bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep endoscopy with simulation bite for prediction of oral appliance treatment outcome
Authors: Vroegop Anneclaire V. M. T. , Vanderveken Olivier M. , Dieltjens Marijke , Wouters Kristien , Saldien Vera , Braem Marc J. , Van de heyning Paul H. 
Published: December 2012

SummaryThe aim of this study was to assess the value of drug‐induced sleep endoscopy (DISE) using a custom‐made simulation bite in maximal comfortable protrusion (MCP) of the mandible, in the prediction of treatment outcome for obstructive sleep apnea (OSA) with a mandibular advancement device (MAD). Two hundred patients (74% male; age 46 ± 9 years; apnea–hypopnea index [AHI] 19 ± 13 h−1 sleep; body mass index [BMI] 27 ± 4 kg m−2) with sleep‐disordered breathing underwent DISE with a simulation bite in MCP. One hundred and thirty‐five patients with an established diagnosis of OSA commenced MAD treatment. The associations between the findings during DISE with simulation bite and treatment outcome were evaluated. Treatment response was defined as a reduction in AHI following MAD treatment of ≥ 50% compared to baseline. Overall MAD treatment response in the studied population was 69%. The results of this study demonstrated a statistically significant association between a positive effect of the simulation bite on the upper airway patency during DISE and treatment response with MAD (P < 0.01). The results of this study suggest that the use of a simulation bite in maximal comfortable protrusion (MCP) of the mandible, as used during DISE in patients with OSA, tends to be effective in predicting treatment response of MAD treatment.
Striving for general validity: a huge sample reveals faint traces in forests
Authors: Wildi Otto 
Published: December 2012

AbstractSpecies composition in forest patches is influenced by distance‐to‐edge within an average range of 748 m. Pellissier et al., in this issue, assess the significance of this pattern using a very large data set, a well‐defined target population and comprehensive logistic models. This is a recipe for overcoming the lack of general validity frequently observed in vegetation science.
Plant community type and small‐scale disturbances, but not altitude, influence the invasibility in subarctic ecosystems
Authors: Milbau Ann , Shevtsova Anna , Osler Nora , Mooshammer Maria , Graae Bente J. 
Published: December 2012

Summary

Little of our knowledge about invasibility comes from arctic and alpine ecosystems, despite increasing plant migration and invasion in those regions. Here, we examine how community type, altitude, and small‐scale disturbances affect invasibility in a subarctic ecosystem.

Over a period of 4 yr, we studied seedling emergence and establishment in 17 species sown in gaps or undisturbed vegetation in four subarctic community types (Salix scrub, meadow, rich heath, poor heath) along an elevation gradient.

Invasibility was lowest in rich heath and highest in Salix scrub. Small disturbances significantly increased the invasibility in most communities, thereby showing the importance of biotic resistance to invasion in subarctic regions. Unexpectedly, invasibility did not decrease with increasing elevation, and it was also not related to summer temperature.

Our data suggest that biotic resistance might be more important than abiotic stress for invasibility in subarctic tundra and that low temperatures do not necessarily limit seedling establishment at high altitudes. High elevations are therefore potentially more vulnerable to invasion than was originally thought. Changes in community composition as a result of species migration or invasion are most likely to occur in Salix scrub and meadow, whereas Empetrum‐dominated rich heath will largely remain unchanged.
Comparison of white and red blood cell estimates in urine sediment with hemocytometer and automated counts in dogs and cats
Authors: O'Neil Elizabeth , Burton Shelley , Horney Barbara , MacKenzie Allan 
Published: December 2012

BackgroundTherapeutic decisions regarding urinalysis are commonly based on the presence of white and red blood cells. Traditionally, numbers per high‐power field are estimated using wet‐mount microscopic examination. This technique is not standardized and counts are likely prone to inaccuracy. In addition, differentiation of leukocyte types is not possible.ObjectivesThe aims of this study were to (1) compare WBC and RBC estimates using wet‐mount examination with counts obtained using a hemocytometer, (2) assess if a hematology automated analyzer (Sysmex ST‐2000iV/XT) provides reliable WBC and RBC counts in urine comparable to hemocytometer counts, and (3) evaluate air‐dried Wright–Giemsa‐stained urine drop sediment preparations for the determination of differential leukocyte counts.MethodsWBC and RBC counts were obtained by performing wet‐mount estimates, manual hemocytometer counts, and Sysmex automated counts on 219 canine and feline urine samples. Results were correlated using Spearman rank correlation. Air‐dried Wright–Giemsa stained sediment drop preparations (n = 215) were examined for differential counts of leukocytes.ResultsA low but significant association was found between WBC estimates on wet‐mount examination and hemocytometer counts (rho = 0.37, P < .01). There was a high and significant association when RBC counts were compared between wet‐mount and hemocytometer evaluation (rho = 0.7, P < .01). There was very high and significant interassay correlation between Sysmex data from duplicate samples for what the analyzer classified as WBC (rho = 0.97, P < .01) and RBC (rho = 0.94, P < .01). Low correlations were found between the Sysmex RBC counts and both wet‐mount estimates and hemocytometer RBC counts (rho = 0.43, P < .01 and rho = 0.39, P < .01, respectively). Cell preservation in the air‐dried sediment preparations was so poor that differential counts could not be performed.ConclusionWBC and RBC estimates on wet‐mount examination agreed with hemocytometer counts and are therefore considered adequate. The Sysmex ST‐2000iV/XT did not provide reliable cell counts under the conditions used.
Calmodulin and calmodulin kinase II mediate emergent bursting activity in the brainstem respiratory network (preBötzinger complex)
Authors: Mironov S. L. 
Published: December 2012

Key points
Rhythmic network activity can be controlled by intracellular signalling pathways but their possible role is largely not yet elucidated.
This study is focused on the mechanisms of emergence and maintenance of synchronous rhythmic activity within the preBötzinger complex (preBötC), an essential part of the respiratory network in the brainstem.
Depression of the bursting activity by brief hypoxia and electrical stimulation correlated well with ADP‐mediated inhibition of TRPM4 channels.
Long‐lasting increases in calcium during the treatments stimulated calmodulin kinase that facilitated glutamatergic synapses and augmented rhythmic activity.
The results will help us better understand how respiratory rhythm is generated and how it is restored in various respiratory disorders
Abstract  Emergence of persistent activity in networks can be controlled by intracellular signalling pathways but the mechanisms involved and their role are not yet fully explored. Using calcium imaging and patch‐clamp we examined the rhythmic activity in the preBötzinger complex (preBötC) in the lower brainstem that generates the respiratory motor output. In functionally intact acute slices brief hypoxia, electrical stimulation and activation of AMPA receptors transiently depressed bursting activity which then recovered with augmentation. The effects were abrogated after chelation of intracellular calcium, blockade of l‐type calcium channels and inhibition of calmodulin (CaM) and CaM kinase (CaMKII). Rhythmic calcium transients and synaptic drive currents in preBötC neurons in the organotypic slices showed similar CaM‐ and CaMKII‐dependent responses. The stimuli increased the amplitude of spontaneous and miniature excitatory synaptic currents indicating postsynaptic changes at glutamatergic synapses. In the acute and organotypic slices, CaM stimulated and ADP inhibited calcium‐dependent TRPM4 channels and CaMKII augmented synaptic drive currents. Experimental data and simulations show the role of ADP and CaMKII in the control of bursting activity and its relation to intracellular signalling. I propose that CaMKII‐mediated facilitation of glutamatergic transmission strengthens emergent synchronous activity within preBötC that is then maintained by periodic surges of calcium during the bursts. This may find implications in restoration and consolidation of autonomous activity in the respiratory disorders.
Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy
Authors: Cammarota Mario , Losi Gabriele , Chiavegato Angela , Zonta Micaela , Carmignoto Giorgio 
Published: December 2012

Key points
In focal epilepsy the propagation of seizure discharges arising at restricted brain sites is opposed by feedforward inhibition. Failure of this inhibition marks focal seizure propagation to distant neurons.
The cellular source of inhibition and the mechanism of inhibition failure are, however, undefined.
Here we reveal that a subclass of GABAergic interneurons, i.e. the parvalbumin‐expressing, fast‐spiking interneurons, are a main source of the inhibitory signal that locally restrains seizures. Furthermore, a firing impairment in these interneurons, probably due to a drastic membrane depolarization, is an important event that by reducing the overall strength of local inhibition allows seizures to propagate across the cortex.
Our data suggest that modulation of fast‐spiking interneuron activity may represent a new therapeutic strategy to prevent generalization of focal epilepsies.
Abstract  In different animal models of focal epilepsy, seizure‐like ictal discharge propagation is transiently opposed by feedforward inhibition. The specific cellular source of this signal and the mechanism by which inhibition ultimately becomes ineffective are, however, undefined. We used a brain slice model to study how focal ictal discharges that were repetitively evoked from the same site, and at precise times, propagate across the cortex. We used Ca2+ imaging and simultaneous single/dual cell recordings from pyramidal neurons (PyNs) and different classes of interneurons in rodents, including G42 and GIN transgenic mice expressing the green fluorescence protein in parvalbumin (Pv)‐fast spiking (FS) and somatostatin (Som) interneurons, respectively. We found that these two classes of interneurons fired intensively shortly after ictal discharge generation at the focus. The inhibitory barrages that were recorded in PyNs occurred in coincidence with Pv‐FS, but not with Som interneuron burst discharges. Furthermore, the strength of inhibitory barrages increased or decreased in parallel with increased or decreased firing in Pv‐FS interneurons but not in Som interneurons. A firing impairment of Pv‐FS interneurons caused by a membrane depolarization was found to precede ictal discharge onset in neighbouring pyramidal neurons. This event may account for the collapse of local inhibition that allows spatially defined clusters of PyNs to be recruited into propagating ictal discharges. Our study demonstrates that Pv‐FS interneurons are a major source of the inhibitory barrages that oppose ictal discharge propagation and raises the possibility that targeting Pv‐FS interneurons represents a new therapeutic strategy to prevent the generalization of human focal seizures.
Study of the Rifampin Monoresistance Mechanism in Mycobacterium tuberculosis
Authors: Pang Yu , Lu Jie , Wang Yufeng , Song Yuanyuan , Wang Shengfen , Zhao Yanlin 
Published: December 2012

ABSTRACT

Rifampin (RIF) susceptibility is a key factor in determining the treatment effectiveness of the standardized treatment regimens. In
Mycobacterium tuberculosis
, both target gene mutation and the efflux pump play major roles in the resistance to antituberculosis drugs. By eliminating RIF-resistant strains with
rpoB
mutation, the choice of RIF-monoresistant strains may allow us to identify the RIF-specific efflux pump genes. This study explored the RIF monoresistance mechanism in
M. tuberculosis
. Data from DNA sequencing and MIC measurements revealed that specific mutations, including Ser531Leu and His526Asp in RpoB, show high-level drug resistance. Three-dimensional structure modeling provided further evidence that the affinity between RIF and RpoB mutants was in accordance with the drug resistance level of the corresponding isolates. Furthermore, transcription-level analysis among the nonmutated isolates indicated that three efflux pumps (Rv0783, Rv2936, and Rv0933) might be involved in exporting RIF from the cell. Compared to 8 μg/ml for wild-type
Escherichia coli
, the MICs for the transgenic
E. coli
strains with either Rv0783 or Rv2936 were 32 and 16 μg/ml, respectively. In conclusion, our study indicated that several RpoB mutant types, including Ser531Leu and His526Asp, show high-level RIF resistance attributed to low affinity between RpoB mutant proteins and RIF. In addition, this work demonstrates that Rv2936 and Rv0783 may be responsible for low-level resistance to RIF by exporting RIF from cells. The predicted structure of RpoB and the newly identified efflux pumps in this study will provide a novel approach to design new drugs and develop novel diagnosis technologies.
Assessing the Essentiality of Leishmania donovani Nitroreductase and Its Role in Nitro Drug Activation
Authors: Wyllie Susan , Patterson Stephen , Fairlamb Alan H. 
Published: December 2012

ABSTRACT

The nitroimidazole fexinidazole has potential as a safe and effective oral drug therapy for the treatment of visceral leishmaniasis. To date, nitroheterocyclics have not been used in the treatment of leishmaniasis, and relatively little is known about their mechanism of action. In African trypanosomes, nitro drugs are reductively activated by a type I nitroreductase (NTR), absent in mammalian cells. Modulation of nitroreductase levels in
Trypanosoma brucei
directly affected sensitivity to nitro compounds, with reduced concentrations of the enzyme leading to moderate nitro drug resistance. In view of the progression of fexinidazole into clinical development for visceral leishmaniasis, here we assess the essentiality of the nitroreductase in
Leishmania donovani
and the effect of modulating nitroreductase levels on susceptibility to fexinidazole. The failure to directly replace both endogenous copies of the
NTR
gene, except in the presence of an ectopic copy of the gene, suggests that the
NTR
gene is essential for the growth and survival of
L. donovani
promastigotes. Loss of a single chromosomal copy of the
L. donovani NTR
gene resulted in parasites that were mildly resistant (<2-fold) to the predominant
in vivo
metabolite of fexinidazole, while parasites overexpressing NTR were 18-fold more susceptible. These data confirm that
Leishmania
NTR plays a pivotal role in fexinidazole activation. Reliance on a single enzyme for prodrug activation may leave fexinidazole vulnerable to the emergence of drug resistance. However, the essentiality of the NTR in
L. donovani
promastigotes, combined with the limited resistance shown by
NTR
single knockout cells, suggests that the potential for the spread of NTR-based resistance to fexinidazole may be limited.
Milbemycins: More than Efflux Inhibitors for Fungal Pathogens
Authors: Silva Luis Vale , Sanguinetti Maurizio , Vandeputte Patrick , Torelli Riccardo , Rochat Bertrand , Sanglard Dominique 
Published: December 2012

ABSTRACTExisting antifungal agents are still confronted to activities limited to specific fungal species and to the development of resistance. Several improvements are possible either by tackling and overcoming resistance or exacerbating the activity of existing antifungal agents. InCandida glabrata, azole resistance is almost exclusively mediated by ABC transporters (includingC. glabrata CDR1[CgCDR1] andCgCDR2) via gain-of-function mutations in the transcriptional activatorCgPDR1or by mitochondrial dysfunctions. We also observed that azole resistance was correlating with increasing virulence and fitness ofC. glabratain animal models of infection. This observation motivated the re-exploitation of ABC transporter inhibitors as a possible therapeutic intervention to decrease not only the development of azole resistance but also to interfere with the virulence ofC. glabrata. Milbemycins are known ABC transporter inhibitors, and here we used commercially available milbemycin A3/A4 oxim derivatives to verify this effect. As expected, the derivatives were inhibitingC. glabrataefflux with the highest activity for A3 oxim below 1 μg/ml. More surprising was that oxim derivatives had intrinsic fungicidal activity above 3.2 μg/ml, thus highlighting effects additional to the efflux inhibition. Similar values were obtained withC. albicans. Our data show that the fungicidal activity could be related to reactive oxygen species formation in these species. Transcriptional analysis performed both inC. glabrataandC. albicansexposed to A3 oxim highlighted a core of commonly regulated genes involved in stress responses, including genes involved in oxidoreductive processes, protein ubiquitination, and vesicle trafficking, as well as mitogen-activated protein kinases. However, the transcript profiles contained also species-specific signatures. Following these observations, experimental treatments of invasive infections were performed in mice treated with the commercial A3/A4 oxim preparation alone or in combination with fluconazole. Tissue burden analysis revealed that oxims on their own were able to decrease fungal burdens in bothCandidaspecies. In azole-resistant isolates, oxims acted synergisticallyin vivowith fluconazole to reduce fungal burden to levels of azole-susceptible isolates. In conclusion, we show here the potential of milbemycins not only as drug efflux inhibitors but also as effective fungal growth inhibitors inC. glabrataandC. albicans.
HIV-1 Dynamics and Coreceptor Usage in Maraviroc-Treated Patients with Ongoing Replication
Authors: Recordon-Pinson P. , Raymond S. , Bellecave P. , Marcelin A. G. , Soulie C. , Descamps D. , Calvez V. , Harrigan P. R. , Fleury H. , Izopet J. , Masquelier B. 
Published: December 2012

ABSTRACT

There is evidence that HIV-1 evolution under maraviroc (MVC) pressure can lead to the selection of either X4-tropic variants and/or R5-tropic, MVC-resistant isolates. However, the viral dynamics of HIV-1 variants in patients with virological failure (VF) on MVC-containing regimens remain poorly studied. Here, we investigated the V3 loop evolution of HIV-1 on MVC in relation to coreceptor usage and the nature of HIV-1 quasispecies before MVC therapy using bulk population sequences and ultradeep sequencing. The majority of patients had no detectable minority X4 variant at baseline. The evolution of tropism was followed up until VF and showed three possibilities for viral evolution in these patients: emergence of preexisting X4 variants,
de novo
selection of R5 variants presenting V3 loop mutations, or replication of R5 variants without selection of known mutations.
Influence of intermittent hypoxia interval training on exercise-dependent erythrocyte NOS activation and blood pressure in diabetic patients
Authors: Ladage Dennis , Braunroth Christian , Lenzen Edward , Berghöfer Sandra , Graf Christine , Bloch Wilhelm , Brixius Klara 
Published: December 2012

NOS-activation in erythrocytes (eryNOS) is impaired in patients suffering from type 2 diabetes. We investigated the effect of physical exercise on eryNOS activation and whether 6 week hypoxia interval training may alter this process. Male patients with diabetes mellitus type 2 (NIDDM, n = 12; age, 61.3 ± 8.4 years; BMI, 29.8 ± 3.7 kg/m2) underwent physical exercise training before and after 6 week hypoxia interval training. Training was conducted 4 times per week for 90 min at 15.4–12.7 Vol% of inspired oxygen. Vital parameters were recorded. Before hypoxia intervention, eryNOS phosphorylation at serine1177decreased significantly during exercise (basal 17.4 ± 12.0 compared with exercise 8.4 ± 9.2 arbitrary grey values (arGV); P < 0.05). After 6 weeks of hypoxia intervention, eryNOS–pSer1177(2.2 ± 2.5 arGV) was significantly lower at baseline. Ergometry showed an increase (7.6 ± 3.0 arGV; P < 0.05) followed by a decrease to almost baseline levels after 30 min (3.8 ± 1.5 arGV). Maximal exercise capacity and O2-uptake ([Formula: see text]  max) increased significantly. The effects were independent from exercise-induced elevation of blood pressure. Exercise-dependent eryNOS phosphorylation at serine1177was increased similar to that described for the endothelium in diabetic patients. EryNOS dysregulation was partially restored after intermittent hypoxia training.
Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors
Authors: Endo Makoto , Yamamoto Hidetaka , Setsu Nokitaka , Kohashi Kenichi , Takahashi Yusuke , Ishii Takeaki , Iida Kei-ichiro , Matsumoto Yoshihiro , Hakozaki Michiyuki , Aoki Mikiko , Iwasaki Hiroshi , Dobashi Yoh , Nishiyama Kenichi , Iwamoto Yukihide , Oda Yoshinao 
Published: December 2012

Abstract
Purpose: Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with poor prognosis. MPNSTs occur frequently in patients with neurofibromatosis type 1 (NF1), in which NF1 gene deficiency leads to Ras hyperactivation. Ras activation causes the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and regulates cellular functions. However, the activation profiles of the AKT/mTOR and MAPK pathways in MPNSTs are poorly understood. The purposes of this study are to examine the correlation between the activation of these pathways and clinicopathologic or prognostic factors and to identify candidate target molecules in MPNST. Moreover, we assessed the antitumor effects of the inhibitor of candidate target.
Experimental Design: Immunohistochemistry was conducted to evaluate the activation profiles of AKT/mTOR and MAPK pathways using 135 tumor specimens. Immunohistochemical expressions were confirmed by Western blotting. Then, an in vitro study was conducted to examine the antitumor effect of the mTOR inhibitor on MPNST cell lines.
Results: Phosphorylated-AKT (p-AKT), p-mTOR, p-S6RP, p-p70S6K, p-4E-BP1, p-MEK1/2, and p-ERK1/2 expressions were positive in 58.2%, 47.3%, 53.8%, 57.1%, 62.6%, 93.4%, and 81.3% of primary MPNSTs, respectively. Positivity for each factor showed no difference between NF1-related and sporadic MPNSTs. Univariate prognostic analysis revealed that p-AKT, p-mTOR, and p-S6RP expressions were associated with poor prognosis. Furthermore, activation of each p-mTOR and p-S6RP was an independent poor prognostic factor by multivariate analysis. mTOR inhibition by Everolimus showed antitumor activity on MPNST cell lines in vitro.
Conclusion: mTOR inhibition is a potential treatment option for both NF1-related and sporadic MPNSTs. Clin Cancer Res; 19(2); 450–61. ©2012 AACR.