by 33%. In aging control patients, the 5-HT6 receptor was expressed by pyramidal cells and occasional stellate cells, not only of layers II-V, but also of layer I, where a distinct label was observed in neurons and surrounding fibers. 5-HT6 receptor expression in AD patients had the same pattern, but was significantly decreased by 40%. CONCLUSION: Our results indicate that a decline in neurons expressing 5-HT2A, but also 5-HT6 receptors may play a role in the etiopathology of neuropsychiatric symptoms in AD.

The information about DNA-binding sites of regulatory protein is important to understanding the regulatory network of DNA-protein interactions in the genome. In this report we integrated chromatin immunoprecipitation with DNA cloning to isolate genomic sites bound in vivo by heat shock factor HsfA1a in Arabidopsis thaliana. Plantlets were subjected to formaldehyde crosslinking, followed by immunoprecipitation of chromatin. The immunoprecipitated DNA was amplified by PCR and cloned. From a library enriched in putative HsfA1a-binding sites, 21 different genomic fragments were identified (65-332 bp). Six fragments contained known HsfA1a-binding motif (perfect heat shock element). Six fragments contained novel HsfA1a-binding motifs: (1) gap-type, (2) TTC-rich-type, (3) stress responsive element (STRE). Representatives of each were verified by in vitro electrophoretic mobility shift assay. About 81% of the isolated fragments contained the HsfA1a-binding motifs, and/or could be bound by HsfA1a, demonstrating that the method is efficient in the isolation of genomic binding sites of a regulatory protein. The nearest downstream genes to the HsfA1a-binding fragments, which were considered as potential HsfA1a target genes, include a set of classical heat shock protein genes: Hsp17.4, Hsp18.2, Hsp21, Hsp81-1, Hsp101, and several novel genes encoding a non-race specific disease resistance protein and a transmembrane CLPTM1 family protein.

Substance abuse and addiction are worldwide concerns. In China, populated with over 1.3 billion people, emerging studies show a steady increase in substance abuse and substance-related problems. Some of the major challenges include a lack of an effective evaluation platform to determine the health status of substance-addicted subjects. It is known that the intestinal microbiota is associated to the occurrence and development of human diseases. However, the changes of bacterial diversity of intestinal microbiota in substance-addicted subjects have not been clearly characterized. Herein, we examined the composition and diversity of intestinal microbiota in 45 patients with substance use disorders (SUDs) and in 48 healthy controls (HCs). The results show that the observed species diversity index and the abundance of Thauera, Paracoccus, and Prevotella are significantly higher in SUDs compared to HCs. The functional diversity of the putative metagenomes analysis reveals that pathways including translation, DNA replication and repair, and cell growth and death are over-represented while cellular processes and signaling, and metabolism are under-represented in SUDs. Overall, the analyses show that there seem to be changes in the microbiota that are associated with substance use across an array of SUDs, providing fundamental knowledge for future research in substance-addiction assessment tests.

Stress ulceration is a common complication in critically ill patients and can result in significant upper gastrointestinal bleeding associated with a high morbidity and mortality. At present, little is known of the molecular mechanisms underlying the incidence of this type of gastric damage. In the present study, we investigated the temporal activation of the redox-sensitive p38 signaling transduction cascade and its roles in a well-defined experimental model of cold immobilization stress-induced gastric ulceration. Exposure of Sprague-Dawley rats to 6 h of cold immobilization stress led to a rapid activation of p38 in the gastric mucosa at as early as 15 min after stress, and this activation was maximal after 1.5 h of stress and still persisted until the end of stress. Selectively blocking p38 by pretreatment with SB 239063, a potent and selective p38 inhibitor, suppressed the stress-promoted TNF-alpha, IL-1beta, and CINC-1 production and then prevented the subsequent neutrophil infiltration, gastric mucosal epithelial necrosis and apoptosis, and the ulcerative lesions formation. Prior administration of the free radical scavengers, tempol and N-acetyl-L-cysteine, abolished the stress induction of p38 activation and the resulting mucosal inflammation and gastric injury. These results demonstrate that reactive oxygen species-mediated p38 activation plays an essential role in the pathogenesis of stress-induced gastric inflammatory damage in the rat model of cold immobilization stress. Our findings suggested that inhibition of p38 activation might be a potential strategy for the prophylaxis and treatment of stress ulceration.

Recent changes in organ allocation based on the model for end-stage liver disease (MELD) prioritize the most ill patients on the waiting list for liver transplantation. While patients undergoing liver transplantation in the MELD era are more acutely ill, the impact of the policy changes on perioperative management has not been completely assessed. We retrospectively reviewed the records of 124 primary adult liver transplant patients. Patients were divided into low (< or = 30) and high MELD (>30) score groups. Preoperative characteristics and intraoperative management were compared between the 2 groups. Patients with high MELD scores had lower baseline hematocrit and fibrinogen levels and were more likely to require ventilatory and vasopressor support before transplantation. Intraoperative transfusion requirements and use of vasopressors were also significantly increased in patients with high MELD scores compared to patients with low MELD scores. In conclusion, these data suggest that pretransplant MELD scores provide important information for perioperative management of patients undergoing liver transplantation.

BACKGROUND: Hyperkalemia poses serious hazards to patients undergoing orthotopic liver transplantation (OLT), and its predictors have not been thoroughly examined. METHODS: We retrospectively studied 1124 consecutive adult patients who underwent OLT. Hyperkalemia was defined as serum K+ > or =5.5 mmol/L. A total of 47 recipient, donor, intraoperative, and laboratory variables were initially analyzed in univariate analyses. Independent predictors of hyperkalemia in three periods of OLT (prereperfusion, early postreperfusion, and late postreperfusion) were determined in multivariate logistic regression analyses. RESULTS: Of 1124 patients, 10.2%, 19.1%, and 7.9% had hyperkalemia in the prereperfusion, early postreperfusion, and late postreperfusion periods, respectively. Higher baseline K+ and red blood cell transfusion were independent predictors of prereperfusion hyperkalemia. Higher baseline K+ (or prereperfusion K+) and donation after cardiac death donor were independent predictors of early postreperfusion hyperkalemia. Higher baseline K+, longer warm ischemia time, longer donor hospital stay, lower intraoperative urine output, and the use of venovenous bypass were independent predictors of late postreperfusion hyperkalemia. CONCLUSIONS: Several laboratory, intraoperative, and donor variables were identified as independent predictors of hyperkalemia in the different periods. Such information may be used for more targeted preemptive interventions in patients who are at risk of developing hyperkalemia during adult OLT.