Transcriptomic response to differentiation induction

BACKGROUND: Microarrays used for gene expression studies yield large amounts of data. The processing of such data typically leads to lists of differentially-regulated genes. A common terminal data analysis step is to map pathways of potentially interrelated genes. METHODS: We applied a transcriptomics analysis tool to elucidate the underlying pathways of leukocyte maturation at the genomic level in an established cellular model of leukemia by examining time-course data in two subclones of U-937 cells. Leukemias such as Acute Promyelocytic Leukemia (APL) are characterized by a block in the hematopoietic stem cell maturation program at a point when expansion of clones which should be destined to mature into terminally-differentiated effector cells get locked into endless proliferation with few cells reaching maturation. Treatment with retinoic acid, depending on the precise genomic abnormality, often releases the responsible promyelocytes from this blockade but clinically can yield adverse sequellae in terms of potentially lethal side effects, referred to as retinoic acid syndrome. RESULTS: Briefly, the list of genes for temporal patterns of expression was pasted into the ABCC GRID Promoter TFSite Comparison Page website tool and the outputs for each pattern were examined for possible coordinated regulation by shared regelems (regulatory elements). We found it informative to use this novel web tool for identifying, on a genomic scale, genes regulated by drug treatment. CONCLUSION: Improvement is needed in understanding the nature of the mutations responsible for controlling the maturation process and how these genes regulate downstream effects if there is to be better targeting of chemical interventions. Expanded implementation of the techniques and results reported here may better direct future efforts to improve treatment for diseases not restricted to APL

Regulation of dynamic polarity switching in bacteria by a Ras-like G-protein and its cognate GAP

The rod-shaped cells of the bacterium Myxococcus xanthus move uni-directionally and occasionally undergo reversals during which the leading/lagging polarity axis is inverted. Cellular reversals depend on pole-to-pole relocation of motility proteins that localize to the cell poles between reversals. We show that MglA is a Ras-like G-protein and acts as a nucleotide-dependent molecular switch to regulate motility and that MglB represents a novel GTPase-activating protein (GAP) family and is the cognate GAP of MglA. Between reversals, MglA/GTP is restricted to the leading and MglB to the lagging pole defining the leading/lagging polarity axis. For reversals, the Frz chemosensory system induces the relocation of MglA/GTP to the lagging pole causing an inversion of the leading/lagging polarity axis. MglA/GTP stimulates motility by establishing correct polarity of motility proteins between reversals and reversals by inducing their pole-to-pole relocation. Thus, the function of Ras-like G-proteins and their GAPs in regulating cell polarity is found not only in eukaryotes, but also conserved in bacteria

Risk and sensitivity quantification of fracture failure employing cohesive zone elements

Many structures are subjected to the risk of fatigue failure. For their reliability-based design, it is thus important to calculate the probability of fatigue failure and assess the relative importance of the involved parameters. Although various studies have analyzed the fatigue failure, the stage of fracture failure has been less focused. In particular, the risk analysis of fracture failure needs to be conducted considering its importance in actual structures. This article proposes a new probabilistic framework for the risk and sensitivity analysis of structural fatigue failure employing cohesive zone elements. The proposed framework comprises three steps, namely finite element analysis using cohesive zone elements, response surface construction, and risk and sensitivity analysis of fatigue failure, which require several mathematical techniques and algorithms. The proposed framework is tested by applying it to an illustrative example, and the corresponding analysis results of fracture failure probability with different threshold values of a limit-state function are presented. In addition, the sensitivities of failure risk with respect to the statistical parameters of random variables are presented and their relative importance is discussed

Androgen secreting steroid cell tumor of the ovary in a young lactating women with acute onset of severe hyperandrogenism: a case report and review of literature

<p>Abstract</p> <p>Introduction</p> <p>Steroid cell tumors of the ovary account for less than 0.1% of all ovarian tumors <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> and these tumours may present at any age in association with interesting presentations related to the hormonal activity and virilizing properties of tumor. Hayes and Scully <abbrgrp><abbr bid="B2">2</abbr></abbrgrp> reported 63 cases in patients ranging from 2 to 80 years of age. The subtype, not otherwise specified, is associated with androgenic changes in approximately one half of patients with this tumour <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. In a series of 63 cases from Massachusetts General Hospital, 94% of the tumors were found to be unilateral and 28.6% were malignant <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>. As most of these tumors are diagnosed at an early stage and do not recur or metastasize, little is known about their response to therapies such as chemotherapy or radiation <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>.</p> <p>Case Presentation</p> <p>We present the case of a 22-year old lactating woman who presented with four months of amenorrhea associated with signs of virilization. Clinical and diagnostic evaluation revealed a right adenexal mass and elevated serum levels of testosterone and she was diagnosed as having a stage 1A androgen secreting steroid cell tumor. In view of the early stage of the disease, she underwent right salpingo-oopherectomy. Histopathological examination and immunohistochemistry confirmed the diagnosis. Two months after surgery she regained normal menses and showed regression of the androgenic changes.</p> <p>Conclusion</p> <p>Surgery remains the mainstay of the treatment of gonadotrophin receptor positive steroid cell tumors although medical therapy using Gonadotrophin Releasing Hormone [GnRH analogues has been tried recently in recurrent or inoperable cases. There is no described effective chemotherapy or radiotherapy for this condition.</p

SCAMP:standardised, concentrated, additional macronutrients, parenteral nutrition in very preterm infants: a phase IV randomised, controlled exploratory study of macronutrient intake, growth and other aspects of neonatal care

<p>Abstract</p> <p>Background</p> <p>Infants born <29 weeks gestation are at high risk of neurocognitive disability. Early postnatal growth failure, particularly head growth, is an important and potentially reversible risk factor for impaired neurodevelopmental outcome. Inadequate nutrition is a major factor in this postnatal growth failure, optimal protein and calorie (macronutrient) intakes are rarely achieved, especially in the first week. Infants <29 weeks are dependent on parenteral nutrition for the bulk of their nutrient needs for the first 2-3 weeks of life to allow gut adaptation to milk digestion. The prescription, formulation and administration of neonatal parenteral nutrition is critical to achieving optimal protein and calorie intake but has received little scientific evaluation. Current neonatal parenteral nutrition regimens often rely on individualised prescription to manage the labile, unpredictable biochemical and metabolic control characteristic of the early neonatal period. Individualised prescription frequently fails to translate into optimal macronutrient delivery. We have previously shown that a standardised, concentrated neonatal parenteral nutrition regimen can optimise macronutrient intake.</p> <p>Methods</p> <p>We propose a single centre, randomised controlled exploratory trial of two standardised, concentrated neonatal parenteral nutrition regimens comparing a standard macronutrient content (maximum protein 2.8 g/kg/day; lipid 2.8 g/kg/day, dextrose 10%) with a higher macronutrient content (maximum protein 3.8 g/kg/day; lipid 3.8 g/kg/day, dextrose 12%) over the first 28 days of life. 150 infants 24-28 completed weeks gestation and birthweight <1200 g will be recruited. The primary outcome will be head growth velocity in the first 28 days of life. Secondary outcomes will include a) auxological data between birth and 36 weeks corrected gestational age b) actual macronutrient intake in first 28 days c) biomarkers of biochemical and metabolic tolerance d) infection biomarkers and other intravascular line complications e) incidence of major complications of prematurity including mortality f) neurodevelopmental outcome at 2 years corrected gestational age</p> <p>Trial registration</p> <p>Current controlled trials: <a href="http://www.controlled-trials.com/ISRCTN76597892">ISRCTN76597892</a>; EudraCT Number: 2008-008899-14</p

Dictyostelium discoideum as a Model to Study Inositol Polyphosphates and Inorganic Polyphosphate

The yeast Saccharomyces cerevisiae has given us much information on the metabolism and function of inositol polyphosphates and inorganic polyphosphate. To expand our knowledge of the metabolic as well as functional connections between inositol polyphosphates and inorganic polyphosphate, we have refined and developed techniques to extract and analyze these molecules in a second eukaryotic experimental model, the amoeba Dictyostelium discoideum. This amoeba, possessing a well-defined developmental program, is ideal to study physiological changes in the levels of inositol polyphosphates and inorganic polyphosphate, since levels of both molecules increase at late stages of development. We detail here the methods used to extract inositol polyphosphates using perchloric acid and inorganic polyphosphate using acidic phenol. We also present the postextraction procedures to visualize and quantify these molecules by polyacrylamide gel electrophoresis and by malachite green assay

Does familial risk for alcohol use disorder predict alcohol hangover?

Positive family history of alcohol use disorder (FHP), a variable associated with propensity for alcohol use disorder (AUD), has been linked with elevated hangover frequency and severity, after controlling for alcohol use. This implies that hangover experiences may be related to AUD. However, inadequate control of alcohol consumption levels, low alcohol dose and testing for hangover during the intoxication phase detract from these findings. Here, we present further data pertinent to understanding the relationship between family history and alcohol hangover. Study 1 compared past year hangover frequency in a survey of 24 FHP and 118 family history negative (FHN) individuals. Study 2 applied a quasi-experimental naturalistic approach assessing concurrent hangover severity in 17 FHP and 32 FHN individuals the morning after drinking alcohol. Both studies applied statistical control for alcohol consumption levels. In Study 1, both FHP status and estimated blood alcohol concentration on the heaviest drinking evening of the past month predicted the frequency of hangover symptoms experienced over the previous 12 months. In Study 2, estimated blood alcohol concentration the previous evening predicted hangover severity but FHP status did not. FHP, indicating familial risk for AUD, was not associated with concurrent hangover severity but was associated with increased estimates of hangover frequency the previous year

Polymorphisms in the cytochrome P450 genes CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1, CYP19A1 and colorectal cancer risk

BACKGROUND: Cytochrome P450 (CYP) enzymes have the potential to affect colorectal cancer (CRC) risk by determining the genotoxic impact of exogenous carcinogens and levels of sex hormones. METHODS: To investigate if common variants of CYP1A2, CYP1B1, CYP3A4, CYP3A5, CYP11A1, CYP17A1 and CYP19A1 influence CRC risk we genotyped 2,575 CRC cases and 2,707 controls for 20 single nucleotide polymorphisms (SNPs) that have not previously been shown to have functional consequence within these genes. RESULTS: There was a suggestion of increased risk, albeit insignificant after correction for multiple testing, of CRC for individuals homozygous for CYP1B1 rs162558 and heterozygous for CYP1A2 rs2069522 (odds ratio [OR] = 1.36, 95% confidence interval [CI]: 1.03-1.80 and OR = 1.34, 95% CI: 1.00-1.79 respectively). CONCLUSION: This study provides some support for polymorphic variation in CYP1A2 and CYP1B1 playing a role in CRC susceptibility

Predictors of gastrointestinal lesions on endoscopy in iron deficiency anemia without gastrointestinal symptoms

<p>Abstract</p> <p>Background</p> <p>Iron deficiency anaemia (IDA) due to occult gastrointestinal (GI) blood loss usually remains unnoticed until patient become symptomatic. There is sparse data in IDA patients without gastrointestinal symptoms. This study was designed to find out the frequency and predictors of endoscopic lesions in IDA without gastrointestinal symptoms. Cross-sectional study performed on a convenience sample of consecutive subjects.</p> <p>Methods</p> <p>Ninety five consecutive patients with laboratory based diagnosis of IDA having no gastrointestinal symptoms were interviewed and their clinical and biochemical variables were recorded. All the study patients underwent esophago-gastroduodenoscopy (EGD) and colonoscopy. Endoscopic findings were documented as presence/absence of bleeding related lesion and presence/absence of cause of IDA. Multiple logistic regressions were performed to identify variables significantly related to outcome variables.</p> <p>Results</p> <p>Possible cause of anaemia was found in 71% and bleeding related lesions were found in 53% of patients. Upper gastrointestinal tract lesions were found in 41% of patients with bleeding related lesions. On multivariable logistic regression; advancing age, low mean corpuscular volume (MCV ≤ 60 fl), and positive fecal occult blood test were predictive factors for bleeding related GI lesions and cause of IDA</p> <p>Conclusion</p> <p>Clinical and Biochemical markers can predict gastrointestinal lesions on endoscopy in IDA patients without gastrointestinal symptoms. High proportion of upper gastrointestinal involvement warrants EGD as initial endoscopic procedure however, this needs validation by further studies.</p

Phylogeography of a Land Snail Suggests Trans-Mediterranean Neolithic Transport

Background: Fragmented distribution ranges of species with little active dispersal capacity raise the question about their place of origin and the processes and timing of either range fragmentation or dispersal. The peculiar distribution of the land snail Tudorella sulcata s. str. in Southern France, Sardinia and Algeria is such a challenging case. Methodology: Statistical phylogeographic analyses with mitochondrial COI and nuclear hsp70 haplotypes were used to answer the questions of the species' origin, sequence and timing of dispersal. The origin of the species was on Sardinia. Starting from there, a first expansion to Algeria and then to France took place. Abiotic and zoochorous dispersal could be excluded by considering the species' life style, leaving only anthropogenic translocation as parsimonious explanation. The geographic expansion could be dated to approximately 8,000 years before present with a 95% confidence interval of 10,000 to 3,000 years before present. Conclusions: This period coincides with the Neolithic expansion in the Western Mediterranean, suggesting a role of these settlers as vectors. Our findings thus propose that non-domesticated animals and plants may give hints on the direction and timing of early human expansion routes