bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Diaper Cream and Wet Wipes on Skin Barrier Properties in Infants: A Prospective Randomized Controlled Trial
Authors: Garcia Bartels Natalie , Lünnemann Lena , Stroux Andrea , Kottner Jan , Serrano José , Blume‐Peytavi Ulrike
Published: November 2014

The effect of different diaper care procedures on skin barrier function in infants has been minimally investigated and may be assessed using objective methods. In a single‐center, prospective trial, 89 healthy 9‐month‐old infants (±8 wks) were randomly assigned to three diaper care regimens: group I used water‐moistened washcloths at diaper changes (n = 30), group II additionally applied diaper cream twice daily (n = 28), and group III used wet wipes and diaper cream twice daily (n = 31). Transepidermal water loss (TEWL), skin hydration (SCH), skin pH, interleukin 1α (IL‐1α) levels, and microbiologic colonization were measured in diapered skin (upper outer quadrant of the buttocks), nondiapered skin (upper leg), and if diaper dermatitis (DD) occurred, using the most affected skin area at day 1 and weeks 4 and 8. Skin condition was assessed utilizing a neonatal skin condition score and diaper rash grade. On diapered skin, SCH decreased in groups II and III, whereas TEWL values were reduced in group II only. Skin pH increased in groups II and III. In general, SCH, skin pH, and IL‐1α levels were higher in healthy diapered skin than in nondiapered skin. The incidence and course of DD was comparable in all groups. Areas with DD had greater TEWL and skin pH than unaffected skin areas. Infants who received diaper cream had lower SCH and TEWL and higher pH levels in the diapered area than on nondiapered skin. No correlation with the occurrence of DD was found.
Coexistence of Aplasia Cutis and Nevus Psiloliparus—Report of a Novel Case
Authors: Tekin Burak , Yücelten Ayşe Deniz , Akpınar İhsan Nuri , Ekinci Gazanfer
Published: November 2014

Nevus psiloliparus is a type of mesodermal nevus of the scalp classically seen with encephalocraniocutaneous lipomatosis. The close association between nevus psiloliparus and aplasia cutis congenita is called didymosis aplasticopsilolipara. Although typically associated with neurologic, ocular, and skeletal findings, didymosis aplasticopsilolipara can be seen without the context of encephalocraniocutaneous lipomatosis.
Ulcerated Infantile Hemangioma: Novel Treatment with Topical Brimonidine‐Timolol
Authors: Beal Brandon T. , Chu Melinda B. , Siegfried Elaine C.
Published: November 2014

We report a 2‐month‐old boy with a painful ulcerated hemangioma on the lower mucosal lip extending to the vermillion border that caused feeding difficulty. It was successfully treated with topical brimonidine 0.2% and timolol 0.5%, a combination selective α2‐adrenergic agonist and nonselective β‐blocker. After 6 weeks of treatment, the lesion reepithelialized and the patient's symptoms and functional complications resolved. Brimonidine 0.2% timolol 0.5% ophthalmic solution is an emerging alternative treatment for hemangiomas, offering the potential to target hemangioma growth through two synergistic mechanisms (β‐inhibition and α2‐agonism) that may be especially effective for ulcerated lesions, the most common complication of infantile hemangiomas.
Utility of the “Magnet Sign” in the Differential Diagnosis of a Firm Papule in the Skin
Authors: Krakowski Andrew C. , Bennett Lauren , Kaifi Samar
Published: November 2014

A symptomatic retained foreign body can be frustrating to physicians and patients alike. Herein we present a case of a retained metal ball bearing from an air gun injury. This brief communication highlights an innovative “bedside” technique that helped to confirm the diagnosis and allow for immediate and definitive management.
Rituximab Induced Psoriasis in an Infant
Authors: Fiorillo Loretta , Wang Charles , Hemmati Imam
Published: November 2014

Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen present on the surface of mature B cells. It has been widely used in the treatment of many dermatologic and rheumatologic conditions. The onset of psoriasis after rituximab therapy has not been reported in children. We report the first case of psoriasis after rituximab therapy in a 16‐month‐old boy with no other risk factors for developing psoriasis.
Purpuric Eruption in a Transfused Neonate Receiving Phototherapy
Authors: By Charya C. , Owens Alexandra , Wesson Stanton K.
Published: November 2014

We describe the clinical and biochemical findings in a neonate requiring multiple blood transfusions and phototherapy for alloimmune hemolytic anemia and unconjugated hyperbilirubinemia, respectively. In this newborn, a severe photosensitivity reaction developed and laboratory testing revealed elevated serum and urine porphyrins at the time of the eruption. The cause of the transient porphyrinemia was likely multifactorial. Possible mechanisms include poor hepatic metabolism and reticulocyte hemolysis. However, the exact pathogenesis remains unclear at this time.
Novel Nickel Contact Dermatitis in a Patient Taking Isotretinoin
Authors: Conely John , Polcari Ingrid
Published: November 2014

There are many reports about contact dermatitis to nickel and side effects of isotretinoin, but the development of contact dermatitis to a previously tolerated allergen while taking isotretinoin is not well described. We report the case of a 19‐year‐old man who developed a new nickel allergy during isotretinoin treatment. We theorize that thinning of the stratum corneum by this medication allows for greater antigen presentation and thus sensitization to contact allergens.
Total Congenital Anonychia
Authors: Afsar Fatma Sule , Karakuzu Ali
Published: November 2014

Total or partial absence of nails at birth is rare. Anonychia can be inherited as an autosomal dominant or recessive trait. An otherwise healthy 4‐year‐old boy whose parents were first‐degree relatives was diagnosed with total congenital anonychia.
Mycoplasma pneumoniae–Associated Mucocutaneous Disease in Children: Dilemmas in Classification
Authors: Prindaville Brea , Newell Brandon D. , Nopper Amy J. , Horii Kimberly A.
Published: November 2014

There is controversy regarding precise definitions for Stevens–Johnson syndrome (SJS) and erythema multiforme (EM) major because of overlap in clinical presentations. SJS and EM major associated with Mycoplasma pneumoniae have been reported to occur in children, but Mycoplasma is more commonly reported with SJS. We sought to further characterize Mycoplasma‐associated mucocutaneous disease. Through retrospective chart review over 10 years, six children hospitalized with a diagnosis of SJS who also tested positive for Mycoplasma infection were reviewed. Using documented physical examinations and photographs, diagnoses of SJS or EM major were retrospectively made based upon cutaneous lesional morphology employing the classification system proposed by Bastuji‐Garin et al. The majority of patients were boys, with limited acral cutaneous lesions. All patients required prolonged hospitalization because of mucosal involvement and had good short‐term outcomes. When the classification system was retrospectively applied, five of the six patients were reclassified with a diagnosis of EM major instead of SJS. Children with Mycoplasma‐associated EM major and SJS in our small retrospective series appeared to have significant mucosal involvement but more limited cutaneous involvement with lesional morphology, which is more characteristic of EM major.
The quest for indigenous aquafeed ingredients: a review
Authors: Teves Jonni Fay C. , Ragaza Janice A.
Published: November 2014

The growing demand for fish food products worldwide heightens the pressure on the current availability of feed ingredients, especially marine resources such as fishmeal and fish oil, for aquaculture feed production. To address this concern, the potential of novel ingredients for use in feed formulations needs to be tapped. This paper highlights recent researches undertaken concerning the dietary inclusion of various indigenous ingredients classified as seaweeds, leaf meals, oilseed meals, vegetable oils and medicinal herbs, and their effects on growth performance, feed intake, feed utilization efficiency, nutrient retention, disease resistance and other physiological activities among consumer species. Moreover, this paper presents information regarding their nutritive values, optimum inclusion levels and recommended protocols that can improve their potential as feed additives or fishmeal replacements.
‘Academic Mobility for Development’ as A Contested Notion: An Analysis of the Reach of the Chinese State in Regulating the Transnational Brains
Authors: Leung Maggi W.H.
Published: November 2014

This paper gauges the reach of the state in regulating the flows of academics and harnessing them for development in China. Drawing upon a review of policy documents, secondary data and fieldwork findings from a research project that studies the developmental impact of academic mobility among Chinese scholars active in the Chinese‐German academic space, this paper challenges the ‘talents sans frontières’ notion on the one hand, and illustrates the limits of the state on the other. Mobile scholars are conceptualised as active agents who are nested in, and hence being regulated by and at the same time shaping the Chinese state and its policies. Mobile scholars (and their local(ised) colleagues) are engaged in multiple relationships (ranging from collaborative, contradictory to conflictual ones) with the state, sometimes reinforcing and at other times toppling its notions of development. These relationalities call for new interpretations of the dynamic, contextualised and complex mobility‐development nexus.
Career Strategies and Spatial Mobility among Skilled Migrants in Germany: The Role of Gender in the Work‐Family Interaction
Authors: Shinozaki Kyoko
Published: November 2014

This paper aims to unravel the gendered career strategies of skilled migrants in Germany's financial and academic sectors. Such careers are being developed not only in tandem, but also often in negotiation, with gender relations in the family. Much of the existing literature in skilled migration studies has concentrated on the principal migrant and work‐related context, treating the family as a rather secondary terrain. Drawing on participant observation and interviews, this paper shows that these two terrains, work and family, are closely interrelated in building skilled migrant workers' career pathways. My analysis of the experiences of migrant, dual‐career couples shows that their transnational career strategies have a strong bearing on the fine balancing act and negotiation of intra‐family gender relations, which are neither pre‐given nor fixed. Key to understanding their strategies are migrants' transnationalising cultural capital, access to childcare provision, a life‐stage perspective, and the role of dual‐career policies.
Modernising Dutch Heritage Conservation: Current Progress and Ongoing Challenges for Heritage‐Based Planning and Management
Authors: Janssen Joks
Published: November 2014

Over the last decades, Dutch heritage conservation shifted from a preservationist and object‐focused to an area‐based and development‐oriented activity. Today's heritage management looks not only at the monument itself, but at its spatial context. The Belvedere Memorandum in 1999 has played a key role in getting the heritage onto the spatial planning agenda. Linking heritage to the spatial challenges of cities and regions was also the primary goal of the ‘Modernisation of Monuments Care’ in 2009, resulting in a revision of the heritage preservation act. However, now that heritage values will be accounted for at the planning stage, spatial planning finds itself in disarray. Area and property development are at a standstill, there is less money, and more and more empty buildings. The heritage community will therefore need all its creativity to maintain the quality of heritage preservation and renewal.
Construction of 3D Volumetric Objects for a 3D Cadastral System
Authors: Ying Shen , Guo Renzhong , Li Lin , Van Oosterom Peter , Stoter Jantien
Published: November 2014

This article presents a new method to illustrate the feasibility of 3D topology creation. We base the 3D construction process on testing real cases of implementation of 3D parcels construction in a 3D cadastral system. With the utilization and development of dense urban space, true 3D geometric volume primitives are needed to represent 3D parcels with the adjacency and incidence relationship. We present an effective straightforward approach to identifying and constructing the valid volumetric cadastral object from the given faces, and build the topological relationships among 3D cadastral objects on‐the‐fly, based on input consisting of loose boundary 3D faces made by surveyors. This is drastically different from most existing methods, which focus on the validation of single volumetric objects after the assumption of the object's creation. Existing methods do not support the needed types of geometry/topology (e.g. non 2‐manifold, singularities) and how to create and maintain valid 3D parcels is still a challenge in practice. We will show that the method does not change the faces themselves and faces in a given input are independently specified. Various volumetric objects, including non‐manifold 3D cadastral objects (legal spaces), can be constructed correctly by this method, as will be shown from the results.
Differential patterns, trends and hotspots of road traffic injuries on different road networks in Vellore district, southern India
Authors: Mohan Venkata Raghava , Sarkar Rajiv , Abraham Vinod Joseph , Balraj Vinohar , Naumova Elena N
Published: November 2014

Objective

To describe spatial and temporal profiles of Road Traffic Injuries (RTIs) on different road networks in Vellore district of southern India.

Methods

Using the information in the police maintained First Information Reports (FIRs), daily time series of RTI counts were created and temporal characteristics were analysed with respect to the vehicle, road types and time of the day for the period January 2005 to May 2007. Daily incidence and trend of RTIs were estimated using a Poisson regression analysis.

Results

Of the reported 3262 RTIs, 52% had occurred on the National Highway (NH). The overall RTI rate on the NH was 8.8/100 000 vehicles per day with significantly higher pedestrian involvement. The mean numbers of RTIs were significantly higher on weekends. Thirteen percentage of all RTIs were associated with fatalities. Hotspots are major town junctions, and RTI rates differ over different stretches of the NH.

Conclusion

In India, FIRs form a valuable source of RTI information. Information on different vehicle profile, RTI patterns, and their spatial and temporal trends can be used by administrators to devise effective strategies for RTI prevention by concentrating on the high‐risk areas, thereby optimising the use of available personnel and resources.
Determinants Associated with Veterinary Antimicrobial Prescribing in Farm Animals in the Netherlands: A Qualitative Study
Authors: Speksnijder D. C. , Jaarsma A. D. C. , van der Gugten A. C. , Verheij T. J. M. , Wagenaar J. A.
Published: November 2014

Antimicrobial use in farm animals might contribute to the development of antimicrobial resistance in humans and animals, and there is an urgent need to reduce antimicrobial use in farm animals. Veterinarians are typically responsible for prescribing and overseeing antimicrobial use in animals. A thorough understanding of veterinarians' current prescribing practices and their reasons to prescribe antimicrobials might offer leads for interventions to reduce antimicrobial use in farm animals. This paper presents the results of a qualitative study of factors that influence prescribing behaviour of farm animal veterinarians. Semi‐structured interviews with eleven farm animal veterinarians were conducted, which were taped, transcribed and iteratively analysed. This preliminary analysis was further discussed and refined in an expert meeting. A final conceptual model was derived from the analysis and sent to all the respondents for validation. Many conflicting interests are identifiable when it comes to antimicrobial prescribing by farm animal veterinarians. Belief in the professional obligation to alleviate animal suffering, financial dependency on clients, risk avoidance, shortcomings in advisory skills, financial barriers for structural veterinary herd health advisory services, lack of farmers' compliance to veterinary recommendations, public health interests, personal beliefs regarding the veterinary contribution to antimicrobial resistance and major economic powers are all influential determinants in antimicrobial prescribing behaviour of farm animal veterinarians. Interventions to change prescribing behaviour of farm animal veterinarians could address attitudes and advisory skills of veterinarians, as well as provide tools to deal with (perceived) pressure from farmers and advisors to prescribe antimicrobials. Additional (policy) measures could probably support farm animal veterinarians in acting as a more independent animal health consultant.
Surface cleaning for enhanced adhesion to packaging surfaces: Effect of oxygen and ammonia plasma
Authors: Gaddam Sneha , Kazi Haseeb , Dong Bin , Driver Marcus , Kelber Jeffry
Published: November 2014

The effects of direct plasma chemistries on carbon removal from silicon nitride (SiNx) and oxynitride (SiOxNy) surfaces have been studied by in-situ x-ray photoelectron spectroscopy (XPS) and ex-situ contact angle measurements. The data indicate that O2 and NH3 capacitively coupled plasmas are effective at removing adventitious carbon from silicon nitride (SiNx) and Si oxynitride (SiOxNy) surfaces. O2 plasma treatment results in the formation of a silica overlayer. In contrast, the exposure to NH3 plasma results in negligible additional oxidation of the SiNx or SiOxNy surface. Ex-situ contact angle measurements show that SiNx and SiOxNy surfaces exposed to oxygen plasma are initially more hydrophilic than surfaces exposed to NH3 plasma, indicating that the O2 plasma-induced SiO2 overlayer is highly reactive toward ambient. At longer ambient exposures (≳10 h), however, surfaces treated by either O2 or NH3 plasma exhibit similar steady state contact angles, correlated with rapid uptake of adventitious carbon, as determined by XPS. Surface passivation by exposure to molecular hydrogen prior to ambient exposure significantly retards the increase in contact angle upon exposure to ambient. The results suggest a practical route to enhancing the time available for effective bonding to surfaces in microelectronics packaging applications.
Entropic forces in Brownian motion
Authors: Roos Nico
Published: November 2014

Interest in the concept of entropic forces has risen considerably since Verlinde proposed in 2011 to interpret the force in Newton's second law and gravity as entropic forces. Brownian motion—the motion of a small particle (pollen) driven by random impulses from the surrounding molecules—may be the first example of a stochastic process in which such forces are expected to emerge. In this article, it is shown that at least two types of entropic force can be identified in three-dimensional Brownian motion. This analysis yields simple derivations of known results of Brownian motion, Hooke's law, and—applying an external (non-radial) force—Curie's law and the Langevin-Debye equation.
A non-isochronous rocking oscillator
Authors: Filipponi A.
Published: November 2014

The behavior of an unbalanced rocking cylinder is investigated as an example of a non-isochronous oscillator. The dependence of the period on the maximum angular swing is found to be more pronounced than in the pendulum case and tunable with a suitable choice of masses and moments of inertia. Computer acquisition of the force exerted on the horizontal plane allows comparison of the dynamical behavior of the system with computational predictions. The system deserves consideration for theoretical and experimental investigations in undergraduate physics courses for the nontrivial effects arising from the displacement of the center of mass from the geometrical cylinder axis and the anharmonic character of the oscillations.
Rapid Cytolysis of Mycobacterium tuberculosis by Faropenem, an Orally Bioavailable β-Lactam Antibiotic
Authors: Dhar Neeraj , Dubée Vincent , Ballell Lluis , Cuinet Guillaume , Hugonnet Jean-Emmanuel , Signorino-Gelo François , Barros David , Arthur Michel , McKinney John D.
Published: November 2014

Recent clinical studies indicate that meropenem, a β-lactam antibiotic, is a promising candidate for therapy of drug-resistant tuberculosis. However, meropenem is chemically unstable, requires frequent intravenous injection, and must be combined with a β-lactamase inhibitor (clavulanate) for optimal activity. Here, we report that faropenem, a stable and orally bioavailable β-lactam, efficiently kills
Mycobacterium tuberculosis
even in the absence of clavulanate. The target enzymes,
l
,
d
-transpeptidases, were inactivated 6- to 22-fold more efficiently by faropenem than by meropenem. Using a real-time assay based on quantitative time-lapse microscopy and microfluidics, we demonstrate the superiority of faropenem to the frontline antituberculosis drug isoniazid in its ability to induce the rapid cytolysis of single cells. Faropenem also showed superior activity against a cryptic subpopulation of nongrowing but metabolically active cells, which may correspond to the viable but nonculturable forms believed to be responsible for relapses following prolonged chemotherapy. These results identify faropenem to be a potential candidate for alternative therapy of drug-resistant tuberculosis.
Analysis of the Phase 3 ESTABLISH Trials of Tedizolid versus Linezolid in Acute Bacterial Skin and Skin Structure Infections
Authors: Shorr Andrew F. , Lodise Thomas P. , Corey G. Ralph , De Anda Carisa , Fang Edward , Das Anita F. , Prokocimer Philippe
Published: November 2014

Tedizolid, a novel oxazolidinone with activity against a wide range of Gram-positive pathogens, was evaluated in two noninferiority phase 3 acute bacterial skin and skin structure infection trials. The data from individual trials showed its noninferior efficacy compared to that of linezolid and a favorable tolerability profile. To evaluate potential differences, the pooled data were analyzed. The patients received 200 mg of tedizolid once daily for 6 days or 600 mg of linezolid twice daily for 10 days. Efficacy was evaluated at 48 to 72 h (primary endpoint), on days 11 to 13 (end of therapy [EOT]), and 7 to 14 days after the EOT (posttherapy evaluation). Treatment-emergent adverse events and hematologic and clinical laboratory parameters were collected. The baseline characteristics were comparable between the treatment groups: 852/1,333 (64%) patients were from North America, and the majority of infections were caused by
Staphylococcus aureus
. Tedizolid was noninferior to linezolid (early clinical responses, 81.6% versus 79.4%, respectively). The early responses remained relatively consistent across various host/disease factors and severity measures. Nausea was the most frequently reported adverse event (tedizolid, 8.2%; linezolid, 12.2%;
P
= 0.02), with onset occurring primarily during the first 6 days. Fewer tedizolid than linezolid patients had platelet counts of <150,000 cells/mm
3
at the EOT (tedizolid, 4.9%; linezolid, 10.8%;
P
= 0.0003) and during the postbaseline period through the last day of active drug visit (tedizolid, 6.4%; linezolid, 12.6%;
P
= 0.0016). Efficacy was achieved with a 6-day once-daily course of therapy with the option of an intravenous/oral regimen, and fewer low platelet counts and gastrointestinal side effects were reported with tedizolid than with linezolid, all of which aligns well with antimicrobial stewardship principles. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01170221 and NCT01421511.)
Influence of Vancomycin Infusion Methods on Endothelial Cell Toxicity
Authors: Drouet Maryline , Chai Feng , Barthélémy Christine , Lebuffe Gilles , Debaene Bertrand , Décaudin Bertrand , Odou Pascal
Published: November 2014

Peripheral intravenous therapy is frequently used in routine hospital practice and, due to various factors, its most common side effect is phlebitis. The infusion of vancomycin is particularly associated with phlebitis despite its widespread use. French guidelines recommend central intravenous infusion for high concentrations of vancomycin, but peripheral intravenous therapy is often preferred in intensive care units. Methods of vancomycin infusion are either intermittent infusion or continuous infusion. A comparison of these methods underin vitroconditions simulating clinical use could result in better infusion efficacy. Human umbilical vein endothelial cells (HUVECs) were therefore challenged with clinical doses of vancomycin over a 24- to 72-h period using these infusion methods. Cell death was measured with the alamarBlue test. Concentration-dependent and time-dependent vancomycin toxicity on HUVECs was noted with a 50% lethal dose at 5 mg/ml after 24 h, reaching 2.5 mg/ml after 72 h of infusion, simulating long-term infusion. This toxicity does not seem to be induced by acidic pH. In comparing infusion methods, we observed that continuous infusion induced greater cell toxicity than intermittent infusion at doses higher than 1 g/day. The increasing use of vancomycin means that new guidelines are required to avoid phlebitis. If peripheral intravenous therapy is used to reduce infusion time, along with intermittent infusion, vein irritation and localized phlebitis may be reduced. Further studies have to be carried out to explore the causes of vancomycin endothelial toxicity.
Genetic Determinants Involved in
p
-Aminosalicylic Acid Resistance in Clinical Isolates from Tuberculosis Patients in Northern China from 2006 to 2012
Authors: Zhang Xiaobing , Liu Liguo , Zhang Yan , Dai Guangming , Huang Hairong , Jin Qi
Published: November 2014

p
-Aminosalicylic acid (PAS) is an important compound for treating multidrug-resistant tuberculosis (TB). Previous studies showed that
thyA
mutations are often related to PAS resistance in clinical isolates. We performed a systematic analysis of isolate genotypes and detected mutations in three folate pathway genes (
folC
,
thyA
, and
ribD
) in 61.1% (127/208) of PAS-resistant isolates, including 11 double mutants. This result expands our knowledge about the distribution and frequency of mutations related to PAS resistance in mycobacterial clinical isolates.
Complete Nucleotide Sequences of Two NDM-1-Encoding Plasmids from the Same Sequence Type 11 Klebsiella pneumoniae Strain
Authors: Studentova V. , Dobiasova H. , Hedlova D. , Dolejska M. , Papagiannitsis C. C. , Hrabak J.
Published: November 2014

The sequence type 11
Klebsiella pneumoniae
strain Kpn-3002cz was confirmed to harbor two NDM-1-encoding plasmids, pB-3002cz and pS-3002cz. pB-3002cz (97,649 bp) displayed extensive sequence similarity with the
bla
NDM-1
-carrying plasmid pKPX-1. pS-3002cz (73,581 bp) was found to consist of an IncR-related sequence (13,535 bp) and a mosaic region (60,046 bp). A 40,233-bp sequence of pS-3002cz was identical to the mosaic region of pB-3002cz, indicating the
en bloc
acquisition of the NDM-1-encoding region from one plasmid by the other.
First-in-Humans Study of the Safety, Tolerability, and Pharmacokinetics of ACT-451840, a New Chemical Entity with Antimalarial Activity
Authors: Bruderer Shirin , Hurst Noémie , de Kanter Ruben , Miraval Tommaso , Pfeifer Thomas , Donazzolo Yves , Dingemanse Jasper
Published: November 2014

Emerging resistance to antimalarial agents raises the need for new drugs. ACT-451840 is a new compound with potent activity against sensitive and resistant
Plasmodium falciparum
strains. This was a first-in-humans single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of ACT-451840 across doses of 10, 50, 200, and 500 mg in healthy male subjects. In the 200- and 500-mg dose groups, the effect of food was investigated, and antimalarial activity was assessed using an
ex vivo
bioassay with
P. falciparum
. No (serious) adverse events leading to discontinuation were reported. At the highest dose level, the peak drug concentration (
C
max
) and the area under the plasma concentration-time curve from zero to infinity of ACT-451840 under fasted conditions reached 11.9 ng/ml and 100.6 ng · h/ml, respectively, and these were approximately 13-fold higher under fed conditions. Food did not affect the half-life (approximately 34 h) of the drug, while the
C
max
was attained 2.0 and 3.5 h postdose under fasted and fed conditions, respectively. The plasma concentrations estimated by the bioassay were approximately 4-fold higher than those measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Several potentially active metabolites were also identified. ACT-451840 was well tolerated across all doses. Exposure to ACT-451840 significantly increased with food. The bioassay indicated the presence of circulating active metabolites. (This study has been registered at ClinicalTrials.gov under registration no. NCT02186002.)
Impact of Drug Resistance-Associated Amino Acid Changes in HIV-1 Subtype C on Susceptibility to Newer Nonnucleoside Reverse Transcriptase Inhibitors
Authors: Basson Adriaan E. , Rhee Soo-Yon , Parry Chris M. , El-Khatib Ziad , Charalambous Salome , De Oliveira Tulio , Pillay Deenan , Hoffmann Christopher , Katzenstein David , Shafer Robert W. , Morris Lynn
Published: November 2014

The objective of this study was to assess the phenotypic susceptibility of HIV-1 subtype C isolates, with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated amino acid changes, to newer NNRTIs. A panel of 52 site-directed mutants and 38 clinically derived HIV-1 subtype C clones was created, and the isolates were assessed for phenotypic susceptibility to etravirine (ETR), rilpivirine (RPV), efavirenz (EFV), and nevirapine (NVP) in anin vitrosingle-cycle phenotypic assay. The amino acid substitutions E138Q/R, Y181I/V, and M230L conferred high-level resistance to ETR, while K101P and Y181I/V conferred high-level resistance to RPV. Y181C, a major NNRTI resistance-associated amino acid substitution, caused decreased susceptibility to ETR and, to a lesser extent, RPV when combined with other mutations. These included N348I and T369I, amino acid changes in the connection domain that are not generally assessed during resistance testing. However, the prevalence of these genotypes among subtype C sequences was, in most cases, <1%. The more common EFV/NVP resistance-associated substitutions, such as K103N, V106M, and G190A, had no major impact on ETR or RPV susceptibility. The low-level resistance to RPV and ETR conferred by E138K was not significantly enhanced in the presence of M184V/I, unlike for EFV and NVP. Among patient samples, 97% were resistant to EFV and/or NVP, while only 24% and 16% were resistant to ETR and RPV, respectively. Overall, only a few, relatively rare NNRTI resistance-associated amino acid substitutions caused resistance to ETR and/or RPV in an HIV-1 subtype C background, suggesting that these newer NNRTIs would be effective in NVP/EFV-experienced HIV-1 subtype C-infected patients.
Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans
Authors: Malmquist Nicholas A. , Sundriyal Sandeep , Caron Joachim , Chen Patty , Witkowski Benoit , Menard Didier , Suwanarusk Rossarin , Renia Laurent , Nosten Francois , Jiménez-Díaz María Belén , Angulo-Barturen Iñigo , Martínez María Santos , Ferrer Santiago , Sanz Laura M. , Gamo Francisco-Javier , Wittlin Sergio , Duffy Sandra , Avery Vicky M. , Ruecker Andrea , Delves Michael J. , Sinden Robert E. , Fuchter Matthew J. , Scherf Artur
Published: November 2014

Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising
in vitro
parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for
in vitro
and
in vivo
efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent
in vitro
activity, with 50% inhibitory concentrations (IC
50
s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory
Plasmodium falciparum
isolates. Activities against
ex vivo
clinical isolates of both
P. falciparum
and
Plasmodium vivax
were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in
in vivo
mouse models of
Plasmodium berghei
and
P. falciparum
infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.
Biochemical Characterization of Recombinant Enterovirus 71 3C Protease with Fluorogenic Model Peptide Substrates and Development of a Biochemical Assay
Authors: Shang Luqing , Zhang Shumei , Yang Xi , Sun Jixue , Li Linfeng , Cui Zhengjie , He Qiuhong , Guo Yu , Sun Yuna , Yin Zheng
Published: November 2014

Enterovirus 71 (EV71), a primary pathogen of hand, foot, and mouth disease (HFMD), affects primarily infants and children. Currently, there are no effective drugs against HFMD. EV71 3C protease performs multiple tasks in the viral replication, which makes it an ideal antiviral target. We synthesized a small set of fluorogenic model peptides derived from cleavage sites of EV71 polyprotein and examined their efficiencies of cleavage by EV71 3C protease. The novel peptide P08 [(2-(
N
-methylamino)benzoyl) (NMA)-IEALFQGPPK(DNP)FR] was determined to be the most efficiently cleaved by EV71 3C protease, with a kinetic constant
k
cat
/

K
m

of 11.8 ± 0.82 mM
−1
min
−1
. Compared with literature reports, P08 gave significant improvement in the signal/background ratio, which makes it an attractive substrate for assay development. A Molecular dynamics simulation study elaborated the interactions between substrate P08 and EV71 3C protease. Arg39, which is located at the bottom of the S2 pocket of EV71 3C protease, may participate in the proteolysis process of substrates. With an aim to evaluate EV71 3C protease inhibitors, a reliable and robust biochemical assay with a
Z
′ factor of 0.87 ± 0.05 was developed. A novel compound (compound 3) (50% inhibitory concentration [IC
50
] = 1.89 ± 0.25 μM) was discovered using this assay, which effectively suppressed the proliferation of EV 71 (strain Fuyang) in rhabdomyosarcoma (RD) cells with a highly selective index (50% effective concentration [EC
50
] = 4.54 ± 0.51 μM; 50% cytotoxic concentration [CC
50
] > 100 μM). This fast and efficient assay for lead discovery and optimization provides an ideal platform for anti-EV71 drug development targeting 3C protease.
Requirement for Serratia marcescens Cytolysin in a Murine Model of Hemorrhagic Pneumonia
Authors: González-Juarbe Norberto , Mares Chris A. , Hinojosa Cecilia A. , Medina Jorge L. , Cantwell Angelene , Dube Peter H. , Orihuela Carlos J. , Bergman Molly A.
Published: November 2014

Serratia marcescens
, a member of the carbapenem-resistant
Enterobacteriaceae
, is an important emerging pathogen that causes a wide variety of nosocomial infections, spreads rapidly within hospitals, and has a systemic mortality rate of ≤41%. Despite multiple clinical descriptions of
S. marcescens
nosocomial pneumonia, little is known regarding the mechanisms of bacterial pathogenesis and the host immune response. To address this gap, we developed an oropharyngeal aspiration model of lethal and sublethal
S. marcescens
pneumonia in BALB/c mice and extensively characterized the latter. Lethal challenge (>4.0 × 10
6
CFU) was characterized by fulminate hemorrhagic pneumonia with rapid loss of lung function and death. Mice challenged with a sublethal dose (<2.0 × 10
6
CFU) rapidly lost weight, had diminished lung compliance, experienced lung hemorrhage, and responded to the infection with extensive neutrophil infiltration and histopathological changes in tissue architecture. Neutrophil extracellular trap formation and the expression of inflammatory cytokines occurred early after infection. Mice depleted of neutrophils were exquisitely susceptible to an otherwise nonlethal inoculum, thereby demonstrating the requirement for neutrophils in host protection. Mutation of the genes encoding the cytolysin ShlA and its transporter ShlB resulted in attenuated
S. marcescens
strains that failed to cause profound weight loss, extended illness, hemorrhage, and prolonged lung pathology in mice. This study describes a model of
S. marcescens
pneumonia that mimics known clinical features of human illness, identifies neutrophils and the toxin ShlA as a key factors important for defense and infection, respectively, and provides a solid foundation for future studies of novel therapeutics for this important opportunistic pathogen.
The Environment of “Mycobacterium avium subsp. hominissuis” Microaggregates Induces Synthesis of Small Proteins Associated with Efficient Infection of Respiratory Epithelial Cells
Authors: Babrak Lmar , Danelishvili Lia , Rose Sasha J. , Kornberg Tiffany , Bermudez Luiz E.
Published: November 2014

“
Mycobacterium avium
subsp.
hominissuis
” is an opportunistic environmental pathogen that causes respiratory illness in immunocompromised patients, such as those with cystic fibrosis as well as other chronic respiratory diseases. Currently, there is no efficient approach to prevent or treat
M. avium
subsp.
hominissuis
infection in the lungs. During initial colonization of the airways,
M. avium
subsp.
hominissuis
forms microaggregates composed of 3 to 20 bacteria on human respiratory epithelial cells, which provides an environment for phenotypic changes leading to efficient mucosal invasion
in vitro
and
in vivo
. DNA microarray analysis was employed to identify genes associated with the microaggregate phenotype. The gene encoding microaggregate-binding protein 1 (MBP-1) (MAV_3013) is highly expressed during microaggregate formation. When expressed in noninvasive
Mycobacterium smegmatis
, MBP-1 increased the ability of the bacteria to bind to HEp-2 epithelial cells. Using anti-MBP-1 immune serum, microaggregate binding to HEp-2 cells was significantly reduced. By far-Western blotting, and verified by coimmunoprecipitation, we observed that MBP-1 interacts with the host cytoskeletal protein vimentin. As visualized by confocal microscopy, microaggregates, as well as MBP-1, induced vimentin polymerization at the site of bacterium-host cell contact. Binding of microaggregates to HEp-2 cells was inhibited by treatment with an antivimentin antibody, suggesting that MBP-1 expression is important for
M. avium
subsp.
hominissuis
adherence to the host cell. MBP-1 immune serum significantly inhibited
M. avium
subsp.
hominissuis
infection throughout the respiratory tracts of mice. This study characterizes a pathogenic mechanism utilized by
M. avium
subsp.
hominissuis
to bind and invade the host respiratory epithelium, suggesting new potential targets for the development of antivirulence therapy.
Coxiella burnetii Effector Proteins That Localize to the Parasitophorous Vacuole Membrane Promote Intracellular Replication
Authors: Larson Charles L. , Beare Paul A. , Voth Daniel E. , Howe Dale , Cockrell Diane C. , Bastidas Robert J. , Valdivia Raphael H. , Heinzen Robert A.
Published: November 2014

The intracellular bacterial pathogen
Coxiella burnetii
directs biogenesis of a parasitophorous vacuole (PV) that acquires host endolysosomal components. Formation of a PV that supports
C. burnetii
replication requires a Dot/Icm type 4B secretion system (T4BSS) that delivers bacterial effector proteins into the host cell cytosol. Thus, a subset of T4BSS effectors are presumed to direct PV biogenesis. Recently, the PV-localized effector protein CvpA was found to promote
C. burnetii
intracellular growth and PV expansion. We predict additional
C. burnetii
effectors localize to the PV membrane and regulate eukaryotic vesicle trafficking events that promote pathogen growth. To identify these vacuolar effector proteins, a list of predicted
C. burnetii
T4BSS substrates was compiled using bioinformatic criteria, such as the presence of eukaryote-like coiled-coil domains. Adenylate cyclase translocation assays revealed 13 proteins were secreted in a Dot/Icm-dependent fashion by
C. burnetii
during infection of human THP-1 macrophages. Four of the Dot/Icm substrates, termed

C
oxiella

v
acuolar
p
rotein B (CvpB), CvpC, CvpD, and CvpE, labeled the PV membrane and LAMP1-positive vesicles when ectopically expressed as fluorescently tagged fusion proteins.
C. burnetii
Δ
cvpB
, Δ
cvpC
, Δ
cvpD
, and Δ
cvpE
mutants exhibited significant defects in intracellular replication and PV formation. Genetic complementation of the Δ
cvpD
and Δ
cvpE
mutants rescued intracellular growth and PV generation, whereas the growth of
C. burnetii
Δ
cvpB
and Δ
cvpC
was rescued upon cohabitation with wild-type bacteria in a common PV. Collectively, these data indicate
C. burnetii
encodes multiple effector proteins that target the PV membrane and benefit pathogen replication in human macrophages.
Protection from Systemic Candida albicans Infection by Inactivation of the Sts Phosphatases
Authors: Naseem Shamoon , Frank David , Konopka James B. , Carpino Nick
Published: November 2014

The human fungal pathogen
Candida albicans
causes invasive candidiasis, characterized by fatal organ failure due to disseminated fungal growth and inflammatory damage. The
s
uppressor of
T
CR
s
ignaling 1 (Sts-1) and Sts-2 are two homologous phosphatases that negatively regulate signaling pathways in a number of hematopoietic cell lineages, including T lymphocytes, mast cells, and platelets. Functional inactivation of both Sts enzymes leads to profound resistance to systemic infection by
C. albicans
, such that greater than 80% of mice lacking Sts-1 and -2 survive a dose of
C. albicans
(2.5 × 10
5
CFU/mouse) that is uniformly lethal to wild-type mice within 10 days. Restriction of fungal growth within the kidney occurs by 24 h postinfection in the mutant mice. This occurs without induction of a hyperinflammatory response, as evidenced by the decreased presence of leukocytes and inflammatory cytokines that normally accompany the antifungal immune response. Instead, the absence of the Sts phosphatases leads to the rapid induction of a unique immunological environment within the kidney, as indicated by the early induction of a proinflammatory cytokine (CXL10). Mice lacking either Sts enzyme individually display an intermediate lethality phenotype. These observations identify an opportunity to optimize host immune responses toward a deadly fungal pathogen.
Clinical Implications of Oral Candidiasis: Host Tissue Damage and Disseminated Bacterial Disease
Authors: Kong Eric F. , Kucharíková Sona , Van Dijck Patrick , Peters Brian M. , Shirtliff Mark E. , Jabra-Rizk Mary Ann
Published: November 2014

The clinical significance of polymicrobial interactions, particularly those between commensal species with high pathogenic potential, remains largely understudied. Although the dimorphic fungal species
Candida albicans
and the bacterium
Staphylococcus aureus
are common cocolonizers of humans, they are considered leading opportunistic pathogens. Oral candidiasis specifically, characterized by hyphal invasion of oral mucosal tissue, is the most common opportunistic infection in HIV
+
and immunocompromised individuals. In this study, building on our previous findings, a mouse model was developed to investigate whether the onset of oral candidiasis predisposes the host to secondary staphylococcal infection. The findings demonstrated that in mice with oral candidiasis, subsequent exposure to
S. aureus
resulted in systemic bacterial infection with high morbidity and mortality. Histopathology and scanning electron microscopy of tongue tissue from moribund animals revealed massive
C. albicans
hyphal invasion coupled with
S. aureus
deep tissue infiltration. The crucial role of hyphae in the process was demonstrated using a non-hypha-producing and a noninvasive hypha-producing mutant strains of
C. albicans
. Further, in contrast to previous findings,
S. aureus
dissemination was aided but not contingent upon the presence of the Als3p hypha-specific adhesion. Importantly, impeding development of mucosal
C. albicans
infection by administering antifungal fluconazole therapy protected the animals from systemic bacterial disease. The combined findings from this study demonstrate that oral candidiasis may constitute a risk factor for disseminated bacterial disease warranting awareness in terms of therapeutic management of immunocompromised individuals.
Cytochromec551and the CytochromecMaturation Pathway Affect Virulence Gene Expression in Bacillus cereus ATCC 14579
Authors: Han Hesong , Sullivan Thomas , Wilson Adam C.
Published: November 2014

Loss of the cytochromecmaturation system inBacillus cereusresults in increased transcription of the major enterotoxin genesnhe,hbl, andcytKand the virulence regulatorplcR. Increased virulence factor production occurs at 37°C under aerobic conditions, similar to previous findings inBacillus anthracis. UnlikeB. anthracis, much of the increased virulence gene expression can be attributed to loss of onlyc551, one of the two smallc-type cytochromes. Additional virulence factor expression occurs with loss ofresBC, encoding cytochromecmaturation proteins, independently of the presence of thec-type cytochrome genes. Hemolytic activity of strains missing eithercccBorresBCis increased relative to that in the parental strain, while sporulation efficiency is unaffected in the mutants. Increased virulence gene expression in the ΔcccBand ΔresBCmutants occurs only in the presence of an intactplcRgene, indicating that this process is PlcR dependent. These findings suggest a new mode of regulation ofB. cereusvirulence and reveal intriguing similarities and differences in virulence regulation betweenB. cereusandB. anthracis.