bluuebunny/crossref_metadata_2025 huggingface dataset:
Adiponectin is sufficient, but not required, for exercise‐induced increases in the expression of skeletal muscle mitochondrial enzymes
Authors: Ritchie Ian R. W. , MacDonald Tara L. , Wright David C. , Dyck David J.
Published: April 2014

Key points

Adiponectin is a regulator of skeletal muscle mitochondrial biogenesis. Previous research using the ob/ob mouse (leptin deficient, low adiponectin) has suggested that the presence of adipokines, including adiponectin, is necessary for exercise‐induced increases in mitochondrial content.

In the current study, we examined the importance of adiponectin as a regulator of skeletal muscle mitochondrial content in response to exercise by comparing wildtype and adiponectin deficient mice.

Adiponectin deficient mice showed no differences in resting , RER, or time to exhaustion during exercise when compared to wildtype mice. There were no differences in various protein markers of mitochondrial content.

A single bout of treadmill running increased the mRNA expression of mitochondrial proteins similarly in wildtype and adiponectin deficient mice. Chronic exercise (8 weeks) also increased the protein content of mitochondrial markers similarly in wildtype and adiponectin deficient mice.

We conclude that Ad is not required for exercise‐induced increases in muscle mitochondrial proteins.

Adiponectin (Ad) has been proposed to be a regulator of mitochondrial biogenesis in skeletal muscle, and necessary for exercise‐induced increases in mitochondrial content. We first confirmed that Ad could acutely increase the expression of mitochondrial proteins during a 10 h incubation in isolated soleus and extensor digitorum longus (EDL) muscles. Next, we further examined the role of Ad as a regulator of mitochondrial content using Ad knockout (AdKO) mice. The AdKO animals showed no differences in resting , respiratory exchange ratio, or in time to exhaustion during exercise when compared to wild‐type (WT) mice. There was a reduction in resting palmitate oxidation in isolated soleus from AdKO animals (−23%, P < 0.05) but not EDL, and 5‐aminoimidazole‐4‐carboxamide (AICAR)‐stimulated palmitate oxidation was similar in both genotypes regardless of muscle. There were no differences in protein markers of mitochondrial content (COX4, CORE1, CS, PDHE1α) in red and white gastrocnemius between WT and AdKO animals. A single bout of treadmill running increased the phosphorylation of AMP‐activated protein kinase (AMPK) and the mRNA expression of mitochondrial proteins in red and white gastrocnemius in both WT and AdKO animals, with no differences between genotypes. Finally, 8 weeks of chronic exercise training increased the protein content of mitochondrial markers similarly (∼25–35%) in red gastrocnemius from both WT and AdKO mice. Collectively, our results demonstrate that the absence of Ad is not accompanied by reductions in mitochondrial protein content, or a reduction in aerobic exercise capacity. We conclude that Ad is not required for the maintenance of mitochondrial content, or for exercise‐induced increases in skeletal muscle mitochondrial proteins.
Damage Assessment of Seismically Excited Buildings Through Incomplete Measurements
Authors: Lin Chi-Chang , Lin Ging-Long , Hsieh Kun-Shu
Published: April 2014

Measuring responses at all degrees of freedom (DOF) of a real structure is impossible and impractical when few sensors are available. This study presents a damage-assessment technique for seismically excited buildings using only a few floor-response measurements. In the first step, the system realization using information matrix (SRIM) identification technique was applied to estimate such modal properties as frequencies and damping ratios of an instrumented building. However, the complete mode shapes cannot be acquired due to a lack of comprehensive measurements. A novel optimal mode-shape-recovery (OMSR) technique was applied to reconstruct the complete first mode shape of the building system. An optimization process was then applied to minimize a prescribed objective function that represents the difference between measured and estimated outputs at instrumented locations. A story damage index (SDI) computed using the first mode shape recovered was applied to determine the degree of story damage. Noisy floor measurements of a five-story shear building under earthquake excitation were utilized for numerical verification. Moreover, a three-story benchmark building was analyzed to assess the accuracy and applicability of the proposed OMSR technique via experimental data. The proposed method obtained results in fairly good agreement with those of full measurements and is of value in practical application. The damage-assessment results obtained with the proposed method agree well with the actual damage, demonstrating that the proposed method is suitable for practical applications.
Alternative Designs of Acoustic Lenses Based on Nonlinear Solitary Waves
Authors: Li Kaiyuan , Rizzo Piervincenzo , Ni Xianglei
Published: April 2014

In the last decade, there has been an increasing attention on the use of highly- and weakly-nonlinear solitary waves in engineering and physics. These waves can form and travel in nonlinear systems such as one-dimensional chains of particles. When compared to linear elastic waves, solitary waves are much slower, nondispersive, and their speed is amplitude-dependent. Moreover, they can be tuned by modifying the particles' material or size, or the chain's precompression. One interesting engineering application of solitary waves is the fabrication of acoustic lenses, which are employed in a variety of fields ranging from biomedical imaging and surgery to defense systems and damage detection in materials. In this paper, we propose the design of acoustic lenses composed by one-dimensional chains of spherical particles arranged to form a line or a circle array. We show, by means of numerical simulations and an experimental validation, that both the line and circle arrays allow the focusing of waves transmitted into a solid or liquid (the host media) and the generation of compact sound bullets of large amplitude. The advantages and limitations of these nonlinear lenses to attain accurate high-energy acoustic pulses with high signal-to-noise ratio are discussed.
Role of Alveolar Topology on Acinar Flows and Convective Mixing
Authors: Hofemeier Philipp , Sznitman Josué
Published: April 2014

Due to experimental challenges, computational simulations are often sought to quantify inhaled aerosol transport in the pulmonary acinus. Commonly, these are performed using generic alveolar topologies, including spheres, toroids, and polyhedra, to mimic the complex acinar morphology. Yet, local acinar flows and ensuing particle transport are anticipated to be influenced by the specific morphological structures. We have assessed a range of acinar models under self-similar breathing conditions with respect to alveolar flow patterns, convective flow mixing, and deposition of fine particles (1.3 μm diameter). By tracking passive tracers over cumulative breathing cycles, we find that irreversible flow mixing correlates with the location and strength of the recirculating vortex inside the cavity. Such effects are strongest in proximal acinar generations where the ratio of alveolar to ductal flow rates is low and interalveolar disparities are most apparent. Our results for multi-alveolated acinar ducts highlight that fine 1 μm inhaled particles subject to alveolar flows are sensitive to the alveolar topology, underlining interalveolar disparities in particle deposition patterns. Despite the simplicity of the acinar models investigated, our findings suggest that alveolar topologies influence more significantly local flow patterns and deposition sites of fine particles for upper generations emphasizing the importance of the selected acinar model. In distal acinar generations, however, the alveolar geometry primarily needs to mimic the space-filling alveolar arrangement dictated by lung morphology.
A Physics-Based Musculoskeletal Driver Model to Study Steering Tasks
Authors: Mehrabi Naser , Sharif Razavian Reza , McPhee John
Published: April 2014

Realistic driver models can play an important role in developing new driver assistance technologies. A realistic driver model can reduce the time-consuming trial-and-error process of designing and testing products, and thereby reduce the vehicle's development time and cost. A realistic model should provide both driver path planning and arm motions that are physiologically possible. The interaction forces between a driver's hand and steering wheel can influence control performance and steering feel. The aim of this work is to develop a comprehensive yet practical model of the driver and vehicle. Consequently, a neuromuscular driver model in conjunction with a high-fidelity vehicle model is developed to learn and understand more about the driver's performance and preferences, and their effect on vehicle control and stability. This driver model can provide insights into task performance and energy consumption of the driver, including fatigue and cocontraction dynamics of a steering task. In addition, this driver model in conjunction with a high-fidelity steering model can be used to develop new steering technologies such as electric power steering.
Quantifying Dispersion of Nanoparticles in Polymer Nanocomposites Through Transmission Electron Microscopy Micrographs
Authors: Li Xiaodong , Zhang Hui , Jin Jionghua , Huang Dawei , Qi Xiaoying , Zhang Zhong , Yu Dan
Published: April 2014

The property of nanocomposites is crucially affected by nanoparticle dispersion. Transmission electron microscopy (TEM) is the “golden standard” in nanoparticle dispersion characterization. A TEM Micrograph is a two-dimensional (2D) projection of a three-dimensional (3D) ultra-thin specimen (50–100 nm thick) along the optic axis. Existing dispersion quantification methods assume complete spatial randomness (CSR) or equivalently the homogeneous Poisson process as the distribution of the centroids of nanoparticles under which nanoparticles are randomly distributed. Under the CSR assumption, absolute magnitudes of dispersion quantification metrics are used to compare the dispersion quality across samples. However, as hard nanoparticles do not overlap in 3D, centroids of nanoparticles cannot be completely randomly distributed. In this paper, we propose to use the projection of the exact 3D hardcore process, instead of assuming CSR in 2D, to firstly account for the projection effect of a hardcore process in TEM micrographs. By employing the exact 3D hardcore process, the thickness of the ultra-thin specimen, overlooked in previous research, is identified as an important factor that quantifies how far the assumption of Poisson process in 2D deviates from the projection of a hardcore process. The paper shows that the Poisson process can only be seen as the limit of the hardcore process as the specimen thickness tends to infinity. As a result, blindly using the Poisson process with limited specimen thickness may generate misleading results. Moreover, because the specimen thickness is difficult to be accurately measured, the paper also provides robust analysis of various dispersion metrics to the error of the claimed specimen thickness. It is found that the quadrat skewness and the K-function are relatively more robust to the misspecification of the specimen thickness than other metrics. Furthermore, analysis of detection power against various clustering degrees is also conducted for these two selected robust dispersion metrics. We find that dispersion metrics based on the K-function is relatively more powerful than the quadrat skewness. Finally, an application to real TEM micrographs is used to illustrate the implementation procedures and the effectiveness of the method.
Hydrogen traps in the outgassing model of a stainless steel vacuum chamber
Authors: Berg Robert F.
Published: April 2014

This article describes a model for hydrogen outgassing into a stainless steel vacuum chamber. It accounts for the geometry of the chamber components, the hydrogen dissolved in those components, and the processes of diffusion, recombination, and trapping. Strongly bound or “trapped” hydrogen, which occurs at heterogeneities such as dislocations and grain boundaries, can hold most of the dissolved hydrogen even though those locations comprise fewer than 0.1% of all lattice sites. Four simplifications allowed practical use of the model: (1) Each component was described as a one-dimensional object. (2) The hydrogen initially dissolved in each component was described as a uniform concentration. (3) Accurate, consistent values were used to describe diffusion and recombination in stainless steel types 304 and 316 [Grant et al., J. Nucl. Mater. 149, 180 (1987); 152, 139 (1988)]. (4) Only one type of hydrogen trap was considered, and trapping was ignored in components made from vacuum remelted stainless steel. The simple model was developed and validated by comparing it to outgassing measurements. Traps were required to describe the outgassing from a component made of drawn stainless steel 304. The initial hydrogen concentration in that component was comparable to concentrations found elsewhere by thermal desorption and almost 100 times larger than in the components made of vacuum remelted 316 stainless steel. The model's usefulness was illustrated by using it to predict the outgassing of a vacuum chamber made of type 304 stainless steel.
Avoiding Inflammation During Apoptosis
Authors: VanHook Annalisa M.
Published: April 2014

Apoptotic cells release AMP to suppress inflammation.
Assessment of Mycobacterium tuberculosis Pantothenate Kinase Vulnerability through Target Knockdown and Mechanistically Diverse Inhibitors
Authors: Reddy B. K. Kishore , Landge Sudhir , Ravishankar Sudha , Patil Vikas , Shinde Vikas , Tantry Subramanyam , Kale Manoj , Raichurkar Anandkumar , Menasinakai Sreenivasaiah , Mudugal Naina Vinay , Ambady Anisha , Ghosh Anirban , Tunduguru Ragadeepthi , Kaur Parvinder , Singh Ragini , Kumar Naveen , Bharath Sowmya , Sundaram Aishwarya , Bhat Jyothi , Sambandamurthy Vasan K. , Björkelid Christofer , Jones T. Alwyn , Das Kaveri , Bandodkar Balachandra , Malolanarasimhan Krishnan , Mukherjee Kakoli , Ramachandran Vasanthi
Published: April 2014

Pantothenate kinase (PanK) catalyzes the phosphorylation of pantothenate, the first committed and rate-limiting step toward coenzyme A (CoA) biosynthesis. In our earlier reports, we had established that the type I isoform encoded by the
coaA
gene is an essential pantothenate kinase in
Mycobacterium tuberculosis
, and this vital information was then exploited to screen large libraries for identification of mechanistically different classes of PanK inhibitors. The present report summarizes the synthesis and expansion efforts to understand the structure-activity relationships leading to the optimization of enzyme inhibition along with antimycobacterial activity. Additionally, we report the progression of two distinct classes of inhibitors, the triazoles, which are ATP competitors, and the biaryl acetic acids, with a mixed mode of inhibition. Cocrystallization studies provided evidence of these inhibitors binding to the enzyme. This was further substantiated with the biaryl acids having MIC against the wild-type
M. tuberculosis
strain and the subsequent establishment of a target link with an upshift in MIC in a strain overexpressing PanK. On the other hand, the ATP competitors had cellular activity only in a
M. tuberculosis
knockdown strain with reduced PanK expression levels. Additionally,
in vitro
and
in vivo
survival kinetic studies performed with a
M. tuberculosis
PanK (
Mt
PanK) knockdown strain indicated that the target levels have to be significantly reduced to bring in growth inhibition. The dual approaches employed here thus established the poor vulnerability of PanK in
M. tuberculosis
.
Bumped Kinase Inhibitor 1294 Treats Established Toxoplasma gondii Infection
Authors: Doggett J. Stone , Ojo Kayode K. , Fan Erkang , Maly Dustin J. , Van Voorhis Wesley C.
Published: April 2014

Toxoplasma gondii
is a unicellular parasite that causes severe brain and eye disease. Current drugs for
T. gondii
are limited by toxicity. Bumped kinase inhibitors (BKIs) selectively inhibit calcium-dependent protein kinases of the apicomplexan pathogens
T. gondii
, cryptosporidia, and plasmodia. A lead anti-
Toxoplasma
BKI, 1294, has been developed to be metabolically stable and orally bioavailable. Herein, we demonstrate the oral efficacy of 1294 against toxoplasmosis
in vivo
.
Evaluation of Imipenem for Prophylaxis and Therapy of Yersinia pestis Delivered by Aerosol in a Mouse Model of Pneumonic Plague
Authors: Heine Henry S. , Louie Arnold , Adamovicz Jeffrey J. , Amemiya Kei , Fast Randy L. , Miller Lynda , Opal Steven M. , Palardy John , Parejo Nicolas A. , Sörgel Fritz , Kinzig-Schippers Martina , Drusano George L.
Published: April 2014

It has been previously shown that mice subjected to an aerosol exposure toYersinia pestisand treated with β-lactam antibiotics after a delay of 42 h died at an accelerated rate compared to controls. It was hypothesized that endotoxin release in antibiotic-treated mice accounted for the accelerated death rate in the mice exposed to aerosolY. pestis. Imipenem, a β-lactam antibiotic, binds to penicillin binding protein 2 with the highest affinity and produces rounded cells. The binding of imipenem causes cells to lyse quickly and thereby to release less free endotoxin. Two imipenem regimens producing fractions of time that the concentration of free, unbound drug was above the MIC (fT>MIC) of approximately 25% (6/24 h) and 40% (9.5/24 h) were evaluated. In the postexposure prophylaxis study, the 40% and 25% regimens produced 90% and 40% survivorship, respectively. In the 42-h treatment study, both regimens demonstrated a 40 to 50% survivorship at therapy cessation and some deaths thereafter, resulting in a 30% survivorship. As this was an improvement over the results with other β-lactams, a comparison of both endotoxin and cytokine levels in mice treated with imipenem and ceftazidime (a β-lactam previously demonstrated to accelerate death in mice during treatment) was performed and supported the original hypotheses; however, the levels observed in animals treated with ciprofloxacin (included as an unrelated antibiotic that is also bactericidal but should cause little lysis due to a different mode of action) were elevated and significantly (7-fold) higher than those with ceftazidime.
In Vitro
and
In Vivo
Efficacy of Novel Flavonoid Dimers against Cutaneous Leishmaniasis
Authors: Wong Iris L. K. , Chan Kin-Fai , Chen Yun-Fu , Lun Zhao-Rong , Chan Tak Hang , Chow Larry M. C.
Published: April 2014

Treatment of leishmaniasis by chemotherapy remains a challenge because of limited efficacy, toxic side effects, and drug resistance. We previously reported that synthetic flavonoid dimers have potent antipromastigote and antiamastigote activity against
Leishmania donovani
, the causative agent of visceral leishmaniasis. Here, we further investigate their leishmanicidal activities against cutaneous
Leishmania
species. One of the flavonoid dimers (compound 39) has marked antipromastigote (50% inhibitory concentrations [IC
50
s], 0.19 to 0.69 μM) and antiamastigote (IC
50
s, 0.17 to 2.2 μM) activities toward different species of
Leishmania
that cause cutaneous leishmaniasis, including
Leishmania amazonensis
,
Leishmania braziliensis
,
Leishmania tropica
, and
Leishmania major
. Compound 39 is not toxic to peritoneal elicited macrophages, with IC
50
values higher than 88 μM. In the mouse model of cutaneous leishmaniasis induced by subcutaneous inoculation of
L. amazonensis
in mouse footpads, intralesional administration of 2.5 mg/kg of body weight of compound 39.HCl can reduce footpad thickness by 36%, compared with that of controls values. The amastigote load in the lesions was reduced 20-fold. The present study suggests that flavonoid dimer 39 represents a new class of safe and effective leishmanicidal agent against visceral and cutaneous leishmaniasis.
In Vitro
and
In Vivo
Activities of HPi1, a Selective Antimicrobial against Helicobacter pylori
Authors: Gavrish Ekaterina , Shrestha Binu , Chen Chao , Lister Ida , North E. Jeffrey , Yang Lei , Lee Richard E. , Han Angel , Williams Bronwyn , Charnuska David , Coleman Ken , Lewis Kim , LaFleur Michael D.
Published: April 2014

A high-throughput screen (HTS) was performed to identify molecules specifically active against
Helicobacter pylori
, the causative agent of peptic ulcer and gastric carcinoma. Currently, treatment of
H. pylori
infection is suboptimal, with failure rates approaching 25%, despite triple therapy with two broad-spectrum antibiotics and a proton pump inhibitor or quadruple therapy with added bismuth. The HTS was performed in 384-well plates, and reduction of the metabolic indicator resazurin was used as a reporter for cell growth. Diverse molecules from commercial sources were identified as hits, and
in vitro
validations included measurements of MIC and time-dependent killing as well as anaerobic susceptibility testing against a panel of gut microbes.
In vivo
validation included testing in the mouse model of
H. pylori
infection. The small molecule HPi1 (3-hydrazinoquinoxaline-2-thiol) had excellent potency, with an MIC of 0.08 to 0.16 μg/ml and good selectivity for
H. pylori
compared to a panel of commensal bacteria. HPi1 was also effective in a mouse model of
H. pylori
infection, reducing colony counts to below the limit of detection after oral dosing of 25 mg/kg/day for 3 days. HPi1 is a promising lead in the search for more effective and specific
H. pylori
therapeutics.
Factors Associated with Ceftriaxone Nonsusceptibility of Streptococcus pneumoniae: Analysis of South African National Surveillance Data, 2003 to 2010
Authors: von Mollendorf Claire , Cohen Cheryl , de Gouveia Linda , Quan Vanessa , Meiring Susan , Feldman Charles , Klugman Keith P. , von Gottberg Anne
Published: April 2014

It is important to monitor β-lactam antimicrobial nonsusceptibility trends for
Streptococcus pneumoniae
to inform empirical treatment guidelines. In this study, we describe penicillin and ceftriaxone susceptibility trends using national laboratory-based pneumococcal surveillance data from 2003 to 2010. A sentinel enhanced-site patient subset (2009 to 2010) contributed to the risk factor and mortality analyses. We included 9,218 invasive pneumococcal disease (IPD) cases for trend analyses and 2,854 IPD cases for risk factor and mortality analyses. Overall, we detected no significant changes in penicillin (patients <5 years of age,
P
= 0.50; patients ≥5 years of age,
P
= 0.05) or ceftriaxone nonsusceptibility rates (patients <5 years of age,
P
= 0.21; patients ≥5 years of age,
P
= 0.60). Factors associated with ceftriaxone nonsusceptibility on multivariate analysis were an age of <5 years (<1 year of age: adjusted odds ratio [aOR], 2.87; 95% confidence interval [CI], 1.70 to 4.86; 1 to 4 years of age: aOR, 2.58; 95% CI, 1.53 to 4.35, versus 25 to 44 years of age), province (Gauteng [aOR, 2.46; 95% CI, 1.26 to 4.84], and Northern Cape [aOR, 4.52; 95% CI, 1.95 to 10.52] versus KwaZulu-Natal), β-lactam use within 24 h preceding admission (aOR, 2.52; 95% CI, 1.41 to 4.53), and 13-valent vaccine serotypes (aOR, 51.64; 95% CI, 7.18 to 371.71). Among patients ≥5 years of age with meningitis who were treated according to current guidelines, HIV-infected patients (aOR, 2.94; 95% CI, 1.32 to 6.54) and patients infected with ceftriaxone-nonsusceptible isolates (aOR, 3.17; 95% CI, 1.27 to 7.89) had increased mortality rates. Among children <5 years of age with meningitis, mortality was increased in HIV-infected patients (aOR, 3.04; 95% CI, 1.40 to 6.56) but not in those with ceftriaxone-nonsusceptible isolates. Penicillin and ceftriaxone nonsusceptibility remained stable over the study period. Ceftriaxone nonsusceptibility was associated with increased mortality among patients ≥5 years of age with meningitis. The introduction of a pneumococcal conjugate vaccine may reduce ceftriaxone-nonsusceptible meningitis.
Characterization of
sal
(A), a Novel Gene Responsible for Lincosamide and Streptogramin A Resistance in Staphylococcus sciuri
Authors: Hot Chloé , Berthet Nicolas , Chesneau Olivier
Published: April 2014

Natural resistance to lincosamides and streptogramins A (LS
A
), which is a species characteristic of
Bacillus subtilis
and
Enterococcus faecalis
, has never been documented in the
Staphylococcus
genus. We investigate here the molecular basis of the LS
A
phenotype exhibited by seven reference strains of
Staphylococcus sciuri
, including the type strains of the three described subspecies. By whole-genome sequencing of strain ATCC 29059, we identified a candidate gene that encodes an ATP-binding cassette protein similar to the Lsa and VmlR resistance determinants. Isolation and reverse transcription-quantitative PCR (qRT-PCR) expression studies confirmed that Sal(A) can confer a moderate resistance to lincosamides (8 times the MIC of lincomycin) and a high-level resistance to streptogramins A (64 times the MIC of pristinamycin II). The chromosomal location of
sal
(A) between two housekeeping genes of the staphylococcal core genome supports the gene's ancient origins and thus innate resistance to these antimicrobials within
S. sciuri
subspecies.
Vaccination with a Single CD4 T Cell Peptide Epitope from a Salmonella Type III-Secreted Effector Protein Provides Protection against Lethal Infection
Authors: Kurtz Jonathan R , Petersen Hailey E. , Frederick Daniel R. , Morici Lisa A. , McLachlan James B.
Published: April 2014

Salmonellainfections affect millions worldwide and remain a significant cause of morbidity and mortality. It is known from mouse studies that CD4 T cells are essential mediators of immunity againstSalmonellainfection, yet it is not clear whether targeting CD4 T cell responses directly with peptide vaccines againstSalmonellacan be effective in combating infection. Additionally, it is not known whether T cell responses elicited againstSalmonellasecreted effector proteins can provide protective immunity against infection. In this study, we investigated both of these possibilities using prime-boost immunization of susceptible mice with a single CD4 T cell peptide epitope fromSalmonellasecreted effector protein I (SseI), a component of theSalmonellatype III secretion system. This immunization conferred significant protection against lethal oral infection, equivalent to that conferred by whole heat-killedSalmonellabacteria. Surprisingly, a well-characterized T cell epitope from the flagellar protein FliC afforded no protection compared to immunization with an irrelevant control peptide. The protective response appeared to be most associated with polyfunctional CD4 T cells raised against the SseI peptide, since no antibodies were produced against any of the peptides and very little CD8 T cell response was observed. Overall, this study demonstrates that eliciting CD4 T cell responses against components of theSalmonellatype III secretion system can contribute to protection against infection and should be considered in the design of futureSalmonellasubunit vaccines.
In Vivo
Splenic Clearance Correlates with
In Vitro
Deformability of Red Blood Cells from Plasmodium yoelii-Infected Mice
Authors: Huang Sha , Amaladoss Anburaj , Liu Min , Chen Huichao , Zhang Rou , Preiser Peter R. , Dao Ming , Han Jongyoon
Published: April 2014

Recent experimental and clinical studies suggest a crucial role of mechanical splenic filtration in the host's defense against malaria parasites. Subtle changes in red blood cell (RBC) deformability, caused by infection or drug treatment, could influence the pathophysiological outcome. However,
in vitro
deformability measurements have not been directly linked
in vivo
with the splenic clearance of RBCs. In this study, mice infected with malaria-inducing
Plasmodium yoelii
revealed that chloroquine treatment could lead to significant alterations to RBC deformability and increase clearance of both infected and uninfected RBCs
in vivo
. These results have clear implications for the mechanism of human malarial anemia, a severe pathological condition affecting malaria patients.
IsdC from Staphylococcus lugdunensis Induces Biofilm Formation under Low-Iron Growth Conditions
Authors: Missineo Antonino , Di Poto Antonella , Geoghegan Joan A. , Rindi Simonetta , Heilbronner Simon , Gianotti Valentina , Arciola Carla Renata , Foster Timothy J. , Speziale Pietro , Pietrocola Giampiero
Published: April 2014

Staphylococcus lugdunensis
is a coagulase-negative staphylococcus that is a commensal of humans and an opportunistic pathogen. It can cause a spectrum of infections, including those that are associated with the ability to form biofilm, such as occurs with endocarditis or indwelling medical devices. The genome sequences of two strains revealed the presence of orthologues of the
ica
genes that are responsible for synthesis of poly-
N
-acetylglucosamine (PNAG) that is commonly associated with biofilm in other staphylococci. However, we discovered that biofilm formed by a panel of
S. lugdunensis
isolates growing in iron-restricted medium was susceptible to degradation by proteases and not by metaperiodate, suggesting that the biofilm matrix comprised proteins and not PNAG. When the iron concentration was raised to 1 mM biofilm formation by all strains tested was greatly reduced. A mutant of strain N920143 lacking the entire locus that encodes iron-regulated surface determinant (Isd) proteins was defective in biofilm formation under iron-limited conditions. An IsdC-null mutant was defective, whereas IsdK, IsdJ, and IsdB mutants formed biofilm to the same level as the parental strain. Expression of IsdC was required both for the primary attachment to unconditioned polystyrene and for the accumulation phase of biofilm involving cell-cell interactions. Purified recombinant IsdC protein formed dimers in solution and
Lactococcus lactis
cells expressing only IsdC adhered to immobilized recombinant IsdC but not to IsdJ, IsdK, or IsdB. This is consistent with a specific homophilic interaction between IsdC molecules on neighboring cells contributing to accumulation of
S. lugdunensis
biofilm
in vivo
.
Deletion of Braun Lipoprotein and Plasminogen-Activating Protease-Encoding Genes Attenuates Yersinia pestis in Mouse Models of Bubonic and Pneumonic Plague
Authors: van Lier Christina J. , Sha Jian , Kirtley Michelle L. , Cao Anthony , Tiner Bethany L. , Erova Tatiana E. , Cong Yingzi , Kozlova Elena V. , Popov Vsevolod L. , Baze Wallace B. , Chopra Ashok K.
Published: April 2014

Currently, there is no FDA-approved vaccine against
Yersinia pestis
, the causative agent of bubonic and pneumonic plague. Since both humoral immunity and cell-mediated immunity are essential in providing the host with protection against plague, we developed a live-attenuated vaccine strain by deleting the Braun lipoprotein (
lpp
) and plasminogen-activating protease (
pla
) genes from
Y. pestis
CO92. The Δ
lpp
Δ
pla
double isogenic mutant was highly attenuated in evoking both bubonic and pneumonic plague in a mouse model. Further, animals immunized with the mutant by either the intranasal or the subcutaneous route were significantly protected from developing subsequent pneumonic plague. In mice, the mutant poorly disseminated to peripheral organs and the production of proinflammatory cytokines concurrently decreased. Histopathologically, reduced damage to the lungs and livers of mice infected with the Δ
lpp
Δ
pla
double mutant compared to the level of damage in wild-type (WT) CO92-challenged animals was observed. The Δ
lpp
Δ
pla
mutant-immunized mice elicited a humoral immune response to the WT bacterium, as well as to CO92-specific antigens. Moreover, T cells from mutant-immunized animals exhibited significantly higher proliferative responses, when stimulated
ex vivo
with heat-killed WT CO92 antigens, than mice immunized with the same sublethal dose of WT CO92. Likewise, T cells from the mutant-immunized mice produced more gamma interferon (IFN-γ) and interleukin-4. These animals had an increasing number of tumor necrosis factor alpha (TNF-α)-producing CD4
+
and CD8
+
T cells than WT CO92-infected mice. These data emphasize the role of TNF-α and IFN-γ in protecting mice against pneumonic plague. Overall, our studies provide evidence that deletion of the
lpp
and
pla
genes acts synergistically in protecting animals against pneumonic plague, and we have demonstrated an immunological basis for this protection.
Vitamin D Deficiency Reduces the Immune Response, Phagocytosis Rate, and Intracellular Killing Rate of Microglial Cells
Authors: Djukic Marija , Onken Marie Luise , Schütze Sandra , Redlich Sandra , Götz Alexander , Hanisch Uwe-Karsten , Bertsch Thomas , Ribes Sandra , Hanenberg Andrea , Schneider Simon , Bollheimer Cornelius , Sieber Cornel , Nau Roland
Published: April 2014

Meningitis and meningoencephalitis caused byEscherichia coliare associated with high rates of mortality and neurological sequelae. A high prevalence of neurological disorders has been observed in geriatric populations at risk of hypovitaminosis D. Vitamin D has potent effects on human immunity, including induction of antimicrobial peptides (AMPs) and suppression of T-cell proliferation, but its influence on microglial cells is unknown. The purpose of the present study was to determine the effects of vitamin D deficiency on the phagocytosis rate, intracellular killing, and immune response of murine microglial cultures after stimulation with the Toll-like receptor (TLR) agonists tripalmitoyl-S-glyceryl-cysteine (TLR1/2), poly(I·C) (TLR3), lipopolysaccharide (TLR4), and CpG oligodeoxynucleotide (TLR9). Upon stimulation with high concentrations of TLR agonists, the release of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was decreased in vitamin D-deficient compared to that in vitamin D-sufficient microglial cultures. Phagocytosis ofE. coliK1 after stimulation of microglial cells with high concentrations of TLR3, -4, and -9 agonists and intracellular killing ofE. coliK1 after stimulation with high concentrations of all TLR agonists were lower in vitamin D-deficient microglial cells than in the respective control cells. Our observations suggest that vitamin D deficiency may impair the resistance of the brain against bacterial infections.
Pancreatitis in scrub typhus: a rare complication
Authors: Dhakal Mona , Dhakal Om Prakash , Bhandari Dhurba
Published: April 2014

Scrub typhus is a zoonosis transmitted by a trombiculid mite which introduces bacteria ofOrientia tsutsugamushiby its bite. The acute febrile illness is characterised by eschar at the site of the bite with maculopapular rashes and local and/or generalised lymphadenopathy. The disease is endemic in the tsutsugamushi triangle. Sikkim, a small Himalayan north-eastern state, is also not unaffected where outbreaks of the disease have been reported. The clinical spectrum of the disease ranges from mild to fatal depending on the virulence of the bacterial strain, susceptibility of the host and promptness of the treatment. In severe cases, there can be multiple organ involvement. Pancreatitis is a serious and unusual complication of this disease, which was seen in our presentation. A 22-year-old man, diagnosed to have scrub typhus, developed pancreatitis in the second week of the illness and responded well to medical treatment.
Bilateral supernumerary kidneys: how much is too much?
Authors: Patel Ruchir , Singh Hanish , Willens David , Drake Sean
Published: April 2014

A middle aged African-American woman with a stable history of carnitine palmitoyl transferase II (CPT II) deficiency presented with myalgias for 1 week. Physical examination and laboratory findings were consistent with severe sepsis secondary to pyelonephritis leading to rhabdomyolysis. Subsequent CT of the abdomen revealed bilateral supernumerary kidneys with non-obstructive calculi within the supernumerary kidneys. Abnormal ureteral development of the supernumerary kidneys likely led to an increased risk for urinary tract infections (UTIs) and renal calculi resulting in pyelonephritis. The stress of this infection overwhelmed the muscle CPT II enzyme load, putting her in a state of rhabdomyolysis. In addition to fluids and antibiotics, she was provided a diet rich in carbohydrates and low in fats so as to limit long-chain fatty acid oxidation. Supernumerary nephrectomy was not considered during this admission. During follow-up, she developed obstructive ureteral calculi requiring placement of a right-sided ureteral stent.
Misdiagnosis of common variable immune deficiency
Authors: Shanks Anne-Marie , Alluri Ratna , Herriot Richard , Dempsey Owen
Published: April 2014

We present details of a man who was originally diagnosed with sarcoidosis, based on a combination of nodal granulomatous inflammation and radiology confirming bilateral hilar lymphadenopathy with pulmonary infiltrates. The patient subsequently developed splenomegaly and idiopathic thrombocytopenic purpura (ITP) and, latterly, a severe cavitating pneumonia. Serum immunoglobulins were checked, confirming panhypogammaglobulinaemia, and his diagnosis was revised to common variable immune deficiency (CVID). CVID is a heterogeneous condition, which can mimic sarcoidosis with granulomatous organ involvement and is commonly complicated by autoimmune disorders, including ITP. Prompt recognition is important to allow early introduction of immunoglobulin replacement therapy to decrease infection frequency, reduce development of secondary disease complications and retard progression of tissue damage. Given the potential for misdiagnosis and delay in recognition of CVID, serum immunoglobulin measurement should be a first-line investigation in patients with suspected sarcoidosis, even if the presentation is ‘typical’. Current international sarcoidosis guidelines should be revised accordingly.
An 11-year-old boy withPlasmodium falciparummalaria and dengue co-infection
Authors: Issaranggoon na ayuthaya Satja , Wangjirapan Anchalee , Oberdorfer Peninnah
Published: April 2014

Malaria and dengue fever are major mosquito-borne public health problems in tropical countries. The authors report a malaria and dengue co-infection in an 11-year-old boy who presented with sustained fever for 10 days. The physical examination revealed a flushed face, injected conjunctivae and left submandibular lymphadenopathy. His peripheral blood smear showed few ring-form trophozoites ofPlasmodium falciparum. His blood tests were positive for dengue NS-1 antigen and IgM antibody, and negative for IgG antibody. After the initiation of antimalarial treatment with artesunate and mefloquine, his clinical condition gradually improved. However, he still had low-grade fever that persisted for 6 days. Finally, he recovered well without fluid leakage, shock or severe bleeding. This case report emphasises that early recognition and concomitant treatment of malaria and dengue co-infection in endemic areas can improve clinical outcome and prevent serious complications.
Is hip strength a risk factor for patellofemoral pain? A systematic review and meta-analysis
Authors: Rathleff M S , Rathleff C R , Crossley K M , Barton C J
Published: April 2014

Objective

To evaluate and synthesise the literature on hip strength among patients with patellofemoral pain (PFP) to address the following: (1) differentiate between hip strength as a risk factor and associated deficit in PFP; (2) describe hip strength in men and women with PFP across different age ranges; (3) investigate the effects of hip strengthening on biomechanical knee variables associated with PFP development.

Methods

MEDLINE, CINAHL, Web of Science, SportDiscus and Google Scholar were searched in November 2013 for studies investigating hip strength among patients with PFP. Two reviewers independently assessed papers for inclusion and quality. Means and SDs were extracted from each included study to allow effect size calculations and comparisons of results.

Results

Moderate-to-strong evidence from prospective studies indicates no association between isometric hip strength and risk of developing PFP. Moderate evidence from cross-sectional studies indicates that men and women with PFP have lower isometric hip musculature strength compared to pain-free individuals. Limited evidence indicates that adolescents with PFP do not have the same strength deficits as adults with PFP.

Conclusions

This review highlights a possible discrepancy between prospective and cross-sectional research. Cross-sectional studies indicate that adult men and women with PFP appear to have lower hip strength compared to pain-free individuals. Contrary to this, a limited number of prospective studies indicate that there may be no association between isometric hip strength and risk of developing PFP. Therefore, reduced hip strength may be a result of PFP rather than the cause.
Barriers to life jacket use among adult recreational boaters
Authors: Quistberg D Alex , Quan Linda , Ebel Beth E , Bennett Elizabeth E , Mueller Beth A
Published: April 2014

Objective

To identify barriers to life jacket use.

Design

Cross-sectional survey.

Setting

Nine public boat ramps in western Washington State, USA, August–November, 2008.

Participants

675 adult boaters (>18 years) on motor boats <26 feet long.

Main outcome

Low or no life jacket use (0–50% of time) versus high life jacket use (51–100% of time).

Results

Low/no life jacket use (0–50% of time) was associated with longer boat length (per foot, risk ratio [RR] 1.03, 95% CI 1.02 to 1.05), alcohol use (RR 1.11, 95% CI 1.01 to 1.20), perception of life jackets as ‘uncomfortable’ (RR 1.29, 95% CI 1.09 to 1.52), perceived greater level of swimming ability (RR 1.25, 95% CI 1.03 to 1.53 for ‘expert swimmer’) and possibly with lack of confidence that a life jacket may save one from drowning (RR 1.13, 95% CI 0.96 to 1.32). Low life jacket use was less likely when an inflatable life jacket was the primary life jacket used by a subject (RR 0.77, 95% CI 0.63 to 0.94), a child was onboard (RR 0.88, 95% CI 0.79 to 0.99) or if the respondent had taken a boating safety class (RR 0.94, 95% CI 0.87 to 1.01).

Conclusions

Life jacket use may increase with more comfortable devices, such as inflatable life jackets, and with increased awareness of their efficacy in preventing drowning. Boater education classes may be associated with increased life jacket use among adults.
A case–control study of boat-related injuries and fatalities in Washington State
Authors: Stempski Sarah , Schiff Melissa , Bennett Elizabeth , Quan Linda
Published: April 2014

Objectives

To identify risk factors associated with boat-related injuries and deaths.

Methods

We performed a case–control study using the Washington Boat Accident Investigation Report Database for 2003–2010. Cases were fatally injured boat occupants, and controls were non-fatally injured boat occupants involved in a boating incident. We evaluated the association between victim, boat and incident factors and risk of death using Poisson regression to estimate RRs and 95% CIs.

Results

Of 968 injured boaters, 26% died. Fatalities were 2.6 times more likely to not be wearing a personal flotation device (PFD) and 2.2 times more likely to not have any safety features on their boat compared with those who survived. Boating fatalities were more likely to be in a non-motorised boat, to have alcohol involved in the incident, to be in an incident that involved capsizing, sinking, flooding or swamping, and to involve a person leaving the boat voluntarily, being ejected or falling than those who survived.

Conclusions

Increasing PFD use, safety features on the boat and alcohol non-use are key strategies and non-motorised boaters are key target populations to prevent boating deaths.
Outcomes of surgery for chronic exertional compartment syndrome in a military population
Authors: Roberts Andrew J , Krishnasamy P , Quayle J M , Houghton J M
Published: April 2014

Aim

To determine the outcome following fasciectomy for chronic exertional compartment syndrome (CECS) in the UK military, and the association between presurgical intramuscular pressure (IMP) and outcome.

Methods

All patients who underwent fasciectomy for anterior CECS were identified between 2007 and 2010. Presurgery and postsurgery military medical grading for leg function was extracted from the medical records system. The Wilcoxon signed-rank test compared grades before and after surgery. Spearman's rank correlation examined the relationship between IMP and outcome.

Results

Presurgery and postsurgery grading was available for 63% of patients. These patients had significantly better leg function after surgery (Z=−3.63, p<0.001). Of these, 49% improved by at least one grade, 36% showed no improvement in grading and 15% had a poorer outcome. There were no significant correlations between IMP and outcome.

Conclusions

A large proportion of patients do not return to full fitness following fasciectomy in the military population. This is in line with a recent study in the US military, but conflicts with most civilian reports. The reasons for these differences are not clear. Furthermore, the lack of a relationship between IMP and outcome questions the role of pressure in this condition. These results suggest that the role of postoperative rehabilitation protocols and other conservative options should be explored.
Adrenal incidentalomas: management in British district general hospitals
Authors: Davenport Emily , Lang Ping Nam Pitsien , Wilson Michael , Reid Alastair , Aspinall Sebastian
Published: April 2014

Introduction

Adrenal incidentalomas have become a common clinical dilemma with the increasing use and resolution of cross sectional imaging modalities.

Objectives

This retrospective observational study examined the management of adrenal incidentalomas in district general hospitals in Northumbria and adherence to current guidelines.

Materials and methods

We searched 4028 abdominal CT scans performed in Northumbria between 1 January and 31 December 2010. All patients with an incidental adrenal lesion were identified and their clinical records reviewed.

Results

75 patients with adrenal incidentalomas were identified. Of these, only 13 (17%) were referred for specialist review with a further two patients undergoing additional evaluation by the primary medical team; 80% received no biochemical investigation or follow-up. Comorbidity may have affected the decision in a proportion, but 36 of 62 patients (58%) had no comorbidities precluding additional evaluation. In contrast, all patients reviewed by an endocrine specialist were appropriately investigated and managed, the majority conservatively, with three requiring adrenalectomy for phaeochromocytoma or cortisol secreting adenomas. In the patients with an incidentaloma, comorbidities which may be attributable to autonomous adrenal cortisol or aldosterone release were higher than regional averages, suggesting possible undiagnosed functional tumours.

Conclusions

The management of adrenal incidentalomas in British district general hospitals in Northumbria shows poor adherence to guidelines. Adherence was significantly better in those patients managed by an endocrine specialist. We suggest a pathway for the management and referral process.