bluuebunny/crossref_metadata_2025 huggingface dataset:
Recurrent aphthous ulcers—a Toll‐like receptor–mediated disease?
Authors: Hietanen Jarkko , Häyrinen‐Immonen Ritva , Al‐Samadi Ahmed , Trokovic Nina , Koskenpato Katja , Konttinen Yrjö T.
Published: September 2011

J Oral Pathol Med (2012) 41: 158–164

Background:  Recurrent aphthous ulcer (RAU) is characterized by acute and painful inflammatory ulcerations, which heal spontaneously but tend to recur. Many pathogens have been proposed as causative agents, but none has been consistently proven. According to our hypothesis, RAU is an autoinflammatory disorder triggered by pathogen‐associated molecular patterns (PAMPs) shared by different pathogenic and commensal microbes.

Methods:  PAMP‐reactive Toll‐like receptors (TLRs) were mapped in oral epithelium in healthy controls compared to RAU.

Results:  In controls, the superficial epithelium formed a TLR−, a PAMP non‐reactive physical barrier zone, but all TLRs were found deeper in the epithelium, usually restricted to suprabasal and basal cell layers. In RAU, the epithelial TLR polarity was lost: TLRs 1, 2, 5, 7, and 8 were found throughout the epithelium, but also TLRs 4, 6, and 10 extended higher up than normally, whereas TLR‐3 was almost lost in RAU. In RAU lesions, connective tissue stroma was heavily infiltrated by TLR+ inflammatory cells.

Conclusions:  Normal TLR architecture prevents inflammatory responses against normal microbes but still contains a deep TLR+, PAMP‐reactive dormant defense zone. In RAU, the TLR+, PAMP‐reactive zone extends to surface or subsurface exposed to microbial PAMPs. TLR reactivity is further enhanced by recruitment of inflammatory leukocytes forming a new deep line of defense. The organization of the TLR system in healthy mucosa and its changes in RAU are compatible with active pathogenic involvement of TLRs, which together with the typical clinical picture and course suggest that RAU is a TLR‐mediated disease.
Identification of Sorting Motifs of AtβFruct4 for Trafficking from the ER to the Vacuole Through the Golgi and PVC
Authors: Jung Chanjin , Lee Gil‐Je , Jang Mihue , Lee Myunghui , Lee Junho , Kang Hyangju , Sohn Eun Ju , Hwang Inhwan
Published: September 2011

Although much is known about the molecular mechanisms involved in transporting soluble proteins to the central vacuole, the mechanisms governing the trafficking of membrane proteins remain largely unknown. In this study, we investigated the mechanism involved in targeting the membrane protein, AtβFructosidase 4 (AtβFruct4), to the central vacuole in protoplasts. AtβFruct4 as a green fluorescent protein (GFP) fusion protein was transported as a membrane protein during transit from the endoplasmic reticulum (ER) through the Golgi apparatus and the prevacuolar compartment (PVC). The N‐terminal cytosolic domain of AtβFruct4 was sufficient for transport from the ER to the central vacuole and contained sequence motifs required for trafficking. The sequence motifs, LL and PI, were found to be critical for ER exit, while the EEE and LCPYTRL sequence motifs played roles in trafficking primarily from the trans Golgi network (TGN) to the PVC and from the PVC to the central vacuole, respectively. In addition, actin filaments and AtRabF2a, a Rab GTPase, played critical roles in vacuolar trafficking at the TGN and PVC, respectively. On the basis of these results, we propose that the vacuolar trafficking of AtβFruct4 depends on multiple sequence motifs located at the N‐terminal cytoplasmic domain that function as exit and/or sorting signals in different stages during the trafficking process.
Hemoglobin Lepore Hollandia in India
Authors: NADKARNI A. , ITALIA K. , SAWANT P. , GHOSH K. , COLAH R.
Published: September 2011

Introduction:  Hb Lepore is a structurally abnormal hemoglobin in which the abnormal globin chain is a hybrid or fused δβ globin chain. In the heterozygous condition, Hb Lepore produces the phenotype of heterozygous β thalassemia with slightly raised HbF levels.

Method:  Using a combination of HPLC and DNA analysis, we have identified eight individuals with Hb Lepore Hollandia from three families including seven heterozygotes and one compound heterozygote with β thalassemia who presented with a severe clinical phenotype.

Results:  All the heterozygotes showed elevated levels of HbF with a mean of 3.2%. Hb Lepore Hollandia genes were associated with a single β globin cluster haplotype [‐ ‐ ‐ ‐ ‐ ‐ +] indicating a common origin.

Conclusion:  Hemoglobin Lepore Hollandia is a relatively uncommon variant in the Indian population and can be identified using a combination of chromatographic, electrophoretic, and molecular analysis.
Counting of leukocytes in samples from G‐CSF mobilized donors, leukapheresis products, and cord blood: the performances of an analyzer with dedicated profiles
Authors: PIERELLI L. , FIORAVANTI D. , PATTI D. , IUDICONE P. , SCOCCHERA R. , PANDOLFI A. , NUTI M.
Published: September 2011

Introduction:  Accurate white blood cell counting (WBC) and differential count by blood analyzers could allow a more informative characterization of granulocyte colony‐stimulating factor (G‐CSF) mobilized blood (MB), leukapheresis products (LP), and cord blood (CB). However, reliable counting by a blood cell analyzer in this setting is a major challenge owing to quali‐quantitative abnormalities of blood cells.

Methods:  We evaluated the performances of the analyzer Pentra DX 120 by Horiba ABX working with dedicated cell‐gating profiles, which generate three‐part differential counts in samples obtained from donors’ MB, LP, and CB. The results of the analyzer were compared to counts obtained by flow cytometry and manual counts, the latter performed for reference validation and in the case of discrepant results between study and reference counts.

Results:  Pentra DX 120 generated highly correlated counts (R > 0.91 in all cases) to those obtained by flow cytometry in all samples (MB, LP, and CB) with high degree of count accuracy in most cases and referred to WBC absolute count and differential count including lymphocytes (LYM) %, monocytes (MON) %, and polymorphonuclear leukocytes (PMN) %. Accuracy, judged by the difference between study and reference counts and expressed as percentage of reference count, ranged from 0.8% to 8.6%, and sporadic loss of accuracy occurred for MON % only in no more than 10% of CB samples.

Conclusion:  The ABX Pentra DX 120 provided accurate WBC count and differential count during MB, LP, and CB analyses and allowed a better characterization of donors’ hematologic status and graft composition.
Addisonian Afterlives: Joseph Addison in Eighteenth‐Century Culture
Authors: KLEIN LAWRENCE E.
Published: September 2011

Eighteenth‐century commentators often used the Bible and sacred inspiration as a tool for measuring the significance of Joseph Addison and his writings. The quasi‐scriptural character of Addison's writings was more than a matter of their popularity; it was an effect of Addison's role in the culture. Aside from being a widely read author and respected normative guide, Addison was taken as a model of social being. The esteem for his writings shaded into an admiration of his personality. While Addison's virtue and elegance embodied polite culture, he could also represent the other‐worldly and pious aspirations invoked by the Scriptures themselves.
Lewis Namier, Herbert Butterfield and Edmund Burke
Authors: SMYTH JAMES
Published: September 2011

Although in respect of historical arguments, methodologies and prose style Herbert Butterfield and Lewis Namier were sharply contrasting (indeed antipathetic) historians, they had more in common that either would have chosen to admit. Paradoxically, those commonalities converged on the figure of Edmund Burke. For Namier, Burke was a political charlatan; Butterfield thought him ‘a mountain of a man’. Both nonetheless had distinctively Burkean conceptions of the limits – and dangers – of human rationality and of ‘organic’ change in the English past.
Diacerein as adjuvant to diclofenac sodium in osteoarthritis knee
Authors: SINGH Kuljinder , SHARMA Rakesh , RAI Jaswant
Published: September 2011

Aim:  To evaluate clinical effectiveness of diacerein as an adjuvant to diclofenac sodium in treatment of Indian patients with symptomatic osteoarthritis (OA) knee.

Methods:  This is a prospective, double‐blind, placebo‐controlled and intention‐to‐treat study. An initial washout period of 1 week, was followed by 3 months treatment period during which patients were randomly divided to receive either capsule diacerein 50 mg or matched placebo once daily for the first month and twice daily for the next 2 months with diclofenac sodium 75 mg sustained release tablet once daily given to both groups. Patients were observed for one more month, using paracetamol as rescue therapy. Treatment efficacy was assessed by a visual analogue scale (VAS) and the Western Ontario and McMaster University (WOMAC) Osteoarthritis Index, patient and physician global assessment of OA, daily paracetamol intake.

Results:  Of 84 patients screened, 74 patients formed the intent‐to‐treat population (37 patients in each group). At baseline, both groups were comparable and at the third month functional index and pain intensity were better in the diacerein group (VAS 15.33 ± 5.07; WOMAC 15.9 ± 2.40) as compared to the placebo group (VAS 22.83 ± 6.90;WOMAC 36.8 ± 2.92; P < 0.05). When analyzed at the fourth month, improvement persisted in the iacerein group (VAS 14.83 ± 5.16; WOMAC 16 ± 2.5) as compared to placebo group (VAS 33 ± 7.72; WOMAC 48.26 ± 3.5; P < 0.05), demonstrating the carry‐over effect of diacerein, which was confirmed by lesser paracetamol consumption in the diacerein group (5.967 ± 0.8087) as compared to the placebo group (12.433 ± 2.128; P < 0.05).

Conclusion:  Use of diacerein and diclofenac sodium together decreases pain and improves joint function significantly more than diclofenac alone in OA knee.
Introduction to the Special Issue: Governing Energy in a Fragmented World
Authors: Florini Ann , Dubash Navroz K.
Published: September 2011

This special issue brings together leading experts from Asia, Europe and North America to examine the international institutions, national governance mechanisms and financing systems that together will determine the future of the energy sector. The enormous environmental externalities imposed by fossil fuel extraction and consumption, the devastating corruption and human rights abuses that have accompanied this energy system, and the geopolitical vulnerabilities that have arisen because of the uneven natural distribution of these resources, have occasioned enormous handwringing – but not, yet, a shift to a more rational system of providing energy services. Although national governments play the dominant role in energy governance, these challenges are beyond the scope of any single national government to manage, making energy policy a key component of global governance and international relations.
40Ar‐39Ar and cosmic‐ray exposure ages of nakhlites—Nakhla, Lafayette, Governador Valadares—and Chassigny
Authors: KOROCHANTSEVA Ekaterina V. , SCHWENZER Susanne P. , BUIKIN Alexei I. , HOPP Jens , OTT Ulrich , TRIELOFF Mario
Published: September 2011

Abstract– We present 40Ar‐39Ar dating results of handpicked mineral separates and whole‐rock samples of Nakhla, Lafayette, and Chassigny. Our data on Nakhla and Lafayette and recently reported ages for some nakhlites and Chassigny (Misawa et al. 2006; Park et al. 2009) point to formation ages of approximately 1.4 Ga rather than 1.3 Ga that is consistent with previous suggestions of close‐in‐time formation of nakhlites and Chassigny. In Lafayette mesostasis, we detected a secondary degassing event at approximately 1.1 Ga, which is not related to iddingsite formation. It may have been caused by a medium‐grade thermal event resetting the mesostasis age but not influencing the K‐Ar system of magmatic inclusions and the original igneous texture of this rock. Cosmic‐ray exposure ages for these meteorites and for Governador Valadares were calculated from bulk rock concentrations of cosmogenic nuclides 3He, 21Ne, and 38Ar. Individual results are similar to literature data. The considerable scatter of T3, T21, and T38 ages is due to systematic uncertainties related to bulk rock and target element chemistry, production rates, and shielding effects. This hampers efforts to better constrain the hypothesis of a single ejection event for all nakhlites and Chassigny from a confined Martian surface terrain (Eugster 2003; Garrison and Bogard 2005). Cosmic‐ray exposure ages from stepwise release age spectra using 38Ar and neutron induced 37Ar from Ca in irradiated samples can eliminate errors induced by bulk chemistry on production rates, although not from shielding conditions.
The effect of background music on the taste of wine
Authors: North Adrian C.
Published: September 2011

Research concerning cross‐modal influences on perception has neglected auditory influences on perceptions of non‐auditory objects, although a small number of studies indicate that auditory stimuli can influence perceptions of the freshness of foodstuffs. Consistent with this, the results reported here indicate that independent groups’ ratings of the taste of the wine reflected the emotional connotations of the background music played while they drank it. These results indicate that the symbolic function of auditory stimuli (in this case music) may influence perception in other modalities (in this case gustation); and are discussed in terms of possible future research that might investigate those aspects of music that induce such effects in a particular manner, and how such effects might be influenced by participants’ pre‐existing knowledge and expertise with regard to the target object in question.
Geometrical Design and Investigation of a New Profile of the Three Screw Pump
Authors: Xu Jian , Feng Quanke , Wu Weifeng
Published: September 2011

This paper presents a new edge blunting method of the three screw pump rotor with an elliptic arc and equations of the rotor profile after edge blunting. Through comparisons of different geometrical parameters of the pump, i.e., flow area, contact line length per lobe, blow hole area, etc., the new profile is proved to be better than the existing profiles of the three screw pump. The new streamlined profile, with a significantly smaller blow hole area, is of reference significance for the optimization design and further improvement of three screw pump.
The Joy of Teaching and Writing Conceptual Physics
Authors: Hewitt Paul G.
Published: September 2011

When I began teaching at City College of San Francisco in 1964, I fell in love with a 1960 text-book that addressed non-science students, Physics for the Inquiring Mind, written by British-born physicist Eric M. Rogers, who taught physics at Princeton University and who later won the 1969 Oersted Medal of the American Association of Physics Teachers. His book was as inspirational as he was and remains a favorite of mine. My request to adopt that book for my physics class was rejected by my department chair, Art Austin, who claimed it was much too bulky and heavy for students to have to haul around. It weighed more than five pounds, with a trim size huge for that time—8 × 11 inches. To further justify its rejection, he also found topics considered important not covered in the book. I would have loved teaching from the Rogers book, but such was not to be.
Preparing Your Students for Careers in Science and Engineering: How Is Your State Doing?
Authors: White Susan , Cottle Paul
Published: September 2011

With one glance at the starting salaries of new bachelor's degree recipients in Fig. 1, a teacher or parent can see the career fields to which their high school students interested in the best economic opportunities might aspire: several engineering fields (chemical, electrical, mechanical), computer science, physics, and mathematics.
The Physics of “String Passing Through Ice”
Authors: Mohazzabi Pirooz
Published: September 2011

One of the oldest yet interesting experiments related to heat and thermodynamics is placing a string on a block of ice and hanging two masses from the ends of the string. Sometime later, it is discovered that the string has passed through the ice without cutting it in half. A simple explanation of this effect is that the pressure caused by the string makes the ice melt just below the string, the string slides down, and the water freezes again just above the string.1–6 This phenomenon, however, is interesting and puzzling enough for many curious science students that it deserves a more detailed and quantitative explanation.
Projectile Motion Gets the Hose
Authors: Goff John Eric , Liyanage Chinthaka
Published: September 2011

Students take a weekly quiz in our introductory physics course. During the week in which material focused on projectile motion, we not-so-subtly suggested what problem the students would see on the quiz. The quiz problem was an almost exact replica of a homework problem1 we worked through in the class preceding the quiz. The goal of the problem is to find the launch speed if the final horizontal and vertical positions and launch angle are given. Figure 1 shows a schematic of the trajectory.
Physics Myth Busting: A Lab-Centered Course for Non-Science Students
Authors: Madsen Martin John
Published: September 2011

There is ongoing interest in how and what we teach in physics courses for non-science students, so-called “physics for poets” courses. Art Hobson has effectively argued that teaching science literacy should be a key ingredient in these courses.1 Hobson uses Jon Millers definition of science literacy, which has two components: first, “a basic knowledge of key scientific concepts,” and second, “an understanding of the process of science.”2 In preparing to teach our course for non-science students, I found that the majority of textbooks and courses focus on the first component. However, I wanted a lab-centered course that would give students hands-on practice doing science. I describe in this article a course I designed and implemented at Wabash College that focused on teaching students “the process of science.” The course was titled “Adventures in Physics: Mythbusters” and was based loosely on the popular Discovery Channel show “MythBusters.”3
A do-it-yourself optical bench
Authors: Dvořák Leoš
Published: September 2011

When teaching geometrical optics, especially the parts concerning lenses, there are many experiments that can be done just by holding the lenses in your (or your pupils') hands. But if you want to measure something, for example focal lengths, or combine two lenses to demonstrate the principle of a telescope, then something that can fix the lenses is needed. Of course, we can do such demonstrations and measurements using a commercially available optical bench. But a classical optical bench is usually a large and heavy construction that is not easy to transport. Often only one (or even none) may be available per classroom. In many school experiments something less robust, simpler, and less expensive would perhaps suit the needs better. Here we describe a simple and flexible optical bench that may be constructed by students themselves. Apart from the price of the lenses, the construction is also very cheap. So, if you have some spare lenses available, you can build a small optical bench for $10 or less. Each group of students can then use their own optical bench to do experiments.
Getting to the Root of Hydrocephalus
Authors: McAllister James P.
Published: September 2011

The blood-borne lipid lysophosphatidic acid and its receptor contribute to fetal-onset hydrocephalus, a severe neurological disorder of newborns.
The Midas Touch
Authors: Tridandapani Srini
Published: September 2011

A gold:gadolinium label can be used to track encapsulated pancreatic islets after transplantation.
Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients
Authors: Sánchez Almudena , Cabrera Salvador , Santos Dolores , Valverde M. Paz , Fuertes Aurelio , Domínguez-Gil Alfonso , García María J. ,   the Tormes Group
Published: September 2011

Despite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C→T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 − 0.00279·GGT)·0.602CYP2B6*6 [G/T]·0.354CYP2B6*6 [T/T]·0.793MRP4 1497C→T, where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C→T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.
Analysis of the Functional Contributions of Asn233 in Metallo-β-Lactamase IMP-1
Authors: Brown Nicholas G. , Horton Lori B. , Huang Wanzhi , Vongpunsawad Sompong , Palzkill Timothy
Published: September 2011

Metallo-β-lactamases, such as IMP-1, are a major global health threat, as they provide for bacterial resistance to a wide range of β-lactam antibiotics, including carbapenems. Understanding the molecular details of the enzymatic process and the sequence requirements for function are essential aids in overcoming β-lactamase-mediated resistance. An asparagine residue is conserved at position 233 in approximately 67% of all metallo-β-lactamases. Despite its conservation, the molecular basis of Asn233 function is poorly understood and remains controversial. It has previously been shown that mutations at this site exhibit context-dependent sequence requirements in that the importance of a given amino acid depends on the antibiotic being tested. To provide a more thorough examination as to the function and sequence requirements at this position, a collection of IMP-1 mutants encoding each of the 19 possible amino acid substitutions was generated. The resistance levels toward four β-lactam antibiotics were measured for
Escherichia coli
containing each of these mutants. The sequence requirements at position 233 for wild-type levels of resistance toward two cephalosporins were the most relaxed, while there were more stringent sequence requirements for resistance to ampicillin or imipenem. Enzyme kinetic analysis and determinations of steady-state protein levels indicated that the effects of the substitutions on resistance are due to changes in the kinetic parameters of the enzyme. Taken together, the results indicate that substitutions at position 233 significantly alter the kinetic parameters of the enzyme, but most substituted enzymes are able to provide for a high level of resistance to a broad range of β-lactams.
Enhanced Neutralization of HIV by Antibodies Displayed on the S-Layer of Caulobacter crescentus
Authors: Duval Mark , Lewis Christopher J. , Nomellini John F. , Horwitz Marc S. , Smit John , Cavacini Lisa A.
Published: September 2011

Innovative methods of prevention are needed to stop the more than two million new HIV-1 infections annually, particularly in women. Local application of anti-HIV antibodies has been shown to be effective at preventing infection in nonhuman primates; however, the concentrations needed are cost prohibitive. Display of antibodies on a particulate platform will likely prolong effectiveness of these anti-HIV agents and lower the cost of goods. Here, we demonstrate that the bacterium
Caulobacter crescentus
and its highly expressed surface-layer (S-layer) protein can provide this antibody display platform. Caulobacters displaying protein G, alone or with CD4 codisplay, successfully captured HIV-1-specific antibodies and demonstrated functional neutralization. Compared to soluble antibodies, a neutralizing anti-HIV antibody displayed on
Caulobacter
was as effective or more effective at neutralizing diverse HIV-1 isolates. Moreover, when an antibody reactive with an epitope induced by CD4 binding (CD4i) was codisplayed with CD4, there was significant enhancement in HIV-1 neutralization. These results suggest that caulobacters displaying anti-HIV antibodies offer a distinct improvement in the use of antibodies as microbicides. Furthermore, these reagents can specifically evaluate anti-HIV antibodies in concert with other HIV-1 blocking agents to assess the most suitable tools for conversion to scFvs, allowing for direct display within the S-layer protein and further reducing cost of goods. In summary,
C. crescentus
, which can be easily produced and chemically stabilized at low cost, is well suited for engineering as an effective platform, offering an inexpensive way to produce and deliver HIV-1-specific microbicides.
Pharmacokinetics and Safety of Single-Dose Tenofovir Disoproxil Fumarate and Emtricitabine in HIV-1-Infected Pregnant Women and Their Infants
Authors: Flynn Patricia M. , Mirochnick Mark , Shapiro David E. , Bardeguez Arlene , Rodman John , Robbins Brian , Huang Sharon , Fiscus Susan A. , Van Rompay Koen K. A. , Rooney James F. , Kearney Brian , Mofenson Lynne M. , Watts D. Heather , Jean-Philippe Patrick , Heckman Barbara , Thorpe Edwin , Cotter Amanda , Purswani Murli ,   the PACTG 394 Study Team
Published: September 2011

Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (
C
24
) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (
C
max
) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (
P
= 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression.
Griffithsin Has Antiviral Activity against Hepatitis C Virus
Authors: Meuleman Philip , Albecka Anna , Belouzard Sandrine , Vercauteren Koen , Verhoye Lieven , Wychowski Czeslaw , Leroux-Roels Geert , Palmer Kenneth E. , Dubuisson Jean
Published: September 2011

Hepatitis C virus (HCV)-infected patients undergoing liver transplantation universally experience rapid reinfection of their new liver graft. Current treatment protocols do not prevent graft reinfection and, in addition, an accelerated disease progression is observed. In the present study, we have evaluated a novel strategy to prevent HCV infection using a lectin, griffithsin (GRFT) that specifically binds N-linked high-mannose oligosaccharides that are present on the viral envelope. The antiviral effect of GRFT was evaluated
in vitro
using the HCV pseudoparticle (HCVpp) and HCV cell culture (HCVcc) systems. We show here that preincubation of HCVpp and HCVcc with GRFT prevents infection of Huh-7 hepatoma cells. Furthermore, GRFT interferes with direct cell-to-cell transmission of HCV. GRFT acts at an early phase of the viral life cycle by interfering in a genotype-independent fashion with the interaction between the viral envelope proteins and the viral receptor CD81. The capacity of GRFT to prevent infection
in vivo
was evaluated using uPA
+/+
-SCID mice (uPA stands for urokinase-type plasminogen activator) that harbor human primary hepatocytes in their liver (chimeric mice). In this proof-of-concept trial, we demonstrated that GRFT can mitigate HCV infection of chimeric mice. Treated animals that did become infected demonstrated a considerable delay in the kinetics of the viral infection. Our data demonstrate that GRFT can prevent HCV infection
in vitro
and mitigate HCV infection
in vivo
. GRFT treatment of chronically infected HCV patients undergoing liver transplantation may be a suitable strategy to prevent infection of the liver allograft.
TMC310911, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, Shows
In Vitro
an Improved Resistance Profile and Higher Genetic Barrier to Resistance Compared with Current Protease Inhibitors
Authors: Dierynck Inge , Van Marck Herwig , Van Ginderen Marcia , Jonckers Tim H. M. , Nalam Madhavi N. L. , Schiffer Celia A. , Raoof Araz , Kraus Guenter , Picchio Gaston
Published: September 2011

TMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC
50
], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC
50
, >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC
50
was ≤4 for 82% of isolates and ≤10 for 96% of isolates. The FC in TMC310911 EC
50
was ≤4 and ≤10 for 72% and 94% of isolates with decreased susceptibility to DRV, respectively.
In vitro
resistance selection (IVRS) experiments with WT virus and TMC310911 selected for mutations R41G or R41E, but selection of resistant virus required a longer time than IVRS performed with WT virus and DRV. IVRS performed with r13025, a multiple-PI-resistant recombinant clinical isolate, and TMC310911 selected for mutations L10F, I47V, and L90M (FC in TMC310911 EC
50
= 16). IVRS performed with r13025 in the presence of DRV required less time and resulted in more PI resistance-associated mutations (V32I, I50V, G73S, L76V, and V82I; FC in DRV EC
50
= 258). The activity against a comprehensive panel of PI-resistant mutants and the limited
in vitro
selection of resistant viruses under drug pressure suggest that TMC310911 represents a potential drug candidate for the management of HIV-1 infection for a broad range of patients, including those with multiple PI resistance.
Development of Dual-Acting Pyrimidinediones as Novel and Highly Potent Topical Anti-HIV Microbicides
Authors: Watson Buckheit Karen , Yang Lu , Buckheit Robert W.
Published: September 2011

In the absence of an effective vaccine against the human immunodeficiency virus (HIV), topical microbicides to prevent the sexual transmission of HIV represent an important strategy to prevent the continued spread of infection. The recent trend in the development of new microbicide candidates includes the utilization of FDA-approved therapeutic drugs that target the early stages of the HIV life cycle, including entry inhibitors and reverse transcriptase inhibitors. We have investigated 12 pyrimidinedione compounds with potent HIV activities and their abilities to inhibit both virus entry and reverse transcription, in an effort to determine a lead microbicide for product development. The candidate compounds were evaluated for efficacy against subtype B, C, and E clinical virus strains in fresh human peripheral blood mononuclear cells and against CCR5-tropic virus strains in both monocyte-macrophages and dendritic cells. Microbicide-specific biological assays and toxicity evaluations were also performed in a variety of established and fresh human cells as well as against
Lactobacillus
strains common to the vaginal environment. These evaluations resulted in the identification of congeners with cyclopropyl and cyclobutyl substituents at the N-1 of the pyrimidinedione as the most active molecules in the structure-activity relationship series. The pyrimidinediones represent excellent microbicide candidates in light of their significantly high efficacies against HIV-1 (subnanomolar concentration range), potencies (therapeutic index, >1 million), solubility profiles, and dual mechanism of antiviral action that includes two early steps of virus replication prior to the integration of the virus that are considered most important for microbicidal activity.
Helicobacter pylori Resistance to Rifabutin in the Last 7 Years
Authors: Nishizawa Toshihiro , Suzuki Hidekazu , Matsuzaki Juntaro , Muraoka Hiroe , Tsugawa Hitoshi , Hirata Kenro , Hibi Toshifumi
Published: September 2011

A low rate of resistance (0.24%) to rifabutin was noted in
Helicobacter pylori
strains isolated from 414 Japanese patients. The only rifabutin-resistant strain detected showed a point mutation in the
rpoB
gene and was isolated from a patient with a history of rifampin treatment for pulmonary tuberculosis.
Antimicrobial Actions of Reactive Oxygen Species
Authors: Fang Ferric C.
Published: September 2011

Everything should be as simple as it can be, but not simpler.

—Attributed to Albert Einstein (1)

IMPORTANCE
Reactive oxygen species (ROS) are produced by host phagocytes and exert antimicrobial actions against a broad range of pathogens. The observable antimicrobial actions of ROS are highly dependent on experimental conditions. This perspective reviews recent controversies regarding ROS in
Salmonella
-phagocyte interactions and attempts to reconcile conflicting observations from different laboratories.
H5N1 Influenza Virus Pathogenesis in Genetically Diverse Mice Is Mediated at the Level of Viral Load
Authors: Boon Adrianus C. M. , Finkelstein David , Zheng Ming , Liao Guochun , Allard John , Klumpp Klaus , Webster Robert , Peltz Gary , Webby Richard J.
Published: September 2011

The genotype of the host is one of several factors involved in the pathogenesis of an infectious disease and may be a key parameter in the epidemiology of highly pathogenic H5N1 influenza virus infection in humans. Gene polymorphisms may affect the viral replication rate or alter the host’s immune response to the virus. In humans, it is unclear which aspect dictates the severity of H5N1 virus disease. To identify the mechanism underlying differential responses to H5N1 virus infection in a genetically diverse population, we assessed the host responses and lung viral loads in 21 inbred mouse strains upon intranasal inoculation with A/Hong Kong/213/03 (H5N1). Resistant mouse strains survived large inocula while susceptible strains succumbed to infection with 1,000- to 10,000-fold-lower doses. Quantitative analysis of the viral load after inoculation with an intermediate dose found significant associations with lethality as early as 2 days postinoculation, earlier than any other disease indicator. The increased viral titers in the highly susceptible strains mediated a hyperinflamed environment, indicated by the distinct expression profiles and increased production of inflammatory mediators on day 3. Supporting the hypothesis that viral load rather than an inappropriate response to the virus was the key severity-determining factor, we performed quantitative real-time PCR measuring the cytokine/viral RNA ratio. No significant differences between susceptible and resistant mouse strains were detected, confirming that it is the host genetic component controlling viral load, and therefore replication dynamics, that is primarily responsible for a host’s susceptibility to a given H5N1 virus.

IMPORTANCE
Highly pathogenic H5N1 influenza virus has circulated in Southeast Asia since 2003 but has been confirmed in relatively few individuals. It has been postulated that host genetic polymorphisms increase the susceptibility to infection and severe disease. The mechanisms and host proteins affected during severe disease are unknown. Inbred mouse strains vary considerably in their ability to resist H5N1 virus and were used to identify the primary mechanism determining disease severity. After inoculation with H5N1, resistant mouse strains had reduced amounts of virus in their lungs, which subsequently resulted in lower production of proinflammatory mediators and less pathology. We therefore conclude that the host genetic component controlling disease severity is primarily influencing viral replication. This is an important concept, as it emphasizes the need to limit virus replication through antiviral therapies and it shows that the hyperinflammatory environment is simply a reflection of more viral genetic material inducing a response.
Conversion of Commensal Escherichia coli K-12 to an Invasive Form via Expression of a Mutant Histone-Like Protein
Authors: Koli Preeti , Sudan Sudhanshu , Fitzgerald David , Adhya Sankar , Kar Sudeshna
Published: September 2011

The HUα
E38K, V42L
mutant of the bacterial histone-like protein HU causes a major change in the transcription profile of the commensal organism
Escherichia coli
K-12 (Kar S, Edgar R, Adhya S, Proc. Natl. Acad. Sci. U. S. A. 102:16397–16402, 2005). Among the upregulated genes are several related to pathogenic interactions with mammalian cells, as evidenced by the expression of curli fibers, Ivy, and hemolysin E. When
E. coli
K-12/ HUα
E38K, V42L
was added to Int-407 cells, there was host cell invasion, phagosomal disruption, and intracellular replication. The invasive trait was also retained in a murine ileal loop model and intestinal explant assays. In addition to invasion, the internalized bacteria caused a novel subversion of host cell apoptosis through modification and regulation of the BH3-only proteins Bim
EL
and Puma. Changes in the transcription profile were attributed to positive supercoiling of DNA leading to the altered availability of relevant promoters. Using the
E. coli
K-12/HUα
E38K, V42L
variant as a model, we propose that traditional commensal
E. coli
can adopt an invasive lifestyle through reprogramming its cellular transcription, without gross genetic changes.

IMPORTANCE
Escherichia coli
K-12 is well established as a benign laboratory strain and a human intestinal commensal. Recent evidences, however, indicate that the typical noninvasive nature of resident
E. coli
can be reversed under specific circumstances even in the absence of any major genomic flux. We previously engineered an
E. coli
strain with a mutant histone-like protein, HU, which exhibited significant changes in nucleoid organization and global transcription. Here we showed that the changes induced by the mutant HU have critical functional consequences: from a strict extracellular existence, the mutant
E. coli
adopts an almost obligate intracellular lifestyle. The internalized
E. coli
exhibits many of the prototypical characteristics of traditional intracellular bacteria, like phagosomal escape, intracellular replication, and subversion of host cell apoptosis. We suggest that
E. coli
K-12 can switch between widely divergent lifestyles in relation to mammalian host cells by reprogramming its cellular transcription program and without gross changes in its genomic content.
Dual-colour HER2/chromosome 17 chromogenic in situ hybridisation enables accurate assessment of HER2 genomic status in ovarian tumours
Authors: Yan Benedict , Choo Shoa Nian , Mulyadi Patricia , Srivastava Supriya , Ong Chee Wee , Yong Kol Jia , Putti Thomas , Salto-Tellez Manuel , Lim Gkeok Stzuan Diana
Published: September 2011

Background

Ovarian cancer is a leading cause of gynaecological cancer-related morbidity and mortality. There has been increasing interest in the potential utility of anti-human epidermal growth factor receptor 2 (anti-HER2) agents in the treatment of this disease, with the attendant need to identify suitable predictive biomarkers of response to treatment.

Aims/methods

The authors studied the prevalence of HER2 genomic amplification and overexpression in 85 ovarian tumours in the local patient cohort of this study, as well as the concordance rate between immunohistochemistry, fluorescent in situ hybridisation (FISH) and a dual-colour HER2/chromosome 17 centromere chromogenic in situ hybridisation (CISH) assay.

Results

The authors identified HER2 genomic amplification and protein overexpression in 35.3% (6/17) and 29.4% (5/17), respectively, of primary ovarian mucinous carcinomas. No other cancer subtypes displayed HER2 amplification or protein overexpression. The authors also found a perfect concordance between FISH and dual-colour CISH analysis (κ coefficient 1.0, p<0.001).

Conclusion

The results of this study support existing reports that HER2 genomic amplification and protein overexpression are predominantly found in primary ovarian mucinous carcinomas. Given the perfect concordance between the FISH and dual-colour CISH assays and the advantages of CISH over FISH analysis, future clinical trials investigating the use of anti-HER2 therapeutics in ovarian carcinomas should incorporate dual-colour CISH as part of the HER2 status assessment algorithm.
Best practice in primary care pathology: review 14
Authors: Cabrera-Abreu J C , Smellie W S A , Bowley R , Shaw N
Published: September 2011

This 14th best practice review is the second of a pair that examines tumour marker requesting primary care situations. This review considers carbohydrate antigen 125, α-fetoprotein and human chorionic gonadotropin. It is presented in question–answer format, referenced for each question. The recommendations represent a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by MEDLINE EMBASE searches to identify relevant primary research documents. They will be updated periodically to take into account new information.
The pathogenesis, diagnosis, investigation and management of osteoporosis
Authors: Sandhu Sunita K , Hampson Geeta
Published: September 2011

With an increasingly ageing population, osteoporosis and osteoporosis-related fractures is fast becoming an important public health problem placing a considerable economic burden on health service resources. This does not account for the substantial pain, disability and indeed mortality incurred after a fracture, particularly a hip fracture. Osteoporosis is a systemic skeletal disorder which results from an imbalance in bone remodeling. This leads to a reduction in bone strength and increased susceptibility to fracture. It affects up to 1 in 2 women and 1 in 5 men. In the past 2 decades, there have been significant advances in bone biology which have helped in the understanding of the pathogenesis of osteoporosis and have led to improved therapies. In developing strategies for fracture prevention, it is important to identify those individuals with the highest fracture risk who will require pharmacological intervention. Treatment is aimed at fracture prevention and includes modification of general lifestyle factors which have been linked to fractures in epidemiological studies and ensuring optimum calcium and vitamin D intake as adjunct to active anti-fracture therapy. A number of drugs are now approved for the treatment of osteoporosis. This review article will describe the pathogenesis of osteoporosis and focus on the methods currently in use for the identification of patients at high fracture risk and will highlight their usefulness and limitations. The existing anti-fracture pharmacotherapies and those in development will be reviewed. Assessment of their effectiveness including the use of biochemical markers of bone turnover in this clinical context will be reviewed.
Delayed diagnosis of Kaposi's sarcoma in a HIV positive man with a high CD4 count and suppressed viral load: Figure 1
Authors: Chan Sum Yee , Pakianathan Mark
Published: September 2011

A HIV positive man with a CD4 count of 777×106/l and suppressed viral load on antiretroviral medication had a delayed diagnosis of Kaposi's sarcoma (KS) affecting his left leg. He was diabetic and on a controlled diet and had a previous deep vein thrombosis affecting the same leg. Factors that have been studied in HIV-related KS as well as classical KS, such as diabetes mellitus, not smoking and previous deep vein thrombosis, may have increased our patient's risk for the development of this disease. Clinicians should consider KS as a possible diagnosis even in patients with well-controlled HIV.
Thermal Therapy in Dialysis Patients — A Randomized Trial
Authors: Lin Chia-Hsien , Lee Li-Shan , Su Ling-Hwa , Huang Tien-Chuan , Liu Chi-Feng
Published: September 2011

The aim of this study is to evaluate the effects of far-infrared (FIR) rays on the meridian in hemodialysis (HD) patients. End-stage renal disease or kidney failure is the last stage of chronic renal failure, and often implies that the renal function cannot be restored and HD or kidney transplantation is required as a life-saving measure. HD patients often feel sick, debilitated, demotivated, and sad. A quasi-experimental design was conducted using convenience sampling with 61 HD patients from a hemodialysis center. Meridian testing and Brief Fatigue Inventory-Taiwan Form (BFI-T) were used as screening test for HD. The experimental group (n = 36) received FIR irradiation on each acupoint for 30 min, thrice a week, for two months, whereas the control group (n = 25) received no intervention. The outcome measures included meridian equipment, the level of hemoglobin (Hb), albumin, blood urea nitrogen (BUN), creatinine (CRE), and BFI-T. Ryodoraku values reveal a significant increase (p < 0.05) in the left small intestine meridian, left large intestine meridian, and yin-yang ratio. Overall, the increase in the meridians of the patients of experimental group is significantly higher than that of the control group. The results establish that FIR treatment on Qihai (RN 6), Guanyuan (RN 4), Zhongji (RN 3), and Tianshu (ST 25) is effective. Based on these findings, one can believe that FIR regulates the Qi of the kidney. The findings of this study would help doctors effectively dealing with thermal therapy treatment of HD patients.