Left Column Research Articles

Erratum: Corrigendum: Drugmakers use real-world patient data to calibrate product development

Nat. Biotechnol. 29, 778–779 (2011); published online 8 September 2011; corrected after print 9 January 2012 In the version of this article initially published, Medco Health Solutions' location was given as Wilmington, Delaware; it should have been Franklin Lakes, New Jersey. On p. 779, in the firstparagraph, left column, UBC is said to be HealthCore's parent company.

Comment on: “Dose-effect study of Gelsemium sempervirens in high dilutions on anxiety-related responses in mice” (Magnani P, Conforti A, Zanolin E, Marzotto M and Bellavite P, Psychopharmacology, 2010)

Dear Editor, In a recent article, “Dose-effect study of Gelsemium sempervirens in high dilutions on anxiety-related response in mice” (Psychopharmacology 2010, 210: 533–545), Magnani et al. claimed to provide solid evidence that Gelsemium sempervirens centesimal dilutions have anxiolytic-like effects in ICRCD1 mice. This was based on the finding that, with a nonlinear relationship, the centesimal (C) dilution of G. sempervirens 5 C, 9 C and 30 C, but not 4 C and 7 C, modified mice behaviour in the Light Dark test. The result was not confirmed in the Open Field test. We want to raise some doubts about the reproducibility of the results and the reliability of protocols used to evaluate mice behaviour. Reproducibility, the degree of accordance between the results of the same experiment performed independently in the same or different laboratories, is a fundamental prerequisite for acceptance of any experimental evidence. This requirement was not met by the authors, who published another article in 2009, “Homeopathic doses of Gelsemium sempervirens improve the behavior of mice in response to novel environments” (2009a, eCAM, 1-10), in which a highly diluted G. sempervirens solution was evaluated in the same strain of mice (CD1, though purchased from a different producer). G. sempervirens 5 C dilution gave precisely the opposite results to those reported in Psychopharmacology. Diazepam, used as a standard anxiolytic drug, was completely ineffective on mouse behaviour in the Open Field, but increased the time in the light compartment and transitions in the Light Dark test (see Tables 1 and 2, p. 4). When the G. sempervirens 5 C, 7 C and 30 C dilutions were evaluated in another strain of mice (C57BL/6J), again, the opposite effect from that reported by Magnani et al. (2010) was found. G. sempervirens centesimal dilutions modified mice behaviour in the Open Field (Table 3, Bellavite et al. 2009a p. 5). No information was given on how the same centesimal diluted solutions affected C57BL/6J behaviour in the Light Dark test. The fact that the authors did not comment on their previous contradictory findings in Psychopharmacology is a serious omission. Surprisingly, the article by Bellavite et al. was cited just to justify the number of mice per group they were going to use (p. 536, line 17), although how Bellavite et al. computed the minimum sample size they required is absolutely not clear since no sample size by power analyses was done. To be objective, Magnani et al. cited another article by Bellavite et al. (2009b; Homeopathy, p. 534, left column, 10 lines from the bottom). This was a sort of review in which the authors re-proposed the data they had obtained in CD1 mice (omitting those in C57/BL6J mice!) and already published by Bellavite et al. (2009a), together with the data they later submitted to Psychopharmacology. This article was cited as evidence of promising anxiolytic-like activity of G. sempervirens in the Open Field test, without mentioning the failure in the Light Dark test. L. Cervo (*) Laboratory of Experimental Psychopharmacology, Department of Neuroscience, “Mario Negri” Institute for Pharmacological Research, Via La Masa 19, 20156 Milan, Italy e-mail: luigi.cervo@marionegri.it

Correction

HomeCirculationVol. 124, No. 16Correction Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection Originally published18 Oct 2011https://doi.org/10.1161/CIR.0b013e3182365a77Circulation. 2011;124:e424This article corrects the followingHeart Disease and Stroke Statistics—2009 UpdateIn the article by Lloyd-Jones et al, “Heart Disease and Stroke Statistics—2009 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee,” which published ahead of print on December 15, 2008, and appears in the January 27, 2009, issue of the journal (Circulation. 2009;119:e21–e181), a correction was needed.On page e72, in the left column, second bullet, the sentence reads, “Within 1 year of TIA, up to one fourth of patients will die.22,26” It should read, “Within 1 year of TIA, about 12% to 13% of patients will die.22,26” Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesHeart Disease and Stroke Statistics—2009 UpdateDonald Lloyd-Jones, et al. Circulation. 2009;119:e21-e181 October 18, 2011Vol 124, Issue 16 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIR.0b013e3182365a77 Originally publishedOctober 18, 2011 PDF download Advertisement SubjectsStatements and Guidelines

Identification of Human Fumarylacetoacetate Hydrolase Domain-containing Protein 1 (FAHD1) as a Novel Mitochondrial Acylpyruvase

The human fumarylacetoacetate hydrolase (FAH) domain-containing protein 1 (FAHD1) is part of the FAH protein superfamily, but its enzymatic function is unknown. In the quest for a putative enzymatic function of FAHD1, we found that FAHD1 exhibits acylpyruvase activity, demonstrated by the hydrolysis of acetylpyruvate and fumarylpyruvate in vitro, whereas several structurally related compounds were not hydrolyzed as efficiently. Conserved amino acids Asp-102 and Arg-106 of FAHD1 were found important for its catalytic activity, and Mg(2+) was required for maximal enzyme activity. FAHD1 was found expressed in all tested murine tissues, with highest expression in liver and kidney. FAHD1 was also found in several human cell lines, where it localized to mitochondria. In summary, the current work identified mammalian FAHD1 as a novel mitochondrial enzyme with acylpyruvate hydrolase activity.

Complex Shapes and Dynamics of Dissolving Drops of Dichloromethane

There is a growing interest in synthetic, chemical systems capable of undergoing autonomous shape changes and/or self-motion. Important examples include solid objects such as catalytic Au/Pt nanorods, mechanically responsive gels driven by oscillating reactions, and liquid systems in which self-motion is induced by surface-tension gradients. The latter class of systems includes iodine/iodide-containing oil droplets on glass surfaces under aqueous solutions of stearyltrimethylammonium chloride as well as drop motion on an alkylsilane-treated silicon surface with spatial “wettability” changes. Droplet motion on air–water interfaces is usually driven by aMarangoni effect involving temperature or concentration gradients. A typical example are pentanol droplets on water, which depending on the drop volume, perform erratic or unidirectional motion and also show very disorganized forms of droplet fission. This fission can extend from the millimeter-scale down to nanoscopic micelles. Herein, we investigate the dynamics of water-saturated dichloromethane (CH2Cl2, 25 mL) droplets on aqueous solutions of cetyltrimethylammonium bromide (CTAB). Figure 1 is a qualitative phase diagram describing the macroscopic dynamics in the CH2Cl2/CTAB system in terms of the elapsed reaction time and the surfactant concentration. The data are representative for the fourth and fifth drops added. The diagram shows a variety of complex drop shapes and dynamics that we identified to be the most characteristic ones. For each concentration we have studied the dynamics of five successive drops. In general these dichloromethane-accumulating experiments reveal no marked differences; however, the fourth and fifth drops deviate from their predecessors during the late stages of dissolution. These altered dynamics typically match the behavior of drops at a slightly higher CTAB concentration. The life time of the dichloromethane drops varies systematically between approximately 20 and 90 s. This large range is mainly caused by changes in the initial induction period during which drops are stationary and have a circular rim. Complex phenomena are found only for surfactant concentrations above a critical value [CTAB]crit 0.25 mmolL . In the absence of surfactant or below [CTAB]crit, the drops spread out over a large area and solubilize rapidly (< 15 s) without noteworthy macroscopic features. For surfactant concentration close to [CTAB]crit (left column in Figure 1), the initial dichloromethane drops are relatively flat. We also observe that the water surface around the drop supports a disk-shaped film. The macroscopic dynamics involve several successive stages: During the first stage, the edge of the film breaks into small droplets that are continuously ejected and quickly disappear. Then the drop abruptly moves away from the center of the film to maneuver back and forth along a nearly stationary line. During these lateral oscillations, each directional change causes the expulsion of a line of small droplets. After a while, the drop starts to move steadily along a circular orbit larger than its own diameter. Finally all motion ceases, the drop becomes circular again, shrinks and vanishes. At a surfactant concentration of 0.5 mmolL 1 (second column in Figure 1), the dichloromethane drops undergo a similar sequence of motion patterns. However, the dynamics Figure 1. Qualitative description of the drop evolution in the CH2Cl2/ CTAB system at five different concentrations of the surfactant CTAB. The typical life time of the dissolving droplets ranges between 20 and 90 s. The time axis is not to scale as the diagram emphasizes distinct, successive states in the drop evolution. Single arrows indicate rotation of the drop around its geometrical center. The double arrow indicates that the drop moves back and forth along a fixed line. The field of view of all frames corresponds to 13 13 mm.

Lateral assembly of the immunoglobulin protein SynCAM 1 controls its adhesive function and instructs synapse formation

Synapses are specialized adhesion sites between neurons that are connected by protein complexes spanning the synaptic cleft. These trans-synaptic interactions can organize synapse formation, but their macromolecular properties and effects on synaptic morphology remain incompletely understood. Here, we demonstrate that the synaptic cell adhesion molecule SynCAM 1 self-assembles laterally via its extracellular, membrane-proximal immunoglobulin (Ig) domains 2 and 3. This cis oligomerization generates SynCAM oligomers with increased adhesive capacity and instructs the interactions of this molecule across the nascent and mature synaptic cleft. In immature neurons, cis assembly promotes the adhesive clustering of SynCAM 1 at new axo-dendritic contacts. Interfering with the lateral self-assembly of SynCAM 1 in differentiating neurons strongly impairs its synaptogenic activity. At later stages, the lateral oligomerization of SynCAM 1 restricts synaptic size, indicating that this adhesion molecule contributes to the structural organization of synapses. These results support that lateral interactions assemble SynCAM complexes within the synaptic cleft to promote synapse induction and modulate their structure. These findings provide novel insights into synapse development and the adhesive mechanisms of Ig superfamily members.

Alveolar Epithelial Cells Undergo Epithelial-to-Mesenchymal Transition in Response to Endoplasmic Reticulum Stress

Expression of mutant surfactant protein C (SFTPC) results in endoplasmic reticulum (ER) stress in type II alveolar epithelial cells (AECs). AECs have been implicated as a source of lung fibroblasts via epithelial-to-mesenchymal transition (EMT); therefore, we investigated whether ER stress contributes to EMT as a possible mechanism for fibrotic remodeling. ER stress was induced by tunicamyin administration or stable expression of mutant (L188Q) SFTPC in type II AEC lines. Both tunicamycin treatment and mutant SFTPC expression induced ER stress and the unfolded protein response. With tunicamycin or mutant SFTPC expression, phase contrast imaging revealed a change to a fibroblast-like appearance. During ER stress, expression of epithelial markers E-cadherin and Zonula occludens-1 decreased while expression of mesenchymal markers S100A4 and α-smooth muscle actin increased. Following induction of ER stress, we found activation of a number of pathways, including MAPK, Smad, β-catenin, and Src kinase. Using specific inhibitors, the combination of a Smad2/3 inhibitor (SB431542) and a Src kinase inhibitor (PP2) blocked EMT with maintenance of epithelial appearance and epithelial marker expression. Similar results were noted with siRNA targeting Smad2 and Src kinase. Together, these studies reveal that induction of ER stress leads to EMT in lung epithelial cells, suggesting possible cross-talk between Smad and Src kinase pathways. Dissecting pathways involved in ER stress-induced EMT may lead to new treatment strategies to limit fibrosis.

How to Evaluate the Financial Health of a Retirement Home

When you evaluate a retirement home a loved one, you are likely to consider the standard of care delivered, the attractiveness of the facility, how friendly the staff is, how convenient the home is to where you live, and other qualitative characteristics. You should also consider the financial sustainability of the home. You want to avoid homes that are stretched financially to avoid the deteriorating care that would likely follow. Further, you want to avoid having to move your loved one again in the future. Demand retirement homes has fallen because of the economic weakness of 2008-2009. This weakens their financial condition and should heighten the concern of potential new residents. Here are methods of gathering information to assess the continuing viability of a home. HOMES IN GENERAL Generally, retirement homes are overseen by state agencies. Ask the home what agency oversees them. Go to the agency's Web site and see what information you can find. Agencies generally grade the homes. Take a look at the Web site known as http://www.carepathways .com ratings on homes. Ask the home to show you their last written review. Is the home accredited? Some homes choose to get accredited by the Continuing Care Accreditation Commission (CCAC). Nationally, only about 15% of retirement homes are accredited. Staff turnover in management is a good indicator of a stable business. How long has the management been there? What is the occupancy rate? Ask what their break-even occupancy is. Ask how they came through the 2008-2009 period. If they tell you everything is wonderful, I would doubt it. Break-even occupancy is probably in the range of 88%-90% occupancy. One or two percentage points of profitability produce a big dollar difference to the owner. Why does this matter? If it is a for profit and the owners are consistently losing money, they will either look to sell or reduce services to cure their losses. How much have the monthly charges or service fees risen each year? Ask if there is any reason why this increase would change in the future. Is the building going to require extraordinary maintenance? Is there a lot of local competition? Where does this retirement home fit in relative to others locally? Is it the most expensive? If the local economy is weak, the most expensive may be likely to lose residents to less expensive homes. Are there any new retirement homes under construction in the local area? If so, do they plan to have services or facilities that are more compelling? Is there a waiting list? This indicates demand the facility. Is the surrounding environment losing population? Have major businesses closed their facilities? The local chamber of commerce can give you population statistics. Retirement homes are either publicly owned or privately owned. If the home is publicly owned, you will have access to lots of information about the financial condition. When a home is privately owned, the amount of hard data about their financial condition may be limited. You can use your intuition to gather a mosaic of the financial strength of the home. Publicly Owned Two of the best known publicly owned home companies are Sunrise Senior Living and Assisted Living Concepts. To evaluate a publicly owned home, start with Yahoo! Finance and enter the name of the company. Start with the basic profile on the Web site. Read the data presented there. Look at the number of homes they own and the geographic locations. The most important piece of information is the operating cash flow. You can find this number on the bottom of the left hand column on the Yahoo! Finance Key Statistics page. You want a home that is profitable to its owners. You can also look at the stock chart a 5-year period. This will give you an idea of how well regarded the company is as a going concern. Go on the company Web site and request a copy of the annual report and 10-K report. …

Corrigendum: Development of Polymer‐Encapsulated Metal Nanoparticles as Surface‐Enhanced Raman Scattering Probes

The SERS enhancement factors in Table 1 were calculated incorrectly on page 200 of Issue 2, Volume 5, Small; the correct table is given below: Consequently, the SERS enhancement factors on Page 200, left column, Line 13 and Line 21 were incorrect; the correct enhancement factors are given below: Line 13: The enhancement factors were estimated to be 7.2 × 102, 1.2 × 103, 1.0 × 104, 6.3 × 104, and 2.2 × 105, for AuNPs of 14, 21, 38, 51, and 62 nm diameters, respectively. Line 21: The ensemble-averaged enhancement factor for (AgNP-1)@polymer (dav = 43.4 nm, see Supporting Information, Figure S16) was estimated to be around 1∼2 × 106. The labels on the y axis of Figure 2B were also incorrect; the correct values should be 1E5 and 2E5.

Biotechnological applications of Listeria's sophisticated infection strategies (Microbial Biotechnology 1: 361–372)

The authors regret that a number of quotations were not properly referenced in the text of their review. These are attributed below. Page 361, right column, lines 13–23, starting ‘In humans, it causes a range . . .’ ending ‘in pregnant women, the placenta (Vazquez‐Boland et al., 2001)’. Text was from Pentecost and colleagues (2006). Page 361, right column, lines 27–32, starting ‘Entry of L. monocytogenes into mammalian cells . . .’ ending ‘. . . harness endocytic pathways to its advantage’. Text was from Hamon and colleagues (2006). Page 362, left column, line 20, starting ‘Invasion of non‐phagocytic cells . . .’ ending page 363, left column, line 12, ‘. . . naturally susceptible to listeriosis (Lecuit et al., 2001)’. Text was from Pentecost and colleagues (2006). Page 363, right column, lines 20–25, starting ‘InlA is anchored convalently to . . .’ ending ‘. . . bacteria entry into target cells (Lecuit et al., 1997)’. Text was from Dons and colleagues (2007). Page 363, right column, line 2 from the bottom, starting ‘E‐cadherin is present . . .’ ending page 364, line 4 ‘. . . E‐cadherin (Lecuit, 2005)’. Text was from Pizarro‐Cerda and Cossart (2006). Page 364, left column, lines 18–29, starting ‘Binding of InlB to its cellular . . .’ ending ‘. . . for the uptake process (Tang et al., 1996; Shen et al., 2000)’. Text was from Hamon and colleagues (2006). Page 364, left column, lines 46–52, starting ‘Protein of the Ena/VASP family . . .’ ending right column, lines 1–8 ‘. . . for the entry of L. monocytogenes (Seveau et al., 2004)’. Text was Hamon and colleagues (2006). Page 364, right column, line 9 from the bottom, starting ‘The hly gene is located . . .’ ending page 365, line 3 ‘. . . plasma membrane’. Text was from Hamon and colleagues (2006). Page 366, left column, lines 2–6, starting ‘ActA is a polarized surface . . .’ ending ‘. . . bacterial membrane (Domann et al., 1992; Kocks et al., 1992)’, and page 366, left column, lines 11–20, starting ‘ActA is able to polymerize . . .’ ending ‘. . . Arp2 and Arp3 (Stradal et al., 2004)’. Text was from Pizarro‐Cerda and Cossart 2006. Page 366, left column, lines 24–34, starting ‘Moreover, Ena/VASP proteins not only enhance . . .’ ending ‘. . . this phenomenon are still unknown’. Text was from Sechi and Wehland 2004. Page 366, right column, lines 9–18, starting ‘Cell extrusion from the villus tips . . .’ ending ‘. . . disease and to disseminate to distant organs’. Text was from Pentecost and colleagues (2006). Page 367, right column, lines 8–18, starting ‘Listeria monocytogenes has become a paradigm . . .’ ending ‘. . . of the best‐studied bacterial pathogens’. Text was from Hamon and colleagues (2006). Page 367, column right, lines 21–27, starting ‘Listeria monocytogenes infection has been . . .’ ending ‘relationship between the bacterium and its host’. Text was Hamon and colleagues (2006). Page 368, left column, lines 12–20, starting ‘The function of LLO as a . . .’ ending ‘. . . vaccine vectors (Provoda and Lee, 2000; Dietrich et al., 2003)’. Text was from Schnupf and Portnoy (2007). Page 368, right column, lines 31–47, starting ‘Listeria monocytogenes have evolved sophisticated . . .’ ending ‘. . . demonstrating the patho‐biotechnology concept’. Text was from Sleator and Hill (2007).

Control of Megakaryocyte Expansion and Bone Marrow Fibrosis by Lysyl Oxidase

Lysyl oxidase (LOX), a matrix cross-linking protein, is known to be selectively expressed and to enhance a fibrotic phenotype. A recent study of ours showed that LOX oxidizes the PDGF receptor-β (PDGFR-β), leading to amplified downstream signaling. Here, we examined the expression and functions of LOX in megakaryocytes (MKs), the platelet precursors. Cells committed to the MK lineage undergo mitotic proliferation to yield diploid cells, followed by endomitosis and acquisition of polyploidy. Intriguingly, LOX expression is detected in diploid-tetraploid MKs, but scarce in polyploid MKs. PDGFR-BB is an inducer of mitotic proliferation in MKs. LOX inhibition with β-aminopropionitrile reduces PDGFR-BB binding to cells and downstream signaling, as well as its proliferative effect on the MK lineage. Inhibition of LOX activity has no influence on MK polyploidy. We next rationalized that, in a system with an abundance of low ploidy MKs, LOX could be highly expressed and with functional significance. Thus, we resorted to GATA-1(low) mice, where there is an increase in low ploidy MKs, augmented levels of PDGF-BB, and an extensive matrix of fibers. MKs from these mice display high expression of LOX, compared with control mice. Importantly, treatment of GATA-1(low) mice with β-aminopropionitrile significantly improves the bone marrow fibrotic phenotype, and MK number in the spleen. Thus, our in vitro and in vivo data support a novel role for LOX in regulating MK expansion by PDGF-BB and suggest LOX as a new potential therapeutic target for myelofibrosis.

Corrections to “Full wave simulation of an electrostatic discharge generator discharging in air discharge mode into a product” [Feb 11 28-37

Summary form only given, as follows. In the above-named work the authors proposed a full wave simulation method to model the air discharge mode of an electrostatic discharge (ESD) generator discharging into a product. Several small corrections should be made. First, in Fig. 3, the legend "Spice model in Fig. 2" should be changed to "Spice model in Fig. 4." Second, in Fig. 10, the dotted line in the legend should be read "Z11 of the ESD generator above a large GND plane"; the solid line in the legend should be read: gives "Z11 of the ESD generator with MP3 player." Third, Fig. 12's title should be "Comparison of the port voltage in the SPICE model and CST model of Case 2." Finally, in the last paragraph of the left column in page 30, "the 110-pF capacitor" should be "the 150-pF capacitor." So the C1 value in the Spice of Fig. 4 is "150-pF."

Correction

HomeCirculationVol. 124, No. 4Correction Free AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCorrectionPDF/EPUBCorrection Originally published26 Jul 2011https://doi.org/10.1161/CIR.0b013e31822771a4Circulation. 2011;124:e145This article corrects the following2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: Executive SummaryIn the article by Brott et al, “2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery,” which published ahead of print on January 31, 2011, and appeared in the July 26, 2011, issue of the journal (Circulation. 2011;124:489–532), several corrections were needed.On page 489, in the footnotes, the web links have been updated in paragraphs 7, 8, and 9.On page 505, the footnote to Table 3, last paragraph, read “Reprinted with permission from Sacco et al.4” It should read “Modified with permission from Sacco et al.4”On page 500, in the left column, “Section 18. Recommendations for Management of Patients With Cervical Artery Dissection,” the Class IIa Recommendation 1 read:For patients with symptomatic cervical artery dissection, anticoagulation with intravenous heparin (dose adjusted to prolong the partial thromboplastin time to 1.5 to 2.0 times the control value) followed by warfarin (dose-adjusted to achieve a target INR of 2.5 [range 2.0 to 3.0]), low-molecular-weight heparin (in the dose recommended for treatment of venous thromboembolism with the selected agent) followed by warfarin (dose-adjusted to achieve a target INR of 2.5 [range 2.0 to 3.0]), or oral anticoagulation without antecedent heparin can be beneficial for 3 to 6 months, followed by antiplatelet therapy with aspirin (81 to 325 mg daily) or clopidogrel (75 mg daily).(Level of Evidence: C)It should read:Antithrombotic treatment with either an anticoagulant (heparin, low-molecular-weight heparin, or warfarin*) or a platelet inhibitor (aspirin, clopidogrel, or the combination of extended-release dipyridamole plus aspirin*) for at least 3 to 6 months is reasonable for patients with extracranial carotid or vertebral arterial dissection associated with ischemic stroke or TIA.72a–72d(Level of Evidence: B)*Drugs are not listed in order of preference.On page 519, in the References, the following were added:72a. Metso TM, Metso AJ, Helenius J, et al. Prognosis and safety of anticoagulation in intracranial artery dissections in adults. Stroke. 2007;38:1837–42.72b. Engelter ST, Brandt T, Debette S, et al, for the Cervical Artery Dissection in Ischemic Stroke Patients (CADISP) Study Group. Antiplatelets versus anticoagulation in cervical artery dissection. Stroke. 2007;38:2605–11.72c. Menon R, Kerry S, Norris JW, Markus HS. Treatment of cervical artery dissection: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2008;79:1122–7.72d. Georgiadis D, Arnold M, von Buedingen HC, et al. Aspirin vs anticoagulation in carotid artery dissection: a study of 298 patients. Neurology. 2009;72:1810–5.These corrections have been made to the print version and to the current online version of the article, which is available at http://circ.ahajournals.org/cgi/reprint/124/4/489. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articles2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: Executive SummaryThomas G. Brott, et al. Circulation. 2011;124:489-532 July 26, 2011Vol 124, Issue 4 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIR.0b013e31822771a4 Originally publishedJuly 26, 2011 PDF download Advertisement

Corrigendum: Backbone Dynamics of Cyclotide MCoTI‐I Free and Complexed with Trypsin

The authors of this Communication have recognized an error in Figure 1 d and Table 1. Because of an error in the scaling of the NOE values for the MCoTI-I/trypsin complex (Figure S2 C and D in the Supporting Information), the reported S2 values for the MCoTI-I/trypsin complex were not accurate. The correct Figure 1 and Table 1 are shown below. NMR analysis of the backbone dynamic of free and trypsin bound MCoTI-I. a) {15N,1H}NMR heteronuclear single quantum correlation (HSQC) spectrum of free MCoTI-I. Chemical shift assignments of the backbone amides are indicated. b) Overlay of the {15N,1H} HSQC spectra of free (black) and trypsin bound MCoTI-I (red). Residues with large average amide chemical shift differences between two different states (>0.3 ppm) are indicated. Peaks that are broadened in trypsin bound MCoTI-I are indicated by grey circles. c) Average amide chemical shift difference for all the assigned residues in free and trypsin bound MCoTI-I. Chemical shift difference was calculated as: ΔΩ=[(ΔΩ2NH+0.04 ΔΩ2N)/2]1/2, where ΔΩNH and ΔΩN are the changes in the amide proton and nitrogen chemical shifts (ppm), respectively. d) Order parameter, S2, for the free (black) and the trypsin bound MCoTI-I (red). The S2 value is a measure of backbone flexibility and represents the degree of angular restriction of the NH vector in the molecular frame. The MCoTI-I loops are shown on top of panels (c) and (d). Small unassigned peaks in the spectra of both free and trypsin-bound of MCoTI-I are from a minor conformation of the protein, and result from a known isomerization of the backbone at an Asp-Gly sequence in loop 6 of MCoTI-I. Structural element Sequence 〈S2〉[a] Free MCoTI-I 〈S2〉[b] Trypsin–MCoTI-I loop 1 3–8 0.81±0.01 0.75±0.29 loop 2 10–14 0.81±0.01 0.93±0.04 loop 3 16–18 0.84±0.02 0.82[c] loop 4 20 0.88[c] 0.98[c] loop 5 22–26 0.92±0.02 0.80±0.24 loop 6 28–34 0.76±0.05 0.71±0.34 cystine knot 2,9,15,19,21,27 0.84±0.02 0.62±0.33 The text that refers to Figure 1 d and Table 1 (page 7032, left column) is also inaccurate. It should read: “Thus, although loop 1 showed 〈S2〉=0.75±0.29, which is slightly lower than the value for the rest of the molecule (〈S2〉=0.78±0.23), Lys4 showed a significant lower value of S2 upon complex formation. Several other residues in loop 2 (Cys9), loop 5 (Cys27 and Arg22), and loop 6 (Val1) also showed significantly lower values of S2 upon complex formation (Figures 1 d and 2 c). It is likely that the increase in mobility observed in these loops may help to accommodate the increased flexibility of Lys4 in the binding loop (Figure 2 c). Since our data clearly shows that backbone flexibility of MCoTI-I cyclotide increases in some of the MCoTI-I residues upon binding to trypsin, we decided to estimate the contribution of these motions to the overall Gibbs free energy of binding (ΔG). The energetic benefit of this increase in backbone flexibility can be estimated from the experimental relaxation data, by using the experimentally measured order parameters, S2.27 The estimated ΔG value was approximately 10 kJ mol−1 at 298 K. This value should be compared to the calculated value from the trypsin inhibitory constant of MCoTI-I (the trypsin inhibitory constant of MCoTI-I (Ki≈20 pM,28 ΔG≈−61 kJ mol−1). The calculated entropic contribution (−T ΔS) at the same temperature was approximately 7 kJ mol−1.” We have also included modified versions of Figure S2 C and D (showing corrected NOE enhancements and Rex values for the MCoTI/trypsin complex), which are included as Supporting Information. The authors would like to point out that this error does not affect the overall interpretation of the results in the Communication. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

A generative model of the crab cardiac neuromuscular system with modulation

The neurogenic crab heart is driven by the cardiac ganglion (CG), a central pattern generator that is embedded within the heart itself. The CG and the heart muscle form a complete closed-loop neuromuscular system. The bursting spike pattern generated by the CG drives the contractions of the muscle. These contractions, as well as previous spiking, then modify future spike generation. The system is extensively regulated by numerous neuromodulators. Here, we present a model of the complete system, with and without modulation. We have modeled the system, at the level of spikes and contractions, as three processes: (1) the production of the contractions by the CG spikes, (2) the dependence of the CG spikes on the contractions, and (3) the dependence of the CG spikes on their own history. Using a system-identification method that we have developed [1], we first characterized each process separately from experimental data collected in the blue crab, Callinectes sapidus. Process (1) was characterized from spike-elicited contraction data in terms of three functions: K, the single-spike contraction kernel, H, a history kernel, and F, a static nonlinear function. These three functions successfully predict the contraction response to arbitrary spike trains. Using a modified version of the same method, we then characterized processes (2) and (3) together from data in which the CG spike pattern was recorded in response to stretches of the muscle. This gave three additional functions: K’, a kernel describing the effect of muscle length change on the generation of CG spikes, H’, a kernel describing the effect of a CG spike on the generation of future CG spikes, and F’, another static nonlinear function. Finally, we repeated all of these steps using data collected in the presence of modulators to find, in each case, six modified kernel functions. Combining the six unmodulated, or modulated, functions then gave a generative model of the complete cardiac system. This model exhibits a number of modes of spike generation, and resulting contraction, including multiple bursting modes, tonic firing, and no firing. It is likely that the modulators take the system from one mode to another. An example of a modeled shift induced by the addition of a modulator is shown in Fig. ​Fig.1,1, where the addition of crustacean cardioactive peptide (CCAP) shortens the cycle period by ~75%. The model can be used to better understand the global actions of the modulators and how their multiple actions allow the cardiac system to respond to physiological demands in a robust, yet flexible manner. Figure 1 An example of the activity of the generative model. The left column shows the activity when the six functions used in the model were obtained from unmodulated data. The “voltage” is the sum of the operations of the functions K’ ...

An Unexpected Outcome from Disentangling

During our recent spectroscopic study of ε Aur (Chadima et al. 2011), we made an attempt to detect weak spectral lines of the secondary, hidden in a dark disk, using the spectral disentangling technique of Simon &amp; Sturm (1994) and Hadrava (1995, 1997, 2004). We used the Dominion Astrophysical Observatory (DAO) and Ondřejov (OND) red electronic spectra, which cover more than one half of the orbital period. To our surprise, two different programs that disentangled the spectrum in Fourier space, KOREL (Hadrava 1995, 2004) and FDBINARY (Ilijić et al. 2001), both yielded apparently good, similar reconstructions of two well-defined spectra for mass ratios near unity. The results (Solution 1) are shown in Fig. 1 (left panels) and Table 1 (left column). This result is hard to accept as real given the existing knowledge about the system: ε Aur is an F-type star with an unseen companion embedded in a cool, dark disk (temperature ~ 500–600 K). A detailed search for any trace of spectral signatures of the secondary in the spectra was carried out (see Bennett et al., these proceedings). Although they found line profile variations that were correlated with orbital phase, these variations were not consistent with the presence of a secondary.

Erratum to “Malaria Burden in Pregnancy at Mulago National Referral Hospital in Kampala, Uganda”

We provide an updated Table 2. The manuscript text has been modified as follows. Method section 2.4, page 3, line 3, (left column): <2500 was changed into ≤2500. Result section 3.1, page 3, line 6-7 (right column): …more literate (0.001),…, used less IPT (<0.0001), was changed into more literate (0.0003),…, used less IPT (0.0002). Discussion, page 8, line 21 (right column): <2500 was changed into ≤2500. Discusson, page 9, line 22–24 (left column): Of note, significantly fewer primigravidae used IPT as compared to multigravidae (Table 2; G1 = 31.6%, G2-3 = 49.3%, ≥G4 = 55.7%) was changed into Of note, significantly fewer primigravidae used IPT as compared to multigravidae (Table 2; G1 = 31.6%, G2-3 = 49.3%, ≥G4 = 55.9%). Page 6, line 24,(headline of Table 5): <2500 was changed into ≤2500. The total number of cases in each gravidity group in Table 2 should be G1 = 196, G2-3 = 142, and ≥G4 = 59. Two cases of G3 were misclassified as G4 giving rise to reduced nr in the G2-3 group and increased nr in the G4 group. The total number of cases as depicted in the first row of the original Table 2 is still correct and should be (G1 = 196, G2-3 = 142, and ≥G4 = 59). The misclassification occurred when a reanalysis of part of Table 2 was performed and the new data was entered in the old table. The headline hence contained the correct total number of cases in each group, but the reanalysed part was based on the misclassified dataset. Since the data was entered as proportions only, the mismatch between the total number of cases in the headline and rest of the table was not detected immediately. In the corrected table, the total number in the G4 group has now decreased by 2 and in the G2-3 increased by 2. In the case of ANC-visit versus gravidity, only one case was shifted between groups as data on the second misclassified case was missing from the start. Of note, the data on placental malaria versus gravidity was not analysed on the same occasion as the other variables in the table and was thus on the correct dataset from the start.

Structural diversity of bacterial flagellar motors

The bacterial flagellum is one of nature's most amazing and well-studied nanomachines. Its cell-wall-anchored motor uses chemical energy to rotate a microns-long filament and propel the bacterium towards nutrients and away from toxins. While much is known about flagellar motors from certain model organisms, their diversity across the bacterial kingdom is less well characterized, allowing the occasional misrepresentation of the motor as an invariant, ideal machine. Here, we present an electron cryotomographical survey of flagellar motor architectures throughout the Bacteria. While a conserved structural core was observed in all 11 bacteria imaged, surprisingly novel and divergent structures as well as different symmetries were observed surrounding the core. Correlating the motor structures with the presence and absence of particular motor genes in each organism suggested the locations of five proteins involved in the export apparatus including FliI, whose position below the C-ring was confirmed by imaging a deletion strain. The combination of conserved and specially-adapted structures seen here sheds light on how this complex protein nanomachine has evolved to meet the needs of different species.

141 Tissue factor pathway inhibitor regulates vascular development in zebrafish

Introduction Angiogenesis requires the coordinate regulation of multiple biological pathways, including haemostasis. Tissue factor pathway inhibitor (TFPI) is a potent anticoagulant molecule, inhibiting tissue factor-led coagulation. However, the role of TFPI in vascular development is unknown. Zebrafish (Danio rerio) provide a unique model system to study vascular development in vertebrates. Despite the divergence of jawed fish (teleosts) over 430 million years ago, there is notable conservation of the constituent molecules of the clotting cascade. Multiple features make this vertebrate model unique, including its genetic accessibility, the ability to titrate the degree of genetic knock-down, external embryonic development, and the transparent nature of the embryos. Methods Using in-situ hybridisation techniques, we demonstrate TFPI expression during early vertebrate development. We then utilise transgenic fish with labelled endothelium (Fli1GFP) and erythrocytes (GATA1dsRed), to study in real time, concomitant fluorescent imaging of both structural development and dynamic blood flow observation, in living zebrafish embryos. Results TFPI expression was identified at 24 h post fertilisation (hpf) in the pronephros (Abstract 141 figure 1—dark blue staining denotes TFPI expression; none seen in control embryos). Subsequently, TFPI mRNA became more abundant, localising to developing kidney, gut, and vasculature. Morpholino (MO)-based knockdown of TFPI resulted in coagulopathy and disordered vascular development (Abstract 141 figure 2. left column: green endothelial Fli1GFP, right column: red erythrocytes. AB: uninjected controls. CD: MO controls. E–P: TFPI knockdown). Abnormally targetted (ie, vessels sprouting from normal site but growing in abnormal direction; grey arrows) and extra vessels (ie, superfluous vessels not seen in controls; white arrows in Abstract 141 figure 2EFHIKL white arrows Abstract 141 figure 2GJMP) in 25.2±2.3% (p Conclusion These data represent the first demonstration of TFPI expression in zebrafish and the first description of a unique phenotype following TFPI knockdown. They support a model in which TFPI acts a molecular break to angiogenesis both in vivo, during early vertebrate embryogenesis, and in vitro in mature human endothelial cells, secondary to constitutive regulation of VEGF signalling.

Transmission of colour and acuity signals by parvocellular cells in marmoset monkeys

The red-green axis of colour vision evolved recently in primate evolutionary history. Signals serving red-green colour vision travel together with signals serving spatial vision, in the parvocellular (PC) division of the subcortical visual pathway. However, the question of whether receptive fields of PC pathway cells are specialized to transmit red-green colour signals remains unresolved. We addressed this question in single-cell recordings from the lateral geniculate nucleus of anaesthetized marmosets. Marmosets show a high proportion of dichromatic (red-green colour-blind) individuals, allowing spatial and colour tuning properties of PC cells to be directly compared in dichromatic and trichromatic visual systems. We measured spatial frequency tuning for sine gratings that provided selective stimulation of individual photoreceptor types. We found that in trichromatic marmosets, the foveal visual field representation is dominated by red-green colour-selective PC cells. Colour selectivity of PC cells is reduced at greater eccentricities, but cone inputs to centre and surround are biased to create more selectivity than predicted by a purely 'random wiring' model. Thus, one-to-one connections in the fovea are sufficient, but not necessary, to create colour-selective responses. The distribution of spatial tuning properties for achromatic stimuli shows almost complete overlap between PC cells recorded in dichromatic and trichromatic marmosets. These data indicate that transmission of red-green colour signals has been enabled by centre-surround receptive fields of PC cells, and has not altered the capacity of PC cells to serve high-acuity vision at high stimulus contrast.