bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergence of Q Fever Arthritis in France
Authors: Angelakis Emmanouil , Edouard Sophie , Lafranchi Marie-Alix , Pham Thao , Lafforgue Pierre , Raoult Didier
Published: January 2014

Osteoarticular infection is an uncommon presentation of Q fever. Positron emission tomography (PET) scanning is a valuable tool for the diagnosis of
Coxiella burnetii
graft prosthesis infection and endocarditis. Our objective was to test a series of culture-negative osteoarticular samples using molecular assays for
Coxiella burnetii
. We tested for
C. burnetii
by molecular assays targeting the IS
1111
and the IS
30A
spacer regions, using culture-negative osteoarticular samples obtained in our laboratory between January 2011and December 2012. We examine a total of 1,410 osteoarticular samples, and we observed two cases of arthritis and subacromial bursitis caused by
C. burnetii
. The infections were localized using PET scanning, and the diagnosis was confirmed through serology. For one, a
C. burnetii
strain with a multispacer sequence type 8 genotype was isolated from synovial fluid culture. Q fever articular infections could be undiagnosed because of the long evolution of articular attack, and patients with high antibody titers against
C. burnetii
should be tested using PET scanning to localize the site of infection.
Methylobacterium and Its Role in Health Care-Associated Infection
Authors: Kovaleva Julia , Degener John E. , van der Mei Henny C.
Published: January 2014

Methylobacterium
species are a cause of health care-associated infection, including infections in immunocompromised hosts. The ability of
Methylobacterium
species to form biofilms and to develop resistance to high temperatures, drying, and disinfecting agents may explain the colonization of
Methylobacterium
in the hospital environment in, e.g., endoscopes. Due to its slow growth, it can be easily missed during microbiological surveillance of endoscope reprocessing. The purpose of this minireview is to present an overview of documented infections and cross-contaminations with
Methylobacterium
related to endoscopic procedures and to illustrate the health care-associated relevance of this slow-growing bacterium.
Attenuating Mutations in nsP1 Reveal Tissue-Specific Mechanisms for Control of Ross River Virus Infection
Authors: Stoermer Burrack Kristina A. , Hawman David W. , Jupille Henri J. , Oko Lauren , Minor Marissa , Shives Katherine D. , Gunn Bronwyn M. , Long Kristin M. , Morrison Thomas E.
Published: January 2014

Ross River virus (RRV) is one of a group of mosquito-transmitted alphaviruses that cause debilitating, and often chronic, musculoskeletal disease in humans. Previously, we reported that replacement of the nonstructural protein 1 (nsP1) gene of the mouse-virulent RRV strain T48 with that from the mouse-avirulent strain DC5692 generated a virus that was attenuated in a mouse model of disease. Here we find that the six nsP1 nonsynonymous nucleotide differences between strains T48 and DC5692 are determinants of RRV virulence, and we identify two nonsynonymous nucleotide changes as sufficient for the attenuated phenotype. RRV T48 carrying the six nonsynonymous DC5692 nucleotide differences (RRV-T48-nsP1
6M
) was attenuated in both wild-type and
Rag1
−/−
mice. Despite the attenuated phenotype, RRV T48 and RRV-T48-nsP1
6M
loads in tissues of wild-type and
Rag1
−/−
mice were indistinguishable from 1 to 3 days postinoculation. RRV-T48-nsP1
6M
loads in skeletal muscle tissue, but not in other tissues, decreased dramatically by 5 days postinoculation in both wild-type and
Rag1
−/−
mice, suggesting that the RRV-T48-nsP1
6M
mutant is more sensitive to innate antiviral effectors than RRV T48 in a tissue-specific manner.
In vitro
, we found that the attenuating mutations in nsP1 conferred enhanced sensitivity to type I interferon. In agreement with these findings, RRV T48 and RRV-T48-nsP1
6M
loads were similar in mice deficient in the type I interferon receptor. Our findings suggest that the type I IFN response controls RRV infection in a tissue-specific manner and that specific amino acid changes in nsP1 are determinants of RRV virulence by regulating the sensitivity of RRV to interferon.

IMPORTANCE
Arthritogenic alphaviruses, including Ross River virus (RRV), infect humans and cause debilitating pain and inflammation of the musculoskeletal system. In this study, we identified coding changes in the RRV nsP1 gene that control the virulence of RRV and its sensitivity to the antiviral type I interferon response, a major component of antiviral defense in mammals. Furthermore, our studies revealed that the effects of these attenuating mutations are tissue specific. These findings suggest that these mutations in nsP1 influence the sensitivity of RRV to type I interferon only in specific host tissues. The new knowledge gained from these studies contributes to our understanding of host responses that control alphavirus infection and viral determinants that counteract these responses.
Do health behaviours change after colonoscopy? A prospective cohort study on diet, alcohol, physical activity and smoking among patients and their partners
Authors: Hubbard Gill , Brown Alistair , Campbell Anna , Campbell Neil , Diament Bob , Fielding Shona , Forbat Liz , Masson Lindsey F , O'Carroll Ronan , Stein Kevin , Morrison David S
Published: January 2014

Objectives

To describe diet, alcohol, physical activity and tobacco use prospectively, that is, before and 10 months after colonoscopy for patients and their partners.

Design

Prospective cohort study of health behaviour change in patients and partners. Comparison groups are patients receiving a normal result notification (NRN) versus patients receiving an abnormal result notification (ARN). Patients and partners (controls) are also compared.

Setting

5 Scottish hospitals.

Participants

Of 5798 colonoscopy registrations, 2577 (44%) patients met the eligibility criteria of whom 565 (22%) were recruited; 460 partners were also recruited.

Measures

International Physical Activity Questionnaire, Scottish Collaborative Group Food Frequency Questionnaire (includes alcohol), smoking status, sociodemographic characteristics, body mass index, medical conditions, colonoscopy result, Multidimensional Health Locus of Control Scale, behaviour-specific self-efficacy scales.

Results

57% of patients were men, with a mean age of 60.8 years (SE 0.5) and 43% were from more affluent areas. 72% (n=387) of patients received an ARN and 28% (n=149) received an NRN. Response rate of the second questionnaire was 68.9%. Overall, 27% of patients consumed <5 measures of fruit and vegetables/day, 20% exceeded alcohol limits, 50% had low levels of physical activity and 21% were obese. At 10-month follow-up, a 5% reduction in excessive alcohol consumption and an 8% increase in low levels of physical activity were observed among patients; no significant changes occurred in partners. Baseline high alcohol consumption and low physical activity were the strongest predictors of these behaviours at follow-up. Low alcohol self-efficacy and increasing age were associated with poorer health-related behaviours at follow-up for alcohol consumption and physical activity, respectively.

Conclusions

Colonoscopy is associated with marginal beneficial changes in some behaviours but not others. Further work is needed to explore how services can optimise increases in beneficial behaviours and mitigate increases in harmful ones.

Registrations

REC REF 10/S0709/24, UKCRN 9911.
Venous thromboembolism: reducing the risk in a Role 3 setting
Authors: Craig Darren G , Adam M G , Proffitt A , Parsons I , Tai N R , d'Arcy J L
Published: January 2014

Background

Venous thromboembolism (VTE) represents a significant preventable cause of hospital mortality. VTE assessment and prophylaxis rates are key patient safety and quality of care indicators. The aim of this study was to audit low molecular weight heparin (LMWH) and graduated elasticated compression stockings (GECS) prescriptions compared with the current Clinical Guidelines for Operations.

Methods

Complete audit loop in the Role 3 Hospital, Camp Bastion, Afghanistan. A multifaceted intervention programme incorporating physician and nurse education and pre-printed medication charts was introduced to improve VTE assessment and prophylaxis rates.

Results

Only 111/301 (36.9%) of patients in the pre-intervention cohort had a VTE risk assessment performed; this improved to 142/155 (91.6%, p<0.0001) post-intervention. A total of 57/88 (64.8%) patients prescribed LMWH pre-intervention had a documented assessment of bleeding risk performed; this rose to 65/66 (98.5%, p=0.0003) post-intervention. In pre-intervention, only 63/213 (29.6%) patients had a documented reassessment of VTE and bleeding risk at 24 h; reassessment rates rose to 68.8% (66/96 patients, p<0.0001) post-intervention. Of those patients at risk of VTE without ongoing bleeding risk, 62/96 (64.6%) had LMWH prescribed pre-intervention; this rose to 57/62 (91.9%) post-intervention (p<0.0001). Inappropriate LMWH prescription rates fell from 26/190 (13.7%) to 4/85 (4.7%, p=0.035) post-intervention. In those patients in whom GECS were not contraindicated, prescription rates rose from 23/95 (24.2%) to 42/62 (67.7%, p<0.0001) post-intervention.

Conclusions

Inclusion of pre-printed LMWH/GECS prescriptions and risk assessment stickers in the mediction chart significantly improved rates of VTE risk assessment and prophylaxis. These easily reproducible and low-cost interventions could improve patient safety on deployment.
Cerebral arterial angioplasty in a patient with Loeys–Dietz syndrome
Authors: Kellner Christopher P , Sussman Eric S , Donaldson Christopher , Connolly E Sander , Meyers Philip M
Published: January 2014

A 14-year-old boy with Loeys–Dietz syndrome (LDS) had an acute neurologic decline 6 days after a subarachnoid hemorrhage. Cerebral angiography at presentation did not show an aneurysmal source of the hemorrhage. However, on post-bleed day 6 the patient experienced an acutely worsening headache and subsequently lost consciousness. Head CT showed new subarachnoid blood and repeat angiography demonstrated a basilar tip aneurysm. Endovascular coil embolization was performed and his neurologic status improved postoperatively until post-bleed day 9 when he became unresponsive. A CT angiogram demonstrated severe proximal vasospasm. After an unsuccessful attempt to treat the vasospasm medically, the patient was transported to the neurointerventional suite for intra-arterial vasodilator treatment, which also failed to ameliorate the vasospasm. The endovascular surgeons were then faced with the conundrum of attempting a high-risk cerebral angioplasty in a pediatric patient with LDS or returning to maximal medical treatment for severe refractory vasospasm.
Molecular phylogeny of black flies in theSimulium tuberosum(Diptera: Simuliidae) species group in Thailand
Authors: Sriphirom Paradee , Sopaladawan Piyamas Nanork , Wongpakam Komgrit , Pramual Pairot
Published: January 2014

Black flies are medically and ecologically significant insects. They are also interesting from an evolutionary standpoint regarding the role of chromosomal change and ecological adaptation. In this study, molecular genetic markers based on multiple gene sequences were used to assess genetic diversity and to infer phylogenetic relationships for a group of cytologically highly diverse black flies of the Simulium tuberosum species group in Thailand. Ecological affinities of the species were also investigated. High levels of genetic diversity were found in cytological species complexes, S. tani and S. doipuiense, and also in S. rufibasis, which was cytologically nearly monomorphic. The results highlight the necessity of integrating multilevel markers for fully understanding black fly biodiversity. Phylogenetic relationships based on multiple gene sequences were consistent with an existing dendrogram inferred from cytological and morphological data. Simulium tani is the most distinctive taxa among the members of the S. tubersosum species group in Thailand based on its divergent morphological characters. Molecular data supported the monophyletic status of S. tani, S. weji, and S. yuphae, but S. doipuiense and S. rufibasis were polyphyletic, most likely due to incomplete lineage sorting and inadequate phylogenetic signals. Ecological analyses revealed that members of the S. tuberosum species group have clearly different ecological niches. The results thus supported previous views of the importance of ecology in black fly evolution.
Regulatory motifs identified from a maize developmental coexpression network
Authors: Downs Gregory S. , Liseron-Monfils Christophe , Lukens Lewis N.
Published: January 2014

Transcriptional control is an important determinant of plant development, and distinct modules of coordinated genes characterize the maize developmental transcriptome. Upstream regulatory sequences are often the primary factors that control gene expression pattern and abundance. Here, we identify 244 regulatory motifs that are significantly enriched within 24 gene expression modules previously constructed from transcript abundances of 34 876 Zea mays (maize) gene models from embryogenesis to senescence. Within modules, we identify motifs that have not been characterized. In addition, we identify motifs similar to experimentally verified motifs, and the functions of these motifs overlap with predicted module functions. This work demonstrates the power of transcript-level coexpression modules to identify both variants of known regulatory motifs and novel motifs that control a species’ developmental transcriptome.
RESERVOIR EFFECT ON A FOUR-LEVEL LEFT-HANDED SYSTEM
Authors: BOUTABBA N.
Published: January 2014

In this paper, we theoretically analyze the electromagnetic properties of a negative refractive index medium configured as a four-level system under thermal bath effect. For different thermal bath coupling strengths, the system shows negative permittivity and permeability as well as a large negative refractive index. This atomic medium is stable against environmental effect in a large experimental reachable domain of parameters which makes it a potential candidate for important applications.
WAVELENGTH DEMULTIPLEXING IN METAL–INSULATOR–METAL PLASMONIC WAVEGUIDES
Authors: YAO XIANKUN
Published: January 2014

In this paper, we have numerically investigated a novel kind of ultra-compact wavelength demultiplexing (WDM) in high-confined metal–insulator–metal (MIM) plasmonic waveguides. It is found that the drop transmission efficiency of the filtering cavity can be strongly enhanced by introducing a side-coupled cavity in the MIM waveguide. The theoretical analysis is verified by the finite-difference time-domain simulations. Through cascading the filtering units, a highly effective triple-wavelength demultiplexer is proposed by selecting the specific separation between the two coupled cavities of filtering units. Our results may find potential applications for the nanoscale WDM systems in highly integrated optical circuits and networks.
Geographical classification of Nanfeng mandarin by near infrared spectroscopy coupled with chemometrics methods
Authors: Zhang Xuan , Du Yiping , Tong Peijin , Wei Yuanlong , Wang Man
Published: January 2014

Near infrared spectroscopy (NIRS), coupled with principal component analysis and wavelength selection techniques, has been used to develop a robust and reliable reduced-spectrum classification model for determining the geographical origins of Nanfeng mandarins. The application of the changeable size moving window principal component analysis (CSMWPCA) provided a notably improved classification model, with correct classification rates of 92.00%, 100.00%, 90.00%, 100.00%, 100.00%, 100.00% and 100.00% for Fujian, Guangxi, Hunan, Baishe, Baofeng, Qiawan, Sanxi samples, respectively, as well as, a total classification rate of 97.52% in the wavelength range from 1007 to 1296 nm. To test and apply the proposed method, the procedure was applied to the analysis of 59 samples in an independent test set. Good identification results (correct rate of 96.61%) were also received. The improvement achieved by the application of CSMWPCA method was particularly remarkable when taking the low complexities of the final model (290 variables) into account. The results of the study showed the great potential of NIRS as a fast, nondestructive and environmentally acceptable method for the rapid and reliable determination for geographical classification of Nanfeng mandarins.
Anti-tumor activities of a novel chlorin derivative for photodynamic therapy in vitro and in vivo
Authors: Zhang Li-Jun , Wang Lai-Xing , Zhang Wei-Li , Yan Yi-Jia , Chen Zhi-Long
Published: January 2014

In this study, a novel photosensitizer meso-tetra (3-pyrrolidinomethyl-4-methoxyphenyl) chlorin (TPMC) was reported. It displays a characteristic long wavelength absorption peak at 656 nm and it shows a singlet oxygen quantum yield of 0.48. After light irradiation with 650 nm laser, it can kill Eca-109 and SMMC-7721 cells in vitro (25 mW/cm2, 1.2 to 3.6 J/cm2) and destroy Eca-109 tumor in nude mice (50 mW/cm2, 90 J/cm2). It has the perspective to be developed as a new anti-tumor drug in photodynamic therapy (PDT) photodiagnosis, and deserves further investigation.
Network simulation task partition method in heterogeneous computing environment
Authors: Wang Xiaofeng , Zhu Wei , Dai Yueming
Published: January 2014

To reduce the running time of network simulation in heterogeneous computing environment, a network simulation task partition method, named LBPHCE, is put forward. In this method, the network simulation task is partitioned in comprehensive consideration of the load balance of both routing computing simulation and packet forwarding simulation. First, through benchmark experiments, the computation ability and routing simulation ability of each simulation machine are measured in the heterogeneous computing environment. Second, based on the computation ability of each simulation machine, the network simulation task is initially partitioned to meet the load balance of packet forwarding simulation in the heterogeneous computing environment, and then according to the routing computation ability, the scale of each partition is fine-tuned to satisfy the balance of the routing computing simulation, meanwhile the load balance of packet forwarding simulation is guaranteed. Experiments based on PDNS indicate that, compared to traditional uniform partition method, the LBPHCE method can reduce the total simulation running time by 26.3% in average, and compared to the liner partition method, it can reduce the running time by 18.3% in average.
MORPHOLOGICAL AND COMPOSITIONAL STUDY AT THE Si/Fe INTERFACE OF (Fe/Si) MULTILAYER
Authors: BADÍA-ROMANO L. , RUBÍN J. , BARTOLOMÉ F. , BARTOLOMÉ J. , OVCHINNIKOV S. , VARNAKOV S. , MAGÉN C. , RUBIO-ZUAZO J. , CASTRO G. R.
Published: January 2014

Diffusion and reaction of elements at the interfaces of nanostructured systems play an important role in controlling their physical and chemical properties for subsequent applications. ( Fe / Si ) nanolayers were prepared by thermal evaporation under ultrahigh vacuum onto a Si (100) substrate. A morphological characterization of these films was performed by combination of scanning transmission electron microscopy (STEM) and X-ray reflectivity (XRR). The compositional depth profile of the ( Fe / Si ) structures was obtained by angle resolved X-ray photoelectron spectroscopy (ARXPS) and hard X-ray photoelectron spectroscopy (HAXPES). Moreover, determination of the stable phases formed at the Si on Fe interfaces was performed using conversion electron Mössbauer spectroscopy. The Si / Fe interface thickness and roughness were determined to be 1.4 nm and 0.6 nm, respectively. A large fraction of the interface is composed of c- Fe 1-x Si paramagnetic phase, though a minoritary ferromagnetic Fe rich silicide phase is also present.
PLANCHEREL–ROTACH FORMULAE FOR AVERAGE CHARACTERISTIC POLYNOMIALS OF PRODUCTS OF GINIBRE RANDOM MATRICES AND THE FUSS–CATALAN DISTRIBUTION
Authors: NEUSCHEL THORSTEN
Published: January 2014

Formulae of Plancherel–Rotach type are established for the average characteristic polynomials of Hermitian products of rectangular Ginibre random matrices on the region of zeros. These polynomials form a general class of multiple orthogonal hypergeometric polynomials generalizing the classical Laguerre polynomials. The proofs are based on a multivariate version of the complex method of saddle points. After suitable rescaling the asymptotic zero distributions for the polynomials are studied and shown to coincide with the Fuss–Catalan distributions. Moreover, introducing appropriate coordinates, elementary and explicit characterizations are derived for the densities as well as for the distribution functions of the Fuss–Catalan distributions of general order.
Minimally invasive method for determining the effective lymphatic pumping pressure in rats using near-infrared imaging
Authors: Nelson Tyler S. , Akin Ryan E. , Weiler Michael J. , Kassis Timothy , Kornuta Jeffrey A. , Dixon J. Brandon
Published: January 2014

The ability to quantify collecting vessel function in a minimally invasive fashion is crucial to the study of lymphatic physiology and the role of lymphatic pump function in disease progression. Therefore, we developed a highly sensitive, minimally invasive research platform for quantifying the pumping capacity of collecting lymphatic vessels in the rodent tail and forelimb. To achieve this, we have integrated a near-infrared lymphatic imaging system with a feedback-controlled pressure cuff to modulate lymph flow. After occluding lymphatic flow by inflating a pressure cuff on the limb or tail, we gradually deflate the cuff while imaging flow restoration proximal to the cuff. Using prescribed pressure applications and automated image processing of fluorescence intensity levels in the vessels, we were able to noninvasively quantify the effective pumping pressure (Peff, pressure at which flow is restored after occlusion) and vessel emptying rate (rate of fluorescence clearance during flow occlusion) of lymphatics in the rat. To demonstrate the sensitivity of this system to changes in lymphatic function, a nitric oxide (NO) donor cream, glyceryl trinitrate ointment (GTNO), was applied to the tails. GTNO decreased Peff of the vessels by nearly 50% and the average emptying rate by more than 60%. We also demonstrate the suitability of this approach for acquiring measurements on the rat forelimb. Thus, this novel research platform provides the first minimally invasive measurements of Peff and emptying rate in rodents. This experimental platform holds strong potential for future in vivo studies that seek to evaluate changes in lymphatic health and disease.
The subfornical organ: a novel site of action of cholecystokinin
Authors: Ahmed Al-Shaimaa F. , Dai Li , Ho Winnie , Ferguson Alastair V. , Sharkey Keith A.
Published: January 2014

The subfornical organ (SFO) is an important sensory circumventricular organ implicated in the regulation of fluid homeostasis and energy balance. We investigated whether the SFO is activated by the hormone cholecystokinin (CCK). CCK1and CCK2receptors were identified in the SFO by RT-PCR. Dissociated SFO neurons that responded to CCK (40/77), were mostly depolarized (9.2 ± 0.9 mV, 30/77), but some were hyperpolarized (−7.3 ± 1.1 mV, 10/77). We next examined the responses of SFO neurons in vivo to CCK (16 μg/kg ip), in the presence and absence of CCK1or CCK2receptor antagonists (devazepide; 600 μg/kg and L-365,260; 100 μg/kg, respectively), using the functional activation markers c-Fos and phosphorylated extracellular signal-related kinase (p-ERK). The nucleus of the solitary tract (NTS) served as a control for CCK-induced activity. There was a significant increase in c-Fos expression in the NTS (259.2 ± 20.8 neurons) compared with vehicle (47.5 ± 2.5). Similarly, in the SFO, c-Fos was expressed in 40.5 ± 10.6 neurons in CCK-treated compared with 6.6 ± 2.7 in vehicle-treated rats ( P < 0.01). Devazepide significantly reduced the effects of CCK in the NTS but not in SFO. L-365,260 blocked the effects of CCK in both brain regions. CCK increased the number of p-ERK neurons in NTS (27.0 ± 4.0) as well as SFO (18.0 ± 4.0), compared with vehicle (8.0 ± 2.6 and 4.3 ± 0.6, respectively; P < 0.05). Both devazepide and L-365,260 reduced CCK-induced p-ERK in NTS, but only L-365,260 reduced it in the SFO. In conclusion, the SFO represents a novel brain region at which circulating CCK may act via CCK2receptors to influence central autonomic control.
ROCK/NF-κB axis-dependent augmentation of angiotensinogen by angiotensin II in primary-cultured preglomerular vascular smooth muscle cells
Authors: Miyata Kayoko , Satou Ryousuke , Shao Weijian , Prieto Minolfa C. , Urushihara Maki , Kobori Hiroyuki , Navar L. Gabriel
Published: January 2014

In angiotensin II (ANG II)-dependent hypertension, the augmented intrarenal ANG II constricts the renal microvasculature and stimulates Rho kinase (ROCK), which modulates vascular contractile responses. Rho may also stimulate angiotensinogen (AGT) expression in preglomerular vascular smooth muscle cells (VSMCs), but this has not been established. Therefore, the aims of this study were to determine the direct interactions between Rho and ANG II in regulating AGT and other renin-angiotensin system (RAS) components and to elucidate the roles of the ROCK/NF-κB axis in the ANG II-induced AGT augmentation in primary cultures of preglomerular VSMCs. We first demonstrated that these preglomerular VSMCs express renin, AGT, angiotensin-converting enzyme, and ANG II type 1 (AT1) receptors. Furthermore, incubation with ANG II (100 pmol/l for 24 h) increased AGT mRNA (1.42 ± 0.03, ratio to control) and protein (1.68 ± 0.05, ratio to control) expression levels, intracellular ANG II levels, and NF-κB activity. In contrast, the ANG II treatment did not alter AT1a and AT1b mRNA levels in the cells. Treatment with H-1152 (ROCK inhibitor, 10 nmol/l) and ROCK1 small interfering (si) RNA suppressed the ANG II-induced AGT augmentation and the upregulation and translocalization of p65 into nuclei. Functional studies showed that ROCK exerted a greater influence on afferent arteriole responses to ANG II in rats subjected to chronic ANG II infusions. These results indicate that ROCK is involved in NF-κB activation and the ROCK/NF-κB axis contributes to ANG II-induced AGT upregulation, leading to intracellular ANG II augmentation.
H-K-ATPase type 2: relevance for renal physiology and beyond
Authors: Crambert Gilles
Published: January 2014

H-K-ATPase type 2 (HKA2), also known as the “nongastric” or “colonic” H-K-ATPase, is broadly expressed, and its presence in the kidney has puzzled experts in the field of renal ion transport systems for many years. One of the most important and robust characteristics of this transporter is that it is strongly stimulated after dietary K+restriction. This result prompted many investigators to propose that it should play a role in allowing the kidney to efficiently retain K+under K+depletion. However, the apparent absence of a clear renal phenotype in HKA2-null mice has led to the idea that this transporter is an epiphenomenon. This review summarizes past and recent findings regarding the functional, structural and physiological characteristics of H-K-ATPase type 2. The findings discussed in this review suggest that, as in the famous story, the ugly duckling of the X-K-ATPase family is actually a swan.
Can modular strategies simplify neural control of multidirectional human locomotion?
Authors: Zelik Karl E. , La Scaleia Valentina , Ivanenko Yuri P. , Lacquaniti Francesco
Published: January 2014

Each human lower limb contains over 50 muscles that are coordinated during locomotion. It has been hypothesized that the nervous system simplifies muscle control through modularity, using neural patterns to activate muscles in groups called synergies. Here we investigate how simple modular controllers based on invariant neural primitives (synergies or patterns) might generate muscle activity observed during multidirectional locomotion. We extracted neural primitives from unilateral electromyographic recordings of 25 lower limb muscles during five locomotor tasks: walking forward, backward, leftward and rightward, and stepping in place. A subset of subjects also performed five variations of forward (unidirectional) walking: self-selected cadence, fast cadence, slow cadence, tiptoe, and uphill (20% incline). We assessed the results in the context of dimensionality reduction, defined here as the number of neural signals needing to be controlled. For an individual task, we found that modular architectures could theoretically reduce dimensionality compared with independent muscle control, but we also found that modular strategies relying on neural primitives shared across different tasks were limited in their ability to account for muscle activations during multi- and unidirectional locomotion. The utility of shared primitives may thus depend on whether they can be adapted for specific task demands, for instance, by means of sensory feedback or by being embedded within a more complex sensorimotor controller. Our findings indicate the need for more sophisticated formulations of modular control or alternative motor control hypotheses in order to understand muscle coordination during locomotion.
Rational Combination Therapy of Vintafolide (EC145) with Commonly Used Chemotherapeutic Drugs
Authors: Reddy Joseph A. , Dorton Ryan , Bloomfield Alicia , Nelson Melissa , Vetzel Marilynn , Guan John , Leamon Christopher P.
Published: January 2014

Purpose: When evaluated in patients with ovarian and other cancer, vintafolide (EC145), a potent folate-targeted vinca alkaloid conjugate, displayed a toxicity profile that seemed to be nonoverlapping with many standard-of-care cancer therapeutics. It was, therefore, hypothesized that combining vintafolide with certain approved anticancer drugs may afford greater therapeutic efficacy compared with single-agent therapy. To explore this concept, vintafolide was evaluated in combination with pegylated liposomal doxorubicin (PLD; DOXIL), cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, and irinotecan against folate receptor (FR)–positive models.

Experimental Design: FR-expressing KB, M109, IGROV, and L1210 cells were first exposed to graded concentrations of vintafolide, either alone or in combination with doxorubicin (active ingredient in PLD), and isobologram plots and combination index values generated. The vintafolide combinations were also studied in mice bearing various FR-expressing tumors.

Results: Vintafolide displayed strong synergistic activity against KB cells when combined with doxorubicin, and no less-than-additive effects resulted when tested against M109, IGROV, and L1210 cells. In contrast, when either desacetylvinblastine hydrazide (DAVLBH; the vinca alkaloid moiety in vintafolide) or vindesine (the vinca alkaloid most structurally similar to DAVLBH) were tested in combination with doxorubicin, less-than-additive antitumor effects were observed. In vivo, all vintafolide drug combinations produced far greater antitumor effect (complete responses and cures) compared with the single agents alone, without significant increase in overall toxicity. Importantly, these benefits were not observed with combinations of PLD and DAVLBH or vindesine.

Conclusions: On the basis of these encouraging preclinical results, clinical studies to evaluate vintafolide drug combination therapies are now under way. Clin Cancer Res; 20(8); 2104–14. ©2014 AACR.
Noninvasive Detection of Response and Resistance in EGFR-Mutant Lung Cancer Using Quantitative Next-Generation Genotyping of Cell-Free Plasma DNA
Authors: Oxnard Geoffrey R. , Paweletz Cloud P. , Kuang Yanan , Mach Stacy L. , O'Connell Allison , Messineo Melissa M. , Luke Jason J. , Butaney Mohit , Kirschmeier Paul , Jackman David M. , Jänne Pasi A.
Published: January 2014

Purpose: Tumor genotyping using cell-free plasma DNA (cfDNA) has the potential to allow noninvasive assessment of tumor biology, yet many existing assays are cumbersome and vulnerable to false-positive results. We sought to determine whether droplet digital PCR (ddPCR) of cfDNA would allow highly specific and quantitative assessment of tumor genotype.

Experimental Design: ddPCR assays for EGFR, KRAS, and BRAF mutations were developed using plasma collected from patients with advanced lung cancer or melanoma of a known tumor genotype. Sensitivity and specificity were determined using cancers with nonoverlapping genotypes as positive and negative controls. Serial assessment of response and resistance was studied in patients with EGFR-mutant lung cancer on a prospective trial of erlotinib.

Results: We identified a reference range for EGFR L858R and exon 19 deletions in specimens from KRAS-mutant lung cancer, allowing identification of candidate thresholds with high sensitivity and 100% specificity. Received operative characteristic curve analysis of four assays demonstrated an area under the curve in the range of 0.80 to 0.94. Sensitivity improved in specimens with optimal cfDNA concentrations. Serial plasma genotyping of EGFR-mutant lung cancer on erlotinib demonstrated pretreatment detection of EGFR mutations, complete plasma response in most cases, and increasing levels of EGFR T790M emerging before objective progression.

Conclusions: Noninvasive genotyping of cfDNA using ddPCR demonstrates assay qualities that could allow effective translation into a clinical diagnostic. Serial quantification of plasma genotype allows noninvasive assessment of response and resistance, including detection of resistance mutations up to 16 weeks before radiographic progression. Clin Cancer Res; 20(6); 1698–705. ©2014 AACR.
Masitinib Antagonizes ATP-Binding Cassette Subfamily C Member 10–Mediated Paclitaxel Resistance: A Preclinical Study
Authors: Kathawala Rishil J. , Sodani Kamlesh , Chen Kang , Patel Atish , Abuznait Alaa H. , Anreddy Nagaraju , Sun Yue-Li , Kaddoumi Amal , Ashby Charles R. , Chen Zhe-Sheng
Published: January 2014

Paclitaxel displays clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multidrug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. In this study, we show that masitinib, a small molecule stem-cell growth factor receptor (c-Kit) tyrosine kinase inhibitor, at nontoxic concentrations, significantly attenuates paclitaxel resistance in HEK293 cells transfected with ABCC10. Our in vitro studies indicated that masitinib (2.5 μmol/L) enhanced the intracellular accumulation and decreased the efflux of paclitaxel by inhibiting the ABCC10 transport activity without altering the expression level of ABCC10 protein. Furthermore, masitinib, in combination with paclitaxel, significantly inhibited the growth of ABCC10-expressing tumors in nude athymic mice in vivo. Masitinib administration also resulted in a significant increase in the levels of paclitaxel in the plasma, tumors, and lungs compared with paclitaxel alone. In conclusion, the combination of paclitaxel and masitinib could serve as a novel and useful therapeutic strategy to reverse paclitaxel resistance mediated by ABCC10. Mol Cancer Ther; 13(3); 714–23. ©2014 AACR.
Curcumin: A Double Hit on Malignant Mesothelioma
Authors: Miller Jill M. , Thompson Joyce K. , MacPherson Maximilian B. , Beuschel Stacie L. , Westbom Catherine M. , Sayan Mutlay , Shukla Arti
Published: January 2014

Inflammation is a key mediator in the development of malignant mesothelioma, which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anticarcinogenic properties through its anti-inflammatory effects. Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of proinflammatory cytokines, interleukin (IL)-1β and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of malignant mesothelioma cells. Using in vitro models with mouse and human malignant mesothelioma cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of high-mobility group box 1 (HMGB1) without processing of IL-1β and IL-18. Absence of IL-1β processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1β priming through inhibition of the NF-κB pathway. Furthermore, curcumin's cytotoxicity in malignant mesothelioma cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death. We also demonstrate that curcumin-mediated caspase-1 activation is oxidant dependent by using N-acetyl-L-cysteine (NAC) to inhibit pyroptosis. PCR array analysis using the human inflammasome template revealed that curcumin significantly downregulated levels of inflammasome-related gene expression involved in inflammation, e.g., NF-κB, toll-like receptors (TLR), and IL-1β. Our data indicate that curcumin has a double effect on malignant mesothelioma cells through induction of pyroptosis while subsequently protecting against inflammation. Cancer Prev Res; 7(3); 330–40. ©2014 AACR.
Effect of Different Immunosuppressive Drugs on Immune Cells from Young and Old Healthy Persons
Authors: Welzl Kathrin , Kern Georg , Mayer Gert , Weinberger Birgit , Säemann Marcus D. , Sturm Gisela , Grubeck-Loebenstein Beatrix , Koppelstaetter Christian
Published: January 2014

Background: Life expectancy, as well as the average age of patients undergoing solid organ transplantation, increases constantly. Consequently, immunosuppressive therapy is no longer limited to young organ recipients. Objective: Here, we investigate how different types of immunosuppressive therapy, namely the calcineurin inhibitors cyclosporin A and tacrolimus, as well as the mTOR inhibitor rapamycin, affect the function of immune cells in young and elderly persons. Methods: Proliferation, cell viability, cytokine production (IL-2, IFN-γ), H2O2 production and telomere length of phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear cells (PBMCs) of young (n = 13; median age 27 years) and old (n = 19; median age 71 years) healthy donors were analyzed. Results: The inhibition of proliferation was dampened in PBMCs from elderly donors, especially after incubation with rapamycin. All three immunosuppressive drugs inhibited the production of IL-2 equally well, whereas the production of IFN-γ was less well inhibited by rapamycin. Both calcineurin inhibitors increased H2O2 concentrations after stimulation with PHA and led to a shortening of telomeres in PBMCs from young and old individuals. Rapamycin had only minor effects on H2O2 production and telomere length. Conclusion: Our results demonstrate that the effects of immunosuppressive drugs on PBMCs differ between young and elderly persons. Calcineurin inhibitors compared to rapamycin have a more pronounced prosenescence effect. These data indicate that specific treatment regimens for the elderly might therefore be considered.
Clinical Course of Asymptomatic Adult Moyamoya Disease
Authors: Jo Kyung-Il , Yeon Je Young , Hong Seung-Chyul , Kim Jong-Soo
Published: January 2014

Background: As regular medical check-ups are becoming more common, the prevalence of asymptomatic moyamoya disease (MMD) is increasing. However, the definition and clinical features are still unclear. The lack of precision has hampered the establishment of guidelines for the management of asymptomatic MMD. The purpose of this study was to define and clarify the clinical characteristics of asymptomatic MMD in adults. Methods: We identified all adults (aged ≥18 years) with MMD who underwent digital subtraction angiography or magnetic resonance angiography at our institution from 1995 through 2010. The authors defined asymptomatic MMD as asymptomatic or nonspecific symptom without any infarction or ischemia on magnetic resonance imaging. In our MMD registry, 40 patients (74 hemispheres) were identified and enrolled in this retrospective cohort study. Their demographic, radiological and clinical findings were evaluated. The log-rank test was used to assess prognostic factors. Pearson's correlation test and the Mann-Whitney U test were used to identify correlation angiographic staging and age or perfusion status. Results: Overall, 6 patients underwent indirect bypass surgery and 36 received antiplatelet medication. On initial single positron emission tomography (35 patients, 67 affected hemispheres), basal and acetazolamide stress brain perfusion were decreased in 19 (28.4%) and 22 (32.8%) hemispheres, respectively. Among 70 angiographically evaluated hemispheres, 6 were unilateral MMD; 27 of 64 affected hemispheres (42.2%) had transdural collateral at evaluation. Age (p = 0.309, Pearson's correlation test) and hemodynamic impairment (p = 0.614, Mann-Whitney U test) did not correlate with angiographic staging. During a median 32-month (range 6-203) clinical follow-up, 3 nonsurgically treated patients had a transient ischemic attack, which was associated with decreased vascular reserve (p < 0.001, log-rank test) and smoking (p = 0.017). Other variables did not show a significant association with clinical progression. During a median 24-month (range 12-108) radiological follow-up, 3 patients displayed angiographic progression and 3 displayed new hemodynamic abnormalities. Radiological progressions were related to hypertension only (p = 0.022). In this case series, there was no case of ischemic or hemorrhagic stroke. Conclusion: The findings suggest that asymptomatic MMD in adults is not a stable disease in our definition. However, stroke rate (0%) was lower than previous reports. Lifestyle modification, stroke risk factor control and/or antiplatelet medication seem to be appropriate initial treatments for patients with normal cerebrovascular reserve. A clear definition of asymptomatic MMD and further clarification of its clinical course are needed to set precise treatment guidelines.
Complication Rate of Endosonography (Endobronchial and Endoscopic Ultrasound): A Systematic Review
Authors: von Bartheld M.B. , van Breda A. , Annema J.T.
Published: January 2014

Background: Endosonography [endoscopic ultrasound (EUS)-guided fine needle aspiration and endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration] is increasingly used for lung cancer staging and the assessment of sarcoidosis. Serious adverse events (SAE) have been reported in case reports, but the true incidence of complications is yet unknown. Objectives: To assess the rate of SAE related to endosonography and to investigate associated risk factors. Materials and Methods: PubMed, EMBASE and Cochrane libraries were searched for eligible references up to April 2012 and these included studies reporting on linear EUS or EBUS for the analysis of mediastinal/hilar nodal or central intrapulmonary lesions. Case series describing complications were excluded. Reported complications were classified into SAE or minor adverse events (AE). Results: 190 studies met the inclusion criteria. Information on follow-up was missing in half of the studies. In 16,181 patients, 23 SAE (0.14%) and 35 AE (0.22%) were reported. No mortality was observed. SAE were more frequent in patients investigated with EUS (0.30%) than in those investigated with EBUS (0.05%). Infectious SAE were most prevalent (0.07%) and predominantly occurred in patients with cystic lesions and sarcoidosis. In lung cancer patients, complications were rare. Discussion: Endosonography for intrathoracic nodal assessment seems safe for lung cancer patients and mortality has not been reported. For cystic lesions and sarcoidosis, there may be a small, but nonnegligible risk of infectious complications. The true incidence of SAE might be higher as accurate documentation of complications is missing in most studies.
Roles of fibrin α- and γ-chain specific cross-linking by FXIIIa in fibrin structure and function
Authors: Duval Cédric , Allan Peter , Connell Simon D. A. , Ridger Victoria C. , Philippou Helen , Ariëns Robert A. S.
Published: January 2014

Factor XIII is responsible for the cross-linking of fibrin γ-chains in the early stages of clot formation, whilst α-chain cross-linking occurs at a slower rate. Although γ- and α-chain cross-linking was previously shown to contribute to clot stiffness, the role of cross-linking of both chains in determining clot structure is currently unknown. Therefore, the aim of this study was to determine the role of individual α- and γ-chain cross-linking during clot formation, and its effects on clot structure. We made use of a recombinant fibrinogen (γQ398N/Q399N/K406R), which does not allow for y-chain cross-linking. In the absence of cross-linking, intact D-D interface was shown to play a potential role in fibre appearance time, clot stiffness and elasticity. Cross-linking of the fibrin α-chain played a role in the thickening of the fibrin fibres over time, and decreased lysis rate in the absence of α2-antiplasmin. We also showed that α-chain cross-linking played a role in the timing of fibre appearance, straightening fibres, increasing clot stiffness and reducing clot deformation. Cross-linking of the γ-chain played a role in fibrin fibre appearance time and fibre density. Our results show that α- and γ-chain cross-linking play independent and specific roles in fibrin clot formation and structure.
Role of Exosomes in Myocardial Remodeling
Authors: Waldenström Anders , Ronquist Gunnar
Published: January 2014

Exosomes are nanovesicles released from cells through exocytosis and are known to be mediators of proximal as well as distant cell-to-cell signaling. They are surrounded by a classical bilayered membrane with an exceptionally high cholesterol/phospholipid ratio. Exosomes were first described in 1977, then named prostasomes, and in 1987 the name exosome was coined. Exosomes contain surface proteins, some of which can act as labels in order to find their target cells. Exosomes also contain messages in the form of proteins and nucleic acids (RNA and DNA) that are transferable to target cells. Little is known and written about cardiac exosomes, although Gupta and Knowlton described exosomes containing HSP60 in 2007. It is now known that exosomes from cardiomyocytes can transfect other cells and that the metabolic milieu of the parental cell decides the quality of exosomes released such that they induce differential gene expression in transfected cells. Future clinical use of exosomes in diagnosis, monitoring disease progress, and treatment is promising.
Does p.Q247X in
TRIM63
Cause Human Hypertrophic Cardiomyopathy?
Authors: Płoski Rafał , Pollak Agnieszka , Müller Sonja , Franaszczyk Maria , Michalak Ewa , Kosinska Joanna , Stawinski Piotr , Spiewak Mateusz , Seggewiss Hubert , Bilinska Zofia T.
Published: January 2014

Rationale:

Variants in
TRIM63
, including a nonsense mutation (p.Q247X), have been suggested recently to cause hypertrophic cardiomyopathy.

Objective:

To verify pathogenicity of
TRIM63
p.Q247X detected by whole-exome sequencing in a symptomless professional sports player seeking medical advice because of a prolonged QT interval found during a routine check-up.

Methods and Results:

Clinical studies were performed in the proband and his mother, who also carried
TRIM63
p.Q247X. No evidence of hypertrophic cardiomyopathy was found in either person.

Conclusions:

The p.Q247X variant in
TRIM63
is not likely to be a highly penetrant variant causing hypertrophic cardiomyopathy.