Efficacy of Preoperative Bilateral Thoracic Paravertebral Block in Cardiac Surgery Requiring Full Heparinization: A Propensity-Matched Study.

OBJECTIVES: To assess the efficacy of preoperative bilateral paravertebral block (PVB) with general anesthesia (GA) in contributing to early extubation and decreasing opioid consumption in cardiac surgery. DESIGN: A propensity score-matched retrospective study. SETTING: A single tertiary medical center between January 2018 and December 2020. PARTICIPANTS: Adult patients undergoing isolated first-time aortic valve replacement and coronary artery bypass grafting with full sternotomy. INTERVENTIONS: A cohort of 44 patients who received PVB with GA (PVB group) was matched with 44 patients who underwent similar surgery with GA only (GA only group). MEASUREMENTS AND MAIN RESULTS: The completion rate of extubation in the operating room was significantly greater in the PVB group (65.9%) than in the GA only group (43.2%; p = 0.032). The completion rate of extubation within eight hours after surgery also was significantly greater in the PVB group (86.4%) than in the GA only group (68.2%; p = 0.042). The median amount of intraoperative fentanyl administered was significantly less in the PVB group (4.8 µg/kg; interquartile range [IQR], 3.3-7.2) than in the GA only group (8.4 µg/kg; IQR, 5.4-12.7; p < 0.001). The median amount of postoperative fentanyl administered was significantly less in the PVB group (6.8 µg/kg; IQR, 3.9-10.6) than in the GA only group (8.1 µg/kg; IQR, 6.2-15.9; p = 0.012). CONCLUSIONS: This study demonstrated that preoperative bilateral PVB combined with GA contributed to early extubation in isolated first-time aortic valve replacement and coronary artery bypass grafting and in the reduction of intraoperative and postoperative fentanyl consumption.

Edible bird's nest extract downregulates epidermal apoptosis and helps reduce damage by ultraviolet radiation in skin of hairless mice.

The purpose of the present study was to examine whether daily intake of edible bird's nest extract reduced ultraviolet-induced damage to skin. Twenty-one female HR-1/Hos mice were divided into control (C, n = 7), low-dose (2 mg/kg body weight/day of edible bird's nest extract) (L, n = 7), and high-dose (20 mg/kg body weight/day of edible bird's nest extract) (H, n = 7) groups. With their left back skin covered with aluminum sheet to prevent exposure, mice were radiated with either ultraviolet A (20 J/cm2) or ultraviolet B (40 mJ/cm2) in an alternate manner once daily for 10 weeks. They were gavaged either a solution of saline or edible bird's nest extract every day. The moisture content of the ultraviolet-exposed right back skin was significantly higher in H than in C or L. Histochemical analysis showed that the number of apoptotic epidermal cells on the ultraviolet-exposed skin was significantly lower in L and H than in C. In H, the mRNA expression of superoxide dismutase 2 was significantly higher on ultraviolet-exposed skin than on unexposed skin. Our data suggested that edible bird's nest extract enhanced superoxide dismutase 2 expression and downregulated apoptosis in their epidermis, which likely helped reduce skin damage.

Notch1 and Notch2 Coordinately Regulate Stem Cell Function in the Quiescent and Activated States of Muscle Satellite Cells.

Satellite cells, the muscle tissue stem cells, express three Notch receptors (Notch1-3). The function of Notch1 and Notch2 in satellite cells has to date not been fully evaluated. We investigated the role of Notch1 and Notch2 in myogenic progression in adult skeletal muscle using tamoxifen-inducible satellite cell-specific conditional knockout mice for Notch1 (N1-scKO), Notch2 (N2-scKO), and Notch1/Notch2 (scDKO). In the quiescent state, the number of satellite cells was slightly reduced in N2-scKO, but not significantly in N1-scKO, and almost completely depleted in scDKO mice. N1-scKO and N2-scKO mice both exhibited a defect in muscle regeneration induced by cardiotoxin injection, while muscle regeneration was severely compromised with marked fibrosis in scDKO mice. In the activated state, ablation of either Notch1 or Notch2 alone in satellite cells prevented population expansion and self-renewal but induced premature myogenesis. Therefore, our results indicate that Notch1 and Notch2 coordinately maintain the stem-cell pool in the quiescent state by preventing activation and regulate stem-cell-fate decision in the activated state, governing adult muscle regeneration. Stem Cells 2018;36:278-285.

α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40.

Among dietary fatty acids with immunologic effects, ω-3 polyunsaturated fatty acids, such as α-linolenic acid (ALA), have been considered as factors that contribute to the differentiation of M2-type macrophages (M2 macrophages). In this study, we examined the effect of ALA and its gut lactic acid bacteria metabolites 13-hydroxy-9(Z),15(Z)-octadecadienoic acid (13-OH) and 13-oxo-9(Z),15(Z)-octadecadienoic acid (13-oxo) on the differentiation of M2 macrophages from bone marrow-derived cells (BMDCs) and investigated the underlying mechanisms. BMDCs were stimulated with ALA, 13-OH, or 13-oxo in the presence of IL-4 or IL-13 for 24 h, and significant increases in M2 macrophage markers CD206 and Arginase-1 (Arg1) were observed. In addition, M2 macrophage phenotypes were less prevalent following cotreatment with GPCR40 antagonists or inhibitors of PLC-ß and MEK under these conditions, suggesting that GPCR40 signaling is involved in the regulation of M2 macrophage differentiation. In further experiments, remarkable M2 macrophage accumulation was observed in the lamina propria of the small intestine of C57BL/6 mice after intragastric treatments with ALA, 13-OH, or 13-oxo at 1 g/kg of body weight per day for 3 d. These findings suggest a novel mechanism of M2 macrophage differentiation involving fatty acids from gut lactic acid bacteria and GPCR40 signaling.-Ohue-Kitano, R., Yasuoka, Y., Goto, T., Kitamura, N., Park, S.-B., Kishino, S., Kimura, I., Kasubuchi, M., Takahashi, H., Li, Y., Yeh, Y.-S., Jheng, H.-F., Iwase, M., Tanaka, M., Masuda, S., Inoue, T., Yamakage, H., Kusakabe, T., Tani, F., Shimatsu, A., Takahashi, N., Ogawa, J., Satoh-Asahara, N., Kawada, T. α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40.

Omega-3 polyunsaturated fatty acids suppress the inflammatory responses of lipopolysaccharide-stimulated mouse microglia by activating SIRT1 pathways.

Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major ω-3 polyunsaturated fatty acids (PUFAs) of fish oil, exhibit various effects, which include shifting microglia to the anti-inflammatory phenotype. To identify the molecular mechanisms involved, we examined the impact of EPA, DHA, and EPA+DHA on the lipopolysaccharide (LPS)-induced cytokine profiles and the associated signaling pathways in the mouse microglial line MG6. Both EPA and DHA suppressed the production of the pro-inflammatory cytokines TNF-α and IL-6 by LPS-stimulated MG6 cells, and this was also observed in LPS-stimulated BV-2 cells, the other microglial line. Moreover, the EPA+DHA mixture activated SIRT1 signaling by enhancing mRNA level of nicotinamide phosphoribosyltransferase (NAMPT), cellular NAD+ level, SIRT1 protein deacetylase activity, and SIRT1 mRNA levels in LPS-stimulated MG6. EPA+DHA also inhibited phosphorylation of the stress-associated transcription factor NF-κB subunit p65 at Ser536, which is known to enhance NF-κB nuclear translocation and transcriptional activity, including cytokine gene activation. Further, EPA+DHA increased the LC3-II/LC3-I ratio, an indicator of autophagy. Suppression of TNF-α and IL-6 production, inhibition of p65 phosphorylation, and autophagy induction were abrogated by a SIRT1 inhibitor. On the other hand, NAMPT inhibition reversed TNF-α suppression but not IL-6 suppression. Accordingly, these ω-3 PUFAs may suppress neuroinflammation through SIRT1-mediated inhibition of the microglial NF-κB stress response and ensue pro-inflammatory cytokine release, which is implicated in NAMPT-related and -unrelated pathways.

Prediction of functional profiles of gut microbiota from 16S rRNA metagenomic data provides a more robust evaluation of gut dysbiosis occurring in Japanese type 2 diabetic patients.

We assessed whether gut microbial functional profiles predicted from 16S rRNA metagenomics differed in Japanese type 2 diabetic patients. A total of 22 Japanese subjects were recruited from our outpatient clinic in an observational study. Fecal samples were obtained from 12 control and 10 type 2 diabetic subjects. 16S rRNA metagenomic data were generated and functional profiles predicted using "Phylogenetic Investigation of Communities by Reconstruction of Unobserved States" software. We measured the parameters of glucose metabolism, gut bacterial taxonomy and functional profile, and examined the associations in a cross-sectional manner. Eleven of 288 "Kyoto Encyclopedia of Genes and Genomes" pathways were significantly enriched in diabetic patients compared with control subjects (p<0.05, q<0.1). The relative abundance of almost all pathways, including the Insulin signaling pathway and Glycolysis/Gluconeogenesis, showed strong, positive correlations with hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) levels. Bacterial taxonomic analysis showed that genus Blautia significantly differed between groups and had negative correlations with HbA1c and FPG levels. Our findings suggest a novel pathophysiological relationship between gut microbial communities and diabetes, further highlighting the significance and utility of combining prediction of functional profiles with ordinal bacterial taxonomic analysis (UMIN Clinical Trails Registry number: UMIN000026592).

[Relationships between ignoring instructions and response bias when completing questionnaires].

Certain participants are insincere, or careless when they respond to questionnaires. To identify such participants, we included three items in a questionnaire that instructed participants to choose a particular response category. Nurses (N = 1,000) responded to this questionnaire in a Web survey. One-hundred-twenty participants failed to follow the instructions for at least one item (non-followers). Analyzing their responses indicated the following: (a) non-followers were more likely to give identical, or midpoint responses; (b) the correlations between their responses to regular and reversed items were low or positive, and their responses to scales containing reversed items tended to show lower internal consistency; and finally, (c) the mean scores of non-followers were closer to the midpoint of the scale, regardless of whether the scale included reversed items. One reason that including reversed items lead to lower internal consistency could be because participants occasionally missed responding to these items. However, the results suggested that non-followers were not diligent in responding to regular items, and merely deleting reversed items from scales will be insufficient to ensure accurate results.

Melatonin promotes adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes.

Melatonin is synthesized in the pineal gland, but elicits a wide range of physiological responses in peripheral target tissues. Recent advances suggest that melatonin controls adiposity, resulting in changes in body weight. The aim of this study was to investigate the effect of melatonin on adipogenesis and mitochondrial biogenesis in 3T3-L1 mouse embryo fibroblasts. Melatonin significantly increased the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipogenesis, and promoted differentiation into adipocytes. Melatonin-treated cells also formed smaller lipid droplets and abundantly expressed several molecules associated with lipolysis, including adipose triglyceride lipase, perilipin, and comparative gene identification-58. Moreover, the hormone promoted biogenesis of mitochondria, as indicated by fluorescent staining, elevated the citrate synthase activity, and upregulated the expression of PPAR-γ coactivator 1 α, nuclear respiratory factor-1, and transcription factor A. The expression of uncoupling protein 1 was also observable both at mRNA and at protein level in melatonin-treated cells. Finally, adiponectin secretion and the expression of adiponectin receptors were enhanced. These results suggest that melatonin promotes adipogenesis, lipolysis, mitochondrial biogenesis, and adiponectin secretion. Thus, melatonin has potential as an anti-obesity agent that may reverse obesity-related disorders.

[Successful Treatment of Malignant Lymphoma Arising from the Left Atrial Myxoma with Acute Myocardial Infarction;Report of a Case].

Primary cardiac malignant lymphoma within a cardiac myxoma is extremely rare. Here we report a case of a previously healthy 71-year-old woman who developed acute myocardial infarction. Transthoracic echocardiography showed a 69×45-mm solid tumor in the left atrium that was moving in a circular manner in the left atrial and ventricular cavities. Coronary angiography revealed an occlusion due to a coronary emboli in the distal part of the right coronary artery. Thrombectomy with an aspiration catheter was successfully performed to remove large red thrombi from the arterial lumen. Emergent surgical removal of the left atrial tumor along with tricuspid valve annuloplasty was performed under cardiopulmonary bypass. The postoperative course was uneventful. Histological examination demonstrated presence of malignant lymphoma within the myxoma. The patient was treated with rituximab, tetrahydropyranyl adriamycin, cyclophosphamide, vincristine, and predonisone (R-THP-COP) and is doing well without recurrence of lymphoma at 18-month follow-up. We emphasise that all surgical cardiac specimens should be sent for histological analysis aiming at the best treatment.

Enhanced Nox1 expression and oxidative stress resistance in c-kit-positive hematopoietic stem/progenitor cells.

Although stem cells are generally thought to be resistant to oxidative stress, the fact and in detail molecular mechanism are still to be clearly identified. We herein tried to understand the overall characterization of redox regulatory signaling in hematopoietic stem cells. We purified c-kit-positive hematopoietic stem/progenitor cells from the bone marrow of healthy mice, and then evaluated their redox regulatory property. Compared to the c-kit-negative matured mononuclear cells, c-kit-positive stem/progenitor cells showed lower basic levels of intracellular reactive oxygen species, faster clearance of the accumulated intracellular reactive oxygen species, and higher resistant to oxidative stress. An overall view on the gene expression profile associated with redox regulation showed to be widely differed between cell types. We confirmed that the c-kit-positive stem/progenitor cells expressed significantly higher of Nox1 and catalase, but less of lactoperoxidase than these matured mononuclear cells. Our data suggests that stem cells keep specific redox regulatory property for defensing against oxidative stress.

Overexpression of leptin reduces the ratio of glycolytic to oxidative enzymatic activities without changing muscle fiber types in mouse skeletal muscle.

Increased spontaneous locomotive activity and oxygen consumption have been reported in transgenic mice overexpressing leptin in the liver. In the present study, we examined whether the overexpression of leptin altered glycolytic and oxidative metabolic enzymatic activities as well as the composition of myosin heavy chain (MHC) isoforms in skeletal muscle. Enzymatic activities of lactate dehydrogenase (LDH) and citrate synthase (CS) were quantified in gastrocnemius muscle (GAS) and the red portion of tibialis anterior muscle (TA) from leptin transgenic (Tg) mice and non-Tg mice. The composition of MHC isoforms was measured in soleus muscle (SOL) and extensor digitorum longus muscle (EDL) from the two groups. In red TA, LDH-to-CS ratio was significantly lower in Tg than in non-Tg (p=0.014), whereas no significant change was observed in GAS. The composition of MHC isoforms was not significantly different in SOL or EDL between Tg and non-Tg groups. Our data indicate that chronic overexpression of leptin reduces the ratio of glycolytic to oxidative capacity without changing muscle fiber types particularly in red muscles. This metabolic change may contribute to the increased spontaneous locomotive activity and oxygen consumption in Tg mice reported previously.

Atomically precise Au and Ag nanoclusters doped with a single atom as model alloy catalysts.

Gold and silver nanoclusters (NCs) composed of <200 atoms are novel catalysts because their catalytic properties differ significantly from those of the corresponding bulk surface and can be dramatically tuned by the size (number of atoms). Doping with other metals is a promising approach for improving the catalytic performance of Au and Ag NCs. However, elucidation of the origin of the doping effects and optimization of the catalytic performance are hampered by the technical challenge of controlling the number and location of the dopants. In this regard, atomically precise Au or Ag (Au/Ag) NCs protected by ligands or polymers have recently emerged as an ideal platform because they allow regioselective substitution of single Au/Ag constituent atoms while retaining the size and morphology of the NC. Heterogeneous Au/Ag NC catalysts doped with a single atom can also be prepared by controlled calcination of ligand-protected NCs on solid supports. Comparison of thermal catalysis, electrocatalysis, and photocatalysis between the single-atom-doped and undoped Au/Ag NCs has revealed that the single-atom doping effect can be attributed to an electronic or geometric origin, depending on the dopant element and position. This minireview summarizes the recent progress of the synthesis and catalytic application of single-atom-doped, atomically precise Au/Ag NC catalysts and provides future prospects for the rational development of active and selective metal NC catalysts.

Pt-doped Ru nanoparticles loaded on 'black gold' plasmonic nanoreactors as air stable reduction catalysts.

This study introduces a plasmonic reduction catalyst, stable only in the presence of air, achieved by integrating Pt-doped Ru nanoparticles on black gold. This innovative black gold/RuPt catalyst showcases good efficiency in acetylene semi-hydrogenation, attaining over 90% selectivity with an ethene production rate of 320 mmol g-1 h-1. Its stability, evident in 100 h of operation with continuous air flow, is attributed to the synergy of co-existing metal oxide and metal phases. The catalyst's stability is further enhanced by plasmon-mediated concurrent reduction and oxidation of the active sites. Finite-difference time-domain simulations reveal a five-fold electric field intensification near the RuPt nanoparticles, crucial for activating acetylene and hydrogen. Kinetic isotope effect analysis indicates the contribution from the plasmonic non-thermal effects along with the photothermal. Spectroscopic and in-situ Fourier transform infrared studies, combined with quantum chemical calculations, elucidate the molecular reaction mechanism, emphasizing the cooperative interaction between Ru and Pt in optimizing ethene production and selectivity.

[Successful treatment using recombinant thrombomodulin for disseminated intravascular coagulation associated with recurrent prosthetic valve endocarditis].

Prosthetic valve endocarditis(PVE)occasionally evokes sepsis and disseminated intravascular coagulation(DIC). A 46-year-old man developed relapsing active PVE with an annular abscess and suffered from exacerbating sepsis and DIC. Despite the administration of antibiotics, his DIC score increased. Anti-DIC treatment with recombinant thrombomodulin (rTM) was initiated, and his DIC was remarkably resolved. Accordingly, the abscess cavity was closed by using a homograft anterior mitral leaflet, and the aortic root was replaced with the homograft. He is doing well without an evidence of recurrent endocarditis 18 months after the operation. rTM is a new and promising drug for the treatment of DIC with infective endocarditis.

Synthesis of active, robust and cationic Au25 cluster catalysts on double metal hydroxide by long-term oxidative aging of Au25(SR)18.

Synthesis of an atomically precise Au25 cluster catalyst was attempted by long-term, low-temperature aging of Au25(BaET)18 (BaET-H = 2-(Boc-amino)ethanethiol) on various double metal hydroxide (DMH) supports. X-ray absorption fine structure analysis revealed that bare Au25 clusters with high loading (1 wt%) were successfully generated on the DMH containing Co and Ce (Co3Ce) by oxidative aging in air at 150 °C for >12 h. X-ray absorption near-edge structure and X-ray photoelectron spectroscopies showed that the Au25 clusters on Co3Ce were positively charged. The Au25/Co3Ce catalyst thus synthesized exhibited superior catalytic performance in the aerobic oxidation of benzyl alcohol under ambient conditions (TOF = 1097 h-1 with >97% selectivity to benzoic acid) and high durability owing to a strong anchoring effect. Based on kinetic experiments, we propose that abstraction of hydride from α-carbon of benzyl alkoxide by Au25 is the rate-determining step of benzyl alcohol oxidation by Au25/Co3Ce.

Effect of malnutrition and frailty status on surgical aortic valve replacement.

OBJECTIVES: To date, assessment of nutritional and frailty status in patients undergoing surgical aortic valve replacement remains unclear. This study aimed to assess the effect of geriatric nutritional risk index (GNRI) and Rockwood clinical frailty scale (CFS) on short-term and mid-term survival in patients who underwent surgical aortic valve replacement for aortic stenosis. METHODS: In total, 219 patients who underwent aortic valve replacement for aortic stenosis between Jan 1 2011 and Dec 31 2018 were retrospectively monitored in a single center. Mid-term survival was assessed using Kaplan-Meier analysis. Logistic and Cox regression analyses were performed to detect independent predictors for early and mid-term mortality. Follow-up was 97.7% complete, and a GNRI score ≤ 98 denoted malnutrition. RESULTS: In the univariable analysis, GNRI [odds ratio (OR) 0.91, 95% confidence interval (CI), 0.86-0.96, p < 0.001] and CFS (OR 2.00 95% CI 1.38-2.94, p < 0.001) were identified as significant risk factors for in-hospital mortality. Mid-term survival was significantly decreased in patients with malnutrition (3 and 5 year survival rates 83.9 and 76.9%, respectively, p < 0.001). Mid-term freedom from major cardiac and cerebrovascular events was significantly decreased in patients with malnutrition (p = 0.039). The CFS (hazard ratio 1.78) and GNRI (hazard ratio 0.95) were independent risk factors for mid-term survival in the univariable and multivariable analyses, respectively. CONCLUSIONS: A lower GNRI is associated with poor mid-term mortality and major cardiac and cerebrovascular events after surgical aortic valve replacement. A lower CFS score is associated with unfavorable mid-term outcomes.

Synergistically Activated Pd Atom in Polymer-Stabilized Au23Pd1 Cluster.

Single Pd atom doped Au23Pd1 clusters stabilized by polyvinylpyrrolidone (Au23Pd1:PVP) were selectively synthesized by kinetically controlled coreduction of the Au and Pd precursor ions. The geometric structure of Au23Pd1:PVP was investigated by density functional theory calculation, aberration-corrected transmission electron microscopy, extended X-ray absorption fine structure analysis, Fourier transform infrared spectroscopy of adsorbed CO, and hydrogenation catalysis. These results showed that Au23Pd1:PVP takes polydisperse but the same atomic arrangements as undoped Au24:PVP while exposing all the atoms including the Pd atom on the surface. Au23Pd1:PVP exhibited a significantly higher catalytic activity than Au24:PVP for the aerobic oxidation of p-substituted benzyl alcohols. The kinetic studies showed that the rate-determining step was the hydride abstraction from the α-carbon of the alkoxides for both systems. The activation energy for hydride abstraction by Au23Pd1:PVP was lower than that by Au24:PVP, indicating that the doped Pd atom acts as the active center.

Revealing hydrogen spillover pathways in reducible metal oxides.

Hydrogen spillover, the migration of dissociated hydrogen atoms from noble metals to their support materials, is a ubiquitous phenomenon and is widely utilized in heterogeneous catalysis and hydrogen storage materials. However, in-depth understanding of the migration of spilled hydrogen over different types of supports is still lacking. Herein, hydrogen spillover in typical reducible metal oxides, such as TiO2, CeO2, and WO3, was elucidated by combining systematic characterization methods involving various in situ techniques, kinetic analysis, and density functional theory calculations. TiO2 and CeO2 were proven to be promising platforms for the synthesis of non-equilibrium RuNi binary solid solution alloy nanoparticles displaying a synergistic promotional effect in the hydrolysis of ammonia borane. Such behaviour was driven by the simultaneous reduction of both metal cations under a H2 atmosphere over TiO2 and CeO2, in which hydrogen spillover favorably occurred over their surfaces rather than within their bulk phases. Conversely, hydrogen atoms were found to preferentially migrate within the bulk prior to the surface over WO3. Thus, the reductions of both metal cations occurred individually on WO3, which resulted in the formation of segregated NPs with no activity enhancement.

The endothelial Dll4-muscular Notch2 axis regulates skeletal muscle mass.

Adult skeletal muscle is a highly plastic tissue that readily reduces or gains its mass in response to mechanical and metabolic stimulation; however, the upstream mechanisms that control muscle mass remain unclear. Notch signalling is highly conserved, and regulates many cellular events, including proliferation and differentiation of various types of tissue stem cell via cell-cell contact. Here we reveal that multinucleated myofibres express Notch2, which plays a crucial role in disuse- or diabetes-induced muscle atrophy. Mechanistically, in both atrophic conditions, the microvascular endothelium upregulates and releases the Notch ligand, Dll4, which then activates muscular Notch2 without direct cell-cell contact. Inhibition of the Dll4-Notch2 axis substantively prevents these muscle atrophy and promotes mechanical overloading-induced muscle hypertrophy in mice. Our results illuminate a tissue-specific function of the endothelium in controlling tissue plasticity and highlight the endothelial Dll4-muscular Notch2 axis as a central upstream mechanism that regulates catabolic signals from mechanical and metabolic stimulation, providing a therapeutic target for muscle-wasting diseases.

Gene expression profiling in the Cynomolgus macaque Macaca fascicularis shows variation within the normal birth range.

BACKGROUND: Although an adverse early-life environment has been linked to an increased risk of developing the metabolic syndrome, the molecular mechanisms underlying altered disease susceptibility as well as their relevance to humans are largely unknown. Importantly, emerging evidence suggests that these effects operate within the normal range of birth weights and involve mechanisms of developmental palsticity rather than pathology. METHOD: To explore this further, we utilised a non-human primate model Macaca fascicularis (Cynomolgus macaque) which shares with humans the same progressive history of the metabolic syndrome. Using microarray we compared tissues from neonates in the average birth weight (50-75th centile) to those of lower birth weight (5-25th centile) and studied the effect of different growth trajectories within the normal range on gene expression levels in the umbilical cord, neonatal liver and skeletal muscle. RESULTS: We identified 1973 genes which were differentially expressed in the three tissue types between average and low birth weight animals (P < 0.05). Gene ontology analysis identified that these genes were involved in metabolic processes including cellular lipid metabolism, cellular biosynthesis, cellular macromolecule synthesis, cellular nitrogen metabolism, cellular carbohydrate metabolism, cellular catabolism, nucleotide and nucleic acid metabolism, regulation of molecular functions, biological adhesion and development. CONCLUSION: These differences in gene expression levels between animals in the upper and lower percentiles of the normal birth weight range may point towards early life metabolic adaptations that in later life result in differences in disease risk.