How bacteria control the CRISPR-Cas arsenal.
Curr Opin Microbiol. 2017 Nov 20;42:87-95
Authors: Leon LM, Mendoza SD, Bondy-Denomy J
CRISPR-Cas systems are adaptive immune systems that protect their hosts from predation by bacteriophages (phages) and parasitism by other mobile genetic elements (MGEs). Given the potent nuclease activity of CRISPR effectors, these enzymes must be carefully regulated to minimize toxicity and maximize anti-phage immunity. While attention has been given to the transcriptional regulation of these systems (reviewed in ), less consideration has been given to the crucial post-translational processes that govern enzyme activation and inactivation. Here, we review recent findings that describe how Cas nucleases are controlled in diverse systems to provide a robust anti-viral response while limiting auto-immunity. We also draw comparisons to a distinct bacterial immune system, restriction-modification.
PMID: 29169146 [PubMed - as supplied by publisher]
The role of seed size, phenology, oogenesis and host distribution in the specificity and genetic structure in seed weevils (Curculio spp.) in mixed forests.
Integr Zool. 2017 Nov 23;:
Authors: Arias-LeClaire H, Bonal R, García-López D, Espelta JM
Synchrony between seed growth and oogenesis are suggested to largely shape trophic breadth of seed-feeding insects and ultimately contribute to their co-existence by means of resource partitioning or in the time when infestation occurs. Here we investigated: i) the role of seed phenology and sexual maturation of females in the host specificity of seed-feeding weevils (Curculio spp) predating in hazel and oak mixed forests and ii) the consequences that trophic breadth and host distribution have in the genetic structure of the weevil populations. DNA analyses were used to establish unequivocally host specificity and to determine the population genetic structure. We identified four species with different specificity, namely C. nucum females matured earlier and infested a unique host (hazelnuts) while three species (C. venosus, C. glandium, C. elephas) predated upon the acorns of the two oaks (Q. ilex and Q. humilis). The high specificity of C. nucum coupled with a more discontinuous distribution of hazel trees resulted in a significant genetic structure among sites. Also, the presence of an excess of local rare haplotypes indicated that C. nucum populations went through genetic expansion after recent bottlenecks. Conversely, these effects were not observed in the more generalist C. glandium predating upon oaks. Ultimately, co-existence of weevil species in this multi-host-parasite system is influenced by both resource and time partitioning. To what extent the restriction in gene flow among C. nucum populations may have negative consequences for their persistence in a time of increasing disturbances (e.g. drought in Mediterranean areas) deserves further research. This article is protected by copyright. All rights reserved.
PMID: 29168606 [PubMed - as supplied by publisher]
Molecular & genetic characteristics of Mycobacterium tuberculosis strains circulating in the southern part of West Siberia.
Indian J Med Res. 2017 Jul;146(1):49-55
Authors: Pasechnik O, Dymova MA, Stasenko VL, Blokh AI, Tatarintseva MP, Kolesnikova LP, Filipenko ML
BACKGROUND & OBJECTIVES: A complicated epidemiological situation characterized by significantly high tuberculosis (TB) morbidity is observed in West Siberia. This study was aimed to investigate the genetic characteristics of Mycobacterium tuberculosis circulating in the southern part of West Siberia (in the Omsk region).
METHODS: From March 2013 to January 2015, 100 isolates of M. tuberculosis were obtained from patients with pulmonary TB living in the Omsk region. Drug susceptibility testing was performed on Lowenstein-Jensen medium (absolute concentration method). Genetic typing of isolates was carried out by variable number tandem repeats of mycobacterial interspersed repetitive units (MIRU-VNTR) typing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The genetic types and characteristics of cluster strains were determined using 15 MIRU-VNTR loci.
RESULTS: Thirty six VNTR types were found. Twenty six (26.0%) isolates had a unique profile, and the remaining 74 were grouped in 10 clusters containing from 2 to 23 isolates. The Beijing genotype was found in 72 isolates, 61 (85.0%) of which were part of five clusters that included two large clusters containing 23 isolates. Other genetic families, such as Latin-American Mediterranean (LAM, 11.0%), S family (2.0%) and Haarlem (4.0%), were also detected. The genetic family of 11 isolates could not be determined. Six different VNTR profiles were found in these non-classified isolates. Only 16 per cent of isolates were sensitive to anti-TB drugs. The katG315 (94.8%) and rpoB531 (92.2%) mutations were identified in 77 multidrug-resistant M. tuberculosis isolates.
INTERPRETATION & CONCLUSIONS: This study showed that the M. tuberculosis population in the Omsk region was heterogeneous. The Beijing genotype predominated and was actively spreading. The findings obtained point to the need for the implementation of more effective preventive measures to stop the spread of drug-resistant M. tuberculosis strains.
PMID: 29168460 [PubMed - in process]
Lipocalin 2 (Lcn2) interferes with iron uptake by Brucella abortus and dampens immunoregulation during infection of RAW 264.7 macrophages.
Cell Microbiol. 2017 Nov 22;:
Authors: Hop HT, Arayan LT, Huy TXN, Reyes AWB, Baek EJ, Min W, Lee HJ, Rhee MH, Watanabe K, Chang HH, Kim S
Lipocalin 2 (Lcn2) is an important innate immunity component against bacterial pathogens. In this study, we report that Lcn2 is induced by Brucella (B.) abortus infection and significantly contributes to the restriction of intracellular survival of Brucella in macrophages. We found that Lcn2 prevented iron uptake by B. abortus through two distinct mechanisms. First, Lcn2 is secreted to capture bacterial siderophore(s) and abrogate iron import by Brucella. Second, Lcn2 decreases the intracellular iron levels during Brucella infection, which probably deprives the invading Brucella of the iron source needed for growth. Suppression of Lcn2 signaling resulted in a marked induction of anti-inflammatory cytokine, interleukin 10 (IL-10) which was shown to play a major role in Lcn2-induced antibrucella immunity. Similarly, IL-6 was also found to be increased when Lcn2 signaling is abrogated; however, this induction was thought to be an alternative pathway that rescues the cell from infection when the effective Lnc2 pathway is repressed. Furthermore, Lcn2 deficiency also caused a marked decrease in brucellacidal effectors, such as reactive oxygen species (ROS) and nitric oxide (NO), but not the phagolysosome fusion. Taken together, our results indicate that Lcn2 is required for the efficient restriction of intracellular B. abortus growth that is through limiting iron acquisition and shifting cells to pro-inflammatory brucellacidal activity in murine macrophages.
PMID: 29168343 [PubMed - as supplied by publisher]
Revision of Podocotyloides Yamaguti, 1934 (Digenea: Opecoelidae), resurrection of Pedunculacetabulum Yamaguti, 1934 and the naming of a cryptic opecoelid species.
Syst Parasitol. 2017 Nov 22;:
Authors: Martin SB, Cutmore SC, Cribb TH
Despite morphological and ecological inconsistencies among species, all plagioporine opecoelids with a pedunculate ventral sucker are currently considered to belong in the genus Podocotyloides Yamaguti, 1934. We revise the genus based on combined morphological and phylogenetic analyses of novel material collected from haemulid fishes in Queensland waters that we interpret to represent species congeneric with the type-species, Pod. petalophallus Yamaguti, 1934, also known from a haemulid, off Japan. Our phylogenetic analysis demonstrates polyphyly of Podocotyloides; prompts us to resurrect Pedunculacetabulum Yamaguti, 1934; and suggests that Pod. brevis Andres & Overstreet, 2013, from a deep-sea congrid in the Caribbean, and Pod. parupenei (Manter, 1963) Pritchard, 1966 and Pod. stenometra Pritchard, 1966, from mullids and chaetodontids, respectively, on the Great Barrier Reef, may each represent a distinct genus awaiting recognition. Our revised concept of Podocotyloides requires a pedunculate ventral sucker, but also a uterine sphincter prior to the genital atrium, a petalloid cirrus appendage, restriction of the vitelline follicles to the hindbody, and for the excretory vesicle to reach to the level of the ventral sucker. Of about 20 nominal species, we recognise just three in Podocotyloides (sensu stricto): Pod. petalophallus, Pod. gracilis (Yamaguti, 1952) Pritchard, 1966 and Pod. magnatestes Aleshkina & Gaevskaya, 1985. We provide new records for Pod. gracilis, and propose two new species of Podocotyloides, Pod. australis n. sp. and Pod. brevivesiculatus n. sp., and one new Pedunculacetabulum species, Ped. inopinipugnus n. sp., all from haemulids. Podocotyloides australis is morphologically indistinguishable from Pod. gracilis, and exploits the same definitive host, but is genetically and biogeographically distinct. It is thus a cryptic species, the first such opecoelid to be formally named.
PMID: 29168149 [PubMed - as supplied by publisher]
TP53 Gene Polymorphisms and Occupational Skin Cancer Risks for Workers of Glass Fiber Manufacture.
Iran J Public Health. 2017 Nov;46(11):1495-1501
Authors: Mukhammadiyeva GF, Karimov DO, Bakirov AB, Karimova LK
Background: Determining the role of genetic markers in individual sensitivity to chemical exposures raises a possibility of risk assessment of occupational diseases and their prevention. This paper focuses on the results of the identification of molecular-genetic markers associated with occupational skin cancer susceptibility. This study aimed to explore an association between polymorphisms of the TP53 tumor suppressor gene and a risk of developing occupational skin neoplasms.
Methods: This case-control study was conducted on 71 workers with occupational skin neoplasms, 99 healthy workers, and 100 healthy population-based controls in Bashkortostan Republic, Russia in 2015. Genotyping of TP53 polymorphisms (rs1042522, rs1625895, and rs17878362) was performed by restriction fragment length polymorphism analysis of genomic DNA extracted from peripheral blood. Odds ratios and 95% confidence intervals were calculated to measure the strength of the association.
Results: Subjects carrying allele C of rs1042522 were associated with an increased risk of occupational skin neoplasms [P=0.027, odds ratio (OR)=1.97, 95% confidence intervals (CI) 1.08-3.63]. An increased risk was also associated with allele 16bp of rs17878362 (P=0.010, OR=3.32, 95 % CI=1.31-8.78) and allele A of rs1625895 (P=0.003, OR = 5.45, 95 % CI = 1.72-19.15).
Conclusion: The polymorphic variants rs1042522, rs1625895 and rs17878362 of the TP53 gene are related to increased risks of occupational skin cancer. This study suggests the potential use of molecular-genetic data to assess increased individual risks of the development and prognosis of occupational skin neoplasms.
PMID: 29167767 [PubMed - in process]
Improving Cardiometabolic Health with Diet, Physical Activity, and Breaking Up Sitting: What about Sleep?
Front Physiol. 2017;8:865
Authors: Vincent GE, Jay SM, Sargent C, Vandelanotte C, Ridgers ND, Ferguson SA
Cardiometabolic disease poses a serious health and economic burden worldwide and its prevalence is predicted to increase. Prolonged sitting, lack of physical activity, poor diet, and short sleep duration are ubiquitous behaviors in modern society, and all are independent risk factors in the development of cardiometabolic disease. Existing evidence demonstrates that breaking up prolonged periods of sitting is beneficial for cardiometabolic health, however, studies have not controlled for prior sleep duration. This article examines how prolonged sitting and short sleep duration independently contribute to cardiometabolic risk, and how breaking up sitting and obtaining adequate sleep may reduce this risk. We suggest that as prolonged sitting and short sleep duration influence the same cardiometabolic parameters, there is potential for short sleep to attenuate the positive impact of breaking up prolonged sitting with physical activity. Likewise, breaking up prolonged sitting and obtaining adequate sleep together could improve predictors of cardiometabolic disease, i.e., the combined effect may be stronger than either alone. To explore these perspectives, we propose a research agenda to investigate the relationship between breaking up prolonged sitting with physical activity and short sleep duration. This will provide an evidence-base for informing the design of interventions to reduce the burden of cardiometabolic disease on communities worldwide.
PMID: 29167645 [PubMed]
Specification of murine ground state pluripotent stem cells to regional neuronal populations.
Sci Rep. 2017 Nov 22;7(1):16001
Authors: Alsanie WF, Niclis JC, Hunt CP, De Luzy IR, Penna V, Bye CR, Pouton CW, Haynes J, Firas J, Thompson LH, Parish CL
Pluripotent stem cells (PSCs) are a valuable tool for interrogating development, disease modelling, drug discovery and transplantation. Despite the burgeoned capability to fate restrict human PSCs to specific neural lineages, comparative protocols for mouse PSCs have not similarly advanced. Mouse protocols fail to recapitulate neural development, consequently yielding highly heterogeneous populations, yet mouse PSCs remain a valuable scientific tool as differentiation is rapid, cost effective and an extensive repertoire of transgenic lines provides an invaluable resource for understanding biology. Here we developed protocols for neural fate restriction of mouse PSCs, using knowledge of embryonic development and recent progress with human equivalents. These methodologies rely upon naïve ground-state PSCs temporarily transitioning through LIF-responsive stage prior to neural induction and rapid exposure to regional morphogens. Neural subtypes generated included those of the dorsal forebrain, ventral forebrain, ventral midbrain and hindbrain. This rapid specification, without feeder layers or embryoid-body formation, resulted in high proportions of correctly specified progenitors and neurons with robust reproducibility. These generated neural progenitors/neurons will provide a valuable resource to further understand development, as well disorders affecting specific neuronal subpopulations.
PMID: 29167563 [PubMed - in process]
Publisher Correction: Sex-Dependent Effects of Caloric Restriction on the Ageing of an Ambush Feeding Copepod.
Sci Rep. 2017 Nov 22;7(1):16392
Authors: Saiz E, Calbet A, Griffell K
A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
PMID: 29167531 [PubMed - in process]
HAdV protein V core protein is targeted by the host SUMOylation machinery to limit essential viral functions.
J Virol. 2017 Nov 22;:
Authors: Freudenberger N, Meyer T, Groitl P, Dobner T, Schreiner S
Human Adenoviruses (HAdV) are non-enveloped containing a linear, double-stranded DNA genome surrounded by an icosahedral capsid. To allow proper viral replication, the genome is imported through the nuclear-pore-complex associated with viral core proteins. Until now, the role of these incoming virion proteins during the early phase of infection was poorly understood.The core protein V is speculated to bridge core and the surrounding capsid. It binds the genome in a sequence-independent manner and localizes in the nucleus of infected cells, accumulating at nucleoli. Here, we show that protein V contains conserved SUMO conjugation motifs (SCMs). Mutation of these consensus motifs resulted in reduced SUMOylation of the protein; thus protein V represents a novel target of the host SUMOylation machinery. To understand the role of protein V SUMO posttranslational modification during productive HAdV infection, we generated a replication-competent HAdV with SCM mutations within the protein V coding sequence. Phenotypic analyses revealed that these SCM mutations are beneficial for adenoviral replication. Blocking protein V SUMOylation at specific sites shifts the onset of viral DNA replication to earlier time points during infection and promotes viral gene expression. Simultanously, these altered kinetics within the viral life cycle are accompanied by more efficient proteasomal degradation of host determinants and increased virus progeny production than observed during wildtype infection.Taken together, our studies show that protein V SUMOylation reduces virus growth; hence, protein V SUMOylation represents an important novel aspect of the host antiviral strategy to limit virus replication and thereby points to potential intervention strategies.ImportanceMany decades of research have revealed that HAdV structural proteins promote viral entry and mainly physical stability of the viral genome in the capsid. Our work over the last years showed that this concept needs expansion, as the functions are more diverse. We showed that capsid protein protein VI is regulating antiviral response by modulation of the transcription factor Daxx during infection. Moreover, core protein VII interacts with SPOC1 restriction factor, being beneficial for efficient viral gene expression. Here, we were able to show that also core protein V represents a novel substrate of the host SUMOylation machinery and contains several conserved SCMs; mutation of these consensus motifs reduced SUMOylation of the protein. Unexpectedly, we observed that introducing these mutations into HAdV promotes adenoviral replication. Conclusively, we offer novel insights into adenovirus core proteins and provide evidence that SUMOylation of HAdV factors regulates replication efficiency.
PMID: 29167340 [PubMed - as supplied by publisher]
Rodent Vertical Sleeve Gastrectomy Alters Maternal Immune Health and Feto-placental Development.
Clin Sci (Lond). 2017 Nov 22;:
Authors: Spann RA, Lawson WJ, Bidwell GL, Zamarripa CA, Maranon RO, Bandyopadhyay S, Taylor ER, Reckelhoff JF, Garrett MR, Grayson BE
Bariatric surgery is increasingly employed to improve fertility and reduce obesity related co-morbidities in obese women. Surgical weight loss not only improves the chance of conception but reduces the risk of pregnancy complications including pre-eclampsia, gestational diabetes, and macrosomia. However, bariatric procedures increase the incidence of intrauterine growth restriction (IUGR), fetal demise, thromboembolism and other gestational disorders. Using our rodent model of vertical sleeve gastrectomy (VSG), we tested the hypothesis that VSG in diet-induced, obese dams would cause immune and placental structural abnormalities that may be responsible for fetal demise during pregnancy. VSG dams studied on gestational day (G) 18 had reduced circulating T cell (CD3+ and CD8+) populations compared to lean or obese controls. Further, local interleukin 1 β and interleukin 1 receptor antagonist mRNA were increased in placenta of VSG dams. Placental barrier function was also affected, with increased trans-placental permeability to small molecules, increased matrix metalloproteinase 9 expression, and increased apoptosis in VSG. Furthermore, we identified increased placental mTOR signaling that may contribute to preserving the body weight of the fetuses during gestation. These changes occurred in the absence of a macronutrient deficit or gestational hypertension in the VSG dams. In summary, previous VSG in dams may contribute to fetal demise by affecting maternal immune system activity and compromise placental integrity.
PMID: 29167317 [PubMed - as supplied by publisher]
Exocrine pancreas glutamate secretion help to sustain enterocyte nutritional needs under protein restriction.
Am J Physiol Gastrointest Liver Physiol. 2017 Nov 22;:ajpgi.00135.2017
Authors: Araya S, Kuster E, Gluch D, Mariotta L, Lutz C, Reding TV, Graf R, Verrey F, Camargo SMR
Glutamine (Gln) is the most concentrated amino acid in blood and considered conditionally essential. Its requirement is increased during physiological stress, such as malnutrition or illness, despite its production by muscle and other organs. In the malnourished state Gln has been suggested to have a trophic effect on the exocrine pancreas and small intestine. However, the Gln transport capacity, the functional relationship of these two organs and the potential role of the Gln-glutamate (Glu) cycle are unknown. We observed that pancreatic acinar cells express lower levels of Glu than Gln transporters. Consistent with this expression pattern the rate of Glu influx into acinar cells was approximately 6-fold lower than that of Gln. During protein restriction, acinar cell glutaminase expression was increased and Gln accumulation maintained. Moreover, Glu secretion by acinar cells into pancreatic juice and thus into the lumen of the small intestine was maintained. In the intestinal lumen, Glu absorption was preserved and glutamate dehydrogenase expression was augmented, potentially providing the substrates for increasing energy production via the TCA cycle. Our findings suggest that one mechanism by which Gln exerts a positive effect on exocrine pancreas and small intestine involves the Gln metabolism in acinar cells and the secretion of Glu into the small intestine lumen. The exocrine pancreas acinar cells not only avidly accumulate Gln; but metabolize Gln to generate energy and to synthesize Glu for secretion in the pancreatic juice. Secreted Glu is suggested to play an important role during malnourishment in sustaining small intestinal homeostasis.
PMID: 29167114 [PubMed - as supplied by publisher]
Postural Control During Different Unipodal Positions in Professional Ballet Dancers.
J Dance Med Sci. 2017 Dec 15;21(4):151-155
Authors: de Mello MC, de Sá Ferreira A, Ramiro Felicio L
Classical ballet involves the performance of complex movements that require high-level motor skills and good postural control. This study explored postural sway in passé en demi-pointe position in dancers and compared single-leg standing sway (with and without visual restriction) between dancers and non-dancers. Fourteen professional dancers and 14 sex- and age-matched volunteers who were not ballet dancers participated in the study. Participants stood on a force plate on the dominant leg in the following positions: 1. single-leg stance with eyes open (reference task) and with eyes closed and blindfolded for 35 seconds; and 2. passé en demi-pointe position with eyes open for 20 seconds (dancers only). The center of pressure signal was used to calculate the following variables: average velocity; anteroposterior and mediolateral velocity peaks; anteroposterior and mediolateral displacement ranges; average displacement; and ellipse area. Significant interaction effects (p < 0.001, η2 = 0.419) were observed between groups and postural tasks, with higher stabilometric values for the dancer group during the single-leg stance with eyes closed and blindfolded task, as evidenced by the average displacement of 241.0 cm in dancers and 147.1 cm in non-dancers (p = 0.025), and by the ellipse area of 9.5 cm2 for dancers and 4.9 cm2 for non-dancers (p = 0.001). In regard to the positions with eyes open, an increase was noted only in the average sway velocity and mediolateral velocity in passé en demi-pointe position compared with the single-leg stance with eyes open (p < 0.001). Greater postural sway might be interpreted as the result of either inadequate postural stability or exploratory behavior to maintain postural stability in more challenging tasks. It is concluded that professional ballet dancers show greater visual dependency for balance adjustment with reduced influence of the supporting base on postural sway.
PMID: 29166985 [PubMed - in process]
Analysis of pre-weaning feeding policies and other risk factors influencing growth rates in calves on 11 commercial dairy farms.
Animal. 2017 Nov 23;:1-11
Authors: Johnson KF, Chancellor N, Burn CC, Wathes DC
Growth rates in pre-weaned calves influence their health, age at first calving and lifetime productivity. Many farms restrict milk rations to encourage solid feed intake and facilitate early weaning, but this can compromise growth. This study determined the milk feeding policies and associated growth rates on 11 commercial dairy farms in South East England, each following their normal management regime. Between 26 and 54 heifers were recruited per farm, providing a final cohort of 492, of which 71% were pure Holstein. Information on calf rearing practices (feeding, weaning, housing) and health was collected via questionnaires and weekly observations. Estimates of actual milk fed (kg solids) between 1 and 63 days were calculated for individual calves. Morphometric data (weight, height, length) were taken at weeks 1, 5 and 9 and at a median age of 7.5 months and growth rates were calculated. Most calves were fed milk replacer via automated feeders (four farms), teat feeder (one) or buckets (four) whereas two farms provided drums of acidified waste milk. Farms fed between 4 and 6 l/day of milk at mixing rates of 10% to 15%, providing 400 to 900 g/day of milk solids. Both skeletal growth rates and average daily weight gain (ADG) increased in the second month of life compared with the first: height growth from 0.17±0.14 to 0.25±0.16 cm/day and ADG from 0.48±0.25 to 0.71±0.28 kg/day. Post-weaning heifers up to 7.5 months had height increases of 0.16±0.035 cm/day and ADG of 0.83±0.16 kg/day. From 1 to 63 days 70% of calves had growth rates <0.7 kg/day and of these 19.6% gained <0.5 kg/day. Mean ADG before 9 weeks varied between farms from 0.52±0.30 to 0.75±0.20 kg/day. This was related to the amount of milk fed at both a farm and individual calf level. Increasing the total milk solids fed between 1 and 63 days from 20.4 to 46.3 kg (the 10th to 90th percentile observed) was associated with an increase of 0.11 kg/day ADG. All farms had a wide variation in growth rates despite single feeding policies. Higher circulating immunoglobulin G and IGF1 concentrations were associated with better growth, whereas low temperatures in month of birth, high scores for diarrhoea, respiratory and umbilical disease and large birth size reduced growth. Many commercially grown dairy heifers therefore experienced growth restriction in the pre-weaned period, potentially reducing their health, welfare and productivity.
PMID: 29166977 [PubMed - as supplied by publisher]
Multiscale positive feedbacks contribute to unidirectional gastric disease progression induced by helicobacter pylori infection.
BMC Syst Biol. 2017 Nov 22;11(1):111
Authors: Ballweg R, Schozer F, Elliott K, Kuhn A, Spotts L, Aihara E, Zhang T
BACKGROUND: Helicobacter Pylori (HP) is the most common risk factor for gastric cancer. Nearly half the world's population is infected with HP, but only a small percentage of those develop significant pathology. The bacteria itself does not directly cause cancer; rather it promotes an environment that is conducive to tumor formation. Upon infection, HP induces transcriptional changes in the host, leading to enhanced proliferation and host immune response. In addition, HP causes direct damage to gastric epithelial cells.
RESULTS: We present a multiscale mechanistic model of HP induced changes. The model includes four modules representing the host transcriptional changes in response to infection, gastric atrophy, the Hedgehog pathway response, and the restriction point that controls cell cycle. This model was able to recapture a number of literature reported observations and was used as an "in silico" representation of the biological system for further analysis. Dynamical analysis of the model revealed that HP might induce the activation of multiple interplayed positive feedbacks, which in turn might result in a "ratchet ladder" system that promotes a unidirectional progression of gastric disease.
CONCLUSIONS: The current multiscale model is able to recapitulate the observed experimental features of HP host interactions and provides dynamic insights on the epidemiologically observed heterogeneity in disease progression. This model provides a solid framework that can be further expanded and validated to include additional experimental evidence, to understand the complex multi-pathway interactions characterizing HP infection, and to design novel treatment protocols for HP induced diseases.
PMID: 29166909 [PubMed - in process]
Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor.
Cell Rep. 2017 Nov 21;21(8):2251-2263
Authors: Wahlestedt M, Ladopoulos V, Hidalgo I, Sanchez Castillo M, Hannah R, Säwén P, Wan H, Dudenhöffer-Pfeifer M, Magnusson M, Norddahl GL, Göttgens B, Bryder D
A gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor hepatic leukemia factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates. Reciprocally, we observed rapid lymphoid commitment upon reduced Hlf activity. The arising phenotypes resulted from Hlf binding to active enhancers of myeloid-competent cells, transcriptional induction of myeloid, and ablation of lymphoid gene programs, with Hlf induction of nuclear factor I C (Nfic) as a functionally relevant target gene. Thereby, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis.
PMID: 29166614 [PubMed - in process]
MMP-3 (-1171 5A/6A; Lys45Glu) variants affect serum levels of matrix metalloproteinase (MMP)-3 and correlate with severity of COPD: a study of MMP-3, MMP-7 and MMP-12 in a Tunisian population.
J Gene Med. 2017 Nov 22;:
Authors: Bchir S, Ben Nasr H, Garrouch A, Ben Anes A, Abbassi A, Tabka Z, Chahed K
OBJECTIVE: The goal of this study was to examine the role of MMP-3 (-1171 5A/6A; Lys45Glu (A/G)), MMP-7 (-181) A/G and MMP-12 (-82 A/G; Asn357Ser (A/G)) variants in the development and severity of chronic obstructive pulmonary disease (COPD) in Tunisians.
METHODS: Plethysmography was performed in all participants to measure FEV1, FVC and FEV1/FVC parameters. Genotyping of MMP-3, MMP-7 and MMP-12 polymorphisms was carried out in 138 patients with COPD and 216 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum levels of MMPs and cytokines (IL-6, TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA).
RESULTS: No significant correlations were observed between genetic variations in MMP-3, MMP-7 and MMP-12 and the risk of development of COPD. Additionally, no impact of MMP-7 (-181) A/G and MMP-12 (-82 A/G; Asn357Ser (A/G)) polymorphisms was observed on the respective protein levels and clinical parameters of the disease. Interestingly, both MMP-3 (-1171) 5A/6A and Lys45Glu (A/G) variants were associated with respiratory function, as well as with serum levels of MMP-3 in COPD patients. A relationship was found between the (-1171) 6A and 45Glu (G) alleles of MMP-3 gene and enhanced airflow limitation among COPD patients. Additionally, carriers of the 6A6A and 45 GG genotypes present higher MMP-3 levels than non carriers.
CONCLUSION: MMP-3 (-1171) 5A/6A and Lys45Glu (A/G) polymorphisms were associated with the decline of lung function among COPD patients. These results could be linked to the upregulation of MMP-3 in serum from COPD patients carrying the -1171 6A and 45G homozygous genotypes.
PMID: 29165854 [PubMed - as supplied by publisher]
Research on the correlation between the fibrinogen β and attack of pediatric pneumonia.
Eur Rev Med Pharmacol Sci. 2017 Oct;21(4 Suppl):100-105
Authors: Liu G, Wu HW, Li ZG
OBJECTIVE: To investigate the correlation of the gene polymorphism of β-148C/T of fibrinogen with the expression of fibrinogen and the attack of pediatric pneumonia.
PATIENTS AND METHODS: We employed polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to detect the gene polymorphism of beta-fibrinogen gene-148C/T (β-148C/T). The expression level of fibrinogen in plasma was measured using enzyme-linked immunosorbent assay (ELISA), and the expression level of fibrinogen β protein was determined using Western-blot method.
RESULTS: Compared with the healthy control group, the expression level of fibrinogen β was significantly higher in patients with pneumonia. Additionally, the frequency of CC genotype, as well as the allele of C, in the pneumonia group were significantly higher than that in the control group. Meanwhile, the frequency of TT genotype and the allele of T were remarkably lower in patients with pneumonia compared to those in the control group. No significant difference was found in comparison with the CT genotype frequency between the two groups. Compared with the patients with TT genotypes, expressions of fibrinogen, IL-6 and CRP were significantly higher in the patients with the CC and CT genotypes. However, the odds ratio (OR) of pediatric pneumonia patients with TT genotype was 0.21, OR of pediatric pneumonia patients with CT genotype was 0.77 and OR of pediatric pneumonia patients with CC genotype was 12.73. The OR of patients with T allele was 1.85 and OR of patients with C allele was 5.15.
CONCLUSIONS: We concluded that β-148C/T gene polymorphism of fibrinogen was correlated with the susceptibility of pediatric pneumonia, suggesting that it may be a genetic risk factor, and fibrinogen β-148C/T gene may be involved in the onset of pediatric pneumonia through affecting the concentration of fibrinogen β in plasma.
PMID: 29165755 [PubMed - in process]
Being Born Too Small and Too Early May Alter Sleep in Childhood.
Sleep. 2017 Nov 20;:
Authors: Yiallourou SR, Arena BC, Wallace EM, Odoi A, Hollis S, Weichard A, Horne RSC
Study Objectives: Fetal growth restriction (FGR) occurs in up to 10% of pregnancies and is associated with increased risk of prematurity and neurodevelopmental impairment. FGR also alters sleep state distribution in utero and maturation in infancy. Currently, limited data on the long-term associations of FGR and childhood sleep exist. Accordingly, we assessed the associations between preterm birth and FGR and sleep in children aged 5-12 years.
Methods: 17 children born preterm and FGR, 15 children born preterm but appropriately grown (AGA) and 20 term AGA children (controls) were studied using overnight polysomnography. Sleep macro-architecture was assessed using standard criteria and sleep micro-architecture was assessed using spectral analysis of the EEG (C4-M1) with Total, Delta (0.5Hz-3.9Hz), Theta (4.0Hz-7.9Hz), Alpha (8.0Hz-11.9Hz), Sigma (12.0Hz-13.9Hz) and Beta Power (14.0Hz-30Hz) calculated.
Results: For sleep macro-architecture, preterm FGR children had higher N2% compared to term AGA children (p<0.05). Preterm AGA children had reduced total sleep time, NREM% and sleep efficiency compared to term AGA children (p<0.05 for all). For sleep micro-architecture, preterm FGR children had a higher amount of Total, delta and alpha power compared to both groups (p<0.05). Sigma and beta power were lowest in the preterm AGA group compared to both groups (p<0.05 for both).
Conclusions: Prematurity and FGR were associated with altered sleep macro- and micro-architecture measures indicative of reduced sleep quantity and quality in childhood. As sleep disturbance can impact both behavior and neurodevelopment in children, sleep in FGR and preterm children warrants further investigation.
PMID: 29165677 [PubMed - as supplied by publisher]
Oral Contraceptives and Cigarette Smoking: A Review of the Literature and Future Directions.
Nicotine Tob Res. 2017 Nov 18;:
Authors: Allen AM, Weinberger AH, Wetherill RR, Howe CL, McKee SA
Introduction: Evidence continues to mount indicating that endogenous sex hormones (e.g., progesterone and estradiol) play a significant role in smoking-related outcomes. Although approximately 1 out of 4 premenopausal smokers use oral contraceptives (OCs), which significantly alter progesterone and estradiol levels, relatively little is known about how OCs may influence smoking-related outcomes. Thus, the goal of this review paper is to describe the state of the literature and offer recommendations for future directions.
Methods: In March 2017, we searched seven databases, with a restriction to articles written in English, using the following keywords: nicotine, smoker(s), smoking, tobacco, cigarettes, abstinence, withdrawal, and craving(s). We did not restrict on the publication date, type or study design.
Results: A total of 13 studies were identified. Three studies indicated faster nicotine metabolism in OC users compared to nonusers. Five of six laboratory studies that examined physiological stress response noted heightened response in OC users compared to nonusers. Three studies examined cessation-related symptomatology (e.g., craving) with mixed results. One cross-sectional study observed greater odds of current smoking among OC users, and no studies have explored the relationship between OC use and cessation outcomes.
Conclusions: Relatively few studies were identified on the role of OCs in smoking-related outcomes. Future work could explore the relationship between OC use and mood, stress, weight gain and brain function/connectivity, as well as cessation outcomes. Understanding the role of OC use in these areas may lead to the development of novel smoking cessation interventions for premenopausal women.
Implications: This is the first review of the relationship between oral contraceptives (OCs) and smoking-related outcomes. The existing literature suggests that the use of OCs is related to increased nicotine metabolism and physiological stress response. However, the relationship between OC use and smoking-related symptoms (e.g., craving) is mixed. Further, no published data were available on OC use and smoking cessation outcomes. Therefore, we recommend additional research be conducted to characterize the relationship between OC use and smoking cessation outcomes, perhaps as a function of the effect of OC use on mood, stress, weight gain and brain function/connectivity.
PMID: 29165663 [PubMed - as supplied by publisher]
The Corticospinal Reserve Capacity: Reorganization of Motor Area and Excitability As a Novel Pathophysiological Concept in Cervical Myelopathy.
Neurosurgery. 2017 Nov 18;:
Authors: Zdunczyk A, Schwarzer V, Mikhailov M, Bagley B, Rosenstock T, Picht T, Vajkoczy P
BACKGROUND: In degenerative cervical myelopathy (DCM), the dynamics of disease progression and the outcome after surgical decompression vary interindividually and do not necessarily correlate with radiological findings.
OBJECTIVE: To improve diagnostic power in DCM by better characterization of the underlying pathophysiology using navigated transcranial magnetic stimulation (nTMS).
METHODS: Eighteen patients with DCM due to cervical spinal canal stenosis were examined preoperatively with nTMS. On the basis of the initial Japanese Orthopedic Association (JOA) Score, 2 patient groups were established (JOA ≤12/>12). We determined the resting motor threshold, recruitment curve, cortical silent period, and motor area. Accordingly, 8 healthy subjects were examined.
RESULTS: Although the resting motor threshold was comparable in both groups (P = .578), the corticospinal excitability estimated by the recruitment curve was reduced in patients (P = .022). In patients with only mild symptoms (JOA > 12), a compensatory higher activation of non-primary motor areas was detected (P < .005). In contrast, patients with severe impairment (JOA ≤ 12) showed a higher cortical inhibition (P < .05) and reduced cortical motor area (P < .05) revealing a functional restriction on the cortical level.
CONCLUSION: Based on these results, we propose a new concept for functional compensation for DCM on the cortical and spinal level, ie corticospinal reserve capacity. nTMS is a useful tool to noninvasively characterize the pattern of functional impairment and compensatory reorganization in patients suffering from DCM. The change in nTMS parameters might serve as a valuable prognostic factor in these patients in the future.
PMID: 29165642 [PubMed - as supplied by publisher]
Con: The role of diet for people with advanced Stage 5 CKD.
Nephrol Dial Transplant. 2017 Nov 17;:
Authors: Woodrow G
Restriction of dietary protein intake has been used in the management of chronic kidney disease (CKD) for many decades, yet remains controversial, with marked variations in its application in clinical practice. There is extensive literature on the subject, with some expert opinion advocating the use of protein restriction based on the balance of the available evidence. The largest randomized trial of low-protein diets is the Modification of Diet in Renal Disease study. Despite multiple secondary analyses, the essential intention-to-treat analysis failed to demonstrate a benefit in the primary outcome of rate of decline of glomerular filtration rate. There are criticisms of many published studies and meta-analyses, including the likelihood of publication bias and unsuitable biochemical endpoints that may be affected by dietary restriction in the absence of effects on kidney function, leading to false positive findings. It is also uncertain whether any benefits observed in these often older studies would be derived in patients undergoing modern standards of CKD management, including blood pressure control and renin-angiotensin blockade. Thus it is unclear whether, even in the strictly controlled environment of a clinical study, low-protein diets significantly slow CKD progression. Important questions exist regarding the applicability of these diets in routine clinical practice. Even in carefully selected study populations with intensive dietetic input, adherence to low-protein diets is poor. It is likely that only a small minority of CKD patients in routine practice could adhere to these diets, and although risks of malnutrition arising from protein restriction are uncertain, they will be greater in less supervised care outside of studies.
PMID: 29165595 [PubMed - as supplied by publisher]
NS3 helicase from dengue virus specifically recognizes viral RNA sequence to ensure optimal replication.
Nucleic Acids Res. 2017 Nov 20;:
Authors: Swarbrick CMD, Basavannacharya C, Chan KWK, Chan SA, Singh D, Wei N, Phoo WW, Luo D, Lescar J, Vasudevan SG
The protein-RNA interactions within the flavivirus replication complex (RC) are not fully understood. Our structure of dengue virus NS3 adenosine triphosphatase (ATPase)/helicase bound to the conserved 5' genomic RNA 5'-AGUUGUUAGUCU-3' reveals that D290 and R538 make specific interactions with G2 and G5 bases respectively. We show that single-stranded 12-mer RNA stimulates ATPase activity of NS3, however the presence of G2 and G5 leads to significantly higher activation. D290 is adjacent to the DEXH motif found in SF2 helicases like NS3 and interacts with R387, forming a molecular switch that activates the ATPase site upon RNA binding. Our structure guided mutagenesis revealed that disruption of D290-R387 interaction increases basal ATPase activity presumably as a result of higher conformational flexibility of the ATPase active site. Mutational studies also showed R538 plays a critical role in RNA interactions affecting translocation of viral RNA through dynamic interactions with bases at positions 4 and 5 of the ssRNA. Restriction of backbone flexibility around R538 through mutation of G540 to proline abolishes virus replication, indicating conformational flexibility around residue R538 is necessary for RNA translocation. The functionally critical sequence-specific contacts in NS3 RNA binding groove in subdomain III reveals potentially novel allosteric anti-viral drug targets.
PMID: 29165589 [PubMed - as supplied by publisher]
Isolation and identification of Acanthamoeba strains from soil and tap water in Yanji, China.
Environ Health Prev Med. 2017 Jun 30;22(1):58
Authors: Xuan Y, Shen Y, Ge Y, Yan G, Zheng S
BACKGROUND: Members of the genus Acanthamoeba are widely distributed throughout the world, and some of them are considered pathogenic, as they are capable of causing corneal and central nervous system diseases. In this study, we isolated Acanthamoeba strains from soil and tap water in Yanji, China.
METHODS: We identified four strains of Acanthamoeba (CJY/S1, CJY/S2, CJY/S3, and CJY/W1) using mitochondrial DNA restriction fragment length polymorphism (mtDNA RFLP) analysis. Nuclear 18S rDNA sequences were used for phylogenetic analysis and species identification.
RESULTS: Genotypic characterization of the isolates showed that they belonged to genotypes T4 (CJY/S1 and CJY/S2), T5 (CJY/S3), and T16 (CJY/W1). Sequence differences between CJY/S1 and Acanthamoeba castellanii Neff, CJY/S2 and Acanthamoeba KA/E7, and CJY/S3 and Acanthamoeba lenticulata 68-2 were 0.31, 0.2, and 0.26%, respectively. 18S ribosomal deoxyribonucleic acid (rDNA) of CJY/W1 had 99% sequence identity to that of Acanthamoeba sp. U/H-C1. Strains CJY/S1 and CJY/S2, isolated from soil, had similar mtDNA RFLP patterns, whereas strain CJY/W1, isolated from tap water, displayed a different pattern.
CONCLUSIONS: To the best of our knowledge, this is the first report on the identification of genotypes T4, T5, and T16 from environmental sources in Yanji, China.
PMID: 29165144 [PubMed - in process]
Immunotherapy with interferon-α-induced dendritic cells for chronic HCV infection (the results of pilot clinical trial).
Immunol Res. 2017 Nov 21;:
Authors: Chernykh E, Leplina O, Oleynik E, Tikhonova M, Tyrinova T, Starostina N, Ostanin A
The key role of T cells in hepatitis C virus (HCV) elimination and the ability of dendritic cells (DCs) to induce antiviral T cell responses suggest that DC vaccines could be a promising approach in the treatment of chronic HCV infection. The aim of our study was to evaluate, whether immunotherapy with DCs is safe and elicits anti-HCV T cell responses. Ten patients with HCV (genotype 1) were vaccinated with monocyte-derived DCs, generated in the presence of IFN-α (IFN-DCs) and pulsed with recombinant HCV Core and NS3 proteins. Treatment schedule included four subcutaneous vaccinations with 1 week interval and six vaccinations with month interval. No serious adverse events or an increase in hepatitis C biochemical activity were registered after vaccination. Using ex vivo assays for the detection of proliferative responses, IFN-γ production and CD8(+) degranulation have shown that immunotherapy elicited antigen-specific responses in all patients although individual heterogeneity existed within their types, magnitude, and timing. Core/NS3-specific proliferative response and CD8(+) T cell degranulation have already been registered after the first course of vaccination. Of note, Core-specific responses had higher magnitude. The appearance of antigen-specific IFN-γ responses was registered after the second vaccination course. Vaccination did not cause Th2 response and expansion of the CD4(+)CD25(+)CD127(-) regulatory T cells. Generated immune responses failed to provide virus elimination. Nevertheless, there were inverse correlations between viral load and NS3-specific proliferation (R S = 0.62; p = 0.05) and IFN-γ secretion (R S = - 0.82; p = 0.001) at 6-month post-treatment period. Immunotherapy with IFN-DCs was safe and elicited HCV-specific T cell responses which were insufficient to eliminate viruses but could be implicated in the restriction of viral replication.
PMID: 29164490 [PubMed - as supplied by publisher]
Platelet-Rich Plasma for Primary Treatment of Partial Ulnar Collateral Ligament Tears: MRI Correlation With Results.
Orthop J Sports Med. 2017 Nov;5(11):2325967117738238
Authors: Deal JB, Smith E, Heard W, O'Brien MJ, Savoie FH
Background: Jobe revolutionized the treatment of medial ulnar collateral ligament (MUCL) tears with his reconstruction technique. However, not all MUCL injuries require operative management; Rettig showed that 42% of MUCL injuries respond to conservative management. This was improved by Podesta, who showed that augmentation of nonoperative management with platelet-rich plasma (PRP) and magnetic resonance imaging (MRI) for detecting partial MUCL tears resulted in significantly higher success rates. Their series used a single injection of leukocyte-rich PRP. However, to our knowledge, no study has established optimal dosing and composition of PRP for augmentation of soft tissue healing. We present a series of patients with partial MUCL tears of the elbow treated with a series of 2 leukocyte-rich PRP injections, bracing, physical therapy, and a structured return-to-throwing protocol.
Hypothesis: Nonoperative management of acute or subacute partial MUCL tears of the elbow with a formal treatment protocol will allow the injured ligament to heal without surgery and will permit a rapid return to sport.
Study Design: Case series; Level of evidence, 4.
Methods: Patients with symptomatic MUCL instability and magnetic resonance arthrography demonstrating grade 2 MUCL tears at the proximal or distal aspect were treated with varus-loading elbow bracing, activity restriction, and physical therapy, supplemented by 2 injections of PRP. The injections were separated by 2 weeks. Two weeks after the second injection, a repeat examination and magnetic resonance arthrogram were obtained to evaluate the response to treatment.
Results: A total of 25 athletes (23 baseball athletes, 2 softball athletes [1 participant also danced]) underwent PRP injections and guided rehabilitation. Of these patients, 23 were diagnosed with primary grade 2 injuries of the MUCL; 22 patients with primary injuries (96%) demonstrated stability of the MUCL after treatment and returned to play at the same or higher level of competition without further intervention. Repeat MRI demonstrated reconstitution of the ligament in all patients, although 2 patients demonstrated only partial reconstitution. Patients were released to play at 6 weeks; due to vagaries of sports seasons, the mean time to return to competitive play was 82 days. Two of the 25 patients had undergone prior surgery (1 MUCL reconstruction and 1 repair). These patients remained unstable and symptomatic on examination after this treatment regimen, did not show complete reconstitution of the ligament on subsequent MRI, and required MUCL reconstruction.
Conclusion: Ouf of 23 primary injury patients who received PRP injections and nonoperative measures, 22 (96%) were able to return to play and demonstrated reconstitution of the MUCL on MRI. Two of the 3 patients for whom PRP therapy failed had undergone previous MUCL surgery. We conclude that a 2-injection regimen of leukocyte-rich PRP is a safe and effective treatment for partial MUCL tears, but it appears to be less effective in patients with previous surgery for MUCL repair or reconstruction.
PMID: 29164165 [PubMed]
Chemokine Signaling during Midline Epithelial Seam Disintegration Facilitates Palatal Fusion.
Front Cell Dev Biol. 2017;5:94
Authors: Suttorp CM, Cremers NA, van Rheden R, Regan RF, Helmich P, van Kempen S, Kuijpers-Jagtman AM, Wagener FADTG
Disintegration of the midline epithelial seam (MES) is crucial for palatal fusion, and failure results in cleft palate. Palatal fusion and wound repair share many common signaling pathways related to epithelial-mesenchymal cross-talk. We postulate that chemokine CXCL11, its receptor CXCR3, and the cytoprotective enzyme heme oxygenase (HO), which are crucial during wound repair, also play a decisive role in MES disintegration. Fetal growth restriction and craniofacial abnormalities were present in HO-2 knockout (KO) mice without effects on palatal fusion. CXCL11 and CXCR3 were highly expressed in the disintegrating MES in both wild-type and HO-2 KO animals. Multiple apoptotic DNA fragments were present within the disintegrating MES and phagocytized by recruited CXCR3-positive wt and HO-2 KO macrophages. Macrophages located near the MES were HO-1-positive, and more HO-1-positive cells were present in HO-2 KO mice compared to wild-type. This study of embryonic and palatal development provided evidence that supports the hypothesis that the MES itself plays a prominent role in palatal fusion by orchestrating epithelial apoptosis and macrophage recruitment via CXCL11-CXCR3 signaling.
PMID: 29164113 [PubMed]
Effect of Chronic Administration of Resveratrol on Cognitive Performance during Aging Process in Rats.
Oxid Med Cell Longev. 2017;2017:8510761
Authors: Navarro-Cruz AR, Ramírez Y Ayala R, Ochoa-Velasco C, Brambila E, Avila-Sosa R, Pérez-Fernández S, Morales-Medina JC, Aguilar-Alonso P
The increase in the elderly population has generated concern to meet health demands. The research efforts to elucidate the mechanisms of damage associated with aging have also been significantly increased, especially in order to avoid the reduction of the cognitive abilities in geriatric patients, resulting from the damage generated mainly at the level of the hippocampus during old age. At present, many studies describe resveratrol as an antiaging component. There are reports that it can activate the Sirt1 gene related to antiaging, emulating the effects obtained by caloric restriction in rodents. The aim of the study was to evaluate the effect of chronic administration of resveratrol (10 mg/kg) on cognitive performance in behavioral tests after 8 months of treatment and on the preservation of cerebral integrity in the cytoarchitecture of regions CA1 and CA2. Results showed that the cytoarchitecture of the CA1 and CA2 regions in the hippocampus retained their integrity over time in rats treated with resveratrol, and the behavioral test performed revealed that chronic resveratrol administration for 8 months showed improvements in cognitive performance. The results indicate that resveratrol may exhibit therapeutic potential for age-related conditions.
PMID: 29163756 [PubMed - in process]
Fiber gene based molecular and biological characterization of hydropericardium-hepatitis syndrome associated avian adenoviruses.
Iran J Vet Res. 2017;18(3):190-196
Authors: Yasmeen S, Siddique N, Athar Abbas M, Ali A, Rafique S, Rashid F, Shah AU, Mehmood F, Begum I, Javaid T, Jaffery SMH, Ali R, Naeem K
This study was designed to perform biological and molecular characterization of avian adenoviruses (AAVs) recovered from suspected cases of hydropericardium-hepatitis syndrome (HHS) in commercial poultry. Initially the samples were screened by Agar Gel Precipitation Test (AGPT) for the presence of AAVs followed by its confirmation and typing through polymerase chain reaction (PCR) focusing on already reported serotypes AAV-4, AAV-8 and AAV-10 elsewhere. These PCR-positive samples were further subjected to amplification of fiber gene, followed by conducting restriction fragment length polymorphism (RFLP) using restriction enzyme Alu. The selected isolates were further propagated through cell culture and pathogenic potential of selected isolates was determined by infecting chickens. In this study, out of a total 190 samples, 57.8% of suspected cases were found positive for AAV presence through AGPT while sub-type identification using PCR revealed 46.3% for these viruses belonging to AAV-4, 41.8% to AAV-8 and 11.8% showed co-infection of AAV-4 and AAV-8. AAV-10 was not detected in any of the tested samples. On the basis of RFLP pattern, AAV-4 isolates were further divided into four sub-groups (A-D) while AAV-8 isolates had identical RFLP pattern. To further evaluate the pathogenic potential of these sub-groups of AAV-4 isolates, specific pathogen free (SPF) chicks were challenged with selected isolates belonging to each of the sub-groups, resulting in variable pattern of pathogenicity. It is concluded that any variation in the fiber gene of AAV-4 isolates may affect its pathogenicity and eventually specificity of the vaccines used against such infections. Therefore, regular monitoring of the circulating AAV serotypes may be helpful in understanding the pathogenic potential of emerging AAVs, which may lead to development of more effective response strategies accordingly.
PMID: 29163648 [PubMed]
Evidence Suggesting Absence of Mitochondrial DNA Methylation.
Front Genet. 2017;8:166
Authors: Mechta M, Ingerslev LR, Fabre O, Picard M, Barrès R
Methylation of nuclear genes encoding mitochondrial proteins participates in the regulation of mitochondria function. The existence of cytosine methylation in the mitochondrial genome is debated. To investigate whether mitochondrial DNA (mtDNA) is methylated, we used both targeted- and whole mitochondrial genome bisulfite sequencing in cell lines and muscle tissue from mouse and human origin. While unconverted cytosines were detected in some portion of the mitochondrial genome, their abundance was inversely associated to the sequencing depth, indicating that sequencing analysis can bias the estimation of mtDNA methylation levels. In intact mtDNA, few cytosines remained 100% unconverted. However, removal of supercoiled structures of mtDNA with the restriction enzyme BamHI prior to bisulfite sequencing decreased cytosine unconversion rate to <1.5% at all the investigated regions: D-loop, tRNA-F+12S, 16S, ND5 and CYTB, suggesting that mtDNA supercoiled structure blocks the access to bisulfite conversion. Here, we identified an artifact of mtDNA bisulfite sequencing that can lead to an overestimation of mtDNA methylation levels. Our study supports that cytosine methylation is virtually absent in mtDNA.
PMID: 29163634 [PubMed]
Current Advances in γδ T Cell-Based Tumor Immunotherapy.
Front Immunol. 2017;8:1401
Authors: Lo Presti E, Pizzolato G, Gulotta E, Cocorullo G, Gulotta G, Dieli F, Meraviglia S
γδ T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of γδ T cells: those that express Vδ1 gene, paired with different Vγ elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, γδ T cells expressing the Vδ2 gene paired with the Vγ9 chain are the predominant (50-90%) γδ T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote γδ T cell activation. γδ T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that αβ T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-γ and tumor necrosis factor-α and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of γδ T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of γδ T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded γδ T cells, particularly the Vγ9Vδ2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that γδ T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the γδ T cell-based immunotherapy of cancer.
PMID: 29163482 [PubMed]
Features of CRISPR-Cas Regulation Key to Highly Efficient and Temporally-Specific crRNA Production.
Front Microbiol. 2017;8:2139
Authors: Rodic A, Blagojevic B, Djordjevic M, Severinov K, Djordjevic M
Bacterial immune systems, such as CRISPR-Cas or restriction-modification (R-M) systems, affect bacterial pathogenicity and antibiotic resistance by modulating horizontal gene flow. A model system for CRISPR-Cas regulation, the Type I-E system from Escherichia coli, is silent under standard laboratory conditions and experimentally observing the dynamics of CRISPR-Cas activation is challenging. Two characteristic features of CRISPR-Cas regulation in E. coli are cooperative transcription repression of cas gene and CRISPR array promoters, and fast non-specific degradation of full length CRISPR transcripts (pre-crRNA). In this work, we use computational modeling to understand how these features affect the system expression dynamics. Signaling which leads to CRISPR-Cas activation is currently unknown, so to bypass this step, we here propose a conceptual setup for cas expression activation, where cas genes are put under transcription control typical for a restriction-modification (R-M) system and then introduced into a cell. Known transcription regulation of an R-M system is used as a proxy for currently unknown CRISPR-Cas transcription control, as both systems are characterized by high cooperativity, which is likely related to similar dynamical constraints of their function. We find that the two characteristic CRISPR-Cas control features are responsible for its temporally-specific dynamical response, so that the system makes a steep (switch-like) transition from OFF to ON state with a time-delay controlled by pre-crRNA degradation rate. We furthermore find that cooperative transcription regulation qualitatively leads to a cross-over to a regime where, at higher pre-crRNA processing rates, crRNA generation approaches the limit of an infinitely abrupt system induction. We propose that these dynamical properties are associated with rapid expression of CRISPR-Cas components and efficient protection of bacterial cells against foreign DNA. In terms of synthetic applications, the setup proposed here should allow highly efficient expression of small RNAs in a narrow time interval, with a specified time-delay with respect to the signal onset.
PMID: 29163425 [PubMed]
More than meets the I: the diverse antiviral and cellular functions of interferon-induced transmembrane proteins.
Retrovirology. 2017 Nov 21;14(1):53
Authors: Shi G, Schwartz O, Compton AA
The first responders of human antiviral immunity are components of the intrinsic immune response that reside within each and every one of our cells. This cell-autonomous arsenal consists of nucleic acid sensors and antiviral effectors strategically placed by evolution to detect and restrict invading viruses. While some factors are present at baseline to allow for constant surveillance of the cell interior, others are upregulated by cytokines (such as interferons) that signal a viral infection underway in neighboring cells. In this review, we highlight the multiple roles played by the interferon-induced transmembrane (IFITM) proteins during viral infection, with focuses on IFITM3 and HIV-1. Moreover, we discuss the cellular pathways in which IFITM proteins are intertwined and the various functions they have been ascribed outside the context of infection. While appreciated as broadly-acting, potent restriction factors that prevent virus infection and pathogenesis in cell culture and in vivo, questions remain regarding their precise mode of action and importance in certain viral contexts. Continued efforts to study IFITM protein function will further cement their status as critical host determinants of virus susceptibility and prioritize them in the development of new antiviral therapies.
PMID: 29162141 [PubMed - in process]
A tailored counseling and home-based rehabilitation program to increase physical activity and improve mobility among community-dwelling older people after hospitalization: protocol of a randomized controlled trial.
BMC Musculoskelet Disord. 2017 Nov 21;18(1):477
Authors: Turunen K, Aaltonen L, Kumpumäki J, Portegijs E, Keikkala S, Kinnunen ML, Finni T, Sipilä S, Nikander R
BACKGROUND: Physical activity (PA) decreases during hospitalization. In particular, the amount of PA engaged in by older people who are hospitalized following musculoskeletal injury is likely to be limited for months after discharge home. Given the importance of an active lifestyle for their recovery and the prevention of future adverse outcomes, there is clearly a need for interventions to increase PA. This article describes the protocol of a randomized controlled trial set up to investigate the effects of a physical activity oriented home rehabilitation program (ProPA) on PA and the restoration of mobility in community-dwelling older people.
METHODS: Men and women aged 60 years or older hospitalized due to a musculoskeletal injury or disorder in the back or lower limbs are recruited. After discharge from hospital to home, participants are randomized into a six-month ProPA program or a standard care (control) group. The ProPA program consists of a motivational interview, goal attainment process, guidance for safe walking, a progressive home exercise program and physical activity counseling. In addition, frail participants who are not able to go outdoors alone receive support from volunteers. Primary outcomes are PA measured using a 3-dimentional accelerometer, and mobility assessed by the Short Physical Performance Battery and self-reports. Secondary outcomes are life space mobility, participation restriction, fear of falling, pain, mood, and grip strength. Information on barriers to and enablers of PA participation are also collected. Data on mortality and use of health services are collected from the national register. In this 6-month intervention, all participants are assessed in their homes at baseline and after three and six months, and at 12 months after randomization they will receive a follow-up questionnaire.
DISCUSSION: This study investigates the effects of a rehabilitation program on PA and mobility among older people at risk for increased sedentary time and mobility problems. If positive effects are observed, the program can be considered for incorporation into the health care system and thereby contribute to the rehabilitation of older people who have recently been discharged from hospital.
TRIAL REGISTRATION: ISRCTN13461584 . Registered 27 January 2016.
PMID: 29162078 [PubMed - in process]
Altered downstream target gene expression of the placental Vitamin D receptor in human idiopathic fetal growth restriction.
Cell Cycle. 2017 Nov 22;:1-29
Authors: Nguyen TP, Yong HE, Chollangi T, Brennecke SP, Fisher SJ, Wallace EM, Ebeling PR, Murthi P
Fetal growth restriction (FGR) affects up to 5% of pregnancies and is associated with significant perinatal complications. Maternal deficiency of vitamin D, a secosteroid hormone, is common in FGR-affected pregnancies. We recently demonstrated that decreased expression of the vitamin D receptor (VDR) in idiopathic FGR placentae could impair trophoblast growth. As strict regulation of cell-cycle genes in trophoblast cells is critical for optimal feto-placental growth, we hypothesised that pathologically decreased placental VDR contributes to aberrant regulation of cell-cycle genes. The study aims were to (i) identify the downstream cell-cycle regulatory genes of VDR in trophoblast cells, and (ii) determine if expression was changed in cases of FGR. Targeted cell-cycle gene cDNA arrays were used to screen for downstream targets of VDR in VDR siRNA-transfected BeWo and HTR-8/SVneo trophoblast-derived cell lines, and in third trimester placentae from FGR and gestation-matched control pregnancies (n = 25 each). The six candidate genes identified were CDKN2A, CDKN2D, HDAC4, HDAC6, TGFB2 and TGFB3. TGFB3 was prioritised for further validation, as its expression is largely unknown in FGR. Significantly reduced mRNA and protein expression of TGFB3 was verified in FGR placentae and the BeWo and HTR-8/SVneo trophoblast cell lines, using real-time PCR and immunoblotting respectively. In summary, decreased placental VDR expression alters the expression of regulatory cell-cycle genes in FGR placentae. Aberrant regulation of cell-cycle genes in the placental trophoblast cells may constitute a mechanistic pathway by which decreased placental VDR reduces feto-placental growth.
PMID: 29161966 [PubMed - as supplied by publisher]
The effect of augmented somatosensory feedback on standing postural sway.
Gait Posture. 2017 Nov 14;60:76-80
Authors: Smalley A, White SC, Burkard R
Impaired balance resulting from reduced postural control occurs with aging and various medical conditions. Sensory input for balance control is provided by the visual, vestibular and somatosensory systems. Previous research suggests that increased proprioceptive feedback from various lower extremity devices improves balance. Mixed results have been reported with the use of orthoses such as ankle foot orthoses (AFOs). In this study, 20 healthy subjects wore footplates in their shoes or straps around their lower legs in order to imitate the somatosensory feedback produced by wearing AFOs, but without providing ankle restriction. Subjects' standing balance was assessed using force plates and computerized dynamic posturography (the sensory organization test-SOT) to determine if either the footplates or the lower-leg straps would affect standing balance. The results revealed no significant difference with the use of the footplates, however, wearing the straps resulted in reduced postural sway for conditions when visual cue deprivation was combined with manipulation of somatosensory or vestibular feedback. This effect was more pronounced in participants with the poorest baseline measures of balance. These findings suggest that lower extremity devices, such as AFOs, may augment somatosensory feedback that could improve balance during challenging sensory deprivation conditions, independent of orthotic support at the ankle.
PMID: 29161626 [PubMed - as supplied by publisher]
[Estimation of time detection limit for human cytochrome b in females of Lutzomyia evansi].
Biomedica. 2017 Mar 29;37(0):187-192
Authors: Vergara JG, Verbel-Vergara D, Montesino AM, Pérez-Doria A, Bejarano EE
INTRODUCTION: Molecular biology techniques have allowed a better knowledge of sources of blood meals in vector insects. However, the usefulness of these techniques depends on both the quantity of ingested blood and the digestion process in the insect.
OBJECTIVE: To identify the time limit for detection of the human cytochrome b (Cyt b) gene in experimentally fed females of Lutzomyia evansi.
MATERIALS AND METHODS: Eight groups of L. evansi females were fed on human blood and sacrificed at intervals of 24 hours post-ingestion. Total DNA was extracted from each female and a segment of 358 bp of Cyt b was amplified. In order to eliminate false positives, amplification products were subjected to a restriction fragment length polymorphism (RFLP) analysis.
RESULTS: The human Cyt b gene segment was detected in 86% (49/57) of the females of L. evansi, from 0 to 168 hours after blood ingestion. In 7% (4/57) of the individuals we amplified insect DNA, while in the remaining 7%, the band of interest was not amplified. We did not find any statistical differences between groups of females sacrificed at different times post-blood meal regarding the amplification of the human Cyt b gene segment or the number of samples amplified.
CONCLUSION: The human Cyt b gene segment was detectable in L. evansi females up to 168 hours after blood ingestion.
PMID: 29161490 [PubMed - in process]
Partial bisulfite conversion for unique template sequencing.
Nucleic Acids Res. 2017 Nov 17;:
Authors: Kumar V, Rosenbaum J, Wang Z, Forcier T, Ronemus M, Wigler M, Levy D
We introduce a new protocol, mutational sequencing or muSeq, which uses sodium bisulfite to randomly deaminate unmethylated cytosines at a fixed and tunable rate. The muSeq protocol marks each initial template molecule with a unique mutation signature that is present in every copy of the template, and in every fragmented copy of a copy. In the sequenced read data, this signature is observed as a unique pattern of C-to-T or G-to-A nucleotide conversions. Clustering reads with the same conversion pattern enables accurate count and long-range assembly of initial template molecules from short-read sequence data. We explore count and low-error sequencing by profiling 135 000 restriction fragments in a PstI representation, demonstrating that muSeq improves copy number inference and significantly reduces sporadic sequencer error. We explore long-range assembly in the context of cDNA, generating contiguous transcript clusters greater than 3,000 bp in length. The muSeq assemblies reveal transcriptional diversity not observable from short-read data alone.
PMID: 29161423 [PubMed - as supplied by publisher]
Transfer and Metabolism of Cortisol by the Isolated Perfused Human Placenta.
J Clin Endocrinol Metab. 2017 Nov 16;:
Authors: Stirrat LI, Sengers BG, Norman JE, Homer NZM, Andrew R, Lewis RM, Reynolds RM
Context: Fetal overexposure to glucocorticoids in utero is associated with fetal growth restriction and is postulated to be a key mechanism linking suboptimal fetal growth with cardiovascular disease in later life.
Objective: To develop a model to predict maternal-fetal glucocorticoid transfer. We hypothesised placental 11β-HSD2 would be the major rate-limiting step in maternal cortisol transfer to the fetus.
Design: We used a deuterated cortisol tracer in the ex vivo placental perfusion model, in combination with computational modelling, to investigate the role of interconversion of cortisol and its inactive metabolite cortisone on transfer of cortisol from mother to fetus.
Participants: Term placentas were collected from five women with uncomplicated pregnancies, at elective caesarean delivery.
Intervention: Maternal artery of the isolated perfused placenta was perfused with D4-cortisol.
Main Outcome Measures: D4-cortisol, D3-cortisone and D3-cortisol were measured in maternal and fetal venous outflows.
Results: D4-cortisol, D3-cortisone and D3-cortisol were detected and increased in maternal and fetal veins as the concentration of D4-cortisol perfusion increased. D3-cortisone synthesis was inhibited when 11β-HSD activity was inhibited. At the highest inlet concentration only 3.0% of the maternal cortisol was transferred to the fetal circulation, while 26.5% was metabolised and 70.5% exited via the maternal vein. Inhibiting 11β-HSD activity increased the transfer to the fetus to 7.3% of the maternal input, while 92.7% exited via the maternal vein.
Conclusions: Our findings challenge the concept that maternal cortisol diffuses freely across the placenta and confirm that 11β-HSD2 acts as a major 'barrier' to cortisol transfer to the fetus.
PMID: 29161409 [PubMed - as supplied by publisher]
Critical care at the end of life: balancing technology with compassion and agreeing when to stop.
Br J Anaesth. 2017 Dec 01;119(suppl_1):i85-i89
Authors: Montgomery H, Grocott M, Mythen M
Modern intensive care saves lives. However, the substantial related financial costs are, for many, married to substantial costs in terms of suffering. In the most sick, the experience of intensive care is commonly associated with the development of profound physical debility, which may last years after discharge. Likewise, the negative psychological impact commonly experienced by such patients during their care is now widely recognized, as is the persistence of psychological morbidity. Such issues become increasingly important as the population of the frail elderly increases, and the health and social care services face budgetary restriction. Efforts must be made to humanize intensive care as much as possible. Meanwhile, an open conversation must be held between those within the medical professions, and between such healthcare workers and the public in general, regarding the balancing of the positive and negative impacts of intensive care. Such conversations should extend to individual patients and their families when considering what care is genuinely in their best interests.
PMID: 29161388 [PubMed - in process]
Genotyping-by-sequencing for estimating relatedness in non-model organisms: avoiding the trap of precise bias.
Mol Ecol Resour. 2017 Nov 21;:
Authors: Attard CRM, Beheregaray LB, Möller LM
There has been remarkably little attention to using the high resolution provided by genotyping-by-sequencing (i.e. RADseq and similar methods) datasets for assessing relatedness in wildlife populations. A major hurdle is the genotyping error, especially allelic dropout, often found in this type of dataset that could lead to downward-biased, yet precise, estimates of relatedness. Here we assess the applicability of genotyping-by-sequencing datasets for relatedness inferences given their relatively high genotyping error rates. Individuals of known relatedness were simulated under genotyping error, allelic dropout, and missing data scenarios based on an empirical ddRAD dataset, and their true relatedness was compared to that estimated by seven relatedness estimators. We found that an estimator chosen through such analyses can circumvent the influence of genotyping error, with the estimator of Ritland (1996) shown to be unaffected by allelic dropout and to be the most accurate when there is genotyping error. We also found that the choice of estimator should not rely solely on the strength of correlation between estimated and true relatedness as a strong correlation does not necessarily mean estimates are close to true relatedness. We also demonstrated how even a large SNP dataset with genotyping error (allelic dropout or otherwise) or missing data still performs better than a perfectly genotyped microsatellite dataset of tens of markers. The simulation-based approach used here can be easily implemented by others on their own genotyping-by-sequencing datasets to confirm the most appropriate and powerful estimator for their dataset. This article is protected by copyright. All rights reserved.
PMID: 29160928 [PubMed - as supplied by publisher]
The Role of RNF213 4810G>A and 4950G>A Variants in Patients with Moyamoya Disease in Korea.
Int J Mol Sci. 2017 Nov 21;18(11):
Authors: Park YS, An HJ, Kim JO, Kim WS, Han IB, Kim OJ, Kim NK, Kim DS
Although a founder variant of RNF213 4810G>A is a major genetic risk factor for moyamoya disease (MMD) in East Asians, the frequency and disease susceptibility of RNF213 variants remain largely unknown. This study investigated the mutation analysis of RNF213 (4448, 4810, 4863, and 4950) between Korean MMD and healthy controls. We performed a polymerase chain reaction-restriction fragment length polymorphism analysis. To identify the association between RNF213 gene polymorphisms and MMD disease, we performed statistical analyses such as multivariable logistic regression and Fisher's exact test. Genetic data from 117 MMD patients were analyzed and compared with 253 healthy controls. We assessed and compared single nucleotide polymorphisms of RNF213 (4448, 4810, 4863, and 4950) between MMD and control groups. We performed genome-wide association studies to investigate the genetic pathophysiology of MMD. Among the RNF213 variants (4448G>A, 4810G>A, 4863G>A, and 4950G>A), RNF213 4810G>A and 4950G>A variants were more frequent in MMD patients. In a subgroup analysis, the RNF213 4810G>A was more frequent in moyamoya disease, and the comparison with GG+AA genotype was also significantly different in moyamoya patients. These results confirm that RNF213 4810G>A and RNF213 4950G>A were more frequent in MMD patients. We have confirmed that RNF213 4810G>A and 4950G>A are strongly associated with Korean MMD in children and adults as well as for the ischemic and hemorrhagic types.
PMID: 29160859 [PubMed - in process]
The unveiling of the Warburg effect and the inscribed innovative approach to a radical non toxic anticancer therapy.
Cell Cycle. 2017 Nov 21;:1-28
Authors: Crociani O, Marzi I, Cipolleschi MG, Mannini A, Contini M, Olivotto M
The purpose of this research has been deciphering the Warburg paradox, the biochemical enigma unsolved since 1923. This paradox consists of the aerobic pyruvate conversion to lactate brought about by anaplastic cancer, through the metabolic pathway known as aerobic glycolysis. This pathway implies a heavy energetic waste. We solved the enigma by demonstrating that its specific character, i.e. the forced aerobic lactate exportation, represents a crucial metabolic device to counteract the cytotoxic effect produced by an excess of pyruvate at the connection of glycolysis with the Krebs cycle. This solution was verified by exposing cancer cells of different histogenesis to pyruvate concentrations higher than the physiological ones, after showing that these concentrations are totally innocuous when injected into mice. The molecular aspects for this cancer selectivity has been explored in vitro and in vivo, providing the following information: i) the growth of highly anaplastic cancers, including melanoma and leukemia cell lines, was up to 90% inhibited by the addition of 10-20 mM pyruvate, while substantially unaffected resulted the bone marrow cells (BMC) and the clonogenic lymphocytes; ii) the metastatic diffusion of the A375 melanoma cells injected into nude mice was drastically inhibited by pre-treatment with pyruvate, which produced the progressive massive cancer apoptosis. The pathophysiological aspects of the pyruvate cytotoxicity were deciphered through the following series of biochemical achievements: the cytotoxicity is a linear function of the rate of its commitment to the respiratory chain through the Krebs cycle, i.e. to the rate of O2 consumption. This commitment engages, up the saturation, the respiratory chain in its function other than the cristae-dependent oxidative phosphorylation. This function is the disposal of the cytosolic reducing equivalents, a crucial step in the regulation of the cytosolic NADP/NADPH ratio. The latter gears all the NADP-dependent dehydrogenations implicated in the multiple metabolic networks, including the conversion of methylene-tetrahydrofolate to methenyl-tetrahydrofolate, whose product is an integral component of the purine ring. On these bases, the mechanism of the pyruvate cytotoxicity relies on the saturation of the respiratory chain, leading to a negative shift of the cytosolic NADP/NADPH ratio and the consequent restriction of the purine synthesis and the related cell apoptosis. The reducing equivalents generated by glycolysis and by cytosolic metabolism compete each other for their disposal trough the respiratory chain; this makes it that the cytotoxicity of pyruvate is inversely related to the mitochondrial number and efficiency of various cell types. Thus, the cytotoxicity is high in anaplastic cancer stem cells, whose mitochondria are extremely few and immature (cristae-poor); on the contrary, no inhibition is brought about in adult differentiated cells, physiologically rich of mature mitochondria. All this generates the pyruvate anticancer selectivity, together with the lack of a general toxicity, making pyruvate represent an ideal candidate for a radical non toxical anticancer treatment.
PMID: 29160745 [PubMed - as supplied by publisher]
Leptin action in normal and pathological pregnancies.
J Cell Mol Med. 2017 Nov 21;:
Authors: Pérez-Pérez A, Toro A, Vilariño-García T, Maymó J, Guadix P, Dueñas JL, Fernández-Sánchez M, Varone C, Sánchez-Margalet V
Leptin is now considered an important signalling molecule of the reproductive system, as it regulates the production of gonadotrophins, the blastocyst formation and implantation, the normal placentation, as well as the foeto-placental communication. Leptin is a peptide hormone secreted mainly by adipose tissue, and the placenta is the second leptin-producing tissue in humans. Placental leptin is an important cytokine which regulates placental functions in an autocrine or paracrine manner. Leptin seems to play a crucial role during the first stages of pregnancy as it modulates critical processes such as proliferation, protein synthesis, invasion and apoptosis in placental cells. Furthermore, deregulation of leptin levels has been correlated with the pathogenesis of various disorders associated with reproduction and gestation, including polycystic ovary syndrome, recurrent miscarriage, gestational diabetes mellitus, pre-eclampsia and intrauterine growth restriction. Due to the relevant incidence of the mentioned diseases and the importance of leptin, we decided to review the latest information available about leptin action in normal and pathological pregnancies to support the idea of leptin as an important factor and/or predictor of diverse disorders associated with reproduction and pregnancy.
PMID: 29160594 [PubMed - as supplied by publisher]
Primum non nocere or primum facere meliorem? Hacking the brain in the 21st century.
Trends Psychiatry Psychother. 2017 Nov 13;:0
Authors: Borrione L, Brunoni AR
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that modulates cortical excitability. It is devoid of serious adverse events and exerts variable effects on cognition, with several research findings suggesting that it can improve memory, verbal and mathematical skills. Because tDCS devices are low-cost, portable and relatively easy to assemble, they have become available outside of the medical setting and used for non-medical ("cosmetic") purposes by laypersons. In this sense, tDCS has become a popular technique aiming to improve cognition and the achievement of a better performance not only at work, but also in other fields such as sports, leisure activities (video games) and even the military. In spite of these unforeseen developments, there has been a general paralysis of the medical and regulatory agencies to develop guidelines for the use of tDCS for cosmetic purposes. Several challenges are present, most importantly, how to restrict tDCS use outside of the medical setting in face of variable and sometimes conflicting results from scientific research. This article aims to describe the popular use of tDCS, in light of the pillars of neuroethics, a branch of bioethics relative to brain research. Between two possible but extreme solutions - total release or total restriction of tDCS - it is paramount to develop a spectrum of alternatives, which may vary over time and in different cultural backgrounds.
PMID: 29160331 [PubMed - as supplied by publisher]
Orbital invasive squamous cell carcinoma with adnexal involvement clinically mimicking feline restrictive orbital myofibroblastic sarcoma: 19 cases (1990-2016).
Vet Ophthalmol. 2017 Nov 21;:
Authors: Diehl KA, Pryor SG, Teixeira LB
OBJECTIVE: To describe the clinical presentations of patients diagnosed with ocular adnexal or orbital squamous cell carcinoma (SCC), which possess features similar to feline restrictive orbital myofibroblastic sarcoma (FROMS).
PROCEDURES: A retrospective review of adnexal and/or orbital SCC was performed. Cases were collected from the University of Georgia College of Veterinary Medicine and the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) (1990-2016). Data included signalment, ophthalmic clinical signs, nonophthalmic history and clinical signs, clinician suspicion of FROMS, advanced imaging results, and subsequent histopathologic diagnosis. FROMS cases from the COPLOW over the same time span were reviewed and compared statistically to the SCC cases with a significance threshold of 0.05.
RESULTS: Nineteen cases (20 eyes) were identified with adnexal SCC with features similar to FROMS, including keratitis and eyelid/third eyelid restriction and/or thickening. There were no statistically significant differences between clinical findings in the SCC cases and the identified and compared FROMS cases (57 cases; 67 eyes), except for exophthalmos and/or resistance to retropulsion, which was less common in SCC cases (20%) than in FROMS cases (47.8%) (P = 0.027); and clinical or imaged presence of an overt eyelid or orbital mass, which was more common in the SCC cases (30%) than in the FROMS cases (4.5%) (P = 0.0010).
CONCLUSIONS: SCC with adnexal involvement has many features similar to FROMS. In addition to FROMS, SCC should be considered a differential diagnosis in cats with restrictive adnexal or orbital signs and corneal changes.
PMID: 29159852 [PubMed - as supplied by publisher]
Fine-mapping of QTLs for individual and total isoflavone content in soybean (Glycine max L.) using a high-density genetic map.
Theor Appl Genet. 2017 Nov 20;:
Authors: Cai Z, Cheng Y, Ma Z, Liu X, Ma Q, Xia Q, Zhang G, Mu Y, Nian H
KEY MESSAGE: Fifteen stable QTLs were identified using a high-density soybean genetic map across multiple environments. One major QTL, qIF5-1, contributing to total isoflavone content explained phenotypic variance 49.38, 43.27, 46.59, 45.15 and 52.50%, respectively. Soybeans (Glycine max L.) are a major source of dietary isoflavones. To identify novel quantitative trait loci (QTL) underlying isoflavone content, and to improve the accuracy of marker-assisted breeding in soybean, a valuable mapping population comprised of 196 F7:8-10 recombinant inbred lines (RILs, Huachun 2 × Wayao) was utilized to evaluate individual and total isoflavone content in plants grown in four different environments in Guangdong. A high-density genetic linkage map containing 3469 recombination bin markers based on 0.2 × restriction site-associated DNA tag sequencing (RAD-seq) technology was used to finely map QTLs for both individual and total isoflavone contents. Correlation analyses showed that total isoflavone content, and that of five individual isoflavone, was significantly correlated across the four environments. Based on the high-density genetic linkage map, a total of 15 stable quantitative trait loci (QTLs) associated with isoflavone content across multiple environments were mapped onto chromosomes 02, 05, 07, 09, 10, 11, 13, 16, 17, and 19. Further, one of them, qIF5-1, localized to chromosomes 05 (38,434,171-39,045,620 bp) contributed to almost all isoflavone components across all environments, and explained 6.37-59.95% of the phenotypic variance, especially explained 49.38, 43.27, 46.59, 45.15 and 52.50% for total isoflavone. The results obtained in the present study will pave the way for a better understanding of the genetics of isoflavone accumulation and reveals the scope available for improvement of isoflavone content through marker-assisted selection.
PMID: 29159422 [PubMed - as supplied by publisher]
Fitness implications of sex-specific catch-up growth in Nephila senegalensis, a spider with extreme reversed SSD.
Authors: Neumann R, Ruppel N, Schneider JM
Background: Animal growth is often constrained by unfavourable conditions and divergences from optimal body size can be detrimental to an individual's fitness, particularly in species with determinate growth and a narrow time-frame for life-time reproduction. Growth restriction in early juvenile stages can later be compensated by means of plastic developmental responses, such as adaptive catch-up growth (the compensation of growth deficits through delayed development). Although sex differences regarding the mode and degree of growth compensation have been coherently predicted from sex-specific fitness payoffs, inconsistent results imply a need for further research. We used the African Nephila senegalensis, representing an extreme case of female-biased sexual size dimorphism (SSD), to study fitness implications of sex-specific growth compensation. We predicted effective catch-up growth in early food-restricted females to result in full compensation of growth deficits and a life-time fecundity (LTF) equivalent to unrestricted females. Based on a stronger trade-off between size-related benefits and costs of a delayed maturation, we expected less effective catch-up growth in males.
Methods: We tracked the development of over one thousand spiders in different feeding treatments, e.g., comprising a fixed period of early low feeding conditions followed by unrestricted feeding conditions, permanent unrestricted feeding conditions, or permanent low feeding conditions as a control. In a second experimental section, we assessed female fitness by measuring LTF in a subset of females. In addition, we tested whether compensatory development affected the reproductive lifespan in both sexes and analysed genotype-by-treatment interactions as a potential cause of variation in life-history traits.
Results: Both sexes delayed maturation to counteract early growth restriction, but only females achieved full compensation of adult body size. Female catch-up growth resulted in equivalent LTF compared to unrestricted females. We found significant interactions between experimental treatments and sex as well as between treatments and family lineage, suggesting that family-specific responses contribute to the unusually large variation of life-history traits in Nephila spiders. Our feeding treatments had no effect on the reproductive lifespan in either sex.
Discussion: Our findings are in line with predictions of life-history theory and corroborate strong fecundity selection to result in full female growth compensation. Males showed incomplete growth compensation despite a delayed development, indicating relaxed selection on large size and a stronger trade-off between late maturation and size-related benefits. We suggest that moderate catch-up growth in males is still adaptive as a 'bet-hedging' strategy to disperse unavoidable costs between life-history traits affected by early growth restriction (the duration of development and adult size).
PMID: 29158981 [PubMed]
Ginsenoside Rk1 bioactivity: a systematic review.
Authors: Elshafay A, Tinh NX, Salman S, Shaheen YS, Othman EB, Elhady MT, Kansakar AR, Tran L, Van L, Hirayama K, Huy NT
Ginsenoside Rk1 (G-Rk1) is a unique component created by processing the ginseng plant (mainly Sung Ginseng (SG)) at high temperatures. The aim of our study was to systematically review the pharmacological effects of G-Rk1. We utilized and manually searched eight databases to select in vivo and in vitro original studies that provided information about biological, pharmaceutical effects of G-Rk1 and were published up to July 2017 with no restriction on language or study design. Out of the 156 papers identified, we retrieved 28 eligible papers in the first skimming phase of research. Several articles largely described the G-Rk1 anti-cancer activity investigating "cell viability", "cell proliferation inhibition", "apoptotic activity", and "effects of G-Rk1 on G1 phase and autophagy in tumor cells" either alone or in combination with G-Rg5. Others proved that it has antiplatelet aggregation activities, anti-inflammatory effects, anti-insulin resistance, nephroprotective effect, antimicrobial effect, cognitive function enhancement, lipid accumulation reduction and prevents osteoporosis. In conclusion, G-Rk1 has a significant anti-tumor effect on liver cancer, melanoma, lung cancer, cervical cancer, colon cancer, pancreatic cancer, gastric cancer, and breast adenocarcinoma against in vitro cell lines. In vivo experiments are further warranted to confirm these effects.
PMID: 29158964 [PubMed]
Role of 3-monthly long-acting injectable paliperidone in the maintenance of schizophrenia.
Neuropsychiatr Dis Treat. 2017;13:2767-2779
Authors: Brasso C, Bellino S, Bozzatello P, Montemagni C, Rocca P
Aims: Paliperidone palmitate 3-month (PP3M) represents a new long-acting injectable antipsychotic therapeutic option. This review aims: 1) to summarize available data relating to efficacy, safety, tolerability and costs of PP3M; 2) to describe hospitalization rate, occupational status, treatment preference, satisfaction, adherence and caregiver burden of patients with schizophrenia who participate in PP3M clinical trials; 3) to examine ethical implications, pros and cons of PP3M use and 4) to propose study designs to further assess PP3M.
Methods: On August 21, 2017, a search on PubMed about PPM3, without any filter restriction, was conducted and all available records were analyzed. Records written in a language other than English were excluded.
Results: Twenty-two records were included in this review: 6 reviews, 1 report, 4 pharmacokinetic studies, 2 cost-effectiveness analyses, 1 open-label clinical trial, 2 randomized controlled trials (RCTs), 5 studies based on these 2 RCTs and 1 observational study.
Discussion: According to these last 9 studies, when compared with placebo, PP3M showed a longer time to relapse and good safety and tolerability profiles. Furthermore, when compared with paliperidone palmitate 1 month (PP1M), PP3M treatment showed: 1) non-inferiority in terms of efficacy, safety, tolerability, rate of hospitalization, symptomatic and functional remission, treatment preference and variations of the occupational status; 2) a longer time to relapse after treatment discontinuation and 3) a similar reduction of the caregiver burden.
Conclusion: PP3M is the only 3-monthly long-acting injectable antipsychotic available on the market. This makes it a unique option of treatment, which could be chosen both in early and advanced phases of illness. Nonetheless, longer naturalistic follow-up studies, two-arm head-to-head superiority trials and mirror studies, based on real-world samples of patients, are needed to further assess long-term safety and advantages of this new option of treatment and to define patients' sub-populations that would most beneficiate from it.
PMID: 29158676 [PubMed]
Deep sequencing of HIV-1 reverse transcripts reveals the multifaceted antiviral functions of APOBEC3G.
Nat Microbiol. 2017 Nov 20;:
Authors: Pollpeter D, Parsons M, Sobala AE, Coxhead S, Lang RD, Bruns AM, Papaioannou S, McDonnell JM, Apolonia L, Chowdhury JA, Horvath CM, Malim MH
Following cell entry, the RNA genome of HIV-1 is reverse transcribed into double-stranded DNA that ultimately integrates into the host-cell genome to establish the provirus. These early phases of infection are notably vulnerable to suppression by a collection of cellular antiviral effectors, called restriction or resistance factors. The host antiviral protein APOBEC3G (A3G) antagonizes the early steps of HIV-1 infection through the combined effects of inhibiting viral cDNA production and cytidine-to-uridine-driven hypermutation of this cDNA. In seeking to address the underlying molecular mechanism for inhibited cDNA synthesis, we developed a deep sequencing strategy to characterize nascent reverse transcription products and their precise 3'-termini in HIV-1 infected T cells. Our results demonstrate site- and sequence-independent interference with reverse transcription, which requires the specific interaction of A3G with reverse transcriptase itself. This approach also established, contrary to current ideas, that cellular uracil base excision repair (UBER) enzymes target and cleave A3G-edited uridine-containing viral cDNA. Together, these findings yield further insights into the regulatory interplay between reverse transcriptase, A3G and cellular DNA repair machinery, and identify the suppression of HIV-1 reverse transcriptase by a directly interacting host protein as a new cell-mediated antiviral mechanism.
PMID: 29158605 [PubMed - as supplied by publisher]
Wild bonobos host geographically restricted malaria parasites including a putative new Laverania species.
Nat Commun. 2017 Nov 21;8(1):1635
Authors: Liu W, Sherrill-Mix S, Learn GH, Scully EJ, Li Y, Avitto AN, Loy DE, Lauder AP, Sundararaman SA, Plenderleith LJ, Ndjango JN, Georgiev AV, Ahuka-Mundeke S, Peeters M, Bertolani P, Dupain J, Garai C, Hart JA, Hart TB, Shaw GM, Sharp PM, Hahn BH
Malaria parasites, though widespread among wild chimpanzees and gorillas, have not been detected in bonobos. Here, we show that wild-living bonobos are endemically Plasmodium infected in the eastern-most part of their range. Testing 1556 faecal samples from 11 field sites, we identify high prevalence Laverania infections in the Tshuapa-Lomami-Lualaba (TL2) area, but not at other locations across the Congo. TL2 bonobos harbour P. gaboni, formerly only found in chimpanzees, as well as a potential new species, Plasmodium lomamiensis sp. nov. Rare co-infections with non-Laverania parasites were also observed. Phylogenetic relationships among Laverania species are consistent with co-divergence with their gorilla, chimpanzee and bonobo hosts, suggesting a timescale for their evolution. The absence of Plasmodium from most field sites could not be explained by parasite seasonality, nor by bonobo population structure, diet or gut microbiota. Thus, the geographic restriction of bonobo Plasmodium reflects still unidentified factors that likely influence parasite transmission.
PMID: 29158512 [PubMed - in process]
BL-Hi-C is an efficient and sensitive approach for capturing structural and regulatory chromatin interactions.
Nat Commun. 2017 Nov 20;8(1):1622
Authors: Liang Z, Li G, Wang Z, Djekidel MN, Li Y, Qian MP, Zhang MQ, Chen Y
In human cells, DNA is hierarchically organized and assembled with histones and DNA-binding proteins in three dimensions. Chromatin interactions play important roles in genome architecture and gene regulation, including robustness in the developmental stages and flexibility during the cell cycle. Here we propose in situ Hi-C method named Bridge Linker-Hi-C (BL-Hi-C) for capturing structural and regulatory chromatin interactions by restriction enzyme targeting and two-step proximity ligation. This method improves the sensitivity and specificity of active chromatin loop detection and can reveal the regulatory enhancer-promoter architecture better than conventional methods at a lower sequencing depth and with a simpler protocol. We demonstrate its utility with two well-studied developmental loci: the beta-globin and HOXC cluster regions.
PMID: 29158486 [PubMed - in process]
Physiological and behavioral responses of an arboreal mammal to smoke and charcoal-ash substrate.
Physiol Behav. 2017 Nov 17;:
Authors: Nowack J, Stawski C, Körtner G, Geiser F
The recent observation that torpor plays a key role in post-fire survival has been mainly attributed to the reduced food resources after fires. However, some of these adjustments can be facilitated or amplified by environmental changes associated with fires, such as the presence of a charcoal-ash substrate. In a previous experiment on a small terrestrial mammal the presence of charcoal and ash linked to food restriction intensified torpor use. However, whether fire cues also act as a trigger of torpor use when food is available and whether they affect other species including arboreal mammals remains elusive. To evaluate whether smoke, charcoal and ash can act as proximate triggers for an impending period of food shortage requiring torpor for mammals, we conducted an experiment on captive sugar gliders (Petaurus breviceps), a small, arboreal marsupial, housed in outside aviaries under different food regimes and natural ambient conditions. When food was available, fire simulation via exposure to smoke and charcoal-ash substrate caused a significant earlier start of activity and a significant decrease in resting body temperature. In contrast, only when food was withheld, did smoke and charcoal-ash exposure significantly enhance torpor depth and duration. Thus, our study not only provides evidence that fire simulation does affect arboreal and terrestrial species similarly, but also suggests that smoke and ash were presumably selected as cues for torpor induction because they indicate an impending lack of food.
PMID: 29158126 [PubMed - as supplied by publisher]
Observation of the effects of different surgical treatments on unilateral masticatory muscle spasm.
World Neurosurg. 2017 Nov 17;:
Authors: Wu G, Ouyang J, Zhang Z, Liu R
BACKGROUND: Unilateral masticatory muscle spasm is a rare disease without a generally accepted and efficacious treatment plan.
OBJECTIVE: To compare the effects of different surgical treatments on unilateral masticatory muscle spasm.
METHODS: Retrospective analysis of the surgical treatment and effects of 10 cases of unilateral masticatory muscle spasm between February 2010 and September 2016. Three cases underwent complete amputation of the trigeminal motor branch, 3 cases underwent partial amputation of the trigeminal motor branch, and 4 cases received only vascular decompression. All patients were followed-up by telephone interview after surgery.
RESULTS: In the simple vascular decompression group, 3 cases were cured and 1 was cured after a delay. Of these 3 cases, 1 case became aggravated 2 years after the operation, 1 case became aggravated 5 years after the operation, and 1 case showed no change during the follow-up period. In the partial amputation group, 2 cases were cured and 1 case was alleviated. Of the 2 patients who were cured, 1 suffered recurrence 2 years later, while the other case showed no recurrence during the follow-up period. In the complete amputation group, 1 case was cured with a delay, and 2 cases were cured immediately with no recurrence during the following-up. Mild atrophy of the temporal muscle occurred gradually with no restriction of mouth opening in 2 cases.
CONCLUSIONS: Complete amputation of the trigeminal nerve did achieve better effect than pure microvascular decompression and partial amputation of the trigeminal motor branch, but may lead to mild temporal muscle atrophy.
PMID: 29158091 [PubMed - as supplied by publisher]
DNA methylation affects the lifespan of honey bee (Apis mellifera L.) workers - Evidence for a regulatory module that involves vitellogenin expression but is independent of juvenile hormone function.
Insect Biochem Mol Biol. 2017 Nov 17;:
Authors: Cardoso-Júnior CAM, Guidugli-Lazzarini KR, Hartfelder K
The canonic regulatory module for lifespan of honey bee (Apis mellifera) workers involves a mutual repressor relationship between juvenile hormone (JH) and vitellogenin (Vg). Compared to vertebrates, however, little is known about a possible role of epigenetic factors. The full genomic repertoire of DNA methyltransferases (DNMTs) makes the honey bee an attractive emergent model for studying the role of epigenetics in the aging process of invertebrates, and especially so in social insects. We first quantified the transcript levels of the four DNMTs encoding genes in the head thorax and abdomens of workers of different age, showing that dnmt1a and dnmt3 expression is up-regulated in abdomens of old workers, whereas dnmt1b and dnmt2 are down-regulated in heads of old workers. Pharmacological genome demethylation by RG108 treatment caused an increase in worker lifespan. Next, we showed that the genomic DNA methylation status indirectly affects vitellogenin gene expression both in vitro and in vivo in young workers, and that this occurs independent of caloric restriction or JH levels, suggesting that a non-canonical circuitry may be acting in parallel with the JH/Vg module to regulate the adult life cycle of honey bee workers. Our data provide evidence that epigenetic factors play a role in regulatory networks associated with complex life history traits of a social insect.
PMID: 29157677 [PubMed - as supplied by publisher]
Medical Considerations in Children and Adolescents with Eating Disorders.
Child Adolesc Psychiatr Clin N Am. 2018 Jan;27(1):1-14
Authors: DerMarderosian D, Chapman HA, Tortolani C, Willis MD
Eating disorders are a group of psychiatric disorders with potentially fatal medical complications. Early integrated care including the family as well as pediatric medicine, nutrition, psychology and psychiatry is critical for improving prognosis and limiting negative outcomes. Mental health services are a critical component of treatment; timely weight restoration maximizes efficacy. Despite being relatively common, there are many misperceptions about eating disorders, their severity, and the associated morbidity and mortality. Opportunities exist within the medical and psychiatric communities for a better understanding of the complexity of diagnosing and treating patients with eating disorders.
PMID: 29157496 [PubMed - in process]
Phylogenetic and recombination analysis of the herpesvirus genus varicellovirus.
BMC Genomics. 2017 Nov 21;18(1):887
Authors: Kolb AW, Lewin AC, Moeller Trane R, McLellan GJ, Brandt CR
BACKGROUND: The varicelloviruses comprise a genus within the alphaherpesvirus subfamily, and infect both humans and other mammals. Recently, next-generation sequencing has been used to generate genomic sequences of several members of the Varicellovirus genus. Here, currently available varicellovirus genomic sequences were used for phylogenetic, recombination, and genetic distance analysis.
RESULTS: A phylogenetic network including genomic sequences of individual species, was generated and suggested a potential restriction between the ungulate and non-ungulate viruses. Intraspecies genetic distances were higher in the ungulate viruses (pseudorabies virus (SuHV-1) 1.65%, bovine herpes virus type 1 (BHV-1) 0.81%, equine herpes virus type 1 (EHV-1) 0.79%, equine herpes virus type 4 (EHV-4) 0.16%) than non-ungulate viruses (feline herpes virus type 1 (FHV-1) 0.0089%, canine herpes virus type 1 (CHV-1) 0.005%, varicella-zoster virus (VZV) 0.136%). The G + C content of the ungulate viruses was also higher (SuHV-1 73.6%, BHV-1 72.6%, EHV-1 56.6%, EHV-4 50.5%) compared to the non-ungulate viruses (FHV-1 45.8%, CHV-1 31.6%, VZV 45.8%), which suggests a possible link between G + C content and intraspecies genetic diversity. Varicellovirus clade nomenclature is variable across different species, and we propose a standardization based on genomic genetic distance. A recent study reported no recombination between sequenced FHV-1 strains, however in the present study, both splitstree, bootscan, and PHI analysis indicated recombination. We also found that the recently sequenced Brazilian CHV-1 strain BTU-1 may contain a genetic signal in the UL50 gene from an unknown varicellovirus.
CONCLUSION: Together, the data contribute to a greater understanding of varicellovirus genomics, and we also suggest a new clade nomenclature scheme based on genetic distances.
PMID: 29157201 [PubMed - in process]
Perinatal outcomes of hypertensive disorders in pregnancy at a tertiary hospital in Ghana.
BMC Pregnancy Childbirth. 2017 Nov 21;17(1):388
Authors: Adu-Bonsaffoh K, Ntumy MY, Obed SA, Seffah JD
BACKGROUND: Hypertensive disorders in pregnancy remain a major global health issue not only because of the associated high adverse maternal outcomes but there is a close accompaniment of significant perinatal morbidity and mortality especially in Sub-Saharan Africa (SSA). However, the perinatal burden of HDP in Ghana has not been explored. We conducted this study to determine the perinatal outcomes of HDP at a tertiary hospital in Ghana.
METHODS: A cross-sectional study conducted between January to February 2013 at Korle Bu Teaching Hospital (KBTH) in Accra, Ghana. Data collection involved baseline review of all the obstetric population who had just delivered to identify those with HDP. An informed consent was obtained after which a structured questionnaire was adminstered to the hypertensive mothers. The medical records of the mothers and their babies were also reviewed to determine the perinatal outcome indicators of relevance to the study. Data obtained were analyzed using SPSS version 20.
RESULTS: We included 368 women with HDP and singleton births with a mean gestational age at delivery of 37.4 ± 3.3 weeks. Adverse perinatal outcomes determined include the following: 91 (24.7%) neonates were admitted to the Neonatal Intensive Care Unit, 56 (15.2%) had neonatal respiratory distress/asphyxia with 14 (3.8%) requiring ventilatory support and 80 (21.7%) were delivered preterm. Also, stillbirth, early neonatal death, intrauterine growth restriction and low birth weight occurred in 25 (6.8%), 14 (3.8%), 23 (6.1%) and 91 (24.7%) respectively with a perinatal mortality rate of 106 per 1000 births. One and 5 minute APGAR scores <7 occurred in 125 (34.0%) and 55 (14.7%) neonates respectively. Most of the adverse perinatal outcomes were significantly more common in those with preeclampsia compared to the other hypertensive disorders.
CONCLUSION: There is a significant burden of perinatal morbidity and mortality associated with HDP in the Ghanaian obstetric population and these adverse outcomes were more prevalent in preeclampsia compared to the other hypertensive disorders. Regular goal-oriented clinical audit into perinatal morbidity and mortality associated with HDP and an active multidisciplinary approach to the management of these disorders in the hospital might improve the clinical outcomes of women with maternal hypertension.
PMID: 29157196 [PubMed - in process]
Mucopolysaccharidosis Type VI in a Great Dane Caused by a Nonsense Mutation in the ARSB Gene.
Vet Pathol. 2017 Jan 01;:300985817732115
Authors: Wang P, Margolis C, Lin G, Buza EL, Quick S, Raj K, Han R, Giger U
Mucopolysaccharidoses are inherited metabolic disorders that result from a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans. Lysosomal glycosaminoglycan accumulation results in cell and organ dysfunction. This study characterized the phenotype and genotype of mucopolysaccharidosis VI in a Great Dane puppy with clinical signs of stunted growth, facial dysmorphia, skeletal deformities, corneal opacities, and increased respiratory sounds. Clinical and pathologic evaluations, urine glycosaminoglycan analyses, lysosomal enzyme assays, and ARSB sequencing were performed. The urine mucopolysaccharide spot test was strongly positive predominantly due to the accumulation of dermatan sulfate. Enzyme assays in leukocytes and tissues indicated a deficiency of arylsulfatase B (ARSB) activity. Histologic examination revealed cytoplasmic vacuoles in many tissues. Analysis of the exonic ARSB DNA sequences from the affected puppy compared to the published canine genome sequence revealed a homozygous nonsense mutation (c.295C>T) in exon 1, replacing glutamine with a premature stop codon (p.Gln99*), predicting no enzyme synthesis. A polymerase chain reaction-based restriction fragment length polymorphism test was established to assist with the clinical diagnosis and breeding of Great Danes. This genotyping test revealed that the clinically healthy parents and some other relatives of the puppy were heterozygous for the mutant allele, but all 200 clinically healthy dogs screened including 15 Great Danes were homozygous for the normal allele. This ARSB mutation is the fourth identified genetic variant causing canine mucopolysaccharidosis VI. Mucopolysaccharidosis VI is the first lysosomal storage disorder described in Great Danes but does not appear to be widespread in this breed.
PMID: 29157190 [PubMed - as supplied by publisher]
The association of first trimester uterine arteries Doppler velocimetry with different clinical phenotypes of hypertensive disorders of pregnancy: a longitudinal study.
J Matern Fetal Neonatal Med. 2017 Nov 20;:1-9
Authors: Stampalija T, Monasta L, Di Martino DD, Quadrifoglio M, Lo Bello L, D'Ottavio G, Zullino S, Mastroianni C, Casati D, Signorelli V, Rosti E, Cecotti V, Ceccarello M, Ferrazzi E
INTRODUCTION: Current classification of hypertensive disorders of pregnancy (HDP) is mostly based on temporal classification differentiating HDP according to early and late onset of the disease. However, epidemiological and clinical data suggest that there are two different clinical phenotypes of HDP that coexist at any gestational age: HDP associated to intrauterine growth restriction (HDP-IUGR) and HDP associated to appropriate for gestational age fetal growth (HDP-AGAf). The aim of the study was to evaluate the association of first trimester uterine arteries (UtA) by Doppler velocimetry, and maternal risk factors with HDP according to two different classifications: one based on gestational age at delivery (early- and late-HDP), and one based on longitudinal ultrasound evaluation of fetal growth (HDP-IUGR and HDP-AGAf), independently of the gestational age.
METHODS: Maternal characteristics and mean pulsatility index (PI) of UtA were collected at 11-13 gestational weeks. A longitudinal ultrasound follow-up of fetal growth in each trimester and clinical outcome were obtained in 4290 singleton pregnancies.
RESULTS: UtA-PI was significantly higher in women who developed HDP-IUGR (n = 22) and the odds ratio (OR) to develop HDP-IUGR from 25 to 39 weeks was 8.6 (p < .0001). HDP-AGAf (n = 112) was significantly associated with a higher BMI, multiparity, and maternal age, but not with UtA-PI (OR 1.3; p = .2). In women with an abnormal UtA-PI, the odds of developing early (n = 15) and late-HDP (n = 119) were 3.0 (p = .03) and 1.7 (p = .002), respectively. The AUCs for HDP-IUGR and early-HDP were 0.84 and 0.71, respectively.
DISCUSSION: UtA Doppler velocimetry in the first trimester was strongly associated with HDP-IUGR all along gestation, as a proxy of placental insufficiency, and showed no association with HDP-AGAf. Our findings suggest an efficacy of first trimester UtA Doppler velocimetry to identify HDP-IUGR independently of the gestational age, and a limited value for HDP not associated with intrauterine growth restriction (IUGR).
PMID: 29157099 [PubMed - as supplied by publisher]
Pregnancy outcome and placental pathology in small for gestational age neonates in relation to the severity of their growth restriction.
J Matern Fetal Neonatal Med. 2017 Nov 20;:1-191
Authors: Gluck O, Schreiber L, Marciano A, Mizrcachi Y, Bar J, Kovo M
PURPOSE: To investigate neonatal outcome and placental pathology in pregnancies complicated with small for gestational age neonates (SGA), in relation to the severity of growth restriction.
METHODS: The medical records and placental histology reports of all neonates with a birth-weight (BW) ≤ 10th percentile, born between 24-42 weeks, during 2010-2015, were reviewed. Placental lesions were classified into maternal and fetal vascular malperfusion (maternal vascular malperfusion (MVM) and fetal vascular malperfusion (FVM)) lesions. Results were compared between neonates with BW < 5th percentile (severe SGA group), neonates with BW between 5th-10th percentile (mild SGA group) and a control group of appropriate for gestational age (AGA) neonates. Composite neonatal outcome was defined as one or more of early complications.
RESULTS: Overall, 753 neonates were included, 238 in the severe SGA group, 266 in the mild SGA group, and 249 in the control group. The severe SGA group had higher rates of composite adverse neonatal outcome as compared with the mild SGA and control groups (37.2 versus 17.6%, versus 24.5%, respectively, p < 0.001). The SGA groups was characterized by higher rates of placental MVM and FVM lesions, compared with controls (p < 0.001 for both). After controlling for confounders, using a multivariate regression analysis, the likelihood of detecting placental MVM and FVM lesions was increased as neonatal birthweight decreased.
CONCLUSION: Worse neonatal outcome and more placental maternal and fetal vascular malperfusion lesions correlate with the severity of neonatal growth restriction in a "dose dependent" manner.
PMID: 29157050 [PubMed - as supplied by publisher]
The Drosha rs10719 T>C polymorphism is associated with preeclampsia susceptibility.
Clin Exp Hypertens. 2017 Nov 20;:1-6
Authors: Rezaei M, Eskandari F, Mohammadpour-Gharehbagh A, Teimoori B, Yaghmaei M, Mokhtari M, Salimi S
PURPOSE: Drosha is a member of the micro RNA (miRNA) processing machinery that affects miRNA processing. Single-nucleotide polymorphisms (SNPs) in the Drosha gene might affect microRNA processing and the expression of various genes. The aim of this study is to investigate the association between SNPs in the Drosha gene and preeclampsia (PE) in the southeast of Iran.
METHODS: Genotyping of Drosha rs10719 and rs6877842 was performed using blood samples from 219 PE women and 205 healthy control subjects by a polymerase chain reaction-restriction fragment length polymorphism method.
RESULTS: The Drosha rs10719TC genotype was significantly associated with 1.6-fold higher risk of PE (odds ratio (OR, 1.6 [95% CI, 1.1-2.4], P = 0.026). In addition, the frequency of the Drosha rs10719CC genotype was significantly higher in PE women and was associated with threefold higher risk of PE (OR 3 [95% CI 1.4-6.3], P = 0.004). There was no association between the Drosha rs6877842 polymorphism and PE susceptibility. The CC-GG combined genotype was associated with 3.4-fold higher risk of PE (OR 3.4 [95% CI 1.4-8.1], P = 0.007). The haplotype-based association analysis showed higher frequency of C-G haplotype of Drosha rs10719 and rs6877842 polymorphisms with the increased risk of PE 1.5-fold (OR 1.5 [95% CI 1.1 - 2], P = 0.01).
CONCLUSIONS: The Drosha rs10719TC and CC genotypes were associated with PE risk. The CC-GG combined genotype and C-G haplotype of Drosha rs10719 and rs6877842 polymorphisms may increase PE susceptibility.
PMID: 29157048 [PubMed - as supplied by publisher]
Neurological development of children born to mothers after kidney transplantation.
J Matern Fetal Neonatal Med. 2017 Nov 20;:1-131
Authors: Schreiber-Zamora J, Monika SS, Drozdowska-Szymczak A, Czaplińska N, Pietrzak B, Wielgos M, Kociszewska-Najman B
BACKGROUND: Pregnancies after kidney transplantation are at high risk of complications such as preterm birth and foetal growth restriction. Until now, the impact of these factors on neurological development of children born to transplant mothers has not been established.
AIMS: A comparison of neurological examinations performed in 36 children of kidney transplant women (study group) and 36 children born to healthy mothers (control group). The children from both groups were born at a similar gestational age and in the similar time period from 12/1996 to 09/2012. Neurological examinations were performed from 07/2010 to 11/2013. Each examination was adjusted to the patient's age and performed after the neonatal period. Three years later children were re-consulted, if they presented neurological deviations or were less than 12 months old at the time of the first examination.
RESULTS: Normal neurological development was found in 86% of children in both groups (p = 0.999). Mild neurological deviations were observed in 4 (11%) children born to kidney transplant mothers and in 5 (14%) children born to healthy mothers (p = 0.999). Moderate deviations were diagnosed in one premature child born to transplant mother, whose pregnancy was complicated with a severe preeclampsia and foetal growth restriction. In the study population no severe neurological disorders were found. Almost all (8/10) children with neurological deviations were born prematurely in good general conditions. The neurological deviations observed in the first year of life were mild and transient. In children over 1 year of age deviations were more pronounced and continued to maintain.
CONCLUSIONS: The neurological development of children of kidney transplant women is similar to that of the general population and possible deviations seem to be the result of intrauterine hypotrophy and prematurity. Therefore, in clinical practice, it is necessary to plan post-transplant pregnancies especially in women at high risk of these complications.
PMID: 29157047 [PubMed - as supplied by publisher]