Molecular Choreography of Acute Exercise.

Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.

Statins Are Associated With Increased Insulin Resistance and Secretion.

Objective: Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. Approach and Results: We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISRAUC) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m2). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P<0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% (P=0.01) and insulin secretion (ISRAUC) by a median of 9% (P<0.001). There were small increases in oral glucose tolerance test glucoseAUC (median increase, 0.05%; P=0.03) and fasting insulin (median increase, 7%; P=0.01). Conclusions: In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion.

The utility of intraoperative endoscopy to assist novice surgeons in the detection of gastric stenosis during laparoscopic sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a commonly performed bariatric surgery. Gastric stenosis and leaks are 2 major complications associated with LSG and revision surgery might be needed. Herein, we report our experience of intraoperative endoscopy (IOE) to evaluate stenosis and leaks during LSG. METHODS: LSG was performed by three surgeons. Patients who underwent LSG and IOE between January 2016 and March 2020 were enrolled and assigned to two groups: group 1 (1st-30th LSG case for each surgeon) and group 2 (> 30th LSG for each surgeon). Patients' anthropometric and biochemical data pre- and post-LSG, as well as IOE findings and follow-up esophagogastroduodenoscopy records were reviewed. RESULTS: In total, 352 patients were enrolled including 90 patients in group 1 and 262 patients in group 2. Three out of 352 patients (0.9%) were found to have stenosis by IOE, which was related to tightly gastropexy stitch or reinforcement stitch, all of which were in group 1. Stenosis was resolved after removal of the stitch during LSG. The incidence of gastric stenosis detected by IOE was 3.3% (3/90) and 0% (0/262) in group 1 and group 2, respectively (P = 0.003). No leakage was found in this study and no patient developed clinical or endoscopic stenosis after LSG. CONCLUSIONS: The existing evidence showed that IOE can help detect gastric stenosis during LSG, especially for novice surgeons, and the stenosis could be resolved during operation.

Nerve growth factor induced farnesoid X receptor upregulation modulates autophagy flux and protects hepatocytes in cholestatic livers.

Upregulation of nerve growth factor (NGF) in parenchymal hepatocytes has been shown to exert hepatoprotective function during cholestatic liver injury. However, the modulatory role of NGF in regulation of liver autophagy remains unclear. This study aimed to scrutinize the regulatory role of NGF in hepatic expression of farnesoid X receptor (FXR), a bile acid (BA)-activated nuclear receptor, and to determine its cytoprotective effect on BA-induced autophagy and cytotoxicity. Livers of human hepatolithiasis and bile duct ligation (BDL)-induced mouse cholestasis were used for histopathological and molecular detection. The regulatory roles of NGF in autophagy flux and FXR expression, as well as its hepatoprotection against BA cytotoxicity were examined in cultured hepatocytes. FXR downregulation in human hepatolithiasis livers showed positive correlation with hepatic NGF levels. NGF administration upregulated hepatic FXR levels, while neutralization of NGF decreased FXR expression in BDL-induced cholestatic mouse livers. In vitro studies demonstrated that NGF upregulated FXR expression, increased cellular LC3 levels, and exerted hepatoprotective effect in cultured primary rat hepatocytes. Conversely, autophagy inhibition abrogated NGF-driven cytoprotection under BA exposure, suggesting involvement of NGF-modulated auophagy flux. Although FXR agonistic GW4064 stimulation did not affect auophagic LC3 levels, FXR activity inhibition significantly potentiated BA-induced cytotoxicity and increased cellular p62/SQSTM1 and Rab7 protein in SK-Hep1 hepatocytes. Moreover, FXR gene silencing abolished the protective effect of NGF under BA exposure. These findings support that NGF modulates autophagy flux via FXR upregulation and protects hepatocytes against BA-induced cytotoxicity. NGF/FXR axis is a novel therapeutic target for treatment of cholestatic liver diseases.

Transcriptome analysis reveals a positive role for nerve growth factor in retinol metabolism in primary rat hepatocytes.

Up-regulation of nerve growth factor (NGF) in parenchymal hepatocytes with cholestatic injury has been previously demonstrated to exert hepatoprotective effects in an autocrine manner; however, the overall impact of NGF up-regulation remains elusive. This study aimed to profile the effects of exogenous NGF on cultured primary rat hepatocytes using transcriptome analysis. Total RNA was isolated from hepatocytes with and without 24 h of NGF exposure, and subjected to RNA enrichment by PCR and RNA sequencing procedures. Comparison of transcriptome profiles between control and NGF-stimulated hepatocytes demonstrated that NGF significantly up-regulated 10 genes and down-regulated 23 genes in hepatocytes. Subsequent KEGG pathway enrichment analysis indicated that NGF significantly affected the retinol metabolism pathway via increased retinol dehydrogenase 16 (RDH16) expression. In a mouse model of bile duct ligation-induced cholestatic liver injury, NGF supplementation significantly enhanced RDH16 expression, whereas administration of anti-NGF neutralizing antibodies prominently decreased RDH16 expression in cholestatic livers, supporting the positive role of NGF in the regulation of RDH16 in diseased livers. In vitro study further demonstrated that NGF triggered de novo synthesis of RDH16 in primary rat hepatocytes, mainly through an NF-κB signaling pathway. In conclusion, this study demonstrates the up-regulation of RDH16 by NGF in cultured rat hepatocytes and mouse cholestatic livers, and provides novel insights on the mechanistic role of NGF in the retinol metabolism of livers.

Involvement of the nuclear high mobility group B1 peptides released from injured hepatocytes in murine hepatic fibrogenesis.

This study investigated the pro-fibrogenic role of high mobility group box 1 (HMGB1) peptides in liver fibrogenesis. An animal model of carbon tetrachloride (CCl4)-induced liver fibrosis was used to examine the serum HMGB1 levels and its intrahepatic distribution. The increased serum HMGB1 levels were positively correlated with elevation of transforming growth factor-ß1 (TGF-ß1) and collagen deposition during fibrogenesis. The cytoplasmic distribution of HMGB1 was noted in the parenchymal hepatocytes of fibrotic livers. In vitro studies confirmed that exposure to hydrogen peroxide and CCl4 induced an intracellular mobilization and extracellular release of nuclear HMGB1 peptides in clone-9 and primary hepatocytes, respectively. An uptake of exogenous HMGB1 by hepatic stellate cells (HSCs) T6 cells indicated a possible paracrine action of hepatocytes on HSCs. Moreover, HMGB1 dose-dependently stimulated HSC proliferation, up-regulated de novo synthesis of collagen type I and α-smooth muscle actin (α-SMA), and triggered Smad2 phosphorylation and its nuclear translocation through a TGF-ß1-independent mechanism. Blockade with neutralizing antibodies and gene silencing demonstrated the involvement of the receptor for advanced glycation end-products (RAGE), but not toll-like receptor 4, in cellular uptake of HMGB1 and the HMGB1-mediated Smad2 and ERK1/2 phosphorylation as well as α-SMA up-regulation in HSC-T6 cells. Furthermore, anti-RAGE treatment significantly ameliorated CCl4-induced liver fibrosis. In conclusion, the nuclear HMGB1 peptides released from parenchymal hepatocytes during liver injuries may directly activate HSCs through stimulating HSC proliferation and transformation, eventually leading to the fibrotic changes of livers. Blockade of HMGB1/RAGE signaling cascade may constitute a therapeutic strategy for treatment of liver fibrosis.

Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant Dravet Syndrome model during development.

Dravet syndrome (DS) is characterized by severe infant-onset myoclonic epilepsy along with delayed psychomotor development and heightened premature mortality. A primary monogenic cause is mutation of the SCN1A gene, which encodes the voltage-gated sodium channel subunit Nav1.1. The nature and timing of changes caused by SCN1A mutation in the hippocampal dentate gyrus (DG) network, a core area for gating major excitatory input to hippocampus and a classic epileptogenic zone, are not well known. In particularly, it is still not clear whether the developmental deficit of this epileptogenic neural network temporally matches with the progress of seizure development. Here, we investigated the emerging functional and structural deficits of the DG network in a novel mouse model (Scn1a(E1099X/+)) that mimics the genetic deficit of human DS. Scn1a(E1099X/+) (Het) mice, similarly to human DS patients, exhibited early spontaneous seizures and were more susceptible to hyperthermia-induced seizures starting at postnatal week (PW) 3, with seizures peaking at PW4. During the same period, the Het DG exhibited a greater reduction of Nav1.1-expressing GABAergic neurons compared to other hippocampal areas. Het DG GABAergic neurons showed altered action potential kinetics, reduced excitability, and generated fewer spontaneous inhibitory inputs into DG granule cells. The effect of reduced inhibitory input to DG granule cells was exacerbated by heightened spontaneous excitatory transmission and elevated excitatory release probability in these cells. In addition to electrophysiological deficit, we observed emerging morphological abnormalities of DG granule cells. Het granule cells exhibited progressively reduced dendritic arborization and excessive spines, which coincided with imbalanced network activity and the developmental onset of spontaneous seizures. Taken together, our results establish the existence of significant structural and functional developmental deficits of the DG network and the temporal correlation between emergence of these deficits and the onset of seizures in Het animals. Most importantly, our results uncover the developmental deficits of neural connectivity in Het mice. Such structural abnormalities likely further exacerbate network instability and compromise higher-order cognitive processing later in development, and thus highlight the multifaceted impacts of Scn1a deficiency on neural development.

Type II diabetes mellitus is associated with a reduced risk of cholangiocarcinoma in patients with biliary tract diseases.

It has not yet been reported whether Type II diabetes mellitus (DM) is associated with an increased cholangiocarcinoma (CC) risk in patients with biliary tract diseases. We identified 123,050 patients concomitantly diagnosed with biliary tract diseases and DM between 1998 and 2010. The control cohort consisted of 122,721 individuals with biliary tract diseases but not DM. Both cohorts were followed-up until the end of 2010 to estimate the risk of CC. We also compared the risk of CC between DM and non-DM cohorts without biliary tract diseases. Overall, the incidence of CC was 21% lower among the DM patients than among the control patients (1.11 vs. 1.41 per 1,000 person-years). DM cohorts exhibited significantly reduced risks for both intrahepatic and extrahepatic CC. A multivariable Cox proportional hazards regression model was used, and the adjusted hazard ratio (HR) of CC was 0.74 (95% confidence interval [CI], 0.66-0.82) for the DM cohort in comparison with the control cohort. The age-specific data indicated that compared with the control patients, the adjusted HRs for the DM patients were significantly lower among patients 50-64 (adjusted HR = 0.67; 95% CI = 0.55-0.82) and 65-74 years old (adjusted HR = 0.70; 95% CI, 0.59-0.84). Furthermore, DM was associated with a lower risk of CC among patients with biliary diseases, regardless of the presence of comorbidities and the status of cholecystectomy. In the patients without biliary tract diseases, DM is associated with significantly increased risk of CC (adjusted HR = 1.58; 95% CI, 1.37-1.82).

Dopamine impairs functional integrity of rat hepatocytes through nuclear factor kappa B activity modulation: An in vivo, ex vivo, and in vitro study.

Dopamine (DA) is commonly used to maintain the hemodynamic stability of brain-dead donors despite its controversial effects on organ functions. This study aimed at examining the hemodynamic effect of DA in a rat brain-dead model in vivo, alteration of hepatocyte integrity in liver grafts after ex vivo preservation, and changes in cultured clone-9 hepatocytes including cellular viability, cell cycle, apoptotic regulators, and lipopolysaccharide (LPS)-stimulated nuclear factor kappa B (NF-κB) signaling machinery. Although in vivo findings demonstrated enhanced portal venous blood flow and hepatic microcirculatory perfusion after DA infusion, no apparent advantage was noted in preserving hepatocyte integrity ex vivo. In vitro, prolonged exposure to high-dose DA reduced proliferation and induced G1 growth arrest of clone-9 hepatocytes with concomitant decreases in B cell lymphoma 2 (BCL2)/B cell lymphoma 2-associated X protein (BAX) and heat shock protein 70/BAX protein ratios and intracellular NF-κB p65. Moreover, DA pretreatment suppressed LPS-elicited inhibitor of κBα phosphorylation and subsequent NF-κB nuclear translocation, suggesting that DA may down-regulate NF-κB signaling, thereby reducing expression of antiapoptotic regulators, such as BCL2. In conclusion, despite augmentation of hepatic perfusion, DA infusion failed to preserve hepatocyte integrity both in vivo and ex vivo. In vitro findings demonstrated that high-dose DA may hamper the function of NF-κB signaling machinery and eventually undermine functional integrity of hepatocytes in liver grafts.

Hospitalization for Inflammatory Bowel Disease is Associated with Increased Risk of Breast Cancer: A Nationwide Cohort Study of an Asian Population.

PURPOSE: To learn whether women with inflammatory bowel disease (IBD) exhibit a higher risk of breast cancer. METHODS: We identified 4,856 women with IBD symptoms from 1998 to 2008 and 19,424 control patients without the disorder, frequency matched by age, sex, and admission year. Both cohorts were followed-up until the end of 2010 to estimate the risk of breast cancer. RESULTS: Overall, the incidence of breast cancer was similar in the IBD and control cohorts (1.31 vs. 1.25 per 1,000 person-years). The adjusted hazard ratio of breast cancer was 0.95 (95 % confidence interval 0.66-1.36) for the IBD patients. Further analysis revealed that neither Crohn disease nor ulcerative colitis was associated with the risk of developing breast cancer in women. The age-specific analysis indicated that the incidence of breast cancer was highest in the 45- to 65-year-old age group in both cohorts. The incidence of breast cancer was significantly increased in patients who required hospitalization twice or more per year, compared with the control cohort (adjusted hazard ratio 8.45; 95 % confidence interval 4.64-15.4). Moreover, age-specific analysis showed that patients aged less than 65 years old (≤44 or 45-65 years of age) exhibited a strong association between IBD hospitalization and breast cancer risk. CONCLUSIONS: The risk of breast cancer was positively proportional to the frequency of admission for IBD. Therefore, careful surveillance of breast cancer should be sought for female IBD patients with 2 or more annual hospitalizations.

Proper BMP Signaling Levels Are Essential for 3D Assembly of Hepatic Cords from Hepatoblasts and Mesenchymal Cells.

BACKGROUND: Because the molecular mechanisms of morphogenesis of the hepatic cord and sinus are unclear, we investigated the involvement of bone morphogenetic protein (BMP4) in hepatic sinusoid morphogenesis. METHODS: We used embryonic chicken livers, which develop rapidly, as our model, and investigated expression of BMP-related genes. BMP4 activity was manipulated by overexpressing BMP4 and its antagonist, noggin. RESULTS: During hepatic cord morphogenesis, BMP4 and its receptors are expressed in both peri-sinusoidal cells and hepatoblasts as the sinusoids form, whereas noggin is expressed transiently in peri-sinusoidal cells at early stages. Suppression of BMP activity with noggin overexpression disrupted normal hepatic sinusoid structure, leading to liver congestion, failure of fibronectin deposition, and markedly reduced numbers of peri-sinusoidal cells. However, overexpression of BMP did not change sinusoidal morphology but increased endothelial cell number. Noggin overexpression resulted in disrupted cord organization, and dilated sinusoidal space, eventually leading to increased apoptosis and failed hepatocyte differentiation. CONCLUSIONS: Our results show that proper BMP signaling mediates peri-sinusoidal cell-hepatoblast interactions during development; this is essential for hepatic cord organization among hepatoblasts, endothelium, and presumptive hepatic stellate cells.

Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation.

Mutation in CUL4B, which encodes a scaffold protein of the E3 ubiquitin ligase complex, has been found in patients with X-linked mental retardation (XLMR). However, early deletion of Cul4b in mice causes prenatal lethality, which has frustrated attempts to characterize the phenotypes in vivo. In this report, we successfully rescued Cul4b mutant mice by crossing female mice in which exons 4-5 of Cul4b were flanked by loxP sequences with Sox2-Cre male mice. In Cul4b-deficient (Cul4b(Δ)/Y) mice, no CUL4B protein was detected in any of the major organs, including the brain. In the hippocampus, the levels of CUL4A, CUL4B substrates (TOP1, ß-catenin, cyclin E and WDR5) and neuronal markers (MAP2, tau-1, GAP-43, PSD95 and syn-1) were not sensitive to Cul4b deletion, whereas the number of parvalbumin (PV)-positive GABAergic interneurons was decreased in Cul4b(Δ)/Y mice, especially in the dentate gyrus (DG). Some dendritic features, including the complexity, diameter and spine density in the CA1 and DG hippocampal neurons, were also affected by Cul4b deletion. Together, the decrease in the number of PV-positive neurons and altered dendritic properties in Cul4b(Δ)/Y mice imply a reduction in inhibitory regulation and dendritic integration in the hippocampal neural circuit, which lead to increased epileptic susceptibility and spatial learning deficits. Our results identify Cul4b(Δ)/Y mice as a potential model for the non-syndromic model of XLMR that replicates the CUL4B-associated MR and is valuable for the development of a therapeutic strategy for treating MR.

Diabetes mellitus and increased postoperative risk of acute renal failure after hepatectomy for hepatocellular carcinoma: a nationwide population-based study.

BACKGROUND: This study aimed to determine the effects of diabetes mellitus (DM) on the risk of surgical mortality and morbidity in patients undergoing hepatectomy for hepatocellular carcinoma (HCC). METHODS: We identified 2,962 DM patients who underwent a hepatectomy for HCC from 2000 to 2010. The non-DM control cohort consisted of 2,962 patients who also received a hepatectomy during the same period. Age, sex, comorbidities, and year of admission were all matched between the 2 cohorts. RESULTS: The prevalence of preoperative coexisting medical conditions was comparable between the DM and non-DM cohorts, except the percentage of patients undergoing major hepatectomy (lobectomy; 18.1 % in the DM cohort vs. 20.4 % in the non-DM cohort; p = 0.02).The hazard ratio (HR) of 30-day postoperative mortality in the DM patients after hepatectomy was 1.17 [95 % confidence interval (CI) 0.75-1.84] after adjustment. The DM cohort exhibited a significantly higher risk of postoperative septicemia (adjusted hazard ratio, 1.45; 95 % CI 1.06-2.00) and acute renal failure (adjusted hazard ratio, 1.70; 95 % CI 1.01-2.84) compared with that of the non-DM cohort, but this higher risk was not associated with the increased risk of other major morbidities, including pneumonia, stroke, and myocardial infarction. Further analysis showed that major hepatectomy (lobectomy) in DM patients carried higher risks of septicemia and acute renal failure. In multiple regression models, preoperative diabetes-related comorbidities were not significantly associated with 30-day postoperative mortality. CONCLUSIONS: DM is associated with a significantly high risk of septicemia and acute renal failure, but not with other major complications or mortality, after hepatectomy for HCC.

Pyridoxamine protects against mechanical defects in cardiac ageing in rats: studies on load dependence of myocardial relaxation.

Our team demonstrated in the past that pyridoxamine attenuated arterial stiffening by targeting the pathogenic formation of glycated collagen cross-links in aged rats. Herein, we examined whether pyridoxamine therapy can protect against mechanical defects in myocardial relaxation by improving arterial wave properties and cardiac contractile performance in senescent animals. Fifteen-month-old male Fisher 344 rats were treated daily with pyridoxamine (1 g l(-1) in drinking water) for 5 months and compared with age-matched untreated control animals (20 months old). Arterial wave properties were characterized by wave transit time (τw) and wave reflection factor (Rf). We measured the contractile status of the myocardium in an intact heart as the left ventricular (LV) end-systolic elastance (Ees). Myocardial relaxation was described according to the time constant of the LV isovolumic pressure decay (τe). Pyridoxamine therapy prevented the age-associated prolongation in LV τe and the diminished Ees in senescent rats. The drug also attenuated the age-related augmentation in afterload imposed on the heart, as evidenced by the increased τw and decreased Rf. We found that the LV τe was significantly influenced by both the arterial τw and Rf (τe = 16.3902 + 8.3123 × Rf - 0.4739 × τw; r = 0.7048, P < 0.005). In the meantime, the LV τe and the LV Ees showed a significant inverse linear correlation (τe = 13.9807 - 0.0068 × Ees; r = 0.6451, P < 0.0005). All these findings suggested that long-term treatment with pyridoxamine might ameliorate myocardial relaxation rate, at least partly through its ability to enhance myocardial contractile performance, increase wave transit time and decrease wave reflection factor in aged rats.

Vaginal microbiomes show ethnic evolutionary dynamics and positive selection of Lactobacillus adhesins driven by a long-term niche-specific process.

The vaginal microbiome's composition varies among ethnicities. However, the evolutionary landscape of the vaginal microbiome in the multi-ethnic context remains understudied. We perform a systematic evolutionary analysis of 351 vaginal microbiome samples from 35 multi-ethnic pregnant women, in addition to two validation cohorts, totaling 462 samples from 90 women. Microbiome alpha diversity and community state dynamics show strong ethnic signatures. Lactobacillaceae have a higher ratio of non-synonymous to synonymous polymorphism and lower nucleotide diversity than non-Lactobacillaceae in all ethnicities, with a large repertoire of positively selected genes, including the mucin-binding and cell wall anchor genes. These evolutionary dynamics are driven by the long-term evolutionary process unique to the human vaginal niche. Finally, we propose an evolutionary model reflecting the environmental niches of microbes. Our study reveals the extensive ethnic signatures in vaginal microbial ecology and evolution, highlighting the importance of studying the host-microbiome ecosystem from an evolutionary perspective.

Nonlinear compression toward high-energy single-cycle pulses by cascaded focus and compression.

The advancement of contemporary ultrafast science requires reliable sources to provide high-energy few-cycle light pulses. Through experiments and simulations, we demonstrate an arrangement of pulse postcompression, referred to as cascaded focus and compression (CASCADE), for generating millijoule-level, single-cycle pulses in a compact fashion. CASCADE is realized by a series of foci in matter, whereas pulse compression is provided immediately after each focus to maintain a high efficiency of spectral broadening. By implementing four stages of CASCADE in argon cells, we achieve 50-fold compression of millijoule-level pulses at 1030 nanometers from 157 to 3.1 femtoseconds, with an output pulse energy of 0.98 millijoules and a transmission efficiency of 73%. When driving high harmonic generation, these single-cycle pulses enable the creation of a carrier-envelope phase-dependent extreme ultraviolet continuum with energies extending up to 180 electron volts, providing isolated attosecond pulses at the output.

Enhanced aortic nerve growth factor expression and nerve sprouting in rats following gastric perforation.

BACKGROUND: Nerve growth factor (NGF) up-regulation during inflammation has been demonstrated to occur in several different tissues. Herein, the expression of aortic nerve growth factor and its association with nerve sprouting in a rodent model of self-limited peritonitis were investigated. MATERIALS AND METHODS: Male Wistar rats were randomized into one of three groups: gastric perforation (GP), sham group, and GP group treated with methylprednisolone (GP-M). Aortic expression of NGF and growth associated protein 43 (GAP43) were evaluated at several different time points (range, 6 h to 2 wk) after GP or sham. RESULTS: Compared with the sham group, expression of NGF was significantly elevated during the inflammatory period (the first week post-GP) in GP rats. The GP group also had enhanced nerve sprouting, which persisted after the peritonitis recovered. Methylprednisolone abrogated NGF up-regulation and nerve sprouting induced by GP. CONCLUSIONS: GP resulted in up-regulation of aortic NGF that coincided with aortic nerve sprouting. Methylprednisolone effectively blocked GP-induced NGF up-regulation. Further studies are necessary to decipher the causality of these observed changes.

High APACHE II score and long length of bowel resection impair the outcomes in patients with necrotic bowel induced hepatic portal venous gas.

BACKGROUND: Hepatic portal venous gas (HPVG) is a rare but potentially lethal condition, especially when it results from intestinal ischemia. Since the literatures regarding the prognostic factors of HPVG are still scarce, we aimed to investigate the risk factor of perioperative mortality in this study. METHODS: We analyzed data for patients with intestinal ischemia induced HPVG by chart review in our hospital between 2000 and 2007. Factors associated with perioperative mortality were specifically analyzed. RESULTS: There were 22 consecutive patients receiving definite bowel resection. 13 cases (59.1%) died after surgical intervention. When analyzing the mortality in patients after bowel resections, high Acute Physiology And Chronic health Evaluation (APACHE) II score (p<0.01) and longer length of bowel resection (p=0.047) were significantly associated with mortality in univariate analyses. The complication rate was 66.7% in alive patients after definite bowel resection. CONCLUSIONS: Bowel resection was the only potential life-saving therapy for patients with mesenteric ischemia induced HPVG. High APACHE II score and severity of underlying necrotic bowel determined the results in patients after bowel resection.

Prevention of Severe Intestinal Barrier Dysfunction Through a Single-Species Probiotics is Associated With the Activation of Microbiome-Mediated Glutamate-Glutamine Biosynthesis.

INTRODUCTION: Intra-abdominal hypertension (IAH), the leading complication in the intensive care unit, significantly disturbs the gut microbial composition by decreasing the relative abundance of Lactobacillus and increasing the relative abundance of opportunistic infectious bacteria. METHODS: To evaluate the preventative effect of Lactobacillus-based probiotics on IAH-induced intestinal barrier damages, a single-species probiotics (L92) and a multispecies probiotics (VSL#3) were introduced orally to Sprague-Dawley rats for 7 days before inducing IAH. The intestinal histology and permeability to macromolecules (fluoresceine isothiocyanate, FITC-dextran, N = 8 for each group), the parameters of immunomodulatory and oxidative responses [monocyte chemotactic protein 1 (MCP-1), interleukin-1ß (IL-1ß), interleukin-4 (IL-4), interleukin-10 (IL-10), malonaldehyde, glutathione peroxidase (GSH- Px), catalase (CAT), and superoxide dismutase; N = 4 for each group], and the microbiome profiling (N = 4 for each group) were analyzed. RESULTS: Seven-day pretreatments of L92 significantly alleviated the IAH-induced increase in intestinal permeability to FITC-dextran and histological damage (P  < 0.0001), accompanied with the suppression of inflammatory and oxidative activation. The increase of MCP-1 and IL-1ß was significantly inhibited (P  < 0.05); the anti-inflammatory cytokines, IL-4, and IL-10 were maintained at high levels; and the suppression of CAT (P  <  0.05) was significantly reversed when pretreated with L92. On the contrary, no significant protective effects were observed in the VSL#3-pretreated group. Among the 84 identified species, 260 MetaCyc pathways, and 217 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, the protective effects of L92 were correlated with an increased relative abundance of Bacteroides finegoldii, Odoribacter splanchnicus, and the global activation of amino acid biosynthesis pathways, especially the glutamate-glutamine biosynthesis pathway. CONCLUSIONS: Seven-day pretreatment with a single-species probiotics can prevent IAH-induced severe intestinal barrier dysfunction, potentially through microbial modulation.

Effects of acetyl-L-carnitine and oxfenicine on aorta stiffness in diabetic rats.

BACKGROUND: We compared the haemodynamic and metabolic effects of acetyl-L-carnitine (one of the carnitine derivatives) and of oxfenicine (a carnitine palmitoyltransferase-1 inhibitor) in streptozotocin-induced diabetes in male Wistar rats. MATERIALS AND METHODS: Diabetes was induced by a single tail vein injection of 55mgkg(-1) streptozotocin. The diabetic animals daily treated with either acetyl-L-carnitine (150mgkg(-1) in drinking water) or oxfenicine (150mgkg(-1) by oral gavage) for 8weeks,were compared with the untreated age-matched diabetic controls. Arterial wave reflection was derived using the impulse response function of the filtered aortic input impedance spectra. Thiobarbituric acid reactive substances (TBARS) measurement was used to estimate malondialdehyde (MDA) content. RESULTS: Oxfenicine, but not acetyl-L-carnitine, increased total peripheral resistance in diabetes, which paralleled its elevation in plasma levels of free fatty acids. By contrast, acetyl-L-carnitine, but not oxfenicine, resulted in a significant increase in wave transit time and a decrease in wave reflection factor, suggesting that acetyl-L-carnitine may attenuate the diabetes-induced deterioration in systolic loading condition for the left ventricle. This was in parallel with its lowering of MDA/TBARS content in plasma and aortic walls in diabetes. Acetyl-L-carnitine therapy also prevented the diabetes-related cardiac hypertrophy, as evidenced by the reduction in ratio of the left ventricular weight to body weight. CONCLUSION: Acetyl-L-carnitine, but not oxfenicine, attenuates aortic stiffening and cardiac hypertrophy, possibly through its decrease of lipid oxidation-derived MDA/TBARS in the rats with insulin deficiency.