A conserved cysteine-based redox mechanism sustains TFEB/HLH-30 activity under persistent stress.

Mammalian TFEB and TFE3, as well as their ortholog in Caenorhabditis elegans HLH-30, play an important role in mediating cellular response to a variety of stress conditions, including nutrient deprivation, oxidative stress, and pathogen infection. In this study, we identify a novel mechanism of TFEB/HLH-30 regulation through a cysteine-mediated redox switch. Under stress conditions, TFEB-C212 undergoes oxidation, allowing the formation of intermolecular disulfide bonds that result in TFEB oligomerization. TFEB oligomers display increased resistance to mTORC1-mediated inactivation and are more stable under prolonged stress conditions. Mutation of the only cysteine residue present in HLH-30 (C284) significantly reduced its activity, resulting in developmental defects and increased pathogen susceptibility in worms. Therefore, cysteine oxidation represents a new type of TFEB post-translational modification that functions as a molecular switch to link changes in redox balance with expression of TFEB/HLH-30 target genes.

Interplay of Postprandial Triglyceride-Rich Lipoprotein Composition and Adipokines in Obese Adolescents.

In the context of the alarming rise of infant obesity and its health implications, the present research aims to uncover disruptions in postprandial lipid metabolism and the composition of triglyceride-rich lipoproteins in obese adolescents. A double-blind, controlled clinical trial in the postprandial phase on 23 adolescents aged 12 to 16 years was carried out. Twelve participants were categorized as obese (BMI > 30 kg/m2 and percentile > 95) and 11 as normal-weight (BMI = 20-25 kg/m2, percentile 5-85). Blood samples were collected after a 12-h overnight fast and postprandially after consumption of a standardized breakfast containing olive oil, tomato, bread, orange juice, and skimmed milk. Obese adolescents exhibited elevated triglyceride concentrations in both fasting and postprandial states and higher TG/apo-B48 ratios, indicating larger postprandial triglyceride-rich lipoprotein (TRL) particle size, which suggests impaired clearance. Obese subjects also exhibited higher n-6 PUFA concentrations, potentially linked to increased TRL hydrolysis and the release of pro-inflammatory adipokines. In contrast, TRL from normal-weight individuals showed higher concentrations of oleic acid and DHA (n-3 PUFA), with possible anti-inflammatory effects. The results indicate an interplay involving postprandial TRL metabolism and adipokines within the context of adolescent obesity, pointing to potential cardiovascular implications in the future.

Heparin versus 0.9% sodium chloride locking for prevention of occlusion in central venous catheters in adults.

BACKGROUND: Intermittent locking of central venous catheters (CVCs) is undertaken to help maintain their patency and performance. There are systematic variations in care: some practitioners use heparin (at different concentrations), whilst others use 0.9% sodium chloride (normal saline). This review looks at the effectiveness and safety of intermittent locking with heparin compared to normal saline, to see if the evidence establishes whether one is better than the other. This is an update of an earlier Cochrane Review. OBJECTIVES: To evaluate the benefits and harms of intermittent locking of CVCs with heparin versus normal saline in adults to prevent occlusion. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 20 October 2021. SELECTION CRITERIA: We included randomised controlled trials in adults ≥ 18 years of age with a CVC that compared intermittent locking with heparin at any concentration versus normal saline. We excluded studies on infants and children from this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were occlusion of CVCs and duration of catheter patency. Our secondary outcomes were CVC-related bloodstream infections and CVC-related colonisation, mortality, haemorrhage, heparin-induced thrombocytopaenia, CVC-related thrombosis, number of additional CVC insertions, abnormality of coagulation profile and allergic reactions to heparin. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified one new RCT with 30 participants for this update. We included a total of 12 RCTs with 2422 participants. Data for meta-analysis were available from all RCTs. We noted differences in methods used by the included studies and variation in heparin concentrations (10 to 5000 IU/mL), time to follow-up (1 to 251.8 days), and the unit of analysis used (participant, catheter, line access). Five studies included ICU (intensive care unit) patients, two studies included oncology patients, and the remaining studies included miscellaneous patients (chronic kidney disease, haemodialysis, home care patients, etc.). Primary outcomes Overall, combined results may show fewer occlusions with heparin compared to normal saline but this is uncertain (risk ratio (RR) 0.70, 95% confidence interval (CI) 0.51 to 0.95; 10 studies; 1672 participants; low-certainty evidence). We pooled studies that used participant or catheter as the unit of analysis. We carried out subgroup analysis by unit of analysis. No clear differences were detected after testing for subgroup differences (P = 0.23). We found no clear evidence of a difference in the duration of catheter patency with heparin compared to normal saline (mean difference (MD) 0.44 days, 95% CI -0.10 to 0.99; 6 studies; 1788 participants; low-certainty evidence). Secondary outcomes We found no clear evidence of a difference in the following outcomes: CVC-related bloodstream infections (RR 0.66, 95% CI 0.08 to 5.80; 3 studies; 1127 participants; very low-certainty evidence); mortality (RR 0.76, 95% CI 0.44 to 1.31; 3 studies; 1100 participants; very low-certainty evidence); haemorrhage (RR 1.54, 95% CI 0.41 to 5.74; 3 studies; 1197 participants; very low-certainty evidence); or heparin-induced thrombocytopaenia (RR 0.21, 95% CI 0.01 to 4.27; 3 studies; 443 participants; very low-certainty evidence). The main reasons for downgrading the certainty of evidence for the primary and secondary outcomes were unclear allocation concealment, suspicion of publication bias, imprecision and inconsistency. AUTHORS' CONCLUSIONS: Given the low-certainty evidence, we are uncertain whether intermittent locking with heparin results in fewer central venous catheter occlusions than intermittent locking with normal saline in adults. Low-certainty evidence suggests that heparin may have little or no effect on catheter patency duration. Although we found no evidence of differences in safety (CVC-related bloodstream infections, mortality, or haemorrhage), the combined studies were not powered to detect rare adverse events such as heparin-induced thrombocytopaenia. Further research conducted over longer periods would reduce the current uncertainties.

Reduction of mRNA export unmasks different tissue sensitivities to low mRNA levels during Caenorhabditis elegans development.

Animal development requires the execution of specific transcriptional programs in different sets of cells to build tissues and functional organs. Transcripts are exported from the nucleus to the cytoplasm where they are translated into proteins that, ultimately, carry out the cellular functions. Here we show that in Caenorhabditis elegans, reduction of mRNA export strongly affects epithelial morphogenesis and germline proliferation while other tissues remain relatively unaffected. Epithelialization and gamete formation demand a large number of transcripts in the cytoplasm for the duration of these processes. In addition, our findings highlight the existence of a regulatory feedback mechanism that activates gene expression in response to low levels of cytoplasmic mRNA. We expand the genetic characterization of nuclear export factor NXF-1 to other members of the mRNA export pathway to model mRNA export and recycling of NXF-1 back to the nucleus. Our model explains how mutations in genes involved in general processes, such as mRNA export, may result in tissue-specific developmental phenotypes.

Disruption of the Caenorhabditis elegans Integrator complex triggers a non-conventional transcriptional mechanism beyond snRNA genes.

Gene expression is generally regulated by recruitment of transcription factors and RNA polymerase II (RNAP II) to specific sequences in the gene promoter region. The Integrator complex mediates processing of small nuclear RNAs (snRNAs) as well as the initiation and release of paused RNAP II at specific genes in response to growth factors. Here we show that in C. elegans, disruption of the Integrator complex leads to transcription of genes located downstream of the snRNA loci via a non-conventional transcription mechanism based on the lack of processing of the snRNAs. RNAP II read-through generates long chimeric RNAs containing snRNA, the intergenic region and the mature mRNA of the downstream gene located in sense. These chimeric sn-mRNAs remain as untranslated long non-coding RNAs, in the case of U1- and U2-derived sn-mRNAs, but can be translated to proteins in the case of SL-derived sn-mRNAs. The transcriptional effect caused by disruption of the Integrator complex is not restricted to genes located downstream of the snRNA loci but also affects key regulators of signal transduction such as kinases and phosphatases. Our findings highlight that these transcriptional alterations may be behind the correlation between mutations in the Integrator complex and tumor transformation.

Maple syrup urine disease: Characteristics of diagnosis and treatment in 45 patients in Chile.

Maple urine syrup disease (MSUD) is an autosomal recessive disorder characterized by deficient activity of the branched-chain alpha ketoacid dehydrogenase (BCKAD) enzymatic complex due to biallelic variants in the alpha (BCKDHA) or beta (BCKDHB) subunits or the acyltransferase component (DBT). Treatment consists in leucine (LEU), isoleucine (ILE), and valine (VAL) (branched-chain amino acids) dietary restriction and strict metabolic control. to determine the characteristics of the Chilean cohort with MSUD currently in follow-up at Instituto de Nutrición y Tecnología de los Alimentos, during the 1990-2017 period Retrospective analytical study in 45 MSUD cases. Measured: biochemical parameters (LEU, ILE, and VAL), anthropometric evaluation, and neurocognitive development. In 18 cases undergoing genetic study were analyzed according to the gene and protein location, number of affected alleles, and type of posttranslational modification affected. Then, 45 patients with MSUD diagnosis were identified during the period: 37 were alive at the time of the study. Average diagnosis age was 71 ± 231 days. Average serum diagnosis LEU concentrations: 1.463 ± 854.1 µmol/L, VAL 550 ± 598 µmol/L and ILE 454 ± 458 µmol/L. BCKDHB variants explain 89% cases, while BCKDHA and DBT variants explain 5.5% of cases each. Variants p.Thr338Ile in BCKDHA, p.Pro240Thr and p.Ser342Asn in BCKDHB have not been previously reported in literature. Average serum follow-up LEU concentrations were 252.7 ± 16.9 µmol/L in the <5 years group and 299 ± 123.2 µmol/L in ≥5 years. Most cases presented some degree of developmental delay. Early diagnosis and treatment is essential to improve the long-term prognosis. Frequent blood LEU measurements are required to optimize metabolic control and to establish relationships between different aspects analyzed.

Cooking a Research Project: New Trends in the Kitchen and in Scientific Policies.

The culture of chefs from the world's best restaurants is substituted by new trends paradigmatically epitomized by the TV program Masterchef. The authors feel that a similar transformation affects modern research. Recent scientific policies constrict the design of research grants with the aim of short-term maximization of the monetary value generated by the researcher.

Case report: Maternal tyrosinemia type 1a under NTBC treatment with tyrosine- and phenylalanine restricted diet in Chile.

We report the case of a 17-year-old girl with Tyrosinemia type 1a who carried a planned pregnancy to term while being under 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, nitisinone) treatment and a tyrosine- and phenylalanine-restricted diet. She was on treatment since 2 months of age with poor metabolic control prior to her pregnancy (tyrosine 838 ± 106 umol/L). NTBC and a low tyrosine and phenylalanine diet were continued during her pregnancy. She unfortunately suffered from urinary tract infection and anemia during her pregnancy, with median plasma tyrosine and phenylalanine levels of 613 ± 106 umol/L (200-400 umol/L) and 40.2 ± 8 umol/L (35-90 umol/L), respectively. After 40 weeks of gestation, the patient gave birth to a healthy boy, with no adverse effects related to the use of NTBC. The newborn presented with a transitory elevation of plasma tyrosine levels and normal phenylalanine, methionine, and succinylacetone levels. By 12 months of age, the child was determined to have normal psychomotor development. At 20 months old, he was diagnosed with a mild developmental delay; however, global cognitive evaluation with the Wechsler Intelligence Scale for Children (WISC) test at 5 years old showed normal performance. Here, we discuss one of the few reported cases of nitisinone treatment during pregnancy and demonstrate a lack of teratogenicity and long-term cognitive disabilities.

GENIUS: web server to predict local gene networks and key genes for biological functions.

Summary: GENIUS is a user-friendly web server that uses a novel machine learning algorithm to infer functional gene networks focused on specific genes and experimental conditions that are relevant to biological functions of interest. These functions may have different levels of complexity, from specific biological processes to complex traits that involve several interacting processes. GENIUS also enriches the network with new genes related to the biological function of interest, with accuracies comparable to highly discriminative Support Vector Machine methods. Availability and Implementation: GENIUS currently supports eight model organisms and is freely available for public use at http://networks.bio.puc.cl/genius . Contact: genius.psbl@gmail.com. Supplementary information: Supplementary data are available at Bioinformatics online.

Cell-Penetrating Peptides Containing Fluorescent d-Cysteines.

A series of fluorescent d-cysteines (Cys) has been synthesized and their optical properties were studied. The key synthetic step is the highly diastereoselective 1,4-conjugate addition of aryl thiols to a chiral bicyclic dehydroalanine recently developed by our group. This reaction is fast at room temperature and proceeds with total chemo- and stereoselectivity. The Michael adducts were easily transformed into the corresponding amino acids to study their optical properties and, in some selected cases, into the corresponding N-Fmoc-d-cysteine derivatives to be used in solid-phase peptide synthesis (SPPS). To further demonstrate the utility of these non-natural Cys-derived fluorescent amino acids, the coumaryl and dansyl derivatives were incorporated into cell-penetrating peptide sequences through standard SPPS and their optical properties were studied in different cell lines. The internalization of these fluorescent peptides was monitored by fluorescence microscopy.

Heparin versus 0.9% sodium chloride locking for prevention of occlusion in central venous catheters in adults.

BACKGROUND: Intermittent locking of central venous catheters (CVCs) is undertaken to help maintain their patency. There are systematic variations in care: some practitioners use heparin (at different concentrations), whilst others use 0.9% NaCl (normal saline). This review looks at the effectiveness and safety of intermittent locking with heparin compared to 0.9% NaCl to see if the evidence establishes whether one is better than the other. This work is an update of a review first published in 2014. OBJECTIVES: To assess the effectiveness and safety of intermittent locking of CVCs with heparin versus normal saline (NS) in adults to prevent occlusion. SEARCH METHODS: The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (last searched 11 June 2018) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 5). Searches were also carried out in MEDLINE, Embase, CINAHL, and clinical trials databases (11 June 2018). SELECTION CRITERIA: We included randomised controlled trials in adults ≥ 18 years of age with a CVC that compared intermittent locking with heparin at any concentration versus NS. We applied no restriction on language. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality, and extracted data. We contacted trial authors to retrieve additional information, when necessary. We carried out statistical analysis using Review Manager 5 and assessed the overall quality of the evidence supporting assessed outcomes using GRADE. We carried out prespecified subgroup analysis. MAIN RESULTS: We identified five new studies for this update (six prior studies were included in the original review), bringing the number of eligible studies to 11, with a total of 2392 participants. We noted differences in methods used by the included studies and variation in heparin concentrations (10 to 5000 IU/mL), time to follow-up (1 to 251.8 days), and the unit of analysis used (participant, catheter, line access).Combined results from these studies showed fewer occlusions with heparin than with NS (risk ratio (RR) 0.70, 95% confidence interval (CI) 0.51 to 0.95; P = 0.02; 1672 participants; 1025 catheters from 10 studies; I² = 14%) and provided very low-quality evidence.We carried out subgroup analysis by unit of analysis (testing for subgroup differences (P = 0.23; I² = 30.3%). When the unit of analysis was the participant, results show no clear differences in all occlusions between heparin and NS (RR 0.79, 95% CI 0.58 to 1.08; P = 0.15; 1672 participants; seven studies). Subgroup analysis using the catheter as the unit of analysis shows fewer occlusions with heparin use (RR 0.53, 95% CI 0.29 to 0.95; P = 0.03; 1025 catheters; three studies). When the unit of analysis was line access, results show no clear differences in occlusions between heparin and NS (RR 1.08, 95% CI 0.84 to 1.40; 770 line accesses; one study).We found no clear differences in the duration of catheter patency (mean difference (MD) 0.44 days, 95% CI -0.10 to 0.99; P = 0.11; 1036 participants; 752 catheters; six studies; low-quality evidence).We found no clear evidence of a difference in the following: CVC-related sepsis (RR 0.74, 95% CI 0.03 to 19.54; P = 0.86; 1097 participants; two studies; low-quality evidence); mortality (RR 0.76, 95% CI 0.44 to 1.31; P = 0.33; 1100 participants; three studies; low-quality evidence); haemorrhage at any site (RR 1.32, 95% CI 0.57 to 3.07; P = 0.52; 1245 participants; four studies; moderate-quality evidence); or heparin-induced thrombocytopaenia (RR 0.21, 95% CI 0.01 to 4.27; P = 0.31; 443 participants; three studies; low-quality evidence).The main reasons for downgrading the quality of evidence were unclear allocation concealment, imprecision, and suspicion of publication bias. AUTHORS' CONCLUSIONS: Given the very low quality of the evidence, we are uncertain whether intermittent locking with heparin results in fewer occlusions than intermittent locking with NS. Low-quality evidence suggests that heparin may have little or no effect on catheter patency. Although we found no evidence of differences in safety (sepsis, mortality, or haemorrhage), the combined trials are not powered to detect rare adverse events such as heparin-induced thrombocytopaenia.

Control of developmental networks by Rac/Rho small GTPases: How cytoskeletal changes during embryogenesis are orchestrated.

Small GTPases in the Rho family act as major nodes with functions beyond cytoskeletal rearrangements shaping the Caenorhabditis elegans embryo during development. These small GTPases are key signal transducers that integrate diverse developmental signals to produce a coordinated response in the cell. In C. elegans, the best studied members of these highly conserved Rho family small GTPases, RHO-1/RhoA, CED-10/Rac, and CDC-42, are crucial in several cellular processes dealing with cytoskeletal reorganization. In this review, we update the functions described for the Rho family small GTPases in spindle orientation and cell division, engulfment, and cellular movements during C. elegans embryogenesis, focusing on the Rho subfamily Rac. Please also see the video abstract here.

Coal emissions adverse human health effects associated with ultrafine/nano-particles role and resultant engineering controls.

There are multiple elements which enable coal geochemistry: (1) boiler and pollution control system design parameters, (2) temperature of flue gas at collection point, (3) feed coal and also other fuels like petroleum coke, tires and biomass geochemistry and (4) fuel feed particle size distribution homogeneity distribution, maintenance of pulverisers, etc. Even though there is a large number of hazardous element pollutants in the coal-processing industry, investigations on micrometer and nanometer-sized particles including their aqueous colloids formation reactions and their behaviour entering the environment are relatively few in numbers. X-ray diffraction (XRD), High Resolution-Transmission Electron microscopy (HR-TEM)/ (Energy Dispersive Spectroscopy) EDS/ (selected-area diffraction pattern) SAED, Field Emission-Scanning Electron Microscopy (FE-SEM)/EDS and granulometric distribution analysis were used as an integrated characterization techniques tool box to determine both geochemistry and nanomineralogy for coal fly ashes (CFAs) from Brazil´s largest coal power plant. Ultrafine/nano-particles size distribution from coal combustion emissions was estimated during the tests. In addition the iron and silicon content was determined as 54.6% of the total 390 different particles observed by electron bean, results aimed that these two particles represent major minerals in the environment particles normally. These data may help in future investigations to asses human health actions related with nano-particles.

Certolizumab pegol (CDP870) for rheumatoid arthritis in adults.

BACKGROUND: Tumour necrosis factor (TNF)-alpha inhibitors are beneficial for the treatment of rheumatoid arthritis (RA) for reducing the risk of joint damage, improving physical function and improving the quality of life. This review is an update of the 2014 Cochrane Review of the treatment of RA with certolizumab pegol. OBJECTIVES: To assess the clinical benefits and harms of certolizumab pegol (CZP) in people with RA who have not responded well to conventional disease-modifying anti-rheumatic drugs (DMARDs). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL: Cochrane Library 2016, Issue 9), MEDLINE, Embase, Web of Knowledge, reference lists of articles, clinicaltrials.gov and ICTRP of WHO. The searches were updated from 2014 (date of the last search for the previous version) to 26 September 2016. SELECTION CRITERIA: Randomised controlled trials that compared certolizumab pegol with any other agent, including placebo or methotrexate (MTX), in adults with active RA, regardless of current or prior treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs), such as MTX. DATA COLLECTION AND ANALYSIS: Two review authors independently checked search results, extracted data and assessed trial quality. We resolved disagreements by discussion or referral to a third review author. MAIN RESULTS: We included 14 trials in this update, three more than previously. Twelve trials (5422 participants) included measures of benefit. We pooled 11 of them, two more than previously. Thirteen trials included information on harms, (5273 participants). The duration of follow-up varied from 12 to 52 weeks and the range of doses of certolizumab pegol varied from 50 to 400 mg given subcutaneously. In Phase III trials, the comparator was placebo plus MTX in seven trials and placebo in five. In the two Phase II trials the comparator was only placebo.The approved dose of certolizumab pegol, 200 mg every other week, produced clinically important improvements at 24 weeks for the following outcomes:- American College of Rheumatology (ACR) 50% improvement (pain, function and other symptoms of RA): 25% absolute improvement (95% confidence interval (CI) 20% to 33%); number need to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 5); risk ratio (RR) 3.80 (95% CI 2.42 to 5.95), 1445 participants, 5 studies.- The Health Assessment Questionnaire (HAQ): -12% absolute improvement (95% CI -9% to -14%); NNTB of 8 (95% CI 7 to 11); mean difference (MD) - 0.35 (95% CI -0.43 to -0.26; 1268 participants, 4 studies) (scale 0 to 3; lower scores mean better function).- Proportion of participants achieving remission (Disease Activity Score (DAS) < 2.6) absolute improvement 10% (95% CI 8% to 16%); NNTB of 8 (95% CI 6 to 12); risk ratio (RR) 2.94 (95% CI 1.64 to 5.28), 2420 participants, six studies.- Radiological changes: erosion score (ES) absolute improvement -0.29% (95% CI -0.42% to -0.17%); NNTB of 6 (95% CI 4 to 10); MD -0.67 (95% CI -0.96 to -0.38); 714 participants, two studies (scale 0 to 230), but not a clinically important difference.-Serious adverse events (SAEs) were statistically but not clinically significantly more frequent for certolizumab pegol (200 mg every other week) with an absolute rate difference of 3% (95% CI 1% to 4%); number needed to treat for an additional harmful outcome (NNTH) of 33 (95% CI 25 to 100); Peto odds ratio (OR) 1.47 (95% CI 1.13 to 1.91); 3927 participants, nine studies.There was a clinically significant increase in all withdrawals in the placebo groups (for all doses and at all follow-ups) with an absolute rate difference of -29% (95% CI -16% to -42%), NNTH of 3 (95% CI 2 to 6), RR 0.47 (95% CI 0.39 to 0.56); and there was a clinically significant increase in withdrawals due to adverse events in the certolizumab groups (for all doses and at all follow-ups) with an absolute rate difference of 2% (95% CI 0% to 3%); NNTH of 58 (95% CI 28 to 329); Peto OR 1.45 (95% CI 1.09 to 1.94) 5236 participants Twelve studies.We judged the quality of evidence to be high for ACR50, DAS remission, SAEs and withdrawals due to adverse events, and moderate for HAQ and radiological changes, due to concerns about attrition bias. For all withdrawals we judged the quality of evidence to be moderate, due to inconsistency. AUTHORS' CONCLUSIONS: The results and conclusions did not change from the previous review. There is a moderate to high certainty of evidence from randomised controlled trials that certolizumab pegol, alone or combined with methotrexate, is beneficial in the treatment of RA for improved ACR50 and health-related quality of life, an increased chance of remission of RA, and reduced joint damage as seen on x-ray. Fewer people stopped taking their treatment, but most of these who did stopped due to serious adverse events. Adverse events were more frequent with active treatment. We found a clinically but not statistically significant risk of serious adverse events.

The embryonic cell lineage of Caenorhabditis elegans: A modern hieroglyph: The best way to acquire knowledge in Developmental Biology is to learn how this knowledge was derived.

Nowadays, in the Internet databases era, certain knowledge is being progressively lost. This knowledge, which we feel is essential and should be acquired through education, is the understanding of how the pioneer researchers faced major questions in their field and made their discoveries.

Multiple functions of the noncanonical Wnt pathway.

Thirty years after the identification of WNTs, understanding of their signal transduction pathways continues to expand. Here, we review recent advances in characterizing the Wnt-dependent signaling pathways in Caenorhabditis elegans linking polar signals to rearrangements of the cytoskeleton in different developmental processes, such as proper mitotic spindle orientation, cell migration, and engulfment of apoptotic corpses. In addition to the well-described transcriptional outputs of the canonical and noncanonical Wnt pathways, new branches regulating nontranscriptional outputs that control RAC (Ras related GTPase) activity are also discussed. These findings suggest that Wnt signaling is a master regulator not only of development, but also of cell polarization.

Oxygen therapy for acute myocardial infarction.

BACKGROUND: Oxygen (O2) is widely used in people with acute myocardial infarction (AMI). Previous systematic reviews concluded that there was insufficient evidence to know whether oxygen reduced, increased or had no effect on heart ischaemia or infarct size. Our first Cochrane review in 2010 also concluded there was insufficient evidence to know whether oxygen should be used. Since 2010, the lack of evidence to support this widely used intervention has attracted considerable attention, prompting further trials of oxygen therapy in myocardial infarction patients. It is thus important to update this Cochrane review. OBJECTIVES: To assess the effects of routine use of inhaled oxygen for acute myocardial infarction (AMI). SEARCH METHODS: We searched the following bibliographic databases on 6 June 2015: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE (OVID), Embase (OVID), CINAHL (EBSCO) and Web of Science (Thomson Reuters). LILACS (Latin American and Caribbean Health Sciences Literature) was last searched in September 2016. We also contacted experts to identify eligible studies. We applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials in people with suspected or proven AMI (ST-segment elevation myocardial infarction (STEMI) or non-STEMI) within 24 hours after onset, in which the intervention was inhaled oxygen (at normal pressure) compared to air, regardless of co-therapies provided to participants in both arms of the trial. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the titles and abstracts of identified studies to see if they met the inclusion criteria and independently undertook the data extraction. We assessed the quality of studies and the risk of bias according to guidance in the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was death. The measure of effect used was the risk ratio (RR) with a 95% confidence interval (CI). We used the GRADE approach to evaluate the quality of the evidence and the GRADE profiler (GRADEpro) to import data from Review Manager 5 and create 'Summary of findings' tables. MAIN RESULTS: The updated search yielded one new trial, for a total of five included studies involving 1173 participants, 32 of whom died. The pooled risk ratio (RR) of all-cause mortality in the intention-to-treat analysis was 0.99 (95% CI 0.50 to 1.95; 4 studies, N = 1123; I2 = 46%; quality of evidence: very low) and 1.02 (95% CI 0.52 to 1.98; 4 studies, N = 871; I2 = 49%; quality of evidence: very low) when only analysing participants with confirmed AMI. One trial measured pain directly, and two others measured it by opiate usage. The trial showed no effect, with a pooled RR of 0.97 for the use of opiates (95% CI 0.78 to 1.20; 2 studies, N = 250). The result on mortality and pain are inconclusive. There is no clear effect for oxygen on infarct size (the evidence is inconsistent and low quality). AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials to support the routine use of inhaled oxygen in people with AMI, and we cannot rule out a harmful effect. Given the uncertainty surrounding the effect of oxygen therapy on all-cause mortality and on other outcomes critical for clinical decision, well-conducted, high quality randomised controlled trials are urgently required to inform guidelines in order to give definitive recommendations about the routine use of oxygen in AMI.

[What should the paediatrician know about hyperphenylalaninaemia?]. / ¿Qué debe saber el pediatra de las hiperfenilalaninemias?

Hyperphenylalaninaemias are defined by a blood phenylalanine over 2mg/dl. The main cause is due to a mutation in the gene that codes the phenylalanine hydroxylase that catalyses the reaction that converts phenylalanine into tyrosine. The hyperphenylalaninaemias are classified into benign or mild hyperphenylalaninaemias, or mild, moderate or classic phenylketonurias. Due to its delayed detection outside the neonatal period it causes severe mental retardation. Its detection along with congenital hypothyroidism has been part of the National Neonatal Screening Program since 1992 in Chile. This article aims to answer the most common questions asked by the paediatrician when faced with a patient with hyperphenylalaninaemias.

Colchicine for pericarditis.

BACKGROUND: Pericarditis is the inflammation of the pericardium, the membranous sac surrounding the heart. Recurrent pericarditis is the most common complication of acute pericarditis, causing severe and disabling chest pains. Recurrent pericarditis affects one in three patients with acute pericarditis within the first 18 months. Colchicine has been suggested to be beneficial in preventing recurrent pericarditis. OBJECTIVES: To review all randomised controlled trials (RCTs) that assess the effects of colchicine alone or combined, compared to any other intervention to prevent further recurrences of pericarditis, in people with acute or recurrent pericarditis. SEARCH METHODS: We searched the following bibliographic databases on 4 August 2014: Cochrane Central Register of Controlled Trials (CENTRAL, Issue 7 of 12, 2014 on The Cochrane Library), MEDLINE (OVID, 1946 to July week 4, 2014), EMBASE (OVID, 1947 to 2014 week 31), and the Conference Proceedings Citation Index - Science on Web of Science (Thomson Reuters) 1990 to 1 Aug 2014. We did not apply any language or time restrictions. SELECTION CRITERIA: RCTs of people with acute or recurrent pericarditis who are receiving colchicine compared to any other treatment, in order to prevent recurrences. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias. The first primary outcome was the time to recurrence, measured by calculating the hazard ratios (HRs). The second primary outcome was the adverse effects of colchicine. Secondary outcomes were the rate of recurrences at 6, 12 and 18 months, and symptom relief. MAIN RESULTS: We included four RCTs, involving 564 participants in this review. We compared the effects of colchicine in addition to a non-steroidal anti-inflammatory drug (NSAID) such as ibuprofen, aspirin or indomethacin to the effects of the NSAID alone. Two comparable trials studied the effects of colchicine in 204 participants with recurrent pericarditis and two trials studied 360 people with acute pericarditis. All trials had a moderate quality for the primary outcomes. We identified two on-going trials; one of these trials examines acute pericarditis and the other assesses recurrent pericarditis.There was moderate quality evidence that colchicine reduces episodes of pericarditis in people with recurrent pericarditis over 18 months follow-up (HR 0.37; 95% confidence interval (CI) 0.24 to 0.58). It is expected that at 18 months, the number needed to treat (NNT) is 4. In people with acute pericarditis, there was moderate quality evidence that colchicine reduces recurrence (HR 0.40; 95% CI 0.27 to 0.61) at 18 months follow-up. Colchicine led to a greater chance of symptom relief at 72 hours (risk ratio (RR) 1.4; 95% CI 1.26 to 1.56; low quality evidence). Adverse effects were mainly gastrointestinal and included abdominal pain and diarrhoea. The pooled RR for adverse events was 1.26 (95% CI 0.75 to 2.12). While the number of people experiencing adverse effects was higher in the colchicine than the control groups (9% versus 7%), the quality of evidence was low owing to imprecision, and there was no statistically significant difference between the treatment groups (P = 0.42). There was moderate quality evidence that treatment with colchicine led to more people stopping treatment due to adverse events (RR 1.87; 95% CI 1.02 to 3.41). AUTHORS' CONCLUSIONS: Colchicine, as adjunctive therapy to NSAIDs, is effective in reducing the number of pericarditis recurrences in patients with recurrent pericarditis or acute pericarditis. However, evidence is based on a limited number of small trials. Patients with multiple resistant recurrences were not represented in any published or on-going trials, and it is these patients that are in the most need for treatment.

Heparin versus 0.9% sodium chloride intermittent flushing for prevention of occlusion in central venous catheters in adults.

BACKGROUND: Heparin intermittent flushing is a standard practice in the maintenance of patency in central venous catheters. However, we could find no systematic review examining its effectiveness and safety. OBJECTIVES: To assess the effectiveness of intermittent flushing with heparin versus 0.9% sodium chloride (normal saline) solution in adults with central venous catheters in terms of prevention of occlusion and overall benefits versus harms. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched December 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 11). Searches were also carried out in MEDLINE, EMBASE, CINAHL and clinical trials databases (December 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) in adults 18 years of age and older with a central venous catheter (CVC) in which intermittent flushing with heparin (any dose with or without other drugs) was compared with 0.9% normal saline were included. No restriction on language was applied. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality and extracted data. Trial authors were contacted to retrieve additional information, when necessary. MAIN RESULTS: Six eligible studies with a total of 1433 participants were included. The heparin concentrations used in these studies were very different (10-5000 IU/mL), and follow-up varied from 20 days to 180 days. The overall risk of bias in the studies was low. The quality of the evidence ranged from very low to moderate for the main outcomes (occlusion of CVC, duration of catheter patency, CVC-related sepsis, mortality and haemorrhage at any site).Combined findings from three trials in which the unit of analysis was the catheter suggest that heparin was associated with reduced CVC occlusion rates (risk ratio (RR) 0.53, 95% confidence interval (CI) 0.29 to 0.94). However, no clear evidence of a similar effect was found when the results of two studies in which the unit of analysis was the participant were combined (RR 0.21, 95% CI 0.03 to 1.70), nor when findings were derived from one study, which considered total line accesses (RR 1.08, 95% CI 0.84 to 1.40). Furthermore, results for other estimated effects were found to be imprecise and compatible with benefit and harm: catheter duration in days (mean difference (MD) 0.41, 95% CI -1.29 to 2.12), CVC-related thrombosis (RR 1.22, 95% CI 0.74 to 1.99), CVC-related sepsis (RR 1.02, 95% CI 0.34 to 3.03), mortality (RR 0.77, 95% CI 0.45 to 1.32) and haemorrhage at any site (RR 1.37, 95% CI 0.49 to 3.85). AUTHORS' CONCLUSIONS: We found no conclusive evidence of important differences when heparin intermittent flushing was compared with 0.9% normal saline flushing for central venous catheter maintenance in terms of efficacy or safety. As heparin is more expensive than normal saline, our findings challenge its continued use in CVC flushing outside the context of clinical trials.