Recombinant Human Parathyroid Hormone Effect on Health-Related Quality of Life in Adults With Chronic Hypoparathyroidism

Context: Reduced health-related quality of life (HRQoL) is common in patients with hypoparathyroidism on conventional therapy with calcium and active vitamin D supplements. Objective: To examine the effects of recombinant human parathyroid hormone (rhPTH[1-84]) on HRQoL as measured by the 36-Item Short Form Health Survey (SF-36) during the multinational, randomized, placebo-controlled REPLACE study. Patients: 122 adults with chronic hypoparathyroidism. Intervention(s): Following an optimization period when calcium and/or active vitamin D supplements were adjusted to reach target serum calcium levels (8.0-9.0 mg/dL; 2.0-2.2 mmol/L), patients were randomized to receive placebo (n=39) or rhPTH(1-84) (n=83) (starting dose 50 mug/day, could be titrated up to 100 mug/day); supplement doses were adjusted to maintain target serum calcium levels. Main Outcome Measure(s): Change from baseline (post-optimization, at randomization) to Week 24 in HRQoL as assessed by the SF-36v2 health survey. Results: Overall, the between-group differences were not statistically significant. However, in the rhPTH(1-84) group, there were significant improvements in the physical component summary score (P=0.004) and in body pain (P<0.05), general health (P<0.05), and vitality (P<0.001) domains as compared with baseline values. In the placebo group, there were no significant changes for any of the domains. The magnitude of change between 0 and 24 weeks in SF-36 scores was negatively correlated with baseline scores, such that patients with lower HRQoL at baseline were more likely to experience improvement in response to treatment. Conclusions: Treatment with rhPTH(1-84) may improve HRQoL in adults with hypoparathyroidism

Students’ Evolving Meaning About Tangent Line with the Mediation of a Dynamic Geometry Environment and an Instructional Example Space

In this paper I report a lengthy episode from a teaching experiment in which fifteen Year 12 Greek students negotiated their definitions of tangent line to a function graph. The experiment was designed for the purpose of introducing students to the notion of derivative and to the general case of tangent to a function graph. Its design was based on previous research results on students’ perspectives on tangency, especially in their transition from Geometry to Analysis. In this experiment an instructional example space of functions was used in an electronic environment utilising Dynamic Geometry software with Function Grapher tools. Following the Vygotskian approach according to which students’ knowledge develops in specific social and cultural contexts, students’ construction of the meaning of tangent line was observed in the classroom throughout the experiment. The analysis of the classroom data collected during the experiment focused on the evolution of students’ personal meanings about tangent line of function graph in relation to: the electronic environment; the pre-prepared as well as spontaneous examples; students’ engagement in classroom discussion; and, the role of researcher as a teacher. The analysis indicated that the evolution of students’ meanings towards a more sophisticated understanding of tangency was not linear. Also it was interrelated with the evolution of the meaning they had about the inscriptions in the electronic environment; the instructional example space; the classroom discussion; and, the role of the teacher

Complications during pharmacological stress echocardiography: a video-case series

BACKGROUND: Stress echocardiography is a cost-effective tool for the modern noninvasive diagnosis of coronary artery disease. Several physical and pharmacological stresses are used in combination with echocardiographic imaging, usually exercise, dobutamine and dipyridamole. The safety of a stress is (or should be) a major determinant in the choice of testing. Although large scale single center experiences and multicenter trial information are available for both dobutamine and dipyridamole stress echo testing, complications or side effects still can occur even in the most experienced laboratories with the most skilled operators. CASE PRESENTATION: We decided to present a case collection of severe complications during pharmacological stress echo testing, including a ventricular tachycardia, cardiogenic shock, transient ischemic attack, torsade de pointe, fatal ventricular fibrillation, and free wall rupture. CONCLUSION: We believe that, in this field, every past complication described is a future complication avoided; what happens in your lab is more true of what you read in journals; and Good Clinical Practice is not "not having complications", but to describe the complications you had

Cognitive architectures as Lakatosian research programmes: two case studies

Cognitive architectures - task-general theories of the structure and function of the complete cognitive system - are sometimes argued to be more akin to frameworks or belief systems than scientific theories. The argument stems from the apparent non-falsifiability of existing cognitive architectures. Newell was aware of this criticism and argued that architectures should be viewed not as theories subject to Popperian falsification, but rather as Lakatosian research programs based on cumulative growth. Newell's argument is undermined because he failed to demonstrate that the development of Soar, his own candidate architecture, adhered to Lakatosian principles. This paper presents detailed case studies of the development of two cognitive architectures, Soar and ACT-R, from a Lakatosian perspective. It is demonstrated that both are broadly Lakatosian, but that in both cases there have been theoretical progressions that, according to Lakatosian criteria, are pseudo-scientific. Thus, Newell's defense of Soar as a scientific rather than pseudo-scientific theory is not supported in practice. The ACT series of architectures has fewer pseudo-scientific progressions than Soar, but it too is vulnerable to accusations of pseudo-science. From this analysis, it is argued that successive versions of theories of the human cognitive architecture must explicitly address five questions to maintain scientific credibility

Surgical rates for Crohn’s Disease are decreasing: a population-based time trend analysis and validation study

Objectives: Temporal changes for intestinal resections for Crohn’s disease (CD) are controversial. We validated administrative database codes for CD diagnosis and surgery in hospitalized patients and then evaluated temporal trends in CD surgical resection rates. Methods: First, we validated International Classification of Disease (ICD)-10-CM coding for CD diagnosis in hospitalized patients and Canadian Classification of Health Intervention coding for surgical resections. Second, we used these validated codes to conduct population-based surveillance between fiscal years 2002 and 2010 to identify adult CD patients undergoing intestinal resection (n=981). Annual surgical rate was calculated by dividing incident surgeries by estimated CD prevalence. Time trend analysis was performed and annual percent change (APC) with 95% confidence intervals (CI) in surgical resection rates were calculated using a generalized linear model assuming a Poisson distribution. Results: In the validation cohort, 101/104 (97.1%) patients undergoing surgery and 191/200 (95.5%) patients admitted without surgery were confirmed to have CD on chart review. Among the 116 administrative database codes for surgical resection, 97.4% were confirmed intestinal resections on chart review. From 2002 to 2010, the overall CD surgical resection rate was 3.8 resections per 100 person-years. During the study period, rate of surgery decreased by 3.5% per year (95% CI: -1.1%, -5.8%), driven by decreasing emergent operations (-10.1% per year [95% CI: -13.4%, -6.7%]) whereas elective surgeries increased by 3.7% per year (95% CI: 0.1%, 7.3%). Conclusions: Overall surgical resection rates in CD are decreasing, but a paradigm shift has occurred whereby elective operations are now more commonly performed than emergent surgeries

Nursing Diagnosis Risk for falls: prevalence and clinical profile of hospitalized patients

Objectives: to identify the prevalence of the Nursing Diagnosis (ND) Risk for falls in the hospitalizations of adult patients in clinical and surgical units, to characterize the clinical profile and to identify the risk factors of the patients with this ND. Method: a cross-sectional study with 174 patients. The data was collected from the computerized nursing care prescriptions system and on-line hospital records, and analyzed statistically. Results: the prevalence of the ND Risk for falls was 4%. The patients’ profile indicated older adults, males (57%), those hospitalized in the clinical units (63.2%), with a median length of hospitalization of 20 (10-24) days, with neurological illnesses (26%), cardio-vascular illnesses (74.1%) and various co-morbidities (3±1.8). The prevalent risk factors were neurological alterations (43.1%), impaired mobility (35.6%) and extremes of age (10.3%). Conclusion: the findings contributed to evidencing the profile of the patients with a risk of falling hospitalized in clinical and surgical wards, which favors the planning of interventions for preventing this adverse event

Molecular evolution of viral multifunctional proteins: the case of Potyvirus HC-Pro

[EN] Our knowledge on the mode of evolution of the multifunctional viral proteins remains incomplete. To tackle this problem, here, we have investigated the evolutionary dynamics of the potyvirus multifunctional protein HC-Pro, with particular focus on its functional domains. The protein was partitioned into the three previously described functional domains, and each domain was analyzed separately and assembled. We searched for signatures of adaptive evolution and evolutionary dependencies of amino acid sites within and between the three domains using the entire set of available potyvirus sequences in GenBank. Interestingly, we identified strongly significant patterns of co-occurrence of adaptive events along the phylogenetic tree in the three domains. These patterns suggest that Domain I, whose main function is to mediate aphid transmission, has likely been coevolving with the other two domains, which are involved in different functions but all requiring the capacity to bind RNA. By contrast, episodes of positive selection on Domains II and III did not correlate, reflecting a trade-off between their evolvability and their evolutionary dependency likely resulting from their functional overlap. Covariation analyses have identified several groups of amino acids with evidence of concerted variation within each domain, but interdomain significant covariations were only found for Domains II and III, further reflecting their functional overlappingThis work was supported by grants BFU2012-30805 (SFE) and BFU2012-36346 (MAF) from the Spanish Direccio´n General de Investigacio´n Cientı´fica y Te´cnica and by an EMBO Short-Term Fellowship and the Mentoring Program from the Foundation for Polish Science (BHJ).Hasiów-Jaroszewska, B.; Fares Riaño, MA.; Elena Fito, SF. (2014). Molecular evolution of viral multifunctional proteins: the case of Potyvirus HC-Pro. Journal of Molecular Evolution. 78(1):75-86. https://doi.org/10.1007/s00239-013-9601-0S7586781Adams MJ, Antoniw JF, Beaudoin F (2005) Overview and analysis of the polyprotein cleavage sites in the family Potyviridae. Mol Plant Pathol 6:471–487Atreya CD, Atryea P, Thornbury DW, Pirone TP (1992) Site-directed mutations in the potyvirus HC-Pro gene affect helper component activity, virus accumulation and symptoms expression in infected tobacco plants. Virology 191:106–111Blanc S, López-Moya JJ, Wang R, García-Lampasona S, Thornbury DW, Pirone TP (1997) A specific interaction between coat protein and helper component correlates with aphid transmission of a potyvirus. Virology 231:141–147Blanc S, Ammar ED, García-Lampasona S, Dolja VV, Llave C, Baker J, Pirone TP (1998) Mutations in the potyvirus helper component protein: effects on interactions with virions and aphid stylets. J Gen Virol 79:3119–3122Cantó T, López-Moya JJ, Serra-Yodi MT, Díaz-Ruiz JR, López-Abella D (1995) Different helper component mutations associated with lack of aphid transmissibility in two isolates of potato virus. Phytopathology 85:1519–1524Carrington JC, Freed DD, Sanders TC (1989) Autocatalytic processing of the potyvirus helper component proteinase in Escherichia coli and in vitro. J Virol 63:4459–4463Chung BY, Miller WA, Atkins JF, Firth AE (2008) An overlapping essential gene in the Potyviridae. Proc Natl Acad Sci USA 105:5897–5902Cronin S, Verchot J, Haldeman-Cahill R, Schaad MC, Carrington JC (1995) Long distance movement factor: a transport function of the potyvirus helper component-proteinase. Plant Cell 7:549–559Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucl Acids Res 32:1792–1797Elena SF, Rodrigo G (2012) Towards and integrated molecular model of plant-virus interactions. Curr Opin Virol 2:713–718Fares MA (2004) SWAPSC: sliding-window analysis procedure to detect selective constraints. Bioinformatics 20:2867–2868Fares MA, McNally D (2006) CAPS: coevolution analysis using protein sequences. Bioinformatics 22:2821–2822Fares MA, Travers AA (2006) A novel method for detecting intramolecular coevolution: adding a further dimension to selective constrains analyses. Genetics 173:9–23Fares MA, Elena SF, Ortiz J, Moya A, Barrio E (2002) A sliding window-based method to detect selective constraints in protein-coding genes and its application to RNA viruses. J Mol Evol 55:509–521Gibbs A, Ohshima K (2010) Potyviruses and the digital revolution. Annu Rev Phytopathol 48:205–223Guo D, Mertis A, Saarma M (1999) Self-association and mapping of interaction domains of helper component of Potato virus A potyvirus. J Gen Virol 80:1127–1131Guo B, Lin J, Ye K (2011) Structure of the autocatalytic cysteine protease domain of potyvirus helper-component proteinase. J Biol Chem 286:21937–21943Haikonen T, Rajamäki ML, Tian YP, Valkonen JPT (2013) Mutation of a short variable region in HC-Pro protein of Potato virus A affects interactions with microtubule-associated protein and induces necrotic responses in tobacco. Mol Plant Microbe Interact 26:721–733Hall TA (1999) BIOEDIT: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser 41:95–98Hughes AL (2009) Small effective population sizes and rare nonsynonymous variants in potyviruses. Virology 393:127–134Jones DT (1999) Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol 292:195–202Kasschau KD, Carrington JC (1995) Requirement for HC-Pro processing during genome amplification of Tobacco etch potyvirus. Virology 209:268–273Kasschau KD, Carrington JC (2001) Long-distance movement and replication maintenance functions correlate with silencing suppression activity of potyviral HC-Pro. Virology 285:71–81Kasschau KD, Cronin S, Carrington JC (1997) Genome amplification and long-distance movement functions associated with the central domain of Tobacco etch potyvirus helper component-proteinase. Virology 228:251–262Kosakovsky Pond SL, Frost SDW (2005a) DATAMONKEY: rapid detection of selective pressure on individual sites of codon alignments. Bioinformatics 21:2531–2533Kosakovsky Pond SL, Frost SDW (2005b) Not so different after all: a comparison of methods for detecting amino acid sites under selection. Mol Biol Evol 22:1208–1222Kosakovsky Pond SL, Posada D, Gravenor MB, Woelk CH, Frost SDW (2006) Automated phylogenetic detection of recombination using a genetic algorithm. Mol Biol Evol 23:1891–1901Lakatos L, Csorba T, Pantaleo V, Chapman EJ, Carrington JC, Liu YP, Dojla VV, Calvino LF, López-Moya JJ, Burgyan J (2006) Small RNA binding is a common strategy to suppress RNA silencing by several viral suppressors. EMBO J 25:2768–2780Lalić J, Elena SF (2012) Magnitude and sign epistasis among deleterious mutations in a positive-sense plant RNA virus. Heredity 109:71–77Leigh JW, Susko E, Baumgartner M, Roger AJ (2008) Testing congruence in phylogenomic analysis. Syst Biol 57:104–115Li WH (1993) Unbiased estimation of the rates of synonymous and nonsynonymous substitution. J Mol Evol 36:96–99Llave C, Kasschau KD, Carrington JC (2000) Virus-encoded suppressor of posttranscriptional gene silencing targets a maintenance step in the silencing pathway. Proc Natl Acad Sci USA 97:13401–13406Maia S, Haenni AL, Bernardi F (1996) Potyviral HC-Pro: a multifunctional protein. J Gen Virol 77:1335–1341Martin DP, Lemey P, Lott M, Moulton V, Posada D, Lefeuvre P (2010) RDP3: a flexible and fast computer program for analyzing recombination. Bioinformatics 26:2462–2463Moroni E, Morra G, Colombo G (2012) Molecular dynamics simulations of Hsp90 with an eye to inhibitor design. Pharmaceuticals 5:944–962Peng YH, Kadoury D, Gaol-On A, Huet H, Wang Y, Raccah B (1998) Mutations in HC-Pro gene of Zucchini yellow mosaic potyvirus: effects on aphid transmission and binding to purified virions. J Gen Virol 79:897–904Plisson C, Drucker M, Blanc S, German-Retana S, Le Gall O, Thomas D, Bron P (2003) Structural characterization of HC-Pro a plant virus multifunctional protein. J Biol Chem 278:23753–23761Posada D, Crandall KA (1998) MODELTEST: testing the model of DNA substitution. Bioinformatics 14:817–818Revers F, Le Gall O, Candresse T, Maule J (1999) New advances in understanding the molecular biology of plant/potyvirus interaction. Mol Plant Microbe Interact 12:367–376Riechmann JL, Lain S, García JA (1992) Highlights and prospects of potyvirus molecular biology. J Gen Virol 73:1–16Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5:725–738Ruiz-Ferrer V, Boskovic J, Alfonso C, Rivas G, Llorca O, López-Abella D, López-Moya JJ (2005) Structural analysis of Tobacco etch potyvirus HC-pro oligomers involved in aphid transmission. J Virol 79:3758–3765Shiboleth YM, Haronsky E, Leibman D, Arazi T, Wassenegger M, Whitham SA, Gaba V, Gal-On A (2007) The conserved FRNK box in HC-Pro, a plant viral suppressor of gene silencing, is required for small RNA binding and mediates symptom development. J Virol 81:13135–13148Smoot M, Ono K, Ruschelnski J, Wang PL, Ideker T (2011) CYTOSCAPE 2.8: new features for data integration and network visualization. Bioinformatics 27:431–432Syller J (2006) The roles and mechanisms of helper component proteins encoded by potyviruses and caulimoviruses. Physiol Mol Plant Pathol 67:119–130Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739Torres-Barceló C, Martín S, Daròs JA, Elena SF (2008) From hypo- to hypersuppression: effect of amino acid substitutions on the RNA-silencing suppressor activity of Tobacco etch potyvirus HC-Pro. Genetics 180:1039–1049Torres-Barceló C, Daròs JA, Elena SF (2010a) Compensatory molecular evolution of HC-Pro, an RNA-silencing suppressor from a plant RNA virus. Mol Biol Evol 27:543–551Torres-Barceló C, Daròs JA, Elena SF (2010b) HC-Pro hypo- and hypersuppressor mutants: differences in viral siRNA accumulation in vivo and siRNA binding activity in vitro. Arch Virol 155:251–254Urcuqui-Inchima S, Walter J, Drugeon G, German-Retans S, Haeni AL, Candresse T, Bernardi F, Le Gall O (1999) Potyvirus HC-Pro self-interaction in the yeast two hybrid system and delineation of the interaction domain involved. Virology 258:95–99Urcuqui-Inchima S, Maia IG, Arruda P, Haenni AL, Bernardi F (2000) Deletion mapping of the potyviral helper component-proteinase reveals two regions involved in RNA binding. Virology 268:104–111Urcuqui-Inchima S, Haenni AL, Bernardi F (2001) Potyvirus proteins: a wealth of functions. Virus Res 74:157–175Varrelmann M, Maiss E, Pilot R, Palkovics L (2007) Use of pentapeptide-insertion scanning mutagenesis for functional mapping of the Plum pox virus helper component proteinase suppressor of gene silencing. J Gen Virol 88:10051015Ward CW, Shukla DD (1991) Taxonomy of potyviruses: current problems and some solutions. Intervirology 32:269–296Wu S, Zhang Y (2007) LOMETS: a local meta-threading-server for protein structure prediction. Nucl Acids Res 35:3375–3382Yang Z, Bielawski JP (2000) Statistical methods for detecting molecular adaptation. Trends Ecol Evol 15:496–503Yap YK, Duangjit J, Panyim S (2009) N-terminal of Papaya ringspot virus type-W (PRSV-W) helper component proteinase (HC-Pro) is essential for PRSV systemic infection in zucchini. Virus Genes 38:461–467Zheng H, Yan F, Lu Y, Sun L, Lin L, Cai L, Hou M, Chen J (2010) Mapping the self-interaction domains of TuMV HC-pro and the subcellular localization of the protein. Virus Genes 42:110–11

The Dynamics of Supply and Demand in mRNA Translation

We study the elongation stage of mRNA translation in eukaryotes and find that, in contrast to the assumptions of previous models, both the supply and the demand for tRNA resources are important for determining elongation rates. We find that increasing the initiation rate of translation can lead to the depletion of some species of aa-tRNA, which in turn can lead to slow codons and queueing. Particularly striking “competition” effects are observed in simulations of multiple species of mRNA which are reliant on the same pool of tRNA resources. These simulations are based on a recent model of elongation which we use to study the translation of mRNA sequences from the Saccharomyces cerevisiae genome. This model includes the dynamics of the use and recharging of amino acid tRNA complexes, and we show via Monte Carlo simulation that this has a dramatic effect on the protein production behaviour of the system

The Tnt1 Retrotransposon Escapes Silencing in Tobacco, Its Natural Host

Retrotransposons' high capacity for mutagenesis is a threat that genomes need to control tightly. Transcriptional gene silencing is a general and highly effective control of retrotransposon expression. Yet, some retrotransposons manage to transpose and proliferate in plant genomes, suggesting that, as shown for plant viruses, retrotransposons can escape silencing. However no evidence of retrotransposon silencing escape has been reported. Here we analyze the silencing control of the tobacco Tnt1 retrotransposon and report that even though constructs driven by the Tnt1 promoter become silenced when stably integrated in tobacco, the endogenous Tnt1 elements remain active. Silencing of Tnt1-containing transgenes correlates with high DNA methylation and the inability to incorporate H2A.Z into their promoters, whereas the endogenous Tnt1 elements remain partially methylated at asymmetrical positions and incorporate H2A.Z upon induction. Our results show that the promoter of Tnt1 is a target of silencing in tobacco, but also that endogenous Tnt1 elements can escape this control and be expressed in their natural host

Spontaneous Local Gamma Oscillation Selectively Enhances Neural Network Responsiveness

Synchronized oscillation is very commonly observed in many neuronal systems and might play an important role in the response properties of the system. We have studied how the spontaneous oscillatory activity affects the responsiveness of a neuronal network, using a neural network model of the visual cortex built from Hodgkin-Huxley type excitatory (E-) and inhibitory (I-) neurons. When the isotropic local E-I and I-E synaptic connections were sufficiently strong, the network commonly generated gamma frequency oscillatory firing patterns in response to random feed-forward (FF) input spikes. This spontaneous oscillatory network activity injects a periodic local current that could amplify a weak synaptic input and enhance the network's responsiveness. When E-E connections were added, we found that the strength of oscillation can be modulated by varying the FF input strength without any changes in single neuron properties or interneuron connectivity. The response modulation is proportional to the oscillation strength, which leads to self-regulation such that the cortical network selectively amplifies various FF inputs according to its strength, without requiring any adaptation mechanism. We show that this selective cortical amplification is controlled by E-E cell interactions. We also found that this response amplification is spatially localized, which suggests that the responsiveness modulation may also be spatially selective. This suggests a generalized mechanism by which neural oscillatory activity can enhance the selectivity of a neural network to FF inputs