Treatments for somnambulism in adults: assessing the evidence.

Abstract: Somnambulism, or sleepwalking, is a parasomnia of non-rapid eye movement (NREM) sleep where movement behaviours usually confined to wakefulness are displayed during sleep.

Abstract: Generally, if sleepwalking is causing distress or danger in spite of safety measures, medical or psychological treatment is indicated.

Abstract: Clinicians will need to assess the evidence for treatment options.

Abstract: MEDLINE, EMBASE, PsycINFO and the Ovid Evidence-Based Medicine Reviews (EBM) multifile databases were searched.

Abstract: No properly powered rigorous controlled trials were found for treatment of sleepwalking in adults.

Abstract: Seven reports described small trials with some kind of control arm, or retrospective case series which included 30 or more patients.

Abstract: With no high quality evidence to underpin recommendations for treatments of somnambulism, full discussion with patients is advised.

Abstract: Adequately powered, well-designed clinical trials are now needed, and multi-centre collaborations may be required to obtain the sample sizes required.


Premature chromosome condensation: evidence for in vivo cell fusion in human malignant tumours.

Abstract: Premature chromosome condensation (PCC) was studied in direct preparations of tissues from patients with haematological diseases and carcinomas of various histological types.

Abstract: PCC was found in 6 out of 166 malignancies (128 haematological cases, 35 carcinomas and 3 malignant effusions) analysed with the GTG-technique.

Abstract: Chromosome analysis revealed S-phase and G1-phase PCC in each case; the frequency of PCC varied between 1, 4 and 8.6% of the metaphases analysed.

Abstract: It is suggested that PCC chromosomes, which represent cell fusion in vivo, are not very rare in naturally-occurring human malignancies, and that cell fusion may affect the malignant phenotype.

Abstract: In conjunction with other factors they may also explain the heterogeneity of tumour cell populations.


Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials

Abstract: Objective: It is unclear whether blockade of the angiotensin system has effects on mental health.

Abstract: Our objective was to determine the impact of angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor (AT1R) blockers on mental health domain of quality of life.

Abstract: Study design: Meta-analysis of published literature.

Abstract: Data sources: PubMed and clinicaltrials.gov databases.

Abstract: The last search was conducted in January 2017.

Abstract: Study selection: Randomized controlled trials comparing any angiotensin converting enzyme inhibitor or AT1R blocker versus placebo or non-angiotensin converting enzyme inhibitor or non-AT1R blocker were selected.

Abstract: Study participants were adults without any major physical symptoms.

Abstract: We adhered to meta-analysis reporting methods as per PRISMA and the Cochrane Collaboration.

Abstract: Data synthesis: Eleven studies were included in the analysis.

Abstract: When compared with placebo or other antihypertensive medications, AT1R blockers and angiotensin converting enzyme inhibitors were associated with improved overall quality of life (standard mean difference = 0.11, 95% confidence interval = [0.08, 0.14], p < 0.0001), positive wellbeing (standard mean difference = 0.11, 95% confidence interval = [0.05, 0.17], p < 0.0001), mental (standard mean difference = 0.15, 95% confidence interval = [0.06, 0.25], p < 0.0001), and anxiety (standard mean difference = 0.08, 95% confidence interval = [0.01, 0.16], p < 0.0001) domains of QoL. No significant difference was found for the depression domain (standard mean difference = 0.05, 95% confidence interval = [0.02, 0.12], p = 0.15).

Abstract: Conclusions: Use of angiotensin blockers and inhibitors for the treatment of hypertension in otherwise healthy adults is associated with improved mental health domains of quality of life.

Abstract: Mental health quality of life was a secondary outcome in the included studies.

Abstract: Research specifically designed to analyse the usefulness of drugs that block the angiotensin system is necessary to properly evaluate this novel psychiatric target.


The role of epigenetics in aging and autoimmunity.

Abstract: The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases.

Abstract: Aging of the immune system, or immunosenescence, is characterized by a decline of both T and B cell function, and paradoxically the presence of low-grade chronic inflammation.

Abstract: There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging.

Abstract: Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders.

Abstract: Here, we will review the potential mechanisms that contribute to the increase in autoimmune responses in aging.

Abstract: In particular, we will discuss how epigenetic alterations, especially DNA methylation and histone acetylation, are accumulated during aging and how these events contribute to autoimmunity risk.


A framework for understanding and targeting residual disease in oncogene-driven solid cancers

Abstract: Molecular targeted therapy has the potential to dramatically improve survival in patients with cancer.

Abstract: However, complete and durable responses to targeted therapy are rare in individuals with advanced-stage solid cancers.

Abstract: Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival.

Abstract: We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing therapeutic strategies to minimize or eliminate residual disease so that we can move from temporary to chronic control of disease, or a cure, for patients with advanced-stage solid cancers.

Abstract: Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms that result in residual disease, to target and limit this disease reservoir.


Long-term inhibition of dipeptidyl peptidase-4 in Alzheimer's prone mice.

Abstract: We tested here the impact of a long-term inhibition of dipeptidyl peptidase-4 (DPP-4) with sitagliptin on the deposition of amyloid-beta within the brain and deficits in memory-related behavioral paradigms in a model of Alzheimer's disease (AD): double transgenic mice B6*Cg-Tg(APPswe,PSEN1dE9)85Dbo/J. Mice began to receive sitagliptin at 7 months of age.

Abstract: Three different dose of sitagliptin (5, 10 and 20 mg/kg), were administered daily for 12 weeks by gastric gavage.

Abstract: The treatments counteracted: (i) the memory impairment in the contextual fear conditioning test; (ii) increased the brain levels of GLP-1; (iii) produced significant reductions of nitrosative stress and inflammation hallmarks within the brain, as well as (iv) a significant diminution in the ultimate number and total area of betaAPP and Abeta deposits.

Abstract: All these effects much more evident for the dose of 20 mg/kg sitagliptin.

Abstract: The long-term inhibition of the endogenous DPP-4 enzymes with sitagliptin can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.


Structural and mechanistic insights into phospholipid transfer by Ups1–Mdm35 in mitochondria

Abstract: Eukaryotic cells are compartmentalized into membrane-bounded organelles whose functions rely on lipid trafficking to achieve membrane-specific compositions of lipids.

Abstract: Here we focused on the Ups1-Mdm35 system, which mediates phosphatidic acid (PA) transfer between the outer and inner mitochondrial membranes, and determined the X-ray structures of Mdm35 and Ups1-Mdm35 with and without PA.

Abstract: The Ups1-Mdm35 complex constitutes a single domain that has a deep pocket and flexible Ω-loop lid.

Abstract: Structure-based mutational analyses revealed that a basic residue at the pocket bottom and the Ω-loop lid are important for PA extraction from the membrane following Ups1 binding.

Abstract: Ups1 binding to the membrane is enhanced by the dissociation of Mdm35.

Abstract: We also show that basic residues around the pocket entrance are important for Ups1 binding to the membrane and PA extraction.

Abstract: These results provide a structural basis for understanding the mechanism of PA transfer between mitochondrial membranes.


Redox regulation of cell migration and adhesion.

Abstract: Reactive oxygen species (ROS), particularly hydrogen peroxide, and the proteins that regulate them play important roles in the migration and adhesion of cells.

Abstract: Stimulation of cell surface receptors with growth factors and chemoattractants generates ROS, which relay signals from the cell surface to key signaling proteins inside the cell.

Abstract: ROS act within cells to promote migration and also in nonmigrating cells to influence the behavior of migrating cells.

Abstract: Hydrogen peroxide has also been suggested to act as a chemoattractant in its own right, drawing immune cells to wounds.

Abstract: We discuss recent progress made towards understanding how organisms use ROS, and to what degree they depend on them, during the related processes of cell migration and adhesion.


Systemic Inflammatory Response Syndrome, Quick Sequential Organ Function Assessment, and Organ Dysfunction: Insights From a Prospective Database of ED Patients With Infection

Abstract: BACKGROUND: A proposed revision of sepsis definitions has abandoned the systemic inflammatory response syndrome (SIRS), defined organ dysfunction as an increase in total Sequential Organ Function Assessment (SOFA) score of ≥ 2, and conceived “qSOFA” (quick SOFA) as a bedside indicator of organ dysfunction.

Abstract: We aimed to (1) determine the prognostic impact of SIRS, (2) compare the diagnostic accuracy of SIRS and qSOFA for organ dysfunction, and (3) compare standard (Sepsis‐2) and revised (Sepsis‐3) definitions for organ dysfunction in ED patients with infection.

Abstract: METHODS: Consecutive ED patients admitted with presumed infection were prospectively enrolled over 3 years.

Abstract: Sufficient observational data were collected to calculate SIRS, qSOFA, SOFA, comorbidity, and mortality.

Abstract: RESULTS: We enrolled 8,871 patients, with SIRS present in 4,176 (47.1%).

Abstract: SIRS was associated with increased risk of organ dysfunction (relative risk [RR] 3.5) and mortality in patients without organ dysfunction (OR 3.2).

Abstract: SIRS and qSOFA showed similar discrimination for organ dysfunction (area under the receiver operating characteristic curve, 0.72 vs 0.73).

Abstract: qSOFA was specific but poorly sensitive for organ dysfunction (96.1% and 29.7%, respectively).

Abstract: Mortality for patients with organ dysfunction was similar for Sepsis‐2 and Sepsis‐3 (12.5% and 11.4%, respectively), although 29% of patients with Sepsis‐3 organ dysfunction did not meet Sepsis‐2 criteria.

Abstract: Increasing numbers of Sepsis‐2 organ system dysfunctions were associated with greater mortality.

Abstract: CONCLUSIONS: SIRS was associated with organ dysfunction and mortality, and abandoning the concept appears premature.

Abstract: A qSOFA score ≥ 2 showed high specificity, but poor sensitivity may limit utility as a bedside screening method.

Abstract: Although mortality for organ dysfunction was comparable between Sepsis‐2 and Sepsis‐3, more prognostic and clinical information is conveyed using Sepsis‐2 regarding number and type of organ dysfunctions.

Abstract: The SOFA score may require recalibration.


Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae.

Abstract: Calorie restriction extends life-span in a wide variety of organisms.

Abstract: Although it has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species produced during respiration, the mechanism by which this regimen slows aging is uncertain.

Abstract: Here, we mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in life-span.

Abstract: This extension was not observed in strains mutant for SIR2 (which encodes the silencing protein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide).

Abstract: These findings suggest that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD.


Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1.

Abstract: Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration.

Abstract: Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1.

Abstract: Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways.

Abstract: Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation.

Abstract: Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.


Effect of enalapril on 12-year survival and life expectancy in patients with left ventricular systolic dysfunction: a follow-up study.

Abstract: BACKGROUND In the studies of left ventricular dysfunction (SOLVD), enalapril reduced mortality in patients with symptomatic but not asymptomatic left ventricular systolic dysfunction during the trial.

Abstract: We did a 12-year follow-up of SOLVD to establish if the mortality reduction with enalapril among patients with heart failure was sustained, and whether a subsequent reduction in mortality would emerge among those with asymptomatic ventricular dysfunction.

Abstract: METHODS Of the 6797 patients previously enrolled in the SOLVD prevention and treatment trials, we ascertained the subsequent vital status of 5165 individuals who were alive when the trials had been completed.

Abstract: Follow-up was done through direct contacts in Belgium and linkages with national death registries and federal beneficiary or historic tax summary files in the USA and Canada.

Abstract: FINDINGS Follow-up was 99.8% (6784/6797) complete.

Abstract: In the prevention trial, 50.9% (1074/2111) of the enalapril group had died compared with 56.4% (1195/2117) of the placebo group (generalised Wilcoxon p=0.001).

Abstract: In the treatment trial, 79.8% (1025/1285) of the enalapril group had died compared with 80.8% (1038/1284) of the placebo group (generalised Wilcoxon p=0.01).

Abstract: The reductions in cardiac deaths were significant and similar in both trials.

Abstract: When data for the prevention and treatment trials were combined, the hazard ratio for death was 0.90 for the enalapril group compared with the placebo group (95% CI 0.84-0.95, generalised Wilcoxon p=0.0003).

Abstract: Enalapril extended median survival by 9.4 months in the combined trials (95% CI 2.8-16.5, p=0.004).

Abstract: INTERPRETATION Treatment with enalapril for 3-4 years led to a sustained improvement in survival beyond the original trial period in patients with left ventricular systolic dysfunction, with an important increase in life expectancy.


TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells.

Abstract: Human embryonic stem cells (hESCs) self-renew indefinitely and give rise to derivatives of all three primary germ layers, yet little is known about the signaling cascades that govern their pluripotent character.

Abstract: Because it plays a prominent role in the early cell fate decisions of embryonic development, we have examined the role of TGFbeta superfamily signaling in hESCs.

Abstract: We found that, in undifferentiated cells, the TGFbeta/activin/nodal branch is activated (through the signal transducer SMAD2/3) while the BMP/GDF branch (SMAD1/5) is only active in isolated mitotic cells.

Abstract: Upon early differentiation, SMAD2/3 signaling is decreased while SMAD1/5 signaling is activated.

Abstract: We next tested the functional role of TGFbeta/activin/nodal signaling in hESCs and found that it is required for the maintenance of markers of the undifferentiated state.

Abstract: We extend these findings to show that SMAD2/3 activation is required downstream of WNT signaling, which we have previously shown to be sufficient to maintain the undifferentiated state of hESCs.

Abstract: Strikingly, we show that in ex vivo mouse blastocyst cultures, SMAD2/3 signaling is also required to maintain the inner cell mass (from which stem cells are derived).

Abstract: These data reveal a crucial role for TGFbeta signaling in the earliest stages of cell fate determination and demonstrate an interconnection between TGFbeta and WNT signaling in these contexts.


The structure and expression of a novel gene activated in early mouse embryogenesis.

Abstract: We report the cloning and sequence determination of the mouse H19 gene.

Abstract: This gene is under the genetic control of two trans-acting loci in the mouse, termed raf and Rif.

Abstract: These loci determine the adult basal and inducible levels, respectively, of H19 mRNA, as well as the mRNA for alpha-fetoprotein.

Abstract: By elucidating the sequence and structure of the H19 gene we show that it is unrelated to the alpha-fetoprotein gene, and therefore must have acquired its regulation by raf and Rif independently.

Abstract: The sequence also indicates that the H19 gene has a very unusual structure.

Abstract: It is composed of five exons, 1307, 135, 119, 127 and 560 bp in size, along with four very small introns whose combined lengths are 270 bases.

Abstract: The largest open reading frame of the gene, sufficient to encode a protein of approximately 14 kd, is contained entirely within the first large exon, 680 bases downstream of the cap site of the mRNA.

Abstract: Preceding the translation initiation codon are four ATG codons, each of which is followed shortly thereafter by translation terminator codons.

Abstract: The rest of the gene, which encompasses all five exons, is presumed to be untranslated.

Abstract: That the long 5' untranslated region may be used to regulate the translation of the mRNA is suggested from in vitro translation studies.

Abstract: Experiments which utilized tissue culture cell lines of the mesodermal lineage suggest that the gene is activated very early during muscle cell differentiation.


Diminished linear growth during intermittent calcitriol therapy in children undergoing CCPD.

Abstract: Daily calcitriol therapy has been reported to improve linear growth in children with renal bone disease, and 1,25-dihydroxyvitamin D is a key regultor of chondrocyte proliferation and differentiation.

Abstract: Whereas large intermittent doses of calcitriol can lower serum parathyroid hormone (PTH) levels and reverse the skeletal changes of secondary hyperparathyroidism, the impact of intermittent calcitriol therapy on linear growth in children is not known.

Abstract: Thus, we studied 16 pre-pubertal patients with bone biopsy-proven secondary hyperparathyroidism who completed a 12-month prospective clinical trial of intermittent calcitriol therapy.

Abstract: Biochemical results and growth data obtained during intermittent calcitriol therapy were compared to values determined during the preceding 12 months of daily calcitriol therapy in each study subject; changes in bone histology were assessed after one year of intermittent calcitriol therapy.

Abstract: Z-scores for height did not change during 12 months of daily calcitriol therapy.

Abstract: Although the skeletal lesions of secondary hyperparathyroidism improved in most patients, Z-scores for height decreased from -1.8 +/-

Abstract: 0.32 to -2.0 +/-

Abstract: 0.33, P < 0.01, during intermittent calcitriol therapy.

Abstract: The largest reductions were seen in patients who developed adynamic bone lesions after 12 months of treatment.

Abstract: Delta Z-scores for height correlated with serum PTH, r = 0.71, P < 0.01, and alkaline phosphatase levels, r = 0.67, P < 0.01, during intermittent calcitriol therapy but not during daily calcitriol therapy.

Abstract: The data suggest that high dose intermittent calcitriol therapy adversely affects linear growth, particularly in patients with the adynamic lesion.

Abstract: The higher doses of calcitriol or the intermittent schedule of calcitriol administration may directly inhibit chondrocyte activity within growth plate cartilage of children with end-stage renal disease.


Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4)

Abstract: Few studies have directly compared the clinical features of neuropathic and non-neuropathic pains.

Abstract: For this purpose, the French Neuropathic Pain Group developed a clinician-administered questionnaire named DN4 consisting of both sensory descriptors and signs related to bedside sensory examination.

Abstract: This questionnaire was used in a prospective study of 160 patients presenting with pain associated with a definite neurological or somatic lesion.

Abstract: The most common aetiologies of nervous lesions (n=89) were traumatic nerve injury, post herpetic neuralgia and post stroke pain.

Abstract: Non-neurological lesions (n=71) were represented by osteoarthritis, inflammatory arthropathies and mechanical low back pain.

Abstract: Each patient was seen independently by two experts in order to confirm the diagnosis of neuropathic or non-neuropathic pain.

Abstract: The prevalence of pain descriptors and sensory dysfunctions were systematically compared in the two groups of patients.

Abstract: The analysis of the psychometric properties of the DN4 questionnaire included: face validity, inter-rater reliability, factor analysis and logistic regression to identify the discriminant properties of items or combinations of items for the diagnosis of neuropathic pain.

Abstract: We found that a relatively small number of items are sufficient to discriminate neuropathic pain.

Abstract: The 10-item questionnaire developed in the present study constitutes a new diagnostic instrument, which might be helpful both in clinical research and daily practice.


Changing the density of alcohol outlets to reduce alcohol-related problems.

Abstract: Increasingly, it seems, legal and political debates regarding the granting of new liquor licences are turning to the issue of whether the number and density of alcohol outlets makes a difference in rates of alcohol consumption and alcohol-related harm.

Abstract: But what is the state of the evidence on this question?

Abstract: In this Harm Reduction Digest Livingston, Chikritzhs and Room review the research literature on the effects of density of alcohol sales outlets on alcohol consumption and alcohol-related problems; suggest a new way of conceptualising the relationships; and discuss the implications for reducing alcohol-related harm.


[Pharmacokinetics and biotransformation of the antimycotic drug ciclopiroxolamine in animals and man after topical and systemic administration].

Abstract: Following the dermal application of the carbon-14 labelled broad spectrum antimycotic 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone, 2-aminoethanol salt (ciclopiroxolamine, Hoe 296, Batrafen) in the form of a 1% aqueous cream to healthy human dorsal skin (penetration time: 6 h; occlusive dressing for 5 h), percutaneous absorption accounted on average for 1.3% of the dose applied.

Abstract: Excretion occurred via the kidney, with biological half-lives of 1.7 h. As can be seen from penetration studies of cadaverous skin, the horny layer contained the highest concentrations, with values of 2300-4500 microgram/cm3.

Abstract: The levels determined in the corium were still above the minimum inhibitory concentrations.

Abstract: These concentrations were already obtained at the first test stage (1.5 h after application) and did not change virtually at all over the longer penetration period.

Abstract: According to studies using histoautoradiography, ciclopirox can penetrate the skin via the epidermis and the hair follicles.

Abstract: When ciclopirox-14C-olamine aqueous cream was spread on the surface of fingernails, the radioactive-labelled compound penetrated right through the nail.

Abstract: The percutaneous absorption in dogs was higher, at 5-15% of the dose, than it was in humans.

Abstract: After vaginal application (1 mg/kg) of ciclopirox-14C-olamine in the form of a 1% aqueous cream to bitches, between 42 and 97% of the dose (depending on the animal) was recovered in the urine and faeces, the remainder having penetrated into the tampon used to close the vagina.

Abstract: Ciclopirox is excreted by dogs and man in the urine, primarily as a glucuronide.

Abstract: In humans another glucuronide with properties similar to those of the original substance was detected.

Abstract: Two conjugated, relatively non-polar metabolites were also present in small amounts.

Abstract: The metabolite patterns after oral and dermal application were similar.

Abstract: The binding of ciclopirox to serum proteins in humans was 96 +/-

Abstract: 2% in a concentration range of 0.01-11.0 microgram/ml.

Abstract: Placental transfer was low in the rats studied.

Abstract: Though there was good absorption by the mother animal, the radioactivity in the foetal tissues was always lower than that of the maternal blood.


Maximizing the diagnostic utility of endoscopic biopsy in dogs and cats with gastrointestinal disease.

Abstract: Flexible endoscopy has become a valuable tool for the diagnosis of many small animal gastrointestinal (GI) diseases, but the techniques must be performed carefully so that the results are meaningful.

Abstract: This article reviews the current diagnostic utility of flexible endoscopy, including practical/technical considerations for endoscopic biopsy, optimal instrumentation for mucosal specimen collection, the correlation of endoscopic indices to clinical activity and to histopathologic findings, and new developments in the endoscopic diagnosis of GI disease.

Abstract: Recent studies have defined endoscopic biopsy guidelines for the optimal number and quality of diagnostic specimens from different regions of the gut.

Abstract: They also have shown the value of ileal biopsy in the diagnosis of canine and feline chronic enteropathies, and have demonstrated the utility of endoscopic biopsy specimens beyond routine hematoxylin and eosin histopathological analysis, including their use in immunohistochemical, microbiological, and molecular studies.


Age-structured red blood cell susceptibility and the dynamics of malaria infections.

Abstract: Malaria parasites and immune responses in an infected human interact on a dynamic landscape, in which a population of replicating parasites depletes a population of replenishing red blood cells (RBCs).

Abstract: These underlying dynamics receive relatively little attention, but they offer unique insights into the processes that control most malaria infections.

Abstract: Here, we focus on the observation that three of the four malaria-parasite species that infect humans are restricted to particular age classes of RBC.

Abstract: We explicitly incorporate this observation in models of infection dynamics to distinguish common from species-specific pressures on host immune responses, and we find that age structuring has profound effects on the course of infection.

Abstract: For all four species conditions exist under which the parasites may persist at low densities, or may clear, even in the absence of an immune response.

Abstract: Catastrophic anemia can occur even with the two species that attack only the youngest RBCs, although only a small fraction of cells are parasitized at any point.

Abstract: Furthermore, with these two, compensatory erythropoetic responses in the host accelerate parasite population growth.

Abstract: A "basic reproduction rate" characterizes these differences in outcomes.


Helicobacter pylori AlpA and AlpB bind host laminin and influence gastric inflammation in gerbils.

Abstract: Helicobacter pylori persistently colonizes humans, causing gastritis, ulcers, and gastric cancer.

Abstract: Adherence to the gastric epithelium has been shown to enhance inflammation, yet only a few H. pylori adhesins have been paired with targets in host tissue.

Abstract: The alpAB locus has been reported to encode adhesins involved in adherence to human gastric tissue.

Abstract: We report that abrogation of H. pylori AlpA and AlpB reduces binding of H. pylori to laminin while expression of plasmid-borne alpA or alpB confers laminin-binding ability to Escherichia coli.

Abstract: An H. pylori strain lacking only AlpB is also deficient in laminin binding.

Abstract: Thus, we conclude that both AlpA and AlpB contribute to H. pylori laminin binding.

Abstract: Contrary to expectations, the H. pylori SS1 mutant deficient in AlpA and AlpB causes more severe inflammation than the isogenic wild-type strain in gerbils.

Abstract: Identification of laminin as the target of AlpA and AlpB will facilitate future investigations of host-pathogen interactions occurring during H. pylori infection.


A quantitative analysis of kinase inhibitor selectivity

Abstract: Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets.

Abstract: The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome.

Abstract: We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome.

Abstract: The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns.

Abstract: To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns.

Abstract: We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.


Ribosomal protein S9 is a novel B23/NPM-binding protein required for normal cell proliferation.

Abstract: B23 (NPM/nucleophosmin) is a multifunctional nucleolar protein and a member of the nucleoplasmin superfamily of acidic histone chaperones.

Abstract: B23 is essential for normal embryonic development and plays an important role in genomic stability, ribosome biogenesis, and anti-apoptotic signaling.

Abstract: Altered protein expression or genomic mutation of B23 is encountered in many different forms of cancer.

Abstract: Although described as multifunctional, a genuine molecular function of B23 is not fully understood.

Abstract: Here we show that B23 is associated with a protein complex consisting of ribosomal proteins and ribosome-associated RNA helicases.

Abstract: A novel, RNA-independent interaction between ribosomal protein S9 (RPS9) and B23 was further investigated.

Abstract: We found that S9 binding requires an intact B23 oligomerization domain.

Abstract: Depletion of S9 by small interfering RNA resulted in decreased protein synthesis and G(1) cell cycle arrest, in association with induction of p53 target genes.

Abstract: We determined that S9 is a short-lived protein in the absence of ribosome biogenesis, and proteasomal inhibition significantly increased S9 protein level.

Abstract: Overexpression of B23 facilitated nucleolar storage of S9, whereas knockdown of B23 led to diminished levels of nucleolar S9.

Abstract: Our results suggest that B23 selectively stores, and protects ribosomal protein S9 in nucleoli and therefore could facilitate ribosome biogenesis.


Vasculature-associated cells expressing nestin in developing bones encompass early cells in the osteoblast and endothelial lineage.

Abstract: Nestin-positive (Nes(+)) cells are important hematopoiesis-supporting constituents in adult bone marrow.

Abstract: However, how these cells originate during endochondral bone development is unknown.

Abstract: Studies using mice expressing GFP under the direction of nestin promoter/enhancer (Nes-GFP) revealed distinct endothelial and nonendothelial Nes(+) cells in the embryonic perichondrium; the latter were early cells of the osteoblast lineage immediately descended from their progenitors upon Indian hedgehog action and Runx2 expression.

Abstract: During vascular invasion and formation of ossification centers, these Nes(+) cells were closely associated with each other and increased in number progressively.

Abstract: Interestingly, cells targeted by tamoxifen-inducible cre recombinase driven by nestin enhancer (Nes-creER) in developing bone marrow were predominantly endothelial cells.

Abstract: Furthermore, Nes(+) cells in postnatal bones were heterogeneous populations, including a range of cells in the osteoblast and endothelial lineage.

Abstract: These findings reveal an emerging complexity of stromal populations, accommodating Nes(+) cells as vasculature-associated early cells in the osteoblast and endothelial lineage.


Public health, academic medicine, and the alcohol industry's corporate social responsibility activities.

Abstract: We explored the emerging relationships among the alcohol industry, academic medicine, and the public health community in the context of public health theory dealing with corporate social responsibility.

Abstract: We reviewed sponsorship of scientific research, efforts to influence public perceptions of research, dissemination of scientific information, and industry-funded policy initiatives.

Abstract: To the extent that the scientific evidence supports the reduction of alcohol consumption through regulatory and legal measures, the academic community has come into increasing conflict with the views of the alcohol industry.

Abstract: We concluded that the alcohol industry has intensified its scientific and policy-related activities under the general framework of corporate social responsibility initiatives, most of which can be described as instrumental to the industry's economic interests.


RET, ROS1 and ALK fusions in lung cancer

Abstract: Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion–positive and 13 ROS1-fusion–positive adenocarcinomas, including for unidentified fusion partners for ROS1.

Abstract: In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas.

Abstract: A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion–positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥50 years, male sex, high pathological stage and negative kinase-fusion status.


Genetic and biochemical interactions among Yar1, Ltv1 and Rps3 define novel links between environmental stress and ribosome biogenesis in Saccharomyces cerevisiae.

Abstract: In the yeast S. cerevisiae, ribosome assembly is linked to environmental conditions by the coordinate transcriptional regulation of genes required for ribosome biogenesis.

Abstract: In this study we show that two nonessential stress-responsive genes, YAR1 and LTV1, function in 40S subunit production.

Abstract: We provide genetic and biochemical evidence that Yar1, a small ankyrin-repeat protein, physically interacts with RpS3, a component of the 40S subunit, and with Ltv1, a protein recently identified as a substoichiometric component of a 43S preribosomal particle.

Abstract: We demonstrate that cells lacking YAR1 or LTV1 are hypersensitive to particular protein synthesis inhibitors and exhibit aberrant polysome profiles, with a reduced absolute number of 40S subunits and an excess of free 60S subunits.

Abstract: Surprisingly, both mutants are also hypersensitive to a variety of environmental stress conditions.

Abstract: Overexpression of RPS3 suppresses both the stress sensitivity and the ribosome biogenesis defect of Deltayar1 mutants, but does not suppress either defect in Deltaltv1 mutants.

Abstract: We propose that YAR1 and LTV1 play distinct, nonessential roles in 40S subunit production.

Abstract: The stress-sensitive phenotypes of strains lacking these genes reveal a hitherto unknown link between ribosome biogenesis factors and environmental stress sensitivity.


Rational design of acridine-based ligands with selectivity for human telomeric quadruplexes.

Abstract: Structure-based modeling methods have been used to design a series of disubstituted triazole-linked acridine compounds with selectivity for human telomeric quadruplex DNAs.

Abstract: A focused library of these compounds was prepared using click chemistry and the selectivity concept was validated against two promoter quadruplexes from the c-kit gene with known molecular structures, as well as with duplex DNA using a FRET-based melting method.

Abstract: Lead compounds were found to have reduced effects on the thermal stability of the c-kit quadruplexes and duplex DNA structures.

Abstract: These effects were further explored with a series of competition experiments, which confirmed that binding to duplex DNA is very low even at high duplex:telomeric quadruplex ratios.

Abstract: Selectivity to the c-kit quadruplexes is more complex, with some evidence of their stabilization at increasing excess over human telomeric quadruplex DNA.

Abstract: Selectivity is a result of the dimensions of the triazole-acridine compounds, and in particular the separation of the two alkyl-amino terminal groups.

Abstract: Both lead compounds also have selective inhibitory effects on the proliferation of cancer cell lines compared to a normal cell line, and one has been shown to inhibit the activity of the telomerase enzyme, which is selectively expressed in tumor cells, where it plays a role in maintaining telomere integrity and cellular immortalization.


Hospital volume and the outcomes of mechanical ventilation.

Abstract: BACKGROUND An increased volume of patients is associated with improved survival in numerous high-risk medical and surgical conditions.

Abstract: The relationship between the number of patients admitted (hospital volume) and outcome among patients with critical illnesses is unknown.

Abstract: METHODS We analyzed data from 20,241 nonsurgical patients receiving mechanical ventilation at 37 acute care hospitals in the Acute Physiology and Chronic Health Evaluation clinical information system from 2002 through 2003.

Abstract: Multivariate analyses were performed to adjust for the severity of illness and other differences in the case mix.

Abstract: RESULTS An increase in hospital volume was associated with improved survival among patients receiving mechanical ventilation in the intensive care unit (ICU) and in the hospital.

Abstract: Admission to a hospital in the highest quartile according to volume (i.e., >400 patients receiving mechanical ventilation per year) was associated with a 37 percent reduction in the adjusted odds of death in the ICU as compared with admission to hospitals in the lowest quartile (< or =150 patients receiving mechanical ventilation per year, P<0.001).

Abstract: In-hospital mortality was similarly reduced (adjusted odds ratio, 0.66; 95 percent confidence interval, 0.52 to 0.83; P<0.001).

Abstract: A typical patient in a hospital in a low-volume quartile would have an adjusted in-hospital mortality of 34.2 percent as compared with 25.5 percent in a hospital in a high-volume quartile.

Abstract: Among survivors, there were no significant trends in the length of stay in the ICU or the hospital.

Abstract: CONCLUSIONS Mechanical ventilation of patients in a hospital with a high case volume is associated with reduced mortality.

Abstract: Further research is needed to determine the mechanism of the relationship between volume and outcome among patients with a critical illness.


A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction.

Abstract: CONTEXT Maternal depressive symptoms during pregnancy have been reported in some, but not all, studies to be associated with an increased risk of preterm birth (PTB), low birth weight (LBW), and intrauterine growth restriction (IUGR).

Abstract: OBJECTIVE To estimate the risk of PTB, LBW, and IUGR associated with antenatal depression.

Abstract: DATA SOURCES AND STUDY SELECTION

Abstract: We searched for English-language and non-English-language articles via the MEDLINE, PsycINFO, CINAHL, Social Work Abstracts, Social Services Abstracts, and Dissertation Abstracts International databases (January 1980 through December 2009).

Abstract: We aimed to include prospective studies reporting data on antenatal depression and at least 1 adverse birth outcome: PTB (<37 weeks' gestation), LBW (<2500 g), or IUGR (<10th percentile for gestational age).

Abstract: Of 862 reviewed studies, 29 US-published and non-US-published studies met the selection criteria.

Abstract: DATA EXTRACTION Information was extracted on study characteristics, antenatal depression measurement, and other biopsychosocial risk factors and was reviewed twice to minimize error.

Abstract: DATA SYNTHESIS Pooled relative risks (RRs) for the effect of antenatal depression on each birth outcome were calculated using random-effects methods.

Abstract: In studies of PTB, LBW, and IUGR that used a categorical depression measure, pooled effect sizes were significantly larger (pooled RR [95% confidence interval] = 1.39 [1.19-1.61], 1.49 [1.25-1.77], and 1.45 [1.05-2.02], respectively) compared with studies that used a continuous depression measure (1.03 [1.00-1.06], 1.04 [0.99-1.09], and 1.02 [1.00-1.04], respectively).

Abstract: The estimates of risk for categorically defined antenatal depression and PTB and LBW remained significant when the trim-and-fill procedure was used to correct for publication bias.

Abstract: The risk of LBW associated with antenatal depression was significantly larger in developing countries (RR = 2.05; 95% confidence interval, 1.43-2.93) compared with the United States (RR = 1.10; 95% confidence interval, 1.01-1.21) or European social democracies (RR = 1.16; 95% confidence interval, 0.92-1.47).

Abstract: Categorically defined antenatal depression tended to be associated with an increased risk of PTB among women of lower socioeconomic status in the United States.

Abstract: CONCLUSIONS Women with depression during pregnancy are at increased risk for PTB and LBW, although the magnitude of the effect varies as a function of depression measurement, country location, and US socioeconomic status.

Abstract: An important implication of these findings is that antenatal depression should be identified through universal screening and treated.


ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a.

Abstract: ATP-dependent chromatin remodeling complexes are a notable group of epigenetic modifiers that use the energy of ATP hydrolysis to change the structure of chromatin, thereby altering its accessibility to nuclear factors.

Abstract: BAF250a (ARID1a) is a unique and defining subunit of the BAF chromatin remodeling complex with the potential to facilitate chromosome alterations critical during development.

Abstract: Our studies show that ablation of BAF250a in early mouse embryos results in developmental arrest (about embryonic day 6.5) and absence of the mesodermal layer, indicating its critical role in early germ-layer formation.

Abstract: Moreover, BAF250a deficiency compromises ES cell pluripotency, severely inhibits self-renewal, and promotes differentiation into primitive endoderm-like cells under normal feeder-free culture conditions.

Abstract: Interestingly, this phenotype can be partially rescued by the presence of embryonic fibroblast cells.

Abstract: DNA microarray, immunostaining, and RNA analyses revealed that BAF250a-mediated chromatin remodeling contributes to the proper expression of numerous genes involved in ES cell self-renewal, including Sox2, Utf1, and Oct4.

Abstract: Furthermore, the pluripotency defects in BAF250a mutant ES cells appear to be cell lineage-specific.

Abstract: For example, embryoid body-based analyses demonstrated that BAF250a-ablated stem cells are defective in differentiating into fully functional mesoderm-derived cardiomyocytes and adipocytes but are capable of differentiating into ectoderm-derived neurons.

Abstract: Our results suggest that BAF250a is a key component of the gene regulatory machinery in ES cells controlling self-renewal, differentiation, and cell lineage decisions.


Metabolic shutdown in Escherichia coli cells lacking the outer membrane channel TolC.

Abstract: The outer membrane channel TolC is a key component of multidrug efflux and type I secretion transporters in Escherichia coli.

Abstract: Mutational inactivation of TolC renders cells highly susceptible to antibiotics and leads to defects in secretion of protein toxins.

Abstract: Despite impairment of various transport functions, no growth defects were reported in cells lacking TolC. Unexpectedly, we found that the loss of TolC notably impairs cell division and growth in minimal glucose medium.

Abstract: The TolC-dependent phenotype was further exacerbated by the loss of ygiB and ygiC genes expressed in the same operon as tolC and their homologues yjfM and yjfC located elsewhere on the chromosome.

Abstract: Our results show that this growth deficiency is caused by depletion of the critical metabolite NAD(+) and high NADH/NAD(+) ratios.

Abstract: The increased amounts of PspA and decreased rates of NADH oxidation in Delta tolC membranes indicated stress on the membrane and dissipation of a proton motive force.

Abstract: We conclude that inactivation of TolC triggers metabolic shutdown in E. coli cells grown in minimal glucose medium.

Abstract: The Delta tolC phenotype is partially rescued by YgiBC and YjfMC, which have parallel functions independent from TolC.


Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates.

Abstract: CONTEXT Ghrelin is an orexigenic hormone that can increase body weight.

Abstract: Its circulating levels increase before meals and are suppressed after food ingestion.

Abstract: Understanding the effects of specific types of ingested macronutrients on ghrelin regulation could facilitate the design of weight-reducing diets.

Abstract: OBJECTIVE We sought to understand how ingestion of carbohydrates, proteins, or lipids affect acyl (bioactive) and total ghrelin levels among human subjects, hypothesizing that lipids might suppress ghrelin levels less effectively than do either carbohydrates or proteins.

Abstract: DESIGN This was a randomized, within-subjects cross-over study.

Abstract: SETTING The study was conducted at a University Clinical Research Center.

Abstract: PARTICIPANTS

Abstract: There were 16 healthy human subjects included in the study.

Abstract: INTERVENTIONS Isocaloric, isovolemic beverages composed primarily of carbohydrates, proteins, or lipids were provided.

Abstract: MAIN OUTCOME MEASURES The magnitude of postprandial suppression of total and acyl ghrelin levels (measured with a novel acyl-selective, two-site ELISA) was determined.

Abstract: RESULTS All beverages suppressed plasma acyl and total ghrelin levels.

Abstract: A significant effect of macronutrient class on decremental area under the curve for both acyl and total ghrelin was observed; the rank order for magnitude of suppression was protein more than carbohydrate more than lipid.

Abstract: Total ghrelin nadir levels were significantly lower after both carbohydrate and protein, compared with lipid beverages.

Abstract: In the first 3 postprandial hours, the rank order for acyl and total ghrelin suppression was carbohydrate more than protein more than lipid.

Abstract: In the subsequent 3 h, there was a marked rebound above preprandial values of acyl and total ghrelin after carbohydrate ingestion alone.

Abstract: CONCLUSIONS These findings suggest possible mechanisms contributing to the effects of high-protein/low-carbohydrate diets to promote weight loss, and high-fat diets to promote weight gain.


Hydrogen sulfide increases nitric oxide production with calcium-dependent activation of endothelial nitric oxide synthase in endothelial cells.

Abstract: Hydrogen sulfide (H(2)S) was recently discovered to be synthesized in mammalian tissues by several different enzymes.

Abstract: Numerous studies have shown that H(2)S has vasodilator and antihypertensive effects in the cardiovascular system.

Abstract: However, intracellular mechanisms of the H(2)S-induced vasodilation and its interactions with other endothelium-derived relaxing factors, such as nitric oxide (NO), remain unclear.

Abstract: We investigated whether H(2)S directly regulates endothelial NO synthase (eNOS) activity and NO production in endothelial cells.

Abstract: NaHS, a H(2)S donor, dose-dependently increased NO production in cultured endothelial cells.

Abstract: This effect was abolished by a calcium chelator (BAPTA-AM), but not by the absence of extracellular calcium.

Abstract: The NaHS-induced NO production was partially blocked by inhibitors of ryanodine receptor (dantrolene) or inositol 1,4,5-triphosphate receptor (xestospongin C).

Abstract: NaHS significantly increased intracellular calcium concentrations, and this effect was attenuated by dantrolene or xestospongin C. NaHS induced phosphorylation of eNOS at the activating phosphoserine residue 1179.

Abstract: The NaHS-induced eNOS phosphorylation and NO production were not affected by a PI3K/Akt inhibitor (wortmannin).

Abstract: The data of this study suggest that H(2)S directly acts on endothelial cells to induce eNOS activation and NO production by releasing calcium from the intracellular store in endoplasmic reticulum, which may explain one of mechanisms of its vasodilator function.


Fear of falling and visual field loss from glaucoma.

Abstract: OBJECTIVE To determine if visual field (VF) loss resulting from glaucoma is associated with greater fear of falling.

Abstract: DESIGN Prospective, observational study.

Abstract: PARTICIPANTS Fear of falling was compared between 83 glaucoma subjects with bilateral VF loss and 60 control subjects with good visual acuity and without significant VF loss recruited from patients followed up for suspicion of glaucoma.

Abstract: METHODS Participants completed the University of Illinois at Chicago Fear of Falling Questionnaire.

Abstract: The extent of fear of falling was assessed using Rasch analysis.

Abstract: MAIN OUTCOME MEASURES Subject ability to perform tasks without fear of falling was expressed in logits, with lower scores implying less ability and greater fear of falling.

Abstract: RESULTS Glaucoma subjects had greater VF loss than control subjects (median better-eye mean deviation [MD] of -8.0 decibels [dB] vs. +0.2 dB; P<0.001), but did not differ with regard to age, race, gender, employment status, the presence of other adults in the home, body mass index (BMI), grip strength, cognitive ability, mood, or comorbid illness (P ≥ 0.1 for all).

Abstract: In multivariate models, glaucoma subjects reported greater fear of falling as compared with controls (β = -1.20 logits; 95% confidence interval [CI], -1.87 to -0.53; P = 0.001), and fear of falling increased with greater VF loss severity (β = -0.52 logits per 5-dB decrement in the better eye VF MD; 95% CI, -0.72 to -0.33; P<0.001).

Abstract: Other variables predicting greater fear of falling included female gender (β = -0.55 logits; 95% CI, -1.03 to -0.06; P = 0.03), higher BMI (β = -0.07 logits per 1-unit increase in BMI; 95% CI, -0.13 to -0.01; P = 0.02), living with another adult (β = -1.16 logits; 95% CI, -0.34 to -1.99 logits; P = 0.006), and greater comorbid illness (β = -0.53 logits/1 additional illness; 95% CI, -0.74 to -0.32; P<0.001).

Abstract: CONCLUSIONS Bilateral VF loss resulting from glaucoma is associated with greater fear of falling, with an impact that exceeds numerous other risk factors.

Abstract: Given the physical and psychological repercussions associated with fear of falling, significant quality-of-life improvements may be achievable in patients with VF loss by screening for, and developing interventions to minimize, fear of falling.


Repeat instability: mechanisms of dynamic mutations

Abstract: Disease-causing repeat instability is an important and unique form of mutation that is linked to more than 40 neurological, neurodegenerative and neuromuscular disorders.

Abstract: DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations.

Abstract: The patterns of inherited and tissue-specific instability are determined by both gene-specific cis-elements and trans-acting DNA metabolic proteins.

Abstract: Repeat instability probably involves the formation of unusual DNA structures during DNA replication, repair and recombination.

Abstract: Experimental advances towards explaining the mechanisms of repeat instability have broadened our understanding of this mutational process.

Abstract: They have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.


Demographic Risk Factors for Alcohol-Related Aggression In and Around Licensed Venues.

Abstract: AIMS Few studies have examined the role of gender and both area-level and individual socio-economic status (SES) as independent predictors of alcohol-related aggression (ARA) in and around licensed venues.

Abstract: METHODS The aim of the present study was to investigate the relationship between gender, area-level SES and individual SES (operationalised as occupational category) and ARA in and around licensed venues.

Abstract: The sample comprised 697 men and 649 women aged 16-47, who completed a patron intercept survey as part of a larger study assessing trends in harm and stakeholders' views surrounding local community level interventions in dealing with alcohol-related problems in the night-time economy.

Abstract: RESULTS Binary logistic regression analyses showed that age, gender, occupational category, area-level SES and level of intoxication at time of interview were all significant predictors of involvement in ARA.

Abstract: Being male doubled the odds of involvement in ARA, while age was a protective factor.

Abstract: Blue collar workers had more than double the odds of ARA involvement of professionals, while those living in the most socio-economically disadvantaged areas were over twice as likely to report experiencing ARA compared to those living in the most advantaged areas.

Abstract: However, assessment of the predictive model by gender revealed that effects of age, occupational category and area-level SES were restricted to male participants, with greater intoxication no longer predictive.

Abstract: CONCLUSIONS ARA among patrons was significantly more likely to occur among men, those in blue collar occupations, and individuals living in low SES areas, suggesting both individual and area-level disadvantage may play a role in ARA.


Schizophrenia susceptibility pathway neuregulin 1–ErbB4 suppresses Src upregulation of NMDA receptors

Abstract: Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia.

Abstract: For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia.

Abstract: However, we show here that neuregulin 1β–ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs.

Abstract: Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src.

Abstract: NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral–CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation.

Abstract: Moreover, NRG1β-ErbB4 signaling prevented theta burst–induced phosphorylation of GluN2B by inhibiting Src kinase activity.

Abstract: We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.


Intestinal bacteria and the regulation of immune cell homeostasis.

Abstract: The human intestine is colonized by an estimated 100 trillion bacteria.

Abstract: Some of these bacteria are essential for normal physiology, whereas others have been implicated in the pathogenesis of multiple inflammatory diseases including IBD and asthma.

Abstract: This review examines the influence of signals from intestinal bacteria on the homeostasis of the mammalian immune system in the context of health and disease.

Abstract: We review the bacterial composition of the mammalian intestine, known bacterial-derived immunoregulatory molecules, and the mammalian innate immune receptors that recognize them.

Abstract: We discuss the influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory disease.

Abstract: We conclude with an examination of successes and future challenges in using bacterial communities or their products in the prevention or treatment of human disease.


Sympathetic activation during early pregnancy in humans.

Abstract: Sympathetic activity has been reported to increase in normotensive pregnant women, and to be even greater in women with gestational hypertension and preeclampsia at term.

Abstract: Whether sympathetic overactivity develops early during pregnancy, remaining high throughout gestation, or whether it only occurs at term providing the substrate for hypertensive disorders is unknown.

Abstract: We tested the hypothesis that sympathetic activation occurs early during pregnancy in humans.

Abstract: Eleven healthy women (29 ± 3 (SD) years) without prior hypertensive pregnancies were tested during the mid-luteal phase (PRE) and early pregnancy (EARLY; 6.2 ± 1.2 weeks of gestation).

Abstract: Muscle sympathetic nerve activity (MSNA) and haemodynamics were measured supine, at 30 deg and 60 deg upright tilt for 5 min each.

Abstract: Blood samples were drawn for catecholamines, direct renin, and aldosterone.

Abstract: MSNA was significantly greater during EARLY than PRE (supine: 25 ± 8 vs. 14 ± 8 bursts min(-1), 60 deg tilt: 49 ± 14 vs. 40 ± 10 bursts min(-1); main effect, P < 0.05).

Abstract: Resting diastolic pressure trended lower (P = 0.09), heart rate was similar, total peripheral resistance decreased (2172 ± 364 vs. 2543 ± 352 dyne s cm(-5); P < 0.05), sympathetic vascular transduction was blunted (0.10 ± 0.05 vs. 0.36 ± 0.47 units a.u.(-1) min(-1); P < 0.01), and both renin (supine: 27.9 ± 6.2 vs. 14.2 ± 8.7 pg ml(-1), P < 0.01) and aldosterone (supine: 16.7 ± 14.1 vs. 7.7 ± 6.8 ng ml(-1), P = 0.05) were higher during EARLY than PRE.

Abstract: These results suggest that sympathetic activation is a common characteristic of early pregnancy in humans despite reduced diastolic pressure and total peripheral resistance.

Abstract: These observations challenge conventional thinking about blood pressure regulation during pregnancy, showing marked sympathetic activation occurring within the first few weeks of conception, and may provide the substrate for pregnancy induced cardiovascular complications.


Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo.

Abstract: The influence of short stature on psychological adaptation in childhood and adolescence is controversial.

Abstract: GH is currently used to treat children with idiopathic short stature (ISS, also known as non-GH-deficient short stature).

Abstract: This study represents the first double-blind, placebo-controlled trial of the effects of GH on the psychological adaptation of children and adolescents with ISS, treated with GH until adult height was attained.

Abstract: Sixty-eight children (53 males, 15 females), 9-16 yr old, with marked ISS (measured height or predicted adult height -2.5 sd or less) received either GH 0.074 mg/kg or placebo sc three times per week until height velocity decreased to less than 1.5 cm/yr.

Abstract: Parents completed the Child Behavior Checklist (CBCL) and children the Self-Perception Profile (SPP) and Silhouette Apperception Technique at baseline and annually thereafter.

Abstract: Baseline behavioral/emotional adjustment (CBCL) and self-concept (SPP) scores for children with ISS were within the normative range.

Abstract: The two study groups exhibited similar behavioral and self-concept profiles (CBCL) during the first 2 yr of the study.

Abstract: However, CBCL behavior problems (internalizing, externalizing, and total problems) appeared to decline, in yr 3 and 4, in the GH-treated group relative to the placebo-treated group.

Abstract: Group differences in CBCL competency domains and the SPP were not observed at any point during the study.

Abstract: Short stature among children with ISS enrolled in this long-term, placebo-controlled study was not associated with problems in psychological adaptation or self-concept with the psychological instruments employed.

Abstract: GH treatment was associated with a trend toward improvement in problem behaviors, as measured by questionnaires (CBCL) completed by study participants' parents.

Abstract: It remains to be determined whether GH treatment significantly impacts adaptation, psychosocial function, or quality of life in children with ISS.


Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction.

Abstract: Induction of the interferon (IFN)-alpha/beta gene transcription in virus-infected cells is an event central to innate immunity.

Abstract: Mice lacking the transcription factor IRF-3 are more vulnerable to virus infection.

Abstract: In embryonic fibroblasts, virus-induced IFN-alpha/beta gene expression levels are reduced and the spectrum of the IFN-alpha mRNA subspecies altered.

Abstract: Furthermore, cells additionally defective in IRF-7 expression totally fail to induce these genes in response to infections by any of the virus types tested.

Abstract: In these cells, a normal profile of IFN-alpha/beta mRNA induction can be achieved by coexpressing both IRF-3 and IRF-7.

Abstract: These results demonstrate the essential and distinct roles of thetwo factors, which together ensure the transcriptional efficiency and diversity of IFN-alpha/beta genes for the antiviral response.


Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa.

Abstract: A sensitive reverse haemolytic plaque assay to detect lymphokine-secreting T cells, and Northern blot analysis to detect expression of lymphokine messenger RNA (mRNA) were used to study interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) production in the mucosa of children with Crohn's disease or ulcerative colitis (UC), and in histologically normal mucosa from patients without inflammatory bowel disease.

Abstract: In the mucosa of most patients with UC and control patients, IL-2- and IFN-gamma-secreting cells were absent or were present at only low levels.

Abstract: In contrast, in mucosa from patients with Crohn's disease, lymphokine-secreting cells were readily detectable (3-18%).

Abstract: IFN-gamma mRNA was detected by Northern blot analysis in 5/6 Crohn's tissues, but only in 1/5 UC samples and none of nine samples of control mucosa.

Abstract: These studies reveal an ongoing cell-mediated immune response in the mucosa in Crohn's disease.


Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.

Abstract: The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood.

Abstract: Here we show that p62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells.

Abstract: The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment.

Abstract: Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.


Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection.

Abstract: Certain pathogens, such as Mycobacterium tuberculosis, survive within the hostile intracellular environment of a macrophage.

Abstract: To identify host factors required for mycobacterial entry and survival within macrophages, we performed a genomewide RNA interference screen in Drosophila macrophage-like cells, using Mycobacterium fortuitum.

Abstract: We identified factors required for general phagocytosis, as well as those needed specifically for mycobacterial infection.

Abstract: One specific factor, Peste (Pes), is a CD36 family member required for uptake of mycobacteria, but not Escherichia coli or Staphylococcus aureus.

Abstract: Moreover, mammalian class B scavenger receptors (SRs) conferred uptake of bacteria into nonphagocytic cells, with SR-BI and SR-BII uniquely mediating uptake of M. fortuitum, which suggests a conserved role for class B SRs in pattern recognition and innate immunity.


Knowledge, attitudes, and practice on second primary cancer screening among cancer survivors: a qualitative study.

Abstract: OBJECTIVE The goal of this study was to examine the knowledge, attitude, and practice on second cancer screening among cancer survivors.

Abstract: METHODS Three focus group interviews were conducted with thirteen disease-free stomach, colorectal, breast and thyroid cancer survivors.

Abstract: Recurrent issues were identified and then placed into thematic categories.

Abstract: RESULTS None of the study participants had heard SPC, and they could not differentiate SPC from 'recurrence' or 'metastasis.'

Abstract: Survivors believed that they had been cured, and they were not aware of their increased risk of SPC.

Abstract: Although they had high awareness of cancer screening, they could not make a distinction between 'cancer screening' and 'routine surveillance test' after cancer treatment.

Abstract: Survivors said that they would have had the screening for SPC if they had known about it.

Abstract: They preferred physicians as the most reliable source for screening information.

Abstract: CONCLUSION Cancer survivors had limited knowledge about SPC, and lack of information was the main barrier for SPC screening.

Abstract: PRACTICE IMPLICATIONS An educational intervention would help cancer survivors to understand their risk of SPC and the needs of screening after the first cancer.


LncRNA HANR Promotes Tumorigenesis and Increase of Chemoresistance in Hepatocellular Carcinoma

Abstract: Background/Aims: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related death.

Abstract: Critical roles for long non-coding RNAs (lncRNAs) have recently been demonstrated for a variety of cancers, including hepatocellular carcinoma.

Abstract: However, the effect and mechanism of lncRNAs in HCC tumorigenesis and chemoresistance have not been extensively characterized.

Abstract: Methods: In the current study, we have identified a HCC-expressed lncRNA termed as HANR (HCC associated long non-coding RNA).

Abstract: We identified HANR by microarray analysis and validated its up-regulated expression by quantitative PCR.

Abstract: RNA pull-down and pathway analyses were conducted to evaluate physical and functional interactions with HANR.

Abstract: In vivo experiments were performed to assess tumorigenesis and increase of chemoresistance.

Abstract: In addition, the HANR expression in HCC specimens was detected by FISH.

Abstract: Xenograft and orthotopic mice model was constructed to observe the effect of HANR on tumorigenesis and chemoresistance in vivo.

Abstract: Results: HANR was demonstrated to be up-regulated in HCC patients and HCC cell lines.

Abstract: Increased HANR expression in HCC predicted short survival of patients.

Abstract: Knock-down of HANR markedly retarded cell proliferation, suppressed HCC xenograft/orthotopic tumor growth, induced apoptosis and enhanced chemosensitivity to doxorubicin, while over-expression of HANR showed the opposite effects.

Abstract: It was found that HANR bind to GSKIP for regulating the phosphorylation of GSK3β in HCC.

Abstract: Conclusion: Our results demonstrate that HANR contributes to the development of HCC and is a promising therapeutic target for chemosensitization of HCC cells to doxorubicin, which may represent a promising therapeutic target in the future.


Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune responses.

Abstract: We generated a series of knockin mouse lines, in which the cytokine receptor gp130-dependent STAT3 and/or SHP2 signals were disrupted, by replacing the mouse gp130 gene with human gp130 mutant cDNAs.

Abstract: The SHP2 signal-deficient mice (gp130F759/F759 were born normal but displayed splenomegaly and lymphadenopathy and an enhanced acute phase reaction.

Abstract: In contrast, the STAT3 signal-deficient mice (gp130FXQ/FXXQ) died perinatally, like the gp130-deficient mice (gp130D/D).

Abstract: The gp130F759/F759 mice showed prolonged gp130-induced STAT3 activation, indicating a negative regulatory role for SHP2.

Abstract: Th1-type cytokine production and IgG2a and IgG2b production were increased in the gp130F759/F759 mice, while they were decreased in the gp130FXXQ/FXXQ immune system.

Abstract: These results indicate that the balance of positive and negative signals generated through gp130 regulates the immune responses.


Viral interleukin-10 expressed by human cytomegalovirus during the latent phase of infection modulates latently infected myeloid cell differentiation.

Abstract: The human cytomegalovirus UL111A gene is expressed during latent and productive infections, and it codes for homologs of interleukin-10 (IL-10).

Abstract: We examined whether viral IL-10 expressed during latency altered differentiation of latently infected myeloid progenitors.

Abstract: In comparison to infection with parental virus or mock infection, latent infection with a virus in which the gene encoding viral IL-10 has been deleted upregulated cytokines associated with dendritic cell (DC) formation and increased the proportion of myeloid DCs.

Abstract: These data demonstrate that viral IL-10 restricts the ability of latently infected myeloid progenitors to differentiate into DCs and identifies an immunomodulatory role for viral IL-10 which may limit the host's ability to clear latent virus.


Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications.

Abstract: Most anticancer chemotherapies are immunosuppressive and induce nonimmunogenic tumor cell death.

Abstract: Bortezomib, a specific inhibitor of 26S proteasome, has shown clinical activity in several human tumors, including myeloma.

Abstract: Here we show that the uptake of human myeloma cells by dendritic cells (DCs) after tumor cell death by bortezomib, but not gamma irradiation or steroids, leads to the induction of antitumor immunity, including against primary tumor cells, without the need for any additional adjuvants.

Abstract: The delivery of activating signal from bortezomib-killed tumor cells to DCs depends on cell-cell contact between DCs and dying tumor cells and is mediated by bortezomib-induced exposure of heat shock protein 90 (hsp90) on the surface of dying cells.

Abstract: The combination of bortezomib and geldanamycin (an hsp90 inhibitor) leads to greater apoptosis of tumor cells but abrogates their immunogenicity.

Abstract: These data identify drug-induced exposure of endogenous heat shock proteins on the surface of dying cells as a mechanism of immunogenic death of human tumors.

Abstract: Specific targeting of bortezomib to tumors may enhance their immunogenicity and the induction of antitumor immunity.


Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells.

Abstract: To identify cancer-specific targets, we have conducted a synthetic lethal screen using a small interfering RNA (siRNA) library targeting approximately 4,000 individual genes for enhanced killing in the DLD-1 colon carcinoma cell line that expresses an activated copy of the K-Ras oncogene.

Abstract: We found that siRNAs targeting baculoviral inhibitor of apoptosis repeat-containing 5 (survivin) significantly reduced the survival of activated K-Ras-transformed cells compared with its normal isogenic counterpart in which the mutant K-Ras gene had been disrupted (DKS-8).

Abstract: In addition, survivin siRNA induced a transient G(2)-M arrest and marked polyploidy that was associated with increased caspase-3 activation in the activated K-Ras cells.

Abstract: These results indicate that tumors expressing the activated K-Ras oncogene may be particularly sensitive to inhibitors of the survivin protein.


Small molecules enable cardiac reprogramming of mouse fibroblasts with a single factor, Oct4.

Abstract: It was recently shown that mouse fibroblasts could be reprogrammed into cells of a cardiac fate by forced expression of multiple transcription factors and microRNAs.

Abstract: For ultimate application of such a reprogramming strategy for cell-based therapy or in vivo cardiac regeneration, reducing or eliminating the genetic manipulations by small molecules would be highly desirable.

Abstract: Here, we report the identification of a defined small-molecule cocktail that enables the highly efficient conversion of mouse fibroblasts into cardiac cells with only one transcription factor, Oct4, without any evidence of entrance into the pluripotent state.

Abstract: Small-molecule-induced cardiomyocytes spontaneously contract and exhibit a ventricular phenotype.

Abstract: Furthermore, these induced cardiomyocytes pass through a cardiac progenitor stage.

Abstract: This study lays the foundation for future pharmacological reprogramming approaches and provides a small-molecule condition for investigation of the mechanisms underlying the cardiac reprogramming process.


A switch from white to brown fat increases energy expenditure in cancer-associated cachexia.

Abstract: Cancer-associated cachexia (CAC) is a wasting syndrome characterized by systemic inflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle.

Abstract: Limited therapeutic options are available and the underlying mechanisms are poorly defined.

Abstract: Here we show that a phenotypic switch from WAT to brown fat, a phenomenon termed WAT browning, takes place in the initial stages of CAC, before skeletal muscle atrophy.

Abstract: WAT browning is associated with increased expression of uncoupling protein 1 (UCP1), which uncouples mitochondrial respiration toward thermogenesis instead of ATP synthesis, leading to increased lipid mobilization and energy expenditure in cachectic mice.

Abstract: Chronic inflammation and the cytokine interleukin-6 increase UCP1 expression in WAT, and treatments that reduce inflammation or β-adrenergic blockade reduce WAT browning and ameliorate the severity of cachexia.

Abstract: Importantly, UCP1 staining is observed in WAT from CAC patients.

Abstract: Thus, inhibition of WAT browning represents a promising approach to ameliorate cachexia in cancer patients.


Potential Mechanisms of Action of Lithium in Bipolar Disorder

Abstract: Lithium has been used for over half a century for the treatment of bipolar disorder as the archetypal mood stabilizer, and has a wealth of empirical evidence supporting its efficacy in this role.

Abstract: Despite this, the specific mechanisms by which lithium exerts its mood-stabilizing effects are not well understood.

Abstract: Given the inherently complex nature of the pathophysiology of bipolar disorder, this paper aims to capture what is known about the actions of lithium ranging from macroscopic changes in mood, cognition and brain structure, to its effects at the microscopic level on neurotransmission and intracellular and molecular pathways.

Abstract: A comprehensive literature search of databases including MEDLINE, EMBASE and PsycINFO was conducted using relevant keywords and the findings from the literature were then reviewed and synthesized.

Abstract: Numerous studies report that lithium is effective in the treatment of acute mania and for the long-term maintenance of mood and prophylaxis; in comparison, evidence for its efficacy in depression is modest.

Abstract: However, lithium possesses unique anti-suicidal properties that set it apart from other agents.

Abstract: With respect to cognition, studies suggest that lithium may reduce cognitive decline in patients; however, these findings require further investigation using both neuropsychological and functional neuroimaging probes.

Abstract: Interestingly, lithium appears to preserve or increase the volume of brain structures involved in emotional regulation such as the prefrontal cortex, hippocampus and amygdala, possibly reflecting its neuroprotective effects.

Abstract: At a neuronal level, lithium reduces excitatory (dopamine and glutamate) but increases inhibitory (GABA) neurotransmission; however, these broad effects are underpinned by complex neurotransmitter systems that strive to achieve homeostasis by way of compensatory changes.

Abstract: For example, at an intracellular and molecular level, lithium targets second-messenger systems that further modulate neurotransmission.

Abstract: For instance, the effects of lithium on the adenyl cyclase and phospho-inositide pathways, as well as protein kinase C, may serve to dampen excessive excitatory neurotransmission.

Abstract: In addition to these many putative mechanisms, it has also been proposed that the neuroprotective effects of lithium are key to its therapeutic actions.

Abstract: In this regard, lithium has been shown to reduce the oxidative stress that occurs with multiple episodes of mania and depression.

Abstract: Further, it increases protective proteins such as brain-derived neurotrophic factor and B-cell lymphoma 2, and reduces apoptotic processes through inhibition of glycogen synthase kinase 3 and autophagy.

Abstract: Overall, it is clear that the processes which underpin the therapeutic actions of lithium are sophisticated and most likely inter-related.


The role of autophagy in cancer development and response to therapy

Abstract: Autophagy is a process in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins and cytoplasmic organelles.

Abstract: This process is an important cellular response to stress or starvation.

Abstract: Many studies have shed light on the importance of autophagy in cancer, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions.

Abstract: What is the present state of our knowledge about the role of autophagy in cancer development, and in response to therapy?

Abstract: And how can the autophagic process be manipulated to improve anticancer therapeutics?


The quest to overcome resistance to EGFR-targeted therapies in cancer

Abstract: All patients with metastatic lung, colorectal, pancreatic or head and neck cancers who initially benefit from epidermal growth factor receptor (EGFR)-targeted therapies eventually develop resistance.

Abstract: An increasing understanding of the number and complexity of resistance mechanisms highlights the Herculean challenge of killing tumors that are resistant to EGFR inhibitors.

Abstract: Our growing knowledge of resistance pathways provides an opportunity to develop new mechanism-based inhibitors and combination therapies to prevent or overcome therapeutic resistance in tumors.

Abstract: We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance.


An organ culture model for the study of metanephric development.

Abstract: A murine whole organ metanephric culture system was designed to study the developmental aspects of mammalian nephrogenesis.

Abstract: Metanephros and ureteric bud were removed from CFI albino mouse embryos at 13.5 +/-

Abstract: 0.4 days gestation, and grown in Dulbecco's modified Eagle's Minimal Essential Medium supplemented with 20 per cent donor bovine serum at 37C in a mixed air--5 per cent CO2 environment.

Abstract: Under the experimental conditions employed, the metanephric explants showed organotypic tubular and glomerular epithelial development.

Abstract: A well-developed proximal tubule with microvilli, and characteristic intracellular organelles and intercellular junctions developed by 72 hours of culture.

Abstract: By 120 hours of culture, unique devascularized glomeruli consisting of parietal and visceral epithelial layers formed.

Abstract: The glomerular visceral epithelial cells formed foot processes and slit pore diaphragms, and produced islands of basement membrane.

Abstract: No endothelial or mesangial elements were present at any stage in organ culture development, indicating that advanced nephrogenesis can occur following initial epithelial-mesenchymal induction despite the absence of vascularization.

Abstract: The whole organ culture model system isolates renal structural development from the influences of perfusion and urine formation.

Abstract: The system thus affords the opportunity to study normal, as well as abnormal mammalian renal development under highly controlled experimental conditions.


Molecular layers underlying cytoskeletal remodelling during cortical development

Abstract: During neural development, the cytoskeleton of newborn neurons undergoes extensive and dynamic remodelling to facilitate the sequential steps of neurogenesis, cell migration and terminal differentiation.

Abstract: It is clear from studying the mechanisms that precipitate these functions that different configurations of the cytoskeleton prefigure the correct execution of each step and define cohorts of proteins the functions of which are indispensable for the control of neuronal migration but not terminal differentiation.

Abstract: These combinatorial protein functions are also predetermined by regulated gene expression and the precise subcellular localisation of their protein products.

Abstract: Here, we expand on this view in the context of recent data on how the cytoskeleton is regulated during the maturation of cortical neurons within the developing brain.


Strong bias in the bacterial CRISPR elements that confer immunity to phage.

Abstract: Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas systems provide adaptive immunity against phage via spacer-encoded CRISPR RNAs that are complementary to invasive nucleic acids.

Abstract: Here, we challenge Streptococcus thermophilus with a bacteriophage, and used PCR-based metagenomics to monitor phage-derived spacers daily for 15 days in two experiments.

Abstract: Spacers that target the host chromosome are infrequent and strongly selected against, suggesting autoimmunity is lethal.

Abstract: In experiments that recover over half a million spacers, we observe early dominance by a few spacer sub-populations and rapid oscillations in sub-population abundances.

Abstract: In two CRISPR systems and in replicate experiments, a few spacers account for the majority of spacer sequences.

Abstract: Nearly all phage locations targeted by the acquired spacers have a proto-spacer adjacent motif (PAM), indicating PAMs are involved in spacer acquisition.

Abstract: We detect a strong and reproducible bias in the phage genome locations from which spacers derive.

Abstract: This may reflect selection for specific spacers based on location and effectiveness.


Chronic hypoxia induces modification of the N-methyl-D-aspartate receptor in rat brain.

Abstract: This study examined [3H]MK-801 binding to the N-methyl-D-aspartate (NMDA) receptor in membranes prepared from cerebral cortex, hippocampus and corpus striatum of 3 week old rats exposed to 10 weeks of intermittent hypobaric hypoxia (4300 m; 450 Torr) and compared results with those of normoxic controls.

Abstract: The cortex, hippocampus and striatum of hypoxic animals had a 36, 35 and 31% reduction in binding sites (Bmax) and a 29, 32 and 17% decrease (reflecting increased affinity) in the dissociation constant (Kd) when compared to controls.

Abstract: In the cerebral cortex, both glutamate (100 microM) and glycine (10 microM) enhanced 3[H]MK-801 binding by two to 3-fold.

Abstract: Coagonist glutamate, however, had a higher EC50 (0.44 microM) in the hypoxic cortical membranes when compared to controls (0.28 microM).

Abstract: No significant differences were found in the EC50 of glycine.

Abstract: The results show that the NMDA receptor is altered in several brain regions of rats developing in a hypoxic environment.


Cannabinoids in Clinical Practice

Abstract: Cannabis has a potential for clinical use often obscured by unreliable and purely anecdotal reports.

Abstract: The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (Δ9-THC); others include cannabidiol (CBD) and cannabigerol (CBG).

Abstract: Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC.

Abstract: A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this.

Abstract: The mechanism of action is still not fully understood, although cannabinoid receptors have been cloned and natural ligands identified.

Abstract: Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasm and pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor.

Abstract: Most of the controlled studies have been carried out with THC rather than cannabis herb and so do not mimic the usual clincal situation.

Abstract: Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and antiinflammatory effects, indicating that there is scope for developing drugs which do not have the psychoactive properties ofTHC.

Abstract: Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety.

Abstract: Cannabinoids are effective in chemotherapy-induced emesis and nabilone has been licensed for this use for several years.

Abstract: Currently, the synthetic cannabinoid HU211 is undergoing trials as a protective agent after brain trauma.

Abstract: Anecdotal reports of cannabis use include case studies in migraine and Tourette’s syndrome, and as a treatment for asthma and glaucoma.

Abstract: Apart from the smoking aspect, the safety profile of cannabis is fairly good.

Abstract: However, adverse reactions include panic or anxiety attacks, which are worse in the elderly and in women, and less likely in children.

Abstract: Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatric hospital admissions found no evidence of this, however, it may exacerbate existing symptoms.

Abstract: The relatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks, especially driving and operating machinery; although driving impairment with cannabis is only moderate, there is a significant interaction with alcohol.

Abstract: Natural materials are highly variable and multiple components need to be standardised to ensure reproducible effects.

Abstract: Pure natural and synthetic compounds do not have these disadvantages but may not have the overall therapeutic effect of the herb.


Large deformation of red blood cell ghosts in a simple shear flow.

Abstract: Red blood cells are known to change shape in response to local flow conditions.

Abstract: Deformability affects red blood cell physiological function and the hydrodynamic properties of blood.

Abstract: The immersed boundary method is used to simulate three-dimensional membrane-fluid flow interactions for cells with the same internal and external fluid viscosities.

Abstract: The method has been validated for small deformations of an initially spherical capsule in simple shear flow for both neo-Hookean and the Evans-Skalak membrane models.

Abstract: Initially oblate spheroidal capsules are simulated and it is shown that the red blood cell membrane exhibits asymptotic behavior as the ratio of the dilation modulus to the extensional modulus is increased and a good approximation of local area conservation is obtained.

Abstract: Tank treading behavior is observed and its period calculated.


Preoperative C-reactive protein predicts long-term mortality and hospital length of stay after primary, nonemergent coronary artery bypass grafting.

Abstract: BACKGROUND Preoperative C-reactive protein (CRP) levels more than 10 mg/l have been shown to be associated with increased morbidity and mortality after cardiac surgery.

Abstract: We examine the value of preoperative CRP levels less than 10 mg/l for predicting long-term, all-cause mortality and hospital length of stay in surgical patients undergoing primary, nonemergent coronary artery bypass graft-only surgery.

Abstract: METHODS We examined the association between preoperative CRP levels stratified into four categories (< 1, 1-3, 3-10, and > 10 mg/l), and 7-yr all-cause mortality and hospital length of stay in 914 prospectively enrolled primary, nonemergent coronary artery bypass graft-only surgical patients using a proportional hazards regression model.

Abstract: RESULTS Eighty-seven patients (9.5%) died during a mean follow-up period of 4.8 +/-

Abstract: 1.5 yr.

Abstract: After proportional hazards adjustment, the 3-10 and > 10 mg/l preoperative CRP groups were associated with long-term, all-cause mortality (hazards ratios [95% CI]: 2.50 [1.22-5.16], P = 0.01 and 2.66 [1.21-5.80], P = 0.02, respectively) and extended hospital length of stay (1.32 [1.07-1.63], P < 0.001 and 1.27 [1.02-1.62], P = 0.001, respectively).

Abstract: CONCLUSION We demonstrate that preoperative CRP levels as low as 3 mg/l are associated with increased long-term mortality and extended hospital length of stay in relatively lower-acuity patients undergoing primary, nonemergent coronary artery bypass graft-only surgery.

Abstract: These important findings may allow for more objective risk stratification of patients who present for uncomplicated surgical coronary revascularization.


Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation.

Abstract: High-throughput mRNA sequencing (RNA-Seq) promises simultaneous transcript discovery and abundance estimation.

Abstract: However, this would require algorithms that are not restricted by prior gene annotations and that account for alternative transcription and splicing.

Abstract: Here we introduce such algorithms in an open-source software program called Cufflinks.

Abstract: To test Cufflinks, we sequenced and analyzed >430 million paired 75-bp RNA-Seq reads from a mouse myoblast cell line over a differentiation time series.

Abstract: We detected 13,692 known transcripts and 3,724 previously unannotated ones, 62% of which are supported by independent expression data or by homologous genes in other species.

Abstract: Over the time series, 330 genes showed complete switches in the dominant transcription start site (TSS) or splice isoform, and we observed more subtle shifts in 1,304 other genes.

Abstract: These results suggest that Cufflinks can illuminate the substantial regulatory flexibility and complexity in even this well-studied model of muscle development and that it can improve transcriptome-based genome annotation.


Sporadic Creutzfeldt-Jakob disease in the United Kingdom: analysis of epidemiological surveillance data for 1970-96.

Abstract: OBJECTIVE To identify changes in the occurrence of Creutzfeldt-Jakob disease that might be related to the epidemic of bovine spongiform encephalopathy.

Abstract: DESIGN Epidemiological surveillance of the United Kingdom population for Creutzfeldt-Jakob disease based on (a) referral of suspected cases by neurologists, neuropathologists, and neurophysiologists and (b) death certificates.

Abstract: SETTING England and Wales during 1970-84, and whole of the United Kingdom during 1985-96.

Abstract: SUBJECTS All 662 patients identified as sporadic cases of Creutzfeldt-Jakob disease.

Abstract: MAIN OUTCOME MEASURES Age distribution of patients, age specific time trends of disease, occupational exposure to cattle, potential exposure to causative agent of bovine spongiform encephalopathy.

Abstract: RESULTS During 1970-96 there was an increase in the number of sporadic cases of Creutzfeldt-Jakob disease recorded yearly in England and Wales.

Abstract: The greatest increase was among people aged over 70.

Abstract: There was a statistically significant excess of cases among dairy farm workers and their spouses and among people at increased risk of contact with live cattle infected with bovine spongiform encephalopathy.

Abstract: During 1994-6 there were six deaths from sporadic Creutzfeldt-Jakob disease in the United Kingdom in patients aged under 30.

Abstract: CONCLUSIONS The increase in the incidence of sporadic Creutzfeldt-Jakob disease and the high incidence in dairy farmers in the United Kingdom may be unrelated to bovine spongiform encephalopathy.

Abstract: The most striking change in the pattern of Creutzfeldt-Jakob disease in the United Kingdom after the epidemic of bovine spongiform encephalopathy is provided by the incidence in a group of exceptionally young patients with a consistent and unusual neuropathological profile.

Abstract: The outcome of mouse transmission studies and the future incidence of the disease in the United Kingdom and elsewhere, will be important in judging whether the agent causing bovine spongiform encephalopathy has infected humans.


Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias.

Abstract: BACKGROUND The association between antecedent head injury and AD is inconsistent.

Abstract: OBJECTIVE To examine the association between early adult head injury, as documented by military hospital records, and dementia in late life; and to evaluate the interaction between head injury and APOE epsilon4 as risk factors for dementia.

Abstract: METHODS The study had a population-based prospective historical cohort design.

Abstract: It included men who were World War II Navy and Marine veterans, and were hospitalized during their military service with a diagnosis of either a nonpenetrating head injury or another unrelated condition.

Abstract: In 1996 to 1997, military medical records were abstracted to document the occurrence and details of closed head injury.

Abstract: The entire sample was then evaluated for dementia and AD using a multistage procedure.

Abstract: There were 548 veterans with head injury and 1228 without head injury who completed all assigned stages of the study.

Abstract: The authors estimated risk of dementia, specifically AD, using proportional hazards models.

Abstract: RESULTS Both moderate head injury (hazard ratio [HR] = 2.32; CI = 1.04 to 5.17) and severe head injury (HR = 4.51; CI = 1.77 to 11.47) were associated with increased risk of AD.

Abstract: Results were similar for dementia in general.

Abstract: The results for mild head injury were inconclusive.

Abstract: When the authors stratified by the number of APOE epsilon4 alleles, they observed a nonsignificant trend toward a stronger association between AD and head injury in men with more epsilon4 alleles.

Abstract: CONCLUSIONS Moderate and severe head injuries in young men may be associated with increased risk of AD and other dementias in late life.

Abstract: However, the authors cannot exclude the possibility that other unmeasured factors may be influencing this association.