Biochanin A impedes STAT3 activation by upregulating p38δ MAPK phosphorylation in IL-6-stimulated macrophages

Inflammation Research - IL-6-induced STAT3 activation is associated with various chronic inflammatory diseases. In this study, we investigated the anti-STAT3 mechanism of the dietary polyphenol,...     

Inhibition of muscle fibrosis results in increases in both utrophin levels and the number of revertant myofibers in Duchenne muscular dystrophy

Duchenne Muscular Dystrophy is characterized by: near absence of dystrophin in skeletal muscles; low percentage of revertant myofibers; up-regulation of utrophin synthesis; and a high degree of muscle fibrosis. In patient quadriceps femoris biopsies (n = 6, ages between 3–9 years) an inverse correlation was observed between the levels of collagen type I – representing fibrosis – and the levels of utrophin. This correlation was independent of the patient''s age and was observed in the entire muscle biopsy sections. In the mdx mice diaphragm (n = 6/group), inhibition of fibrosis by halofuginone resulted in increases in the levels of utrophin. The utrophin/fibrosis relationships were not limited to collagen type I, but also applied to other constituents of the fibrosis machinery. The inverse correlation was found also in old mdx mice with established fibrosis. In addition, inhibition of collagen type I levels was associated with increases in the numbers of revertant myofibers, both as single myofibers and in clusters in the diaphragm and the gastrocnemius.In summary, our results demonstrate an inverse correlation between the level of muscle fibrosis and the level of utrophin and that of the number of revertant myofibers. These findings may reveal common links between the fibrotic and utrophin-synthesis pathways and offer new insights into the regulation of utrophin synthesis.     

First Hour Initiation of Breastfeeding and Exclusive Breastfeeding at Six Weeks: Prevalence and Predictors in a Tertiary Care Setting

Objective

To assess the prevalence of first hour breastfeeding initiation and exclusive breastfeeding at 6 wk and identify its barriers in healthy term babies born in a tertiary hospital setting.

Methods

A prospective observational cohort study was carried out in consecutively selected 400 mothers who delivered (normal, instrumental or cesarean) term healthy babies in a tertiary care hospital setting. All mother-infant dyads were enroled within 48 h of delivery.

Results

Breastfeeding was initiated within first hour in 255 out of 400, i.e., 64 % of babies. Cesarean delivery and male gender were strongest risk factors for delayed initiation of breastfeeding [OR (95 % CI)?=?1.99 (1.14–3.48) and 34.17 (17.10–70.40) respectively]. Among the babies followed up till 6–8 wk, 83 % were exclusively breastfed. Breast milk substitutes were given in 172/400 (43 %) babies on day one, which emerged as an independent predictor of failure to continue exclusive breastfeeding at 6 wk (OR 2.96; 95 % CI 1.09–8.06). Odds of exclusive breastfeeding were two times higher in babies breastfed within first hour (n?=?255/400, 64 %) when compared to babies initiated breastfeeds beyond first hour (n?=?145/400, 36 %) (OR 2.01;05 % CI 1.12–3.61).

Conclusions

Cesarean section and male gender emerged as significant risk factors for delayed initiation (beyond first hour) of breastfeeding in the index study cohort. In addition, use of breast milk substitute emerged as the only predictor for failure to continue exclusive breastfeeding at six weeks in a tertiary care hospital.     

A novel homozygous SLC25A1 mutation with impaired mitochondrial complex V: Possible phenotypic expansion

SLC25A1 mutations are associated with combined D,L‐2‐hydroxyglutaric aciduria (DL‐ 2HGA; OMIM #615182), characterized by muscular hypotonia, severe neurodevelopmental dysfunction and intractable seizures. SLC25A1 encodes the mitochondrial citrate carrier (CIC), which mediates efflux of the mitochondrial tricarboxylic acid (TCA) cycle intermediates citrate and isocitrate in exchange for cytosolic malate. Only a single family with an SLC25A1 mutation has been described in which mitochondrial respiratory chain dysfunction was documented, specifically in complex IV. Five infants of two consanguineous Bedouin families of the same tribe presented with small head circumference and neonatal‐onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development culminating in early death. Ventricular septal defects (VSD) were demonstrated in three patients. Blood and CSF lactate were elevated with normal levels of plasma amino acids and free carnitine and increased 2‐OH‐glutaric acid urinary exertion. EEG was compatible with white matter disorder. Brain MRI revealed ventriculomegaly, thin corpus callosum with increased lactate peak on spectroscopy. Mitochondrial complex V deficiency was demonstrated in skeletal muscle biopsy of one infant. Homozygosity mapping and sequencing ruled out homozygosity of affected individuals in all known complex V‐associated genes. Whole exome sequencing identified a novel homozygous SLC25A1 c.713A>G (p.Asn238Ser) mutation, segregating as expected in the affected kindred and not found in 220 control alleles. Thus, SLC25A1 mutations might be associated with mitochondrial complex V deficiency and should be considered in the differential diagnosis of mitochondrial respiratory chain defects.

     

Down-regulation of tricarboxylic acid (TCA) cycle genes blocks progression through the first mitotic division in Caenorhabditis elegans embryos

The cell cycle is a highly regulated process that enables the accurate transmission of chromosomes to daughter cells. Here we uncover a previously unknown link between the tricarboxylic acid (TCA) cycle and cell cycle progression in the Caenorhabditis elegans early embryo. We found that down-regulation of TCA cycle components, including citrate synthase, malate dehydrogenase, and aconitase, resulted in a one-cell stage arrest before entry into mitosis: pronuclear meeting occurred normally, but nuclear envelope breakdown, centrosome separation, and chromosome condensation did not take place. Mitotic entry is controlled by the cyclin B–cyclin-dependent kinase 1 (Cdk1) complex, and the inhibitory phosphorylation of Cdk1 must be removed in order for the complex to be active. We found that following down-regulation of the TCA cycle, cyclin B levels were normal but CDK-1 remained inhibitory-phosphorylated in one-cell stage-arrested embryos, indicative of a G2-like arrest. Moreover, this was not due to an indirect effect caused by checkpoint activation by DNA damage or replication defects. These observations suggest that CDK-1 activation in the C. elegans one-cell embryo is sensitive to the metabolic state of the cell, and that down-regulation of the TCA cycle prevents the removal of CDK-1 inhibitory phosphorylation. The TCA cycle was previously shown to be necessary for the development of the early embryo in mammals, but the molecular processes affected were not known. Our study demonstrates a link between the TCA cycle and a specific cell cycle transition in the one-cell stage embryo.The developmental program of any organism must be precisely executed. In Caenorhabditis elegans embryos, immediately after fertilization, two pronuclei form at opposite poles of the embryo: one containing the maternal chromosomes and the other containing the paternal ones (1, 2). These pronuclei then move toward each other, and at the same time centrosomes separate and begin to assemble a spindle. After pronuclear meeting, the cell enters its first mitosis, resulting in nuclear envelope breakdown, chromatin condensation, and the subsequent alignment of chromosomes on the metaphase plate, followed by chromosome segregation (2). Entry into mitosis depends on the mitotic cyclin B–cyclin-dependent kinase 1 (Cdk1) complex. The activity of this complex is regulated by both cyclin B levels and regulatory phosphorylation of Cdk1. In particular, Cdk1 activity is inhibited by Wee1 phosphorylation, which is removed at the onset of mitosis by the Cdc25 phosphatase (3, 4). Cdk1 activation is also subjected to various checkpoints that inhibit mitotic progression in the presence of intracellular damage (5). However, in organisms that undergo rapid embryonic divisions, including C. elegans, checkpoints are inoperative during the first few cell cycles (6).Although it is clear that cell cycle progression requires energy, the link, if any, between metabolic pathways and progression through mitosis is poorly understood. Genes and proteins involved in various aspects of metabolism (e.g., nucleotide biosynthesis and lipid metabolism) are regulated by the cell cycle machinery, and cells will not commit to a new cell cycle if nutrients are scarce (7). However, to what extent the metabolic state of the cell is sensed by the cell cycle machinery once cells have passed into S phase is not clear (8).We have previously conducted a visual screen in C. elegans embryos for genes that when down-regulated by RNAi lead to an abnormal nuclear morphology (9). Most genes whose inactivation affected early embryonic development did so without arresting cell cycle progression. It was therefore striking when we came across a set of genes, coding for enzymes of the tricarboxylic acid (TCA) cycle, that when down-regulated, led to a one-cell stage arrest with paired nuclei. The TCA cycle, also known as the Krebs cycle, uses the oxidation of acetate (in the form of acetyl CoA) derived from carbohydrates, proteins, or lipids, to generate intermediates (i.e., NADH and FADH₂) that are used by the electron transport chain for ATP production. Intermediates of the TCA cycle are also important for various anabolic pathways, such as fatty acid synthesis, and the synthesis of nucleotides. In this study, we examine the relationship between TCA cycle down-regulation and cell cycle progression in the one-cell C. elegans embryo. Our data suggest that down-regulation of the TCA cycle leads to a G2-like arrest at the one-cell stage embryo by preventing the activation of cyclin B–Cdk1.     

Dsteosynthesis with long volar locking plates for meta- physeal-diaphyseal fractures of the distal radius

Objective：Metaphyseal-diaphyseal fractures of the distal radius are a major treatment dilemma and orthopaedic surgeons have to pay due consideration to restoration of anatomy of distal radius together with rotation of the radial shaft and maintenance of radial bow and interosseous space.We performed this study to evaluate the clinic-radiological outcome of metaphyseal-diaphyseal fractures of the distal radius treated with long volar locking plates.Methods：This prospective study involved 27 patients （22 males and 5 females） with metaphyseal-diaphyseal fracture of the distal radius.Their mean age was （30.12±11.48） years （range 19-52 years） and the follow-up was 26.8 months （range 22-34 months）.All patients underwent open reduction and internal fixation with a long volar locking plate.According to AO/OTA classification,there were 7 type A3,13 type C2 and 7 type C3 fractures.Subjective assessment was done based on the disabilities of the arm,shoulder and hand （DASH） questionnaire.Functional evaluation was done by measuring grip strength and range of motion around the wrist and the radiological determinants included radial angle,radial length,volar angle and ulnar variance.The final assessment was done according to Gartland and Werley scoring system.Results：Postoperative radiological parameters were well maintained throughout the trial,and there was significant improvement in the functional parameters from 6 weeks to final follow-up.The average DASH scores improved from 37.5 at 6 weeks to 4.2 at final follow-up.Final assessment using Gartland and Werley scoring system revealed 66.67%（n=l8） excellent and 33.33% （n=9） good results.There was one case of superficial infection which responded to antibiotics and another carpel tunnel syndrome which was managed conservatively.Conclusion：Volar locking plate fixation for metaphyseal-diaphyseal fractures of distal radius is associated with excellent to good functional outcome,early rehabilitation and minimal complications.     

Design and Development of a Medical Image Databank for Assisting Studies in Radiomics

Journal of Digital Imaging - CompreHensive Digital ArchiVe of Cancer Imaging - Radiation Oncology (CHAVI-RO) is a multi-tier WEB-based medical image databank. It supports archiving de-identified...