bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro cultivation model for Heterosporis saurida (Microsporidia) isolated from lizardfish, Saurida undosquamis (Richardson)
Authors: Kumar G , Saleh M , Abdel‐Baki A‐A S , Al‐Quraishy S , El‐Matbouli M
Published: August 2013

Heterosporis saurida is a microsporidian that infects lizardfish, Saurida undosquamis (Richardson, 1848), in the Arabian Sea. Spores were isolated from infected lizardfish and used to infect derived fish cell lines: common carp brain (CCB), epithelioma papulosum cyprinid (EPC), fathead minnow epithelial (FHM), rainbow trout gonad (RTG), bluegill fry (BF‐2) and chinook salmon embryo (CHSE). Non‐fish cell lines were also tested that include: insect (SF‐9), rabbit (RK‐13) and African green monkey (Vero E6). No growth of H. saurida was observed in any fish cell line, SF‐9 or Vero E6 cell lines. H. saurida spores grew only in RK‐13 cell line and were detected by immunofluorescence. Developmental stages of H. saurida were seen in RK‐13 cells by light and transmission electron microscopy, and species identification was confirmed by sequencing. This study demonstrated that H. saurida was able to proliferate in the mammalian RK‐13 cell line, which thus represents an in vitro model for conducting molecular genetics and cell–pathogen interaction studies of Heterosporis.
Efficient 3D porous microstructure reconstruction via Gaussian random field and hybrid optimization
Authors: JIANG Z. , CHEN W. , BURKHART C.
Published: August 2013

Obtaining an accurate three‐dimensional (3D) structure of a porous microstructure is important for assessing the material properties based on finite element analysis. Whereas directly obtaining 3D images of the microstructure is impractical under many circumstances, two sets of methods have been developed in literature to generate (reconstruct) 3D microstructure from its 2D images: one characterizes the microstructure based on certain statistical descriptors, typically two‐point correlation function and cluster correlation function, and then performs an optimization process to build a 3D structure that matches those statistical descriptors; the other method models the microstructure using stochastic models like a Gaussian random field and generates a 3D structure directly from the function. The former obtains a relatively accurate 3D microstructure, but computationally the optimization process can be very intensive, especially for problems with large image size; the latter generates a 3D microstructure quickly but sacrifices the accuracy due to issues in numerical implementations. A hybrid optimization approach of modelling the 3D porous microstructure of random isotropic two‐phase materials is proposed in this paper, which combines the two sets of methods and hence maintains the accuracy of the correlation‐based method with improved efficiency. The proposed technique is verified for 3D reconstructions based on silica polymer composite images with different volume fractions. A comparison of the reconstructed microstructures and the optimization histories for both the original correlation‐based method and our hybrid approach demonstrates the improved efficiency of the approach.
Cell tracking using phase‐adaptive shape prior
Authors: LAW Y.N.
Published: August 2013

Automated tracking of cell population is very crucial for quantitative measurements of dynamic cell‐cycle behaviour of individual cells. This problem involves several subproblems and a high accuracy of each step is essential to avoid error propagation. In this paper, we propose a holistic three‐component system to tackle this problem. For each phase, we first learn a mean shape as well as a model of the temporal dynamics of transformation, which are used for estimating a shape prior for the cell in the current frame. We then segment the cell using a level set‐based shape prior model. Finally, we identify its phase based on the goodness‐of‐fit of the data to the segmentation model. This phase information is also used for fine‐tuning the segmentation result. We evaluate the performance of our method empirically in various aspects and in tracking individual cells from HeLa H2B‐GFP cell population. Highly accurate validation results confirm the robustness of our method in many realistic scenarios and the essentiality of each component of our integrating system.
Transitional experiences in patients following intracranial aneurysm rupture
Authors: von Vogelsang Ann‐Christin , Wengström Yvonne , Svensson Mikael , Forsberg Christina
Published: August 2013

Aims and objectives

To describe changes and transitions in everyday life in the first two years following an intracranial aneurysm rupture.

Background

An intracranial aneurysm rupture causes a haemorrhagic stroke, and the physical and mental consequences of this condition are numerous and complex. In Sweden, some, but not all, patients receive rehabilitation for this condition. Patients with this type of stroke are not included in the national stroke registry; thus, information on the recovery period for these particular patients is lacking.

Design

A longitudinal mixed methods study design was used.

Methods

The sample was consecutive and consisted of 88 patients (84·6% of 104 eligible), acutely admitted to a neurosurgical clinic in Stockholm for intracranial aneurysm rupture. Data were collected through a postal study‐specific questionnaire at 6 months, 1 year and 2 years postaneurysm rupture. Intramethod mixing was used in the data collection, and quantitative and qualitative data were analysed parallel with statistical and qualitative content analysis.

Results

A majority of participants perceived changes in their everyday lives during the first two years following aneurysm rupture, and the changes were ongoing with little differences reported between 6 months and 2 years after the onset. Internal changes, or transitions, were revealed within changes in personality, changed social roles and relationships and changed abilities and behaviour.

Conclusions

Recovering from an intracranial aneurysm rupture involves a period of intense changes and transitions, a vulnerable period for many people that may be made easier to manage by the intervention of nurses.

Relevance to clinical practice

Patients experiencing transitions in the recovery period after intracranial aneurysm rupture may benefit from nursing interventions that support them through the transitional process. Nurse‐led follow‐up care by a specialist nurse from the neurosurgical clinic may be a possible way to provide support.
The endothelin axis in head and neck cancer: a promising therapeutic opportunity?
Authors: McKenzie Gordon A. G. , Hinsley Emma E. , Hunter Keith , Lambert Daniel W.
Published: August 2013

The incidence of head and neck cancer, predominantly consisting of squamous cell carcinomas (HNSCCs), is continuing to rise worldwide. InvasiveHNSCCcarries a poor prognosis, and the detrimental sequelae of surgical resection motivate identification of novel modes of therapeutic intervention. The endothelin (ET) axis consists ofET‐1, 2 and 3, which are generated by endothelin‐converting enzyme (ECE) and engage with the receptorsETARandETBR. TheETaxis plays a role in the development and progression of various human malignancies.ETaxis components have been found to be overexpressed inHNSCC;ET‐1 antagonism and inhibition ofECEmay therefore represent viable therapeutic opportunities.ET‐1 can promoteHNSCCprogressionviastromal–epithelial interactions, suggesting that the stroma may also hold potential for therapies targeting components of theETaxis. TheETaxis may also offer components that can be used as biomarkers – for screening, diagnosis, monitoring disease recurrence and prognostic risk stratification of patients – and targets for localised analgesia offering less systemic side effects. This review summarises the current knowledge and potential for clinical opportunities related to theETaxis.
Influence of recombinant duck follistatin protein on embryonic muscle development and gene expressions
Authors: Liu H. , Zhang R. , Li X. , Sun L. , Wang H. , Yang C. , Li L. , Wang J. , Xu F.
Published: August 2013

Follistatin (FST) acts as a positive regulator of muscle development by inhibiting the activities and expression of myostatin. The recombinant duck FST protein was injected into hatching eggs and was also added to the medium of duck myoblast to study its role on duck embryonic muscle development and gene expressions. Duck embryo weight increased 3.49% (p > 0.05) in FST treatment group as compared with control group, but minor effects were found on leg or breast muscle weights of ducklings at 2 days post‐hatching (p > 0.05). Relative expression of Pax7 was upregulated in both leg and breast muscle tissues (p < 0.05), while MyoD was only upregulated in leg muscle (p < 0.05), and Myf5 was only upregulated in breast muscle (p < 0.05). Relative expression of myostatin was downregulated in both muscle tissues researched (p < 0.05). In vitro studies also showed some maker genes relevant to protein synthesis and degradation, cells’ proliferation and differentiation had significant changes in myoblasts after treated with FST. These results suggested that in ovo feeding of recombinant FST protein to duck hatching eggs had an effect on duck embryo development but have less roles on the duck embryonic muscle development.
Effects of pistachio by‐products in replacement of alfalfa hay on populations of rumen bacteria involved in biohydrogenation and fermentative parameters in the rumen of sheep
Authors: Ghaffari M. H. , Tahmasbi A.‐M. , Khorvash M. , Naserian A.‐A. , Ghaffari A. H. , Valizadeh H.
Published: August 2013

The objective of this study was to investigate the effect of sundried pistachio by‐products (PBP) as a replacement of alfalfa hay (AH) on blood metabolites, rumen fermentation and populations of rumen bacteria involved in biohydrogenation (BH) in Baluchi sheep. Four adult male Baluchi sheep (41 ± 1.3 kg, BW) fitted with ruminal cannulae were randomly assigned to four experimental diets in a 4 × 4 Latin square design. The dietary treatments were as follows: (i) control, (ii) 12% PBP (0.33 of AH in basal diet replaced by PBP), (iii) 24% PBP (0.66 of AH in basal diet replaced by PBP) and (iv) 36% PBP (all of AH in basal diet replaced by PBP). The basal diet was 360 g/kg dry matter (DM) alfalfa hay, 160 g/kg DM wheat straw and 480 g/kg DM concentrate. The trial consisted of four periods, each composed of 16 days adaptation and 4 days data collection including measurement of blood metabolites, rumen fermentation and population of bacteria. No differences were observed in rumen pH among the treatments, while rumen ammonia‐N concentrations were decreased (p< 0.05) with increasing PBP by up to 36% DM of the diets. Using of 36% PBP in the diet reduced (p < 0.05) total volatile fatty acids (VFA) concentrations and the molar proportion of acetate, while the concentration of propionate, butyrate and acetate to propionate ratio were similar to all other treatments. The concentration of blood urea nitrogen (BUN) decreased (p < 0.01) with increasing PBP by up to 36% DM in the diets of sheep. However, other blood metabolites were not affected by the experimental diets. It was concluded that PBP in replacement of AH had no effects on the relative abundance of Butyrivibrio fibrisolvens and Butyrivibrio proteoclasticus in relation to the control diet.
Issues in Austroasiatic Classification
Authors: Sidwell Paul
Published: August 2013

The Austroasiatic phylum spans South and Southeast Asia, with more than 150 languages over at least a dozen branches. Comparative‐historical work on Austroasiatic has been done for over a century, yet it has proceeded only in fits and starts, such that today we are still not sure how the branches fit together as a family. In this review, the history of efforts to understand the classification of Austroasiatic is examined, and the features that distinguish each of the constituent branches are described.
Contrasting primary successional trajectories of fungi and bacteria in retreating glacier soils
Authors: Brown Shawn P. , Jumpponen Ari
Published: August 2013

Early community assembly of soil microbial communities is essential for pedogenesis and development of organic legacies. We examined fungal and bacterial successions along a well‐established temperate glacier forefront chronosequence representing ~70 years of deglaciation to determine community assembly. As microbial communities may be heavily structured by establishing vegetation, we included nonvegetated soils as well as soils from underneath four plant species with differing mycorrhizal ecologies (Abies lasiocarpa, ectomycorrhizal; Luetkea pectinata, arbuscular mycorrhizal; Phyllodoce empetriformis, ericoid mycorrhizal; Saxifraga ferruginea, nonmycorrhizal). Our main objectives were to contrast fungal and bacterial successional dynamics and community assembly as well as to decouple the effects of plant establishment and time since deglaciation on microbial trajectories using high‐throughput sequencing. Our data indicate that distance from glacier terminus has large effects on biomass accumulation, community membership, and distribution for both fungi and bacteria. Surprisingly, presence of plants rather than their identity was more important in structuring bacterial communities along the chronosequence and played only a very minor role in structuring the fungal communities. Further, our analyses suggest that bacterial communities may converge during assembly supporting determinism, whereas fungal communities show no such patterns. Although fungal communities provided little evidence of convergence in community structure, many taxa were nonrandomly distributed across the glacier foreland; similar taxon‐level responses were observed in bacterial communities. Overall, our data highlight differing drivers for fungal and bacterial trajectories during early primary succession in recently deglaciated soils.
Analytical Model for Estimation of Maximum Normal Stress in Steel Beam‐Columns Based on Wireless Measurement of Average Strains from Vibrating Wire Strain Gages
Authors: Lee Hong Min , Choi Se Woon , Jung Dong‐jo , Park Hyo Seon
Published: August 2013

In this article, an analytical model is developed for estimation of the maximum normal stress in a beam‐column member subjected simultaneously to an axial load and bending moments. The analytical model is derived by defining the relationship between the maximum strain and average strains measured wirelessly from vibrating wire strain gages. On the basis of the experimental tests on a two‐dimensional steel frame structure with beam‐column members, the performance of the estimation model is evaluated by comparing the maximum strains directly obtained from electrical strain gages and the estimated maximum strains from the model. Using the model, a practical monitoring of the maximum stress in steel beam‐columns is made possible by measuring three average strains at arbitrary locations.
Active Tendon Control of Torsionally Irregular Structures under Near‐Fault Ground Motion Excitation
Authors: Nigdeli S. Melih , Boduroğlu M. Hasan
Published: August 2013

In this study, torsionally irregular single‐story and multistory structures under the effect of near‐fault ground motion excitation were controlled by active tendons. Near‐fault ground motions contain two impulsive characters. These impulsive characters are the directivity effect perpendicular to fault and the flint step parallel to fault. The structural models were simulated under bidirectional earthquake records superimposed with impulsive motions to examine the response of active control under near‐fault effects. Also, the structures were analyzed only under the effect of bidirectional impulsive pulses. The control signals were obtained by Proportional–Integral–Derivative (PID) type controllers and the parameters of the controllers were obtained by using a numerical algorithm depending on time domain analyses. Time delay effect was also considered for active control system. Different cases of orientation of active tendons were examined and the results of the single‐story structure were compared with another control strategy using frequency domain responses in the optimization process. As a conclusion, the control concept is significantly effective on reducing maximum responses in translational and rotational directions and obtaining a steady‐state response.
Bile duct carcinoma involving the common channel associated with pancreaticobiliary maljunction shows an extension pattern similar to ductal carcinoma of the pancreas
Authors: Yoshida Nao , Esaki Minoru , Kishi Yoji , Shimada Kazuaki , Ojima Hidenori , Kanai Yae , Hiraoka Nobuyoshi
Published: August 2013

Biliary tract cancer occurs frequently in patients with pancreaticobiliary maljunction (PBM), although no details of its clinicopathological characteristics have been reported. Here we describe a case of bile duct (BD) cancer that developed in association with PBM. This BD cancer involved the common channel, extended to the main pancreatic duct (MPD) via the common channel, and invaded the pancreatic parenchyma, where its growth and spread, and features of its recurrence, were similar to those of ductal carcinoma of the pancreas. We assumed that MPD extension of BD cancer via the common channel was the reason for its deep spread to the pancreas, since BD cancer usually spreads along the BD and rarely reaches the common channel of the ampulla of Vater. During the follow‐up of patients with PBM, attention should be paid to involvement of the common channel by BD cancer and also to cancer developing silently in the pancreas after extrahepatic BD resection.
Shifting Administrative Burden to the State: The Case of Medicaid Take‐Up
Authors: Herd Pamela , DeLeire Thomas , Harvey Hope , Moynihan Donald P.
Published: August 2013

Administrative burden is an individual's experience of policy implementation as onerous. Such burdens may be created because of a desire to limit payments to ineligible claimants, but they also serve to limit take‐up of benefits by eligible claimants. For citizens, this burden may occur through learning about a program; complying with rules and discretionary bureaucratic behavior to participate; and the psychological costs of participating in an unpopular program. Using a mixed‐method approach, the authors explain process changes that reduced individual burden and demonstrate how this resulted in increased take‐up in Medicaid in the state of Wisconsin. The findings inform the planned expansion of Medicaid under the Patient Protection and Affordable Care Act. A key design principle for Medicaid and other means‐tested programs is that it is possible to increase program take‐up while maintaining program integrity by shifting administrative burdens from the citizen to the state.
Medicaid's Next Metamorphosis
Authors: Brecher Charles , Rose Shanna
Published: August 2013

Medicaid's transformation since its inception rivals the biological changes of metamorphosis, and this process is not yet over. Past metamorphoses include the change from a small program with eligibility linked to the states’ cash welfare benefits to one with national eligibility standards covering many not receiving cash benefits; from a traditional fee‐for‐service payment program to one dominated by capitated managed care arrangements; and, under the Patient Protection and Affordable Care Act of 2010, to a widely accepted component of a national system for near‐universal insurance coverage. An analysis of the forces behind these significant changes suggests that future transformations are likely. Four potential scenarios are presented and assessed.
Burst generation mediated by cholinergic input in terminal nerve‐gonadotrophin releasing hormone neurones of the goldfish
Authors: Kawai Takafumi , Abe Hideki , Oka Yoshitaka
Published: August 2013

Key points

Burst firing activities are effective for the release of neuropeptides from peptidergic neurones.

A peptidergic neurone, the terminal nerve (TN)‐gonadotrophin releasing hormone (GnRH) neurone, shows spontaneous burst firing activities only infrequently.

Only a single pulse electrical stimulation of the neuropil surrounding the TN‐GnRH neurones induces transient burst activities in TN‐GnRH neurones via cholinergic mechanisms.

The activation of muscarinic acetylcholine receptors results in a long‐lasting hyperpolarisation, inducing rebound burst activities in TN‐GnRH neurones.

These new findings suggest a novel type of cholinergic regulation of burst activities in peptidergic neurones, which should contribute to the release of neuropeptides.

Abstract  Peptidergic neurones play a pivotal role in the neuromodulation of widespread areas in the nervous system. Generally, it has been accepted that the peptide release from these neurones is regulated by their firing activities. The terminal nerve (TN)‐gonadotrophin releasing hormone (GnRH) neurones, which are one of the well‐studied peptidergic neurones in vertebrate brains, are characterised by their spontaneous regular pacemaker activities, and GnRH has been suggested to modulate the sensory responsiveness of animals. Although many peptidergic neurones are known to exhibit burst firing activities when they release the peptides, TN‐GnRH neurones show spontaneous burst firing activities only infrequently. Thus, it remains to be elucidated whether the TN‐GnRH neurones show burst activities and, if so, how the mode switching between the regular pacemaking and bursting modes is regulated in these neurones. In this study, we found that only a single pulse electrical stimulation of the neuropil surrounding the TN‐GnRH neurones reproducibly induces transient burst activities in TN‐GnRH neurones. Our combined physiological and morphological data suggest that this phenomenon occurs following slow inhibitory postsynaptic potentials mediated by cholinergic terminals surrounding the TN‐GnRH neurones. We also found that the activation of muscarinic acetylcholine receptors induces persistent opening of potassium channels, resulting in a long‐lasting hyperpolarisation. This long hyperpolarisation induces sustained rebound depolarisation that has been suggested to be generated by a combination of persistent voltage‐gated Na+ channels and low‐voltage‐activated Ca2+ channels. These new findings suggest a novel type of cholinergic regulation of burst activities in peptidergic neurones, which should contribute to the release of neuropeptides.
Orexin neurons are indispensable for prostaglandin E2‐induced fever and defence against environmental cooling in mice
Authors: Takahashi Yoshiko , Zhang Wei , Sameshima Kohei , Kuroki Chiharu , Matsumoto Ami , Sunanaga Jinko , Kono Yu , Sakurai Takeshi , Kanmura Yuichi , Kuwaki Tomoyuki
Published: August 2013

Key points

We recently showed that orexin neurons in the hypothalamus are indispensable for stress‐induced thermogenesis.

In this study we examined whether the orexin neurons are also important for other forms of thermogenic processes, including brain prostaglandin E2 (PGE2) injection that mimics inflammatory fever and environmental cold exposure.

As was the case with stress‐induced thermogenesis, orexin neuron‐ablated (ORX‐AB) mice exhibited a blunted PGE2‐induced fever and intolerance to cold (5°C) exposure.

Injection of retrograde tracer into the medullary raphe nucleus, where sympathetic premotor neurons regulating thermogenesis by the brown adipose tissue are located, revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX‐AB mice.

These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress‐induced thermogenesis.

Abstract  We recently showed using prepro‐orexin knockout (ORX‐KO) mice and orexin neuron‐ablated (ORX‐AB) mice that orexin neurons in the hypothalamus, but not orexin peptides per se, are indispensable for stress‐induced thermogenesis. To examine whether orexin neurons are more generally involved in central thermoregulatory mechanisms, we applied other forms of thermogenic perturbations, including brain prostaglandin E2 (PGE2) injections which mimic inflammatory fever and environmental cold exposure, to ORX‐KO mice, ORX‐AB mice and their wild‐type (WT) litter mates. ORX‐AB mice, but not ORX‐KO mice, exhibited a blunted PGE2‐induced fever and intolerance to cold (5°C) exposure, and these findings were similar to the results previously obtained with stress‐induced thermogenesis. PGE2‐induced shivering was also attenuated in ORX‐AB mice. Both mutants responded similarly to environmental heating (39°C). In WT and ORX‐KO mice, the administration of PGE2 and cold exposure activated orexin neurons, as revealed by increased levels of expression of c‐fos. Injection of retrograde tracer into the medullary raphe nucleus revealed direct and indirect projection from the orexin neurons, of which the latter seemed to be preserved in the ORX‐AB mice. In addition, we found that glutamate receptor antagonists (d‐(–)‐2‐amino‐5‐phosphonopentanoic acid and 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione) but not orexin receptor antagonists (SB334867 and OX2 29) successfully inhibited PGE2‐induced fever in WT mice. These results suggest that orexin neurons are important in general thermogenic processes, and their importance is not restricted to stress‐induced thermogenesis. In addition, these results indicate the possible involvement of glutamate in orexin neurons implicated in PGE2‐induced fever.
The secret life of CFTR as a calcium‐activated chloride channel
Authors: Billet Arnaud , Hanrahan John W.
Published: August 2013

Abstract  cAMP‐stimulated anion conductance is defective in cystic fibrosis (CF). The regulatory domain of CFTR, the anion channel protein encoded by the CF gene, possesses an unusually high density of consensus sequences for phosphorylation by protein kinase A (14 in a stretch of <200 amino acids). Thus it is not surprising that CFTR is viewed primarily as a cAMP‐stimulated anion channel, and most studies have focused on this mode of activation. However, there is growing evidence that CFTR also responds to Ca2+‐mobilizing secretagogues and contributes substantially to cholinergic and purinergic responses in native tissues. G protein‐coupled receptors that signal through Gαq can stimulate CFTR channels by activating Ca2+‐dependent adenylyl cyclase and tyrosine kinases, and also by inhibiting protein phosphatase type 2A. Here we review evidence for these novel mechanisms of CFTR activation and discuss how they may help explain previous observations.
Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis
Authors: Wenzler Tanja , Yang Sihyung , Braissant Olivier , Boykin David W. , Brun Reto , Wang Michael Zhuo
Published: August 2013

Human African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasites
Trypanosoma brucei gambiense
and
T. brucei rhodesiense
. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected with
T. b. rhodesiense
or
T. b. brucei
parasites. The current study examined the pharmacokinetics,
in vitro
and
in vivo
activity against
T. b. gambiense
, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstanding
in vivo
efficacy in mice infected with parasites of
T. b. gambiense
strains, despite having higher
in vitro
50% inhibitory concentrations (IC
50
s) than against
T. b. rhodesiense
strain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with different
T. b. gambiense
strains. No cross-resistance was observed between DB829 and pentamidine in
T. b. gambiense
strains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry and
in vivo
time-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by both
Trypanosoma brucei
subspecies.
Risk Factors for Treatment Failure of Polymyxin B Monotherapy for Carbapenem-Resistant Klebsiella pneumoniae Infections
Authors: Dubrovskaya Yanina , Chen Ting-Yi , Scipione Marco R. , Esaian Diana , Phillips Michael S. , Papadopoulos John , Mehta Sapna A.
Published: August 2013

Polymyxins are reserved for salvage therapy of infections caused by carbapenem-resistant
Klebsiella pneumoniae
(CRKP). Though synergy has been demonstrated for the combination of polymyxins with carbapenems or tigecycline,
in vitro
synergy tests are nonstandardized, and the clinical effect of synergy remains unclear. This study describes outcomes for patients with CRKP infections who were treated with polymyxin B monotherapy. We retrospectively reviewed the medical records of patients with CRKP infections who received polymyxin B monotherapy from 2007 to 2011. Clinical, microbiology, and antimicrobial treatment data were collected. Risk factors for treatment failure were identified by logistic regression. Forty patients were included in the analysis. Twenty-nine of 40 (73%) patients achieved clinical cure as defined by clinician-documented improvement in signs and symptoms of infections, and 17/32 (53%) patients with follow-up culture data achieved microbiological cure. End-of-treatment mortality was 10%, and 30-day mortality was 28%. In a multivariate analysis, baseline renal insufficiency was associated with a 6.0-fold increase in clinical failure after adjusting for septic shock (odds ratio [OR] = 6.0; 95% confidence interval [CI] = 1.22 to 29.59). Breakthrough infections with organisms intrinsically resistant to polymyxins occurred in 3 patients during the treatment. Eighteen of 40 (45%) patients developed a new CRKP infection a median of 23 days after initial polymyxin B treatment, and 3 of these 18 infections were polymyxin resistant. The clinical cure rate achieved in this retrospective study was 73% of patients with CRKP infections treated with polymyxin B monotherapy. Baseline renal insufficiency was a risk factor for treatment failure after adjusting for septic shock. Breakthrough infections with organisms intrinsically resistant to polymyxin B and development of resistance to polymyxin B in subsequent CRKP isolates are of concern.
CYP2J2 and CYP2C19 Are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems
Authors: Wu Zhexue , Lee Doohyun , Joo Jeongmin , Shin Jung-Hoon , Kang Wonku , Oh Sangtaek , Lee Do Yup , Lee Su-Jun , Yea Sung Su , Lee Hye Suk , Lee Taeho , Liu Kwang-Hyeon
Published: August 2013

Albendazole and fenbendazole are broad-spectrum anthelmintics that undergo extensive metabolism to form hydroxyl and sulfoxide metabolites. Although CYP3A and flavin-containing monooxygenase have been implicated in sulfoxide metabolite formation, the enzymes responsible for hydroxyl metabolite formation have not been identified. In this study, we used human liver microsomes and recombinant cytochrome P450s (P450s) to characterize the enzymes involved in the formation of hydroxyalbendazole and hydroxyfenbendazole from albendazole and fenbendazole, respectively. Of the 10 recombinant P450s, CYP2J2 and/or CYP2C19 was the predominant enzyme catalyzing the hydroxylation of albendazole and fenbendazole. Albendazole hydroxylation to hydroxyalbendazole is primarily mediated by CYP2J2 (0.34 μl/min/pmol P450, which is a rate 3.9- and 8.1-fold higher than the rates for CYP2C19 and CYP2E1, respectively), whereas CYP2C19 and CYP2J2 contributed to the formation of hydroxyfenbendazole from fenbendazole (2.68 and 1.94 μl/min/pmol P450 for CYP2C19 and CYP2J2, respectively, which are rates 11.7- and 8.4-fold higher than the rate for CYP2D6). Correlation analysis between the known P450 enzyme activities and the rate of hydroxyalbendazole and hydroxyfenbendazole formation in samples from 14 human liver microsomes showed that albendazole hydroxylation correlates with CYP2J2 activity and fenbendazole hydroxylation correlates with CYP2C19 and CYP2J2 activities. These findings were supported by a P450 isoform-selective inhibition study in human liver microsomes. In conclusion, our data for the first time suggest that albendazole hydroxylation is primarily catalyzed by CYP2J2, whereas fenbendazole hydroxylation is preferentially catalyzed by CYP2C19 and CYP2J2. The present data will be useful in understanding the pharmacokinetics and drug interactions of albendazole and fenbendazolein vivo.
Preclinical Characterization of GLS4, an Inhibitor of Hepatitis B Virus Core Particle Assembly
Authors: Wu Guoyi , Liu Bo , Zhang Yingjun , Li Jing , Arzumanyan Alla , Clayton Marcia M. , Schinazi Raymond F. , Wang Zhaohe , Goldmann Siegfried , Ren Qingyun , Zhang Faxhou , Feitelson Mark A.
Published: August 2013

Hepatitis B virus (HBV)-associated chronic liver diseases are treated with nucleoside analogs that target the virus polymerase. While these analogs are potent, drugs are needed to target other virus-encoded gene products to better block the virus replication cycle and chronic liver disease. This work further characterized GLS4 and compared it to the related BAY 41-4109, both of which trigger aberrant HBV core particle assembly, where the virus replication cycle occurs. This was done in HepAD38 cells, which replicate HBV to high levels.
In vitro
, GLS4 was significantly less toxic for primary human hepatocytes (
P
< 0.01 up to 100 μM), inhibited virus accumulation in the supernantant of HepAD38 cells (
P
< 0.02 up to 100 nM), inhibited HBV replicative forms in the liver with a significantly lower 50% effective concentration (EC
50
) (
P
< 0.02), and more strongly inhibited core gene expression (
P
< 0.001 at 100 to 200 nM) compared to BAY 41-4109.
In vivo
characterization was performed in nude mice inoculated with HepAD38 cells, which grew out as tumors, resulting in viremia. Treatment of mice with GLS4 and BAY 41-4109 showed strong and sustained suppression of virus DNA to about the same extents both during and after treatment. Both drugs reduced the levels of intracellular core antigen in the tumors. Alanine aminotransferase levels were normal. Tumor and total body weights were not affected by treatment. Thus, GLS4 was as potent as the prototype, BAY 41-4109, and was superior to lamivudine, in that there was little virus relapse after the end of treatment and no indication of toxicity.
In VitroandIn VivoActivities of AIC292, a Novel HIV-1 Nonnucleoside Reverse Transcriptase Inhibitor
Authors: Wildum Steffen , Paulsen Daniela , Thede Kai , Ruebsamen-Schaeff Helga , Zimmermann Holger
Published: August 2013

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important and frequently used elements of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. However, the development of drug resistance, as well as the side effects of existing drugs, defines a medical need for novel NNRTIs with excellent tolerability, improved activity against NNRTI-resistant viruses, and a low barrier to resistance. Within the chemical class of diarylpyrazole-[imidazolidinone]-carboxamides, AIC292 was identified as a promising novel HIV-1 NNRTI and has successfully completed single-dose clinical phase I studies. Here, we report on the antiviral activity of AIC292, evaluatedin vitroagainst wild-type and NNRTI-resistant HIV-1 isolates andin vivousing an engineered mouse xenograft model. AIC292 inhibited wild-type HIV-1 laboratory strains at low nanomolar concentrations, was well tolerated in different cell lines, and showed excellent selectivity in a lead profiling screen. In addition, activity of AIC292 could be demonstrated against a broad panel of wild-type HIV-1 group M and group O clinical isolates. AIC292 also retained activity against viruses harboring NNRTI resistance-associated mutations (RAMs), including the most prevalent variants, K103N, Y181C, and G190A. Interestingly, viruses bearing the L100I RAM were hypersusceptible to AIC292. Two-drug combination assays showed no antagonistic interactions between AIC292 and representative marketed HIV drugs with regard to antiviral activity. Furthermore, AIC292 displayed potent antiviralin vivoefficacy in a mouse xenograft model when applied once daily. Taken together, these data show that AIC292 represents a molecule with the antiviral properties of a novel NNRTI for the treatment of HIV-1 infection.
Acute respiratory failure secondary to mesalamine-induced interstitial pneumonitis
Authors: Abraham Albin , Karakurum Ali
Published: August 2013

Interstitial pneumonitis as an adverse effect of mesalamine therapy is a rare but potentially serious complication. Patients typically have a mild disease course with no documented cases of respiratory failure in published literature. Given its variable latent period and non-specific signs and symptoms, it may be difficult to diagnose. We present the case of a 65-year-old man who presented with symptoms of fever, shortness of breath and a non-productive cough, 2 weeks after initiation of therapy with mesalamine. His hospital course was complicated by acute respiratory failure requiring intubation and mechanical ventilation. Radiographic studies revealed bilateral lower lobe infiltrates and bronchosopy with bronchoalveolar lavage and transbronchial biopsy were consistent with a diagnosis of drug-induced interstitial pneumonitis. The aim of this paper is to highlight the importance of considering a diagnosis of mesalamine-induced lung injury in patients presenting with respiratory symptoms while on mesalamine therapy and to review relevant literature.
Multiple haemangiomas, diaphragmatic eventration and Beckwith-Wiedemann syndrome: an unusual association
Authors: Francisco Telma , Gonçalves Rui Miguel , Borges Cristina , Neto Maria Teresa
Published: August 2013

A 6-month-old girl with Beckwith-Wiedemann syndrome, multiple haemangiomas (axillary, laryngeal, pulmonary and hepatic) and diaphragmatic eventration was reported. All tumours responded to treatment with propranolol. The surgical correction of diaphragmatic eventration was crucial to a better outcome.
Unusual delayed presentation of head trauma complicating outcome of facial nerve decompression surgery
Authors: Thakur J S , Shekar Vidya , Saluja Manika , Mohindroo N K
Published: August 2013

Late presentation of head trauma is rare. A young boy presented with a traumatic facial paralysis after head trauma. A CT scan of the head showed temporal bone fracture without intracranial insult. Facial nerve decompression was performed and paralysis started improving. However, he presented with vertigo and sensorineural hearing loss after 2 months. Clinical examination also showed cerebellar sign. We suspected iatrogenic injury to the cochlea; however, brain MRI showed haemorrhage in the area of anterior inferior cerebellar artery. The patient was managed conservatively and the vertigo improved. This case stresses on unusual late presentation of head trauma and cerebellar artery injury that complicated the outcome of facial nerve paralysis.
A giant spinal arterial aneurysm in a child presenting as quadriparesis
Authors: Santana-Ramírez Adrian , Farias-Serratos Felipe , Garzon-Muvdi Tomas , Quiñones-Hinojosa Alfredo
Published: August 2013

A giant spinal aneurysm from anterior spinal artery not associated with arteriovenous (AV) malformations is unusual and no such cases have been reported in children. Few cases have been described as part of AV malformation complex and coarctation of the aorta. We report a case of anterior spinal aneurysm in a 1-year-old girl causing a subarachnoid haemorrhage and a cervical cord lesion. The diagnosis was confirmed with a multislice CT angiography. A microsurgical decompression was performed and excision of aneurysm was unsuccessful but neurological deficits were improved. No further approach was accepted by the parents. The mechanism for the development of spinal isolated aneurysms is not clear; it can be related to congenital vessel abnormalities and genetic origin. The multislice CT angiography is a very useful method to demonstrate the features of this entity. Previous reports of isolated spinal aneurysm are reviewed.
Associations of metabolic factors and adipokines with pain in incipient upper extremity soft tissue disorders: a cross-sectional study
Authors: Rechardt Martti , Shiri Rahman , Lindholm Harri , Karppinen Jaro , Viikari-Juntura Eira
Published: August 2013

Objectives

Earlier studies have suggested associations between metabolic factors and musculoskeletal pain or disorders. We studied the associations of obesity, lipids, other features of the metabolic syndrome and adipokines (adiponectin, leptin, resistin, visfatin) with upper extremity pain in a clinical population with incipient upper extremity soft tissue disorders (UESTDs).

Design

A cross-sectional study.

Setting

Primary healthcare (occupational health service) with further examinations at a research institute.

Participants

Patients (N=163, 86% were women) seeking medical advice in the occupational health service due to incipient upper extremity symptoms with symptom duration of <1 month were referred for consultation to the Finnish Institute of Occupational Health from Spring 2006 to Fall 2008. We included all actively working subjects meeting diagnostic criteria based on physical examination. We excluded subjects meeting predetermined conditions.

Outcome measure

Pain intensity was assessed with visual analogue scale and dichotomised at the highest tertile (cut-point 60).

Results

Obesity (adjusted OR for high waist circumference 2.9, 95% CI 1.1 to 7.3), high-density lipoprotein cholesterol (OR 3.9, 95% CI 1.4 to 10.1 for low level) and triglycerides (OR 2.6, 95% CI 1.0 to 6.8 for high level) were associated with pain intensity. Of four adipokines studied, only visfatin was associated with upper extremity pain (adjusted OR 1.4, 95% CI 1.0 to 2.1 for 1SD increase in level).

Conclusions

Abdominal obesity and lipids may have an impact on pain intensity in UESTDs. They may intensify pain through proinflammatory pain-modifying molecular pathways or by causing soft tissue pathology and dysfunction of their supplying arteries. Of four adipokines studied only one (visfatin) was associated with pain intensity. In the future, further studies are required to better understand the relationship between metabolic factors and UESTDs.
Is teenage pregnancy an obstetric risk in a welfare society? A population-based study in Finland, from 2006 to 2011
Authors: Leppälahti Suvi , Gissler Mika , Mentula Maarit , Heikinheimo Oskari
Published: August 2013

Objective

To assess obstetric outcomes in teenage pregnancies in a country with a low teenage delivery rate and comprehensive high-quality prenatal care.

Design

Retrospective population-based register study.

Setting

Finland.

Participants

All nulliparous teenagers (13–15 years (n=84), 16–17 years (n=1234), 18–19 years (n=5987)) and controls (25-year-old to 29-year-old women (n=51 142)) with singleton deliveries in 2006–2011.

Main outcome measures

Risk of adverse obstetric outcomes adjusted for demographic factors and clinically relevant pregnancy complications, with main focus on maternal pregnancy complications.

Results

Teenage mothers were more likely than controls to live in rural areas (16% (n=1168) vs 11.8% (n=6035)), smoke (36.4% (n=2661) vs 7% (n=3580)) and misuse alcohol or drugs (1.1% (n=82) vs 0.2% (n=96); p<0.001 for all). Teenagers made a good mean number of antenatal clinic visits (16.4 vs 16.5), but were more likely to have attended fewer than half of the recommended visits (3% (n=210) vs 1.4% (n=716)). Teenagers faced increased risks of several obstetric complications, for example, anaemia (adjusted OR 1.8, 95% CI 1.6 to 2.1), proteinuria (1.8, 1.2 to 2.6), urinary tract infection (UTI; 2.9, 1.8 to 4.8), pyelonephritis (6.3, 3.8 to 10.4) and eclampsia (3.2, 1.4 to 7.3), the risks increasing with descending age for most outcomes. Elevated risks of pre-eclampsia (3.7, 1.5 to 9.0) and preterm delivery (2.5, 1.2 to 5.3) were also found among 13-year-olds to 15-year-olds. However, teenage mothers were more likely to have vaginal delivery (1.9, 1.7 to 2.0) without complications. Inadequate prenatal care among teenagers was a risk factor of eclampsia (12.6, 2.6 to 62.6), UTI (5.8, 1.7 to 19.7) and adverse neonatal outcomes.

Conclusions

Pregnant teenagers tended to be socioeconomically disadvantaged versus controls and faced higher risks of various pregnancy complications. Special attention should be paid to enrolling teenagers into adequate prenatal care in early pregnancy.
Basis set effects in simple compounds of heavy rare gases
Authors: Fitzsimmons Amelia , Klobukowski Mariusz
Published: August 2013

Rare-gas hydrides of the type HRgX (Rg = Xe or Rn and X = F, Cl, Br, or I) have been studied using Møller–Plesset and density functional theory methods. Six model core potentials and their associated basis sets were used, with relativistic effects included implicitly. The effects of polarization, correlating, and diffuse basis functions were investigated. Molecular geometries of the metastable hydrides and transition states along the decomposition pathway were computed together with corresponding energies of formation and decomposition. The results of quantum theory of atoms in molecules analysis further elucidate the interactions between atoms in HRgX species and confirm the results of analyses obtained from the natural bond orbitals approach.
The resilience of the forest field layer to anthropogenic disturbances depends on site productivity
Authors: Kohv Kaupo , Zobel Martin , Liira Jaan
Published: August 2013

The resilience of the boreal forest field layer (herbs plus dwarf shrubs) to anthropogenic disturbances is insufficiently understood because of the multitude of direct or indirect driver pathways and environmental conditions involved. We hypothesized that the impact of the forest-management-induced disturbances on field layer varies along the gradient of site productivity. To explore that we proposed a method for estimating the proportional effect of each driver on the field-layer composition, in a survey data of 273 mature or overgrown boreal forests, by combining variogram analysis with multifactorial general linear modelling. In forest types of very low and high productivity, field-layer composition was sensitive to the management disturbances in general and, particularly, to the management-controlled variations in the structure of the stand and its understory, i.e., in environmentally stressful conditions the main limiting factors were light availability and its spatiotemporal variability. At intermediate productivity, instead, the natural heterogeneity of ground layer conditions was the dominant driver, pointing to the limitation of regeneration microsites. Accordingly, on soils with low and high productivity, biodiversity-oriented sustainable forestry should diversify silvicultural approaches among stands and (or) enhance the within-stand mosaic, whereas small-scale natural disturbances of the ground-level “organic blanket” should be promoted in forests of intermediate productivity.
ON THE REPRESENTATION OF Aκ(d) ALGEBRA
Authors: CHUNG WON SANG
Published: August 2013

In this paper, the representation of Aκ(2) algebra given by Daoud and Kibler [J. Phys. A 43, 115303 (2010); J. Phys. A 45, 244036 (2012)] is generalized to the multi-mode case. The representation of the multi-mode extension of Aκ(2) algebra, which is called Aκ(d) algebra, is also obtained. The positivity condition of the energy spectrum and the coherent state are also investigated for Aκ(d) algebra.