bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of idiopathic immune‐mediated hemolytic anemia with mycophenolate mofetil in five dogs
Authors: West Laura D. , Hart John R. 
Published: November 2013

AbstractBackgroundThe optimal treatment for immune‐mediated hemolytic anemia (IMHA) in dogs remains unknown. Mycophenolate mofetil (MMF) is being used with increasing frequency in veterinary medicine for immune‐mediated diseases. The goal of this pilot study was to evaluate a series of dogs diagnosed with idiopathic IMHA treated with MMF and other standard therapies. Study endpoints included all cause mortality, hospitalization length, time to resolution of spherocytosis and anemia, time to discontinuation of medications, transfusion requirement, relapse events, and MMF‐induced adverse events.Key FindingsFive dogs diagnosed with idiopathic IMHA received prednisone, MMF, and low‐dose aspirin, along with transfusions and supportive therapies as indicated. One dog was euthanized on day 20 for progressive IMHA. One dog was euthanized on day 115 for intolerable MMF‐induced gastrointestinal (GI) toxicity. Three dogs survived >1 year beyond the initial diagnosis and are alive at the time of this writing. The median length of hospitalization was 48 hours. The median time to resolution of the spherocytosis and anemia was 13 days and 44 days, respectively. The overall median time to discontinuation of MMF was 165 days. Two dogs required the use of modified cyclosporine (one with MMF, one without MMF). All dogs had suspected MMF‐induced GI toxicity, including vomiting, anorexia, or diarrhea; in 2 dogs, these side effects necessitated discontinuation of the MMF.SignificanceAlthough the study demonstrated a potential use of MMF in the induction of remission of IMHA in 4 out of 5 dogs evaluated, the level of significant MMF‐induced GI toxicity cannot justify its use with the dosage regime described here.
Retrospective Study of Cryptosporidiosis Among Diarrhoeic Children in the Arid Region of North‐Eastern Nigeria
Authors: Aniesona A. T. , Bamaiyi P. H. 
Published: November 2013

SummaryA retrospective study was carried out to investigate the prevalence of Cryptosporidium oocysts among diarrhoeic children (n = 650), aged between 0 and 15 years, living in Maiduguri metropolis (n = 220), Bama local government area (n = 278) and Gwoza local government area (n = 152). Stool samples were concentrated using the ethyl acetate sedimentation method. Data of stool samples with Cryptosporidium oocysts from patients within the specified age groups were collected and analysed. The overall prevalence was 42.9%. The prevalence was higher in Maiduguri metropolis 45.0%, which is an urban area as compared to Gwoza and Bama combined together 41.8% which are rural areas but not statistically significant at 95% confidence level (P > 0.05; OR = 1.14; CI = 0.82, 1.58). According to age, the prevalence in age group A (0–10 years) was higher (46.8%) as compared to age group B (11 < 15 years), which was 20.8%, and this was statistically significant at 95% confidence level (P < 0.05; OR = 3.34; CI = 1.98, 5.61). According to gender, males showed a higher prevalence (52.5%) compared with females (47.5%), but this was not statistically significant at 95% confidence level (P > 0.05; OR = 1.13; CI = 0.82, 1.53). Seasonal prevalence showed that hot dry months of March and April were higher compared with other months. Our findings indicate the presence of the pathogen in children in Borno State, Nigeria, with higher odds of the infection in younger children, and dry months may be more associated with the infection. Control and preventive measures should be taken to protect younger children from the infection.
Detection and Molecular Characterization of Escherichia coli CTX-M-15 and Klebsiella pneumoniae SHV-12 β-Lactamases from Bovine Mastitis Isolates in the United Kingdom
Authors: Timofte Dorina , Maciuca Iuliana E. , Evans Nicholas J. , Williams Helen , Wattret Andrew , Fick Jenny C. , Williams Nicola J. 
Published: November 2013

ABSTRACT

Recent reports raised concerns about the role that farm stock may play in the dissemination of extended-spectrum β-lactamase (ESBL)-producing bacteria. This study characterized the ESBLs in two
Escherichia coli
and three
Klebsiella pneumoniae
subsp.
pneumoniae
isolates from cases of clinical bovine mastitis in the United Kingdom. Bacterial culture and sensitivity testing of bovine mastitic milk samples identified Gram-negative cefpodoxime-resistant isolates, which were assessed for their ESBL phenotypes. Conjugation experiments and PCR-based replicon typing (PBRT) were used for characterization of transferable plasmids.
E. coli
isolates belonged to sequence type 88 (ST88; determined by multilocus sequence typing) and carried
bla
CTX-M-15
and
bla
TEM-1
, while
K. pneumoniae
subsp.
pneumoniae
isolates carried
bla
SHV-12
and
bla
TEM-1
. Conjugation experiments demonstrated that
bla
CTX-M-15
and
bla
TEM-1
were carried on a conjugative plasmid in
E. coli
, and PBRT identified this to be an IncI1 plasmid. The resistance genes were nontransferable in
K. pneumoniae
subsp.
pneumoniae
isolates. Moreover, in the
E. coli
isolates, an association of IS
Ecp
1 and IS
26
with
bla
CTX-M-15
was found where the IS
26
element was inserted upstream of both IS
Ecp1
and the
bla
CTX-M
promoter, a genetic arrangement highly similar to that described in some United Kingdom human isolates. We report the first cases in Europe of bovine mastitis due to
E. coli
CTX-M-15 and also of bovine mastitis due to
K. pneumoniae
subsp.
pneumoniae
SHV-12 β-lactamases in the United Kingdom. We also describe the genetic environment of
bla
CTX-M-15
and highlight the role that IncI1 plasmids may play in the spread and dissemination of ESBL genes, which have been described in both human and cattle isolates.
Plasma Drug Activity in Patients on Treatment for Multidrug-Resistant Tuberculosis
Authors: Mpagama Stellah G. , Ndusilo Norah , Stroup Suzanne , Kumburu Happiness , Peloquin Charles A. , Gratz Jean , Houpt Eric R. , Kibiki Gibson S. , Heysell Scott K. 
Published: November 2013

ABSTRACT

Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured
Mycobacterium tuberculosis
versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (
C
2
) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a −2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the
C
2
values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin
C
2
/MIC ratios than subjects with a TDA of ≥1.5 (9.8 ± 8.7 versus 27.0 ± 19.1;
P
= 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ≤2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (
P
= 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity
ex vivo
. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.
Antimalarial Efficacy of Hydroxyethylapoquinine (SN-119) and Its Derivatives
Authors: Sanders Natalie G. , Meyers David J. , Sullivan David J. 
Published: November 2013

ABSTRACT

Quinine and other cinchona-derived alkaloids, although recently supplanted by the artemisinins (ARTs), continue to be important for treatment of severe malaria. Quinine and quinidine have narrow therapeutic indices, and a safer quinine analog is desirable, particularly with the continued threat of antimalarial drug resistance. Hydroxyethylapoquinine (HEAQ), used at 8 g a day for dosing in humans in the 1930s and halving mortality from bacterial pneumonias, was shown to cure bird malaria in the 1940s and was also reported as treatment for human malaria cases. Here we describe synthesis of HEAQ and its novel stereoisomer hydroxyethylapoquinidine (HEAQD) along with two intermediates, hydroxyethylquinine (HEQ) and hydroxyethylquinidine (HEQD), and demonstrate comparable but elevated antimalarial 50% inhibitory concentrations (IC
50
) of 100 to 200 nM against
Plasmodium falciparum
quinine-sensitive strain 3D7 (IC
50
, 56 nM). Only HEAQD demonstrated activity against quinine-tolerant
P. falciparum
strains Dd2 and INDO with IC
50
s of 300 to 700 nM. HEQD had activity only against Dd2 with an IC
50
of 313 nM. In the lethal mouse malaria model
Plasmodium berghei
ANKA, only HEQD had activity at 20 mg/kg of body weight comparable to that of the parent quinine or quinidine drugs measured by parasite inhibition and 30-day survival. In addition, HEQ, HEQD, and HEAQ (IC
50
≥ 90 μM) have little to no human ether-à-go-go-related gene (hERG) channel inhibition expressed in CHO cells compared to HEAQD, quinine, and quinidine (hERG IC
50
s of 27, 42, and 4 μM, respectively). HEQD more closely resembled quinine
in vitro
and
in vivo
for
Plasmodium
inhibition and demonstrated little hERG channel inhibition, suggesting that further optimization and preclinical studies are warranted for this molecule.
Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia coli
Authors: Opperman Timothy J. , Kwasny Steven M. , Kim Hong-Suk , Nguyen Son T. , Houseweart Chad , D'Souza Sanjay , Walker Graham C. , Peet Norton P. , Nikaido Hiroshi , Bowlin Terry L. 
Published: November 2013

ABSTRACT

Members of the resistance-nodulation-division (RND) family of efflux pumps, such as AcrAB-TolC of
Escherichia coli
, play major roles in multidrug resistance (MDR) in Gram-negative bacteria. A strategy for combating MDR is to develop efflux pump inhibitors (EPIs) for use in combination with an antibacterial agent. Here, we describe MBX2319, a novel pyranopyridine EPI with potent activity against RND efflux pumps of the
Enterobacteriaceae
. MBX2319 decreased the MICs of ciprofloxacin (CIP), levofloxacin, and piperacillin versus
E. coli
AB1157 by 2-, 4-, and 8-fold, respectively, but did not exhibit antibacterial activity alone and was not active against AcrAB-TolC-deficient strains. MBX2319 (3.13 μM) in combination with 0.016 μg/ml CIP (minimally bactericidal) decreased the viability (CFU/ml) of
E. coli
AB1157 by 10,000-fold after 4 h of exposure, in comparison with 0.016 μg/ml CIP alone. In contrast, phenyl-arginine-β-naphthylamide (PAβN), a known EPI, did not increase the bactericidal activity of 0.016 μg/ml CIP at concentrations as high as 100 μM. MBX2319 increased intracellular accumulation of the fluorescent dye Hoechst 33342 in wild-type but not AcrAB-TolC-deficient strains and did not perturb the transmembrane proton gradient. MBX2319 was broadly active against
Enterobacteriaceae
species and
Pseudomonas aeruginosa
. MBX2319 is a potent EPI with possible utility as an adjunctive therapeutic agent for the treatment of infections caused by Gram-negative pathogens.
In Vitro
Spatial and Temporal Analysis of Mycoplasma pneumoniae Colonization of Human Airway Epithelium
Authors: Prince Oliver A. , Krunkosky Thomas M. , Krause Duncan C. 
Published: November 2013

ABSTRACT

Mycoplasma pneumoniae
is an important cause of respiratory disease, especially in school-age children and young adults. We employed normal human bronchial epithelial (NHBE) cells in air-liquid interface culture to study the interaction of
M. pneumoniae
with differentiated airway epithelium. These airway cells, when grown in air-liquid interface culture, polarize, form tight junctions, produce mucus, and develop ciliary function. We examined both qualitatively and quantitatively the role of mycoplasma gliding motility in the colonization pattern of developing airway cells, comparing wild-type
M. pneumoniae
and mutants thereof with moderate to severe defects in gliding motility. Adherence assays with radiolabeled mycoplasmas demonstrated a dramatic reduction in binding for all strains with airway cell polarization, independent of acquisition of mucociliary function. Adherence levels dropped further once NHBE cells achieved terminal differentiation, with mucociliary activity strongly selecting for full gliding competence. Analysis over time by confocal microscopy demonstrated a distinct colonization pattern that appeared to originate primarily with ciliated cells, but lateral spread from the base of the cilia was slower than expected. The data support a model in which the mucociliary apparatus impairs colonization yet cilia provide a conduit for mycoplasma access to the host cell surface and suggest acquisition of a barrier function, perhaps associated with tethered mucin levels, with NHBE cell polarization.
Geotectonic evolution of Midland Scotland from Cambrian to Silurian: a review
Authors: Bluck B.J. 
Published: November 2013

Synopsis

During its Lower Palaeozoic history, the Midland Valley of Scotland was subject to compression from the blocks on either side, confirming the views of Kennedy (1958). Cambrian–Llanvirn-aged rocks of the Hebridean craton formed part of a passive margin, which extended to the ESE and is now replaced by the metamorphic complexes of the Moine and Dalradian. Both blocks had undergone metamorphism, uplift and shedding of their covers elsewhere. The ophiolitic part of the Highland Border Complex, which may be a continuation of the structurally foreshortened and rotated Ballantrae Complex, was obducted at
c
.490 Ma and may have interacted with rocks of the Hebridean passive margin.

Ordovician rocks at Girvan are a small remnant of a one-time far larger forearc basin, which formed to the south of a major arc complex, originally situated in the Midland Valley and probably extending from somewhere in the North Sea to offshore Ireland and beyond. The Highland Border Complex includes rocks coeval with the Midland Valley arc at
c
.470 Ma that formed a back-arc basin.

The Southern Uplands have converged on the Midland Valley, with the forearc sequence apparently missing in Scotland. Part of that convergence history is recorded in the Silurian conglomerates of the southern Midland Valley. Silurian sequences in this area contain conglomerates and breccias, derived from the south that record the presence of an igneous and possibly also a metamorphic complex in the region now occupied by the trench sequence of the Southern Uplands. It is suggested that the trench was later thrust over this source block and that the Southern Upland Fault forms part of that thrust sequence.
The metamorphic complexes to the north, replacing the Hebridean passive margin, did not interact with the Midland Valley until Lower Devonian times. It follows that there was no mountain-building orogeny in Scotland, other than an arc, a sliver of trench, and numerous examples of crustal contraction by strike-slip and/or thrusting.
The High-Affinity CXCR4 Antagonist BKT140 Is Safe and Induces a Robust Mobilization of Human CD34+ Cells in Patients with Multiple Myeloma
Authors: Peled Amnon , Abraham Michal , Avivi Irit , Rowe Jacob M. , Beider Katia , Wald Hanna , Tiomkin Lena , Ribakovsky Lena , Riback Yossi , Ramati Yaron , Aviel Sigal , Galun Eithan , Shaw Howard Laurence , Eizenberg Orly , Hardan Izhar , Shimoni Avichai , Nagler Arnon 
Published: November 2013

AbstractPurpose: CXCR4 plays an important role in the retention of stem cells within the bone marrow. BKT140 (4F-benzoyl-TN14003) is a 14-residue bio stable synthetic peptide, which binds CXCR4 with a greater affinity compared with plerixafor (4 vs. 84 nmol/L). Studies in mice demonstrated the efficient and superior mobilization and transplantation of stem cells collected with GCSF-BKT140, compared with those obtained when using stem cells obtained with each one of these mobilizing agent alone. These results have served as a platform for the present clinical phase I study.Experimental Design: Eighteen patients with multiple myeloma who were preparing for their first autologous stem cell transplantation were included. Patients received a standard multiple myeloma mobilization regimen, consisting of 3 to 4 g/m2 cyclophosphamide (day 0), followed by granulocyte colony—stimulating factor (G-CSF) at 5 μg/kg/d starting on day 5 and administered between 8 and 10 pm until the end of stem cell collection. A single injection of BKT140 (0.006, 0.03, 0.1, 0.3, and 0.9 mg/kg) was administered subcutaneously on day 10 in the early morning, followed by G-CSF 12 hours later.Results: BKT140 was well tolerated at all concentrations, and none of the patients developed grade 3 and 4 toxicity. A single administration of BKT140 at the highest dose, 0.9 mg/kg, resulted in a robust mobilization and collection of CD34+ cells (20.6 ± 6.9 × 106/kg), which were obtained through a single apheresis. All transplanted patients received ∼5.3 × 106 CD34+ cells/kg, which rapidly engrafted (n = 17). The median time to neutrophil and platelet recovery was 12 and 14 days, respectively, at the highest dose (0.9 mg/kg).Conclusions: When combined with G-CSF, BKT140 is a safe and efficient stem cell mobilizer that enabled the collection of a high number of CD34+ cells in 1 and 2 aphaeresis procedures, resulting in successful engraftment. Clin Cancer Res; 20(2); 469–79. ©2013 AACR.
Tumoral Immune Suppression by Macrophages Expressing Fibroblast Activation Protein-α and Heme Oxygenase-1
Authors: Arnold James N. , Magiera Lukasz , Kraman Matthew , Fearon Douglas T. 
Published: November 2013

AbstractThe depletion of tumor stromal cells that are marked by their expression of the membrane protein fibroblast activation protein-α (FAP) overcomes immune suppression and allows an anticancer cell immune response to control tumor growth. In subcutaneous tumors established with immunogenic Lewis lung carcinoma cells expressing ovalbumin (LL2/OVA), the FAP+ population is comprised of CD45+ and CD45− cells. In the present study, we further characterize the tumoral FAP+/CD45+ population as a minor subpopulation of F4/80hi/CCR2+/CD206+ M2 macrophages. Using bone marrow chimeric mice in which the primate diphtheria toxin receptor is restricted either to the FAP+/CD45+ or to the FAP+/CD45− subset, we demonstrate by conditionally depleting each subset that both independently contribute to the immune-suppressive tumor microenvironment. A basis for the function of the FAP+/CD45+ subset is shown to be the immune inhibitory enzyme, heme oxygenase-1 (HO-1). The FAP+/CD45+ cells are the major tumoral source of HO-1, and an inhibitor of HO-1, Sn mesoporphyrin, causes the same extent of immune-dependent arrest of LL2/OVA tumor growth as does the depletion of these cells. Because this observation of immune suppression by HO-1 expressed by the FAP+/CD45+ stromal cell is replicated in a transplanted model of pancreatic ductal adenocarcinoma, we conclude that pharmacologically targeting this enzyme may improve cancer immunotherapy. Cancer Immunol Res; 2(2); 121–6. ©2013 AACR.
Myocardial Damage Detected by Late Gadolinium Enhancement Cardiovascular Magnetic Resonance Is Associated With Subsequent Hospitalization for Heart Failure
Authors: Wong Timothy C. , Piehler Kayla M. , Zareba Karolina M. , Lin Kathie , Phrampus Ashley , Patel Agam , Moon James C. , Ugander Martin , Valeti Uma , Holtz Jonathan E. , Fu Bo , Chang Chung‐Chou H. , Mathier Michael , Kellman Peter , Butler Javed , Gheorghiade Mihai , Schelbert Erik B. 
Published: November 2013

Background

Hospitalization for heart failure (
HHF
) is among the most important problems confronting medicine. Late gadolinium enhancement (
LGE
) cardiovascular magnetic resonance (
CMR
) robustly identifies intrinsic myocardial damage.
LGE
may indicate inherent vulnerability to
HHF
, regardless of etiology, across the spectrum of heart failure stage or left ventricular ejection fraction (
LVEF
).

Methods and Results

We enrolled 1068 consecutive patients referred for
CMR
where 448 (42%) exhibited
LGE
. After a median of 1.4 years (Q1 to Q3: 0.9 to 2.0 years), 57
HHF
events occurred, 15 deaths followed
HHF
, and 43 deaths occurred without antecedent
HHF
(58 total deaths). Using multivariable
C
ox regression adjusting for
LVEF
, heart failure stage, and other covariates,
LGE
was associated with first
HHF
after
CMR
(
HR
: 2.70, 95%
CI
: 1.32 to 5.50), death (
HR
: 2.13, 95%
CI
: 1.08 to 4.21), or either death or
HHF
(
HR
: 2.52, 95%
CI
: 1.49 to 4.25). Quantifying
LGE
extent yielded similar results; more
LGE
equated higher risks.
LGE
improved model discrimination (
IDI
: 0.016, 95%
CI
: 0.005 to 0.028,
P
=0.002) and reclassification of individuals at risk (continuous
NRI
: 0.40, 95%
CI
: 0.05 to 0.70,
P
=0.024). Adjustment for competing risks of death that shares common risk factors with
HHF
strengthened the
LGE
and
HHF
association (
HR
: 4.85, 95%
CI
: 1.40 to 16.9).

Conclusions

The presence and extent of
LGE
is associated with vulnerability for
HHF,
including higher risks of
HHF
across the spectrum of heart failure stage and
LVEF
. Even when
LVEF
is severely decreased, those without
LGE
appear to fare reasonably well.
LGE
may enhance risk stratification for
HHF
and may enhance both clinical and research efforts to reduce
HHF
through targeted treatment.
The Doctrines of Public Policy and Competence in Investor–State Arbitration
Authors: Ayad Mary B. 
Published: November 2013

Abstract
International commercial arbitration (ICA) and international investment arbitration (IIA), as they are currently practiced in the Middle East and North Africa (MENA) inter alia, cannot be seen in isolation. Long-standing historical forces have brought about both the development of jurisprudence as well as its current problems. In arbitrations in which one party is a MENA State, from the early oil concessions throughout the present, ICA and IIA law and practise have demonstrated that the central problem therein has to do with a conflict of laws. What is proposed herein is that common legal principles found in civil, common and Islamic law, which form part or all of the legal systems in the MENA, can be distilled to create a new ICA law code for adoption in the MENA; a code which addresses many of the doctrinal issues that arise in ICA and IIA proceedings. To this end, this article presents the results of this highly practical research which represents a synthesis of theory and practise.
Developing the Legal Environment for Business in the Kingdom of Saudi Arabia: Comments and Suggestions
Authors: Alshubaiki Torki A. 
Published: November 2013

Abstract
Closing the door of ijtihād or independent reasoning in the 10th century resulted in a legal system that was often at odds with the modern world, especially in the area of contracts. Although it is considered to be a big breakthrough at the present time that some of the religious figures or ulama in Saudi Arabia have finally expressed their interest in the codification of laws, the issue has to be dealt with from a different, not only religious, perspective. The importance of comparative law must be expressed when dealing with all commercial matters. Promoting and encouraging intellectual curiosity in different legal areas through academic institutions and research centres will drive the scholars to study the commercial law subjects from a number of different perspectives. In that process, they will develop a better understanding of their own system and know the way of developing it.