Viral population estimation using pyrosequencing

The diversity of virus populations within single infected hosts presents a major difficulty for the natural immune response as well as for vaccine design and antiviral drug therapy. Recently developed pyrophosphate based sequencing technologies (pyrosequencing) can be used for quantifying this diversity by ultra-deep sequencing of virus samples. We present computational methods for the analysis of such sequence data and apply these techniques to pyrosequencing data obtained from HIV populations within patients harboring drug resistant virus strains. Our main result is the estimation of the population structure of the sample from the pyrosequencing reads. This inference is based on a statistical approach to error correction, followed by a combinatorial algorithm for constructing a minimal set of haplotypes that explain the data. Using this set of explaining haplotypes, we apply a statistical model to infer the frequencies of the haplotypes in the population via an EM algorithm. We demonstrate that pyrosequencing reads allow for effective population reconstruction by extensive simulations and by comparison to 165 sequences obtained directly from clonal sequencing of four independent, diverse HIV populations. Thus, pyrosequencing can be used for cost-effective estimation of the structure of virus populations, promising new insights into viral evolutionary dynamics and disease control strategies.Comment: 23 pages, 13 figure

Robust optical delay lines via topological protection

Phenomena associated with topological properties of physical systems are naturally robust against perturbations. This robustness is exemplified by quantized conductance and edge state transport in the quantum Hall and quantum spin Hall effects. Here we show how exploiting topological properties of optical systems can be used to implement robust photonic devices. We demonstrate how quantum spin Hall Hamiltonians can be created with linear optical elements using a network of coupled resonator optical waveguides (CROW) in two dimensions. We find that key features of quantum Hall systems, including the characteristic Hofstadter butterfly and robust edge state transport, can be obtained in such systems. As a specific application, we show that the topological protection can be used to dramatically improve the performance of optical delay lines and to overcome limitations related to disorder in photonic technologies.Comment: 9 pages, 5 figures + 12 pages of supplementary informatio

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results: In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Eva Birosova, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid V Rauch, Christina Uhlmann, Harald Kugel and Udo Dannlowsk

Hyponatremia revisited: Translating physiology to practice

The complexity of hyponatremia as a clinical problem is likely caused by the opposite scenarios that accompany this electrolyte disorder regarding pathophysiology (depletional versus dilutional hyponatremia, high versus low vasopressin levels) and therapy (rapid correction to treat cerebral edema versus slow correction to prevent osmotic demyelination, fluid restriction versus fluid resuscitation). For a balanced differentiation between these opposites, an understanding of the pathophysiology of hyponatremia is required. Therefore, in this review an attempt is made to translate the physiology of water balance regulation to strategies that improve the clinical management of hyponatremia. A physiology-based approach to the patient with hyponatremia is presented, first addressing the possibility of acute hyponatremia, and then asking if and if so why vasopressin is secreted non-osmotically. Additional diagnostic recommendations are not to rely too heavily of the assessment of the extracellular fluid volume, to regard the syndrome of inappropriate antidiuresis as a diagnosis of exclusion, and to rationally investigate the pathophysiology of hyponatremia rather than to rely on isolated laboratory values with arbitrary cutoff values. The features of the major hyponatremic disorders are discussed, including diuretic-induced hyponatremia, adrenal and pituitary insufficiency, the syndrome of inappropriate antidiuresis, cerebral salt wasting, and exercise-associated hyponatremia. The treatment of hyponatremia is reviewed from simple saline solutions to the recently introduced vasopressin receptor antagonists, including their promises and limitations. Given the persistently high rates of hospital-acquired hyponatremia, the importance of improving the management of hyponatremia seems both necessary and achievable. Copyrigh

Moving out of the shadows: accomplishing bisexual motherhood

Our qualitative study explored the ways in which bisexual mothers came to identify as such and how they structured their relationships and parenting within hetero-patriarchal society. The experiences of seven self-identified White bisexual women (aged from 28 to 56-years-old) from across England and the Republic of Ireland were investigated through semi-structured interviews. Participants’ children were aged 8 months to 28 years old at the time of their interviews. A thematic narrative analysis highlighted the following issues that participants had encountered in constructing their self-identity: prioritizing children; connecting and disconnecting with others and finessing self-definition; questioning societal relationship expectations. Nevertheless, participants varied considerably in how each of the themes identified were reflected in their lives, in particular depending upon each participant’s interpretation of her local social context. Both motherhood and self-identifying as bisexual gave a sense of meaning and purpose to participants’ life stories, although participants sometimes foregrounded their commitment to their children even at a personal cost to their bisexual identity. Using three different theoretical perspectives from feminist theory, queer theory and life course theory, the narratives analysed revealed ways in which bisexual motherhood not only had been influenced both intentionally and unintentionally by heteronormative expectations but also had directly and indirectly challenged these expectations

A Surprising Prevention Success: Why Did the HIV Epidemic Decline in Zimbabwe?

Daniel Halperin and colleagues examine reasons for the remarkable decline in HIV in Zimbabwe, in the context of severe social, political, and economic disruption

The efficacy of hypotonic and near-isotonic saline for parenteral fluid therapy given at low maintenance rate in preventing significant change in plasma sodium in post-operative pediatric patients: protocol for a prospective randomized non-blinded study

<p>Abstract</p> <p>Background</p> <p>Hyponatremia is the most frequent electrolyte abnormality observed in post-operative pediatric patients receiving intravenous maintenance fluid therapy. If plasma sodium concentration (p-Na⁺) declines to levels below 125 mmol/L in < 48 h, transient or permanent brain damage may occur. There is an intense debate as to whether the administered volume (full rate <it>vs. </it>restricted rate of infusion) and the composition of solutions used for parenteral maintenance fluid therapy (hypotonic <it>vs. </it>isotonic solutions) contribute to the development of hyponatremia. So far, there is no definitive pediatric data to support a particular choice of parenteral fluid for maintenance therapy in post-surgical patients.</p> <p>Methods/Design</p> <p>Our prospective randomized non-blinded study will be conducted in healthy children and adolescents aged 1 to 14 years who have been operated for acute appendicitis. Patients will be randomized either to intravenous hypotonic (0.23% or 0.40% sodium chloride in glucose, respectively) or near-isotonic (0.81% sodium chloride in glucose) solution given at approximately three-fourths of the average maintenance rate. The main outcome of interest from this study is to evaluate 24 h post-operatively whether differences in p-Na⁺between treatment groups are large enough to be of clinical relevance. In addition, water and electrolyte balance as well as regulatory hormones will be measured.</p> <p>Discussion</p> <p>This study will provide valuable information on the efficacy of hypotonic and near-isotonic fluid therapy in preventing a significant decrease in p-Na⁺. Finally, by means of careful electrolyte and water balance and by measuring regulatory hormones our results will also contribute to a better understanding of the physiopathology of post-operative changes in p-Na⁺in a population at risk for hyponatremia.</p> <p>Trial registration</p> <p>The protocol for this study is registered with the current controlled trials registry; registry number: <a href="http://www.controlled-trials.com/ISRCTN43896775">ISRCTN43896775</a>.</p

Abnormal function of the vasopressin-cyclic-AMP-aquaporin2 axis during urine concentrating and diluting in patients with reduced renal function. A case control study

<p>Abstract</p> <p>Background</p> <p>The kidneys ability to concentrate and dilute urine is deteriorated during progressive renal insufficiency. We wanted to test the hypothesis that these phenomena could be attributed to an abnormal function of the principal cells in the distal part of the nephron.</p> <p>Methods</p> <p>Healthy control subjects and patients with chronic kidney diseases were studied. Group 1 comprised healthy subjects, n = 10. Groups 2-4 comprised patients with chronic kidney disease (Group 2, n = 14, e-GFR ? 90 m1/min; Group 3, n = 11, 60 m1/min ? e-GFR < 90 ml/min; and Group 4, n = 16, 15 ml/min ? e-GFR < 60 ml/min). The subjects collected urine during 24 hours. A urine concentrating test was done by thirsting during the following 12 hours. Thereafter, a urine diluting test was performed with a water load of 20 ml/kg body weight. The effect variables were urinary excretions of aquaporin2 (u-AQP2), cyclic-AMP (u-c-AMP), urine volume (UV), free water clearance (C_H2O), urine osmolarity (u-Osm), and plasma arginine vasopressin (p-AVP).</p> <p>Results</p> <p>After fluid deprivation, u-Osm increased. In all groups, UV and C_H2Odecreased and u-AQP2 and u-c-AMP increased in Groups 1 and 2, but were unchanged in Group 3 and 4. P-AVP was significantly higher in Group 4 than in the other groups. During urine diluting, UV and C_H2Oreached significantly higher levels in Groups 1-3 than Group 4. Both before and after water loading, u-AQP2 and p-AVP were significantly higher and u-c-AMP was significantly lower in Group 4 than the other groups. Estimated-GFR was correlated negatively to p-AVP and positively to u-c-AMP.</p> <p>Conclusions</p> <p>Patients with moderately severe chronic kidney disease have a reduced renal concentrating and diluting capacity compared to both patients with milder chronic kidney disease and healthy control subjects. These phenomena can be attributed, at least partly, to an abnormally decreased response in the AVP-c-AMP-AQP2 axis.</p> <p>ClinicalTrials.Gov Identifier: NCT00313430</p