bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multidimensional Inequalities in Health Care Distribution in Provincial China: A Case Study of Henan Province
Authors: Li Yingru , Wei Yehua Dennis 
Published: January 2014

AbstractThis paper analyses multidimensional inequalities in health care distribution for Henan Province in central China. The paper has two objectives: (1) examining the multi‐scale health care inequality in Henan from two dimensions, urban‐rural and core‐periphery and (2) revealing the spatial effects of China's multiple transitions, provincial development strategies, and local economic development on health care distribution. The authors used geographic information systems‐based spatial statistical methods to detect the spatial‐temporal variation of health care distribution, and applied geographically weighted regression to reveal the effects of multiple transitions on the health care sector. The results illustrate that urban‐rural and core‐periphery gaps in Henan are still significant even though health care reforms and recent provincial policies have improved the access of rural and peripheral areas to health care. Health care inequality is sensitive to geographical scale and clustering, and spatial patterns of health care are shaped by the interwoven forces at national, provincial, and local scales.
On the Spatial Dimension of the Gender Division of Paid Work in Two‐Parent Families: The Case of Amsterdam, the Netherlands
Authors: Boterman Willem R. , Karsten Lia 
Published: January 2014

AbstractResearch shows that female participation rates are lower in suburbs than in urban areas. In this paper we explore the residential patterns of the gender division of family households at the level of the neighbourhood. We draw on national register data (SSB) to define various arrangements of the way in which parents with dependent children divide paid work. These household arrangements are plotted onto maps to sketch the geography of division of paid work in Amsterdam. Our findings show that family households with specific gender divisions of paid work tend to cluster in specific residential environments: (1) families who work with a traditional division of labour are concentrated in social‐housing estates in neighbourhoods with high shares of non‐Western minorities; (2) one‐and‐a‐half earner families are clustered in the most suburban parts of the city; and (3) symmetrical and female‐breadwinner households concentrate in central gentrification areas of the city.
Deontic Tense Logic With Historical Necessity, Frame Constants, and a Solution to the Epistemic Obligation Paradox (The “Knower”)
Authors: Åqvist Lennart 
Published: January 2014

AbstractIn an earlier paper by the author, Åqvist (1999), I presented an approach to the logic of historical necessity, or inevitability, in the sense of a “two‐dimensional” combination of tense and modal logic for worlds, or histories, with the same time order, known as T × W logic. Distinctive features of that approach were, apart from its two‐dimensionality, its being based on discrete and finite time, and its use of so‐called systematic frame constants in order to enable us to indicate longitudes (x‐values) and latitudes (y‐values) of any points in the co‐ordinate systems under consideration. This led us to study and axiomatize an infinite hierarchy HTWxy of two‐dimensional modal tense logics with the characteristic operators for historical necessity and possibility added to the original basic vocabulary. The main purpose of the present paper is then twofold: (A) to extend the logics HTWxy to the interesting branch of philosophical logic constituted by deontic logic as combined with tense (or temporal) logic; and (B) to deal with a curious puzzle known as the so‐called epistemic obligation paradox – a well known stumbling‐block in this area of research in philosophical logic. We argue for a solution to both these problems, which appeals to a new infinite hierarchy DHTWxym of extensions of the HTWxy in the sense of logics combining dyadic deontic modalities with temporal ones such as those for historical necessity and other two‐dimensional modalities.
Partnership on Rotational ViscoElastic Test Standardization (PROVETS): Evidence‐based guidelines on rotational viscoelastic assays in veterinary medicine
Authors: Goggs Robert , Brainard Benjamin , de Laforcade Armelle M. , Flatland Bente , Hanel Rita , McMichael Maureen , Wiinberg Bo 
Published: January 2014

AbstractObjectiveTo systematically examine the evidence relating to the performance of rotational viscoelastic testing in companion animals, to develop assay guidelines, and to identify knowledge gaps.DesignMultiple questions were considered within 5 parent domains, specifically system comparability, sample handling, assay activation and test protocol, definitions and data reporting, and nonstandard assays. Standardized, systematic evaluation of the literature was performed. Relevant articles were categorized according to level of evidence and assessed for quality. Consensus was developed regarding conclusions for application of concepts to clinical practice.SettingAcademic and referral veterinary medical centers.ResultsDatabases searched included Medline, Commonwealth Agricultural Bureaux abstracts, and Google Scholar. Worksheets were prepared evaluating 28 questions across the 5 domains and generating 84 assay guidelines.ConclusionsEvidence‐based guidelines for the performance of thromboelastography in companion animals were generated through this process. Some of these guidelines are well supported while others will benefit from additional evidence. Many knowledge gaps were identified and future work should be directed to address these gaps and to objectively evaluate the impact of these guidelines on assay comparability within and between centers.
Peripherally driven low‐threshold inhibitory inputs to lamina I local‐circuit and projection neurones: a new circuit for gating pain responses
Authors: Luz Liliana L. , Szucs Peter , Safronov Boris V. 
Published: January 2014

Key points
Spinal lamina I is a key element of the pain processing system which relays peripheral inputs to supraspinal areas.
In this study, we focused on signal processing in identified lamina I local‐circuit and projection neurones in their functionally preserved network in an isolated spinal cord preparation.
We found that local‐circuit neurones generate spontaneous rhythmic firing, which persists in the presence of blockers of fast synaptic transmission.
We describe a novel, low‐threshold, primary afferent‐driven inhibitory input to lamina I neurones, which temporally preceded classical high‐threshold excitatory inputs and may function as a postsynaptic gate controlling pain.
One‐third of local‐circuit neurones and two‐thirds of projection neurones responded to substance P application.
These results help us understand the role of lamina I neurones in a new circuit for gating pain responses.
AbstractSpinal lamina I is a key element of the pain processing system which relays primary afferent input to supraspinal areas. However, little is known about how the signal is modulated by its intrinsic network including local‐circuit neurones (LCNs) and much less numerous anterolateral tract projection neurones (PNs). Here, we used whole‐cell patch clamp recordings in an isolated spinal cord preparation to examine properties of identified LCNs (n = 85) and PNs (n = 73) in their functionally preserved local networks. Forty LCNs showed spontaneous rhythmic firing (2–7 Hz) at zero current injection, which persisted in the presence of blockers of fast synaptic transmission. In the remaining cases, most LCNs and PNs fired tonically in response to depolarizing current injections. We identified LCNs and PNs receiving low‐threshold primary afferent‐driven inhibitory inputs, which in many cases were disynaptic and temporally preceded classical high‐threshold excitatory inputs. This direct inhibitory link between low‐threshold afferents and PNs can function as a postsynaptic gate controlling the nociceptive information flow in the spinal cord. The LCNs were found to be integrated into the superficial dorsal horn network by their receipt of monosynaptic and disynaptic inputs from other lamina I and II neurones. One‐third of LCNs and two‐thirds of PNs tested responded to substance P application. Thus, substance P released by a noxious afferent stimulation may excite PNs in two ways: directly, and via the activation of presynaptic LCN circuitries. In conclusion, we have described important properties of identified lamina I neurones and their roles in a new circuit for gating pain responses.
Single-Dose Pharmacokinetics of Cidofovir in Continuous Venovenous Hemofiltration
Authors: Vossen Matthias G. , Gattringer Klaus-Bernhard , Jäger Walter , Kraff Stefanie , Thalhammer Florian 
Published: January 2014

ABSTRACT
Dosage recommendations for cidofovir are available for renally competent as well as impaired patients; however, there are no data for patients undergoing continuous renal replacement therapy. We determined the single-dose concentration-versus-time profile of cidofovir in a critically ill patient undergoing continuous venovenous hemofiltration (CVVH). One dose of 450 mg cidofovir (5 mg/kg) was administered intravenously due to a proven cytomegalovirus (CMV) infection and failure of first-line antiviral therapy. Additionally, 2 g of probenecid was administered orally 3 h prior to and 1 g was administered 2 h as well as 8 h after completion of the infusion. The concentrations of cidofovir in serum and ultrafiltrate were assessed by high-performance liquid chromatography. The peak serum concentration measured at 60 min postinfusion was 28.01 mg/liter at the arterial port. The trough serum level was 19.33 mg/liter at the arterial port after 24 h. The value of the area under the concentration-versus-time curve from 0 to 24 h was 543.8 mg · h/liter. The total body clearance was 2.46 ml/h/kg, and the elimination half-life time was 53.32 h. The sieving coefficient was 0.138 ± 0.022. Total removal of the drug was 30.99% after 24 h. Because of these data, which give us a rough idea of the concentration profile of cidofovir in patients undergoing CVVH, a toxic accumulation of the drug following repeated doses may be expected. Further trials have to be done to determine the right dosage of cidofovir in patients undergoing CVVH to avoid toxic accumulation of the drug.
Pharmacological Properties of NAI-603, a Well-Tolerated Semisynthetic Derivative of Ramoplanin
Authors: Jabes Daniela , Brunati Cristina , Candiani GianPaolo , Riva Simona , Romanó Gabriella , Maffioli Sonia , Rossi Rosaria , Simone Matteo , Gaspari Eleonora , Donadio Stefano 
Published: January 2014

ABSTRACT

NAI-603 is a ramoplanin derivative designed to overcome the tolerability issues of the parent drug as a systemic agent. NAI-603 is highly active against aerobic and anaerobic Gram-positive bacteria, with MICs ranging from 0.008 to 8 μg/ml. MICs were not significantly affected by pH (range, 6 to 8), by inoculum up to 10
8
CFU/ml, or by addition of 50% human serum. Against staphylococci and enterococci, NAI-603 was rapidly bactericidal, with minimum bactericidal concentration (MBC)/MIC ratios never exceeding 4. The frequency of spontaneous resistance was low at 2× to 4× MIC (≤1 × 10
−6
to ≤1 × 10
−8
) and below the detection limit (about ≤1 × 10
−9
) at 8× MIC. Serial subcultures at 0.5× MIC yielded at most an 8-fold increase in MICs. In a systemic infection induced by methicillin-resistant
Staphylococcus aureus
(MRSA), the 50% effective dose (ED
50
) of intravenous (i.v.) NAI-603 was 0.4 mg/kg, lower than that of oral (p.o.) linezolid (1.4 mg/kg) and subcutaneous (s.c.) teicoplanin (1.4 mg/kg) or vancomycin (0.6 mg/kg). In neutropenic mice infected with vancomycin-resistant enterococci (VRE), the ED
50
s for NAI-603 were 1.1 to 1.6 mg/kg i.v., compared to 0.5 mg/kg i.v. of ramoplanin. The bactericidal activity was confirmed
in vivo
in the rat granuloma pouch model induced by MRSA, where NAI-603, at 40 mg/kg i.v., induced about a 2- to 3-log
10
-reduction in viable bacteria in the exudates, which persisted for more than 72 h. The pharmacokinetic (PK) profiles of NAI-603 and ramoplanin at 20 mg/kg show similar half-lives (3.27 and 3.80 h, respectively) with the maximum concentration (
C
max
) markedly higher for NAI-603 (207 μg/ml versus 79 μg/ml). The favorable pharmacological profile of NAI-603, coupled with the absence of local tolerability issues, supports further investigation.
DSTP-27 Prevents Entry of Human Cytomegalovirus
Authors: Paeschke Rebekka , Woskobojnik Ina , Makarov Vadim , Schmidtke Michaela , Bogner Elke 
Published: January 2014

ABSTRACT

Human cytomegalovirus (HCMV) can cause life-threatening diseases in neonates and immunocompromised patients. Due to multiple problems caused by the current available drugs, development of new antiviral compounds is urgently needed. In this study, we characterize the anti-HCMV spectrum and mechanism of action of the
N-N
′-(bis-5 nitropyrimidyl)dispirotripiperazine derivate 27 (DSTP-27). DSTP-27 exhibited strong antiviral activity against two laboratory HCMV strains with different cell tropism as well as ganciclovir (GCV)-sensitive and GCV-resistant clinical isolates in plaque reduction assays and viral growth kinetics experiments. Interestingly, neither infectious nor noninfectious viral particles were observed by electron microscopy. Pretreatment of cell-free virus with DSTP-27 prevented virus infection. The results from time of addition assays, in which DTSP-27 was added to cells (i) before infection, (ii) during virus adsorption, or (iii) after adsorption, demonstrated an inhibitory effect on early steps of the HCMV replication cycle. This observation was confirmed by immunofluorescence as well as Western blot analysis, whereby reduced levels of the immediate early protein IE1, the processivity factor pUL44, and the tegument protein pp28 were detected. Results from attachment and penetration analyses of prechilled human embryonic lung fibroblasts revealed that virus attachment is not blocked. In addition, DSTP-27 inactivated HCMV by stable binding. Taken together, these results demonstrate that DSTP-27 (i) blocks viral penetration by interacting with the host cell and (ii) inactivates HCMV by interacting with the virus.
Overexpression of MexCD-OprJ Reduces Pseudomonas aeruginosa Virulence by Increasing Its Susceptibility to Complement-Mediated Killing
Authors: Martínez-Ramos Inmaculada , Mulet Xavier , Moyá Bartolomé , Barbier Mariette , Oliver Antonio , Albertí Sebastián 
Published: January 2014

ABSTRACTWe evaluated the resistance to complement-mediated killing of a collection of isogenicPseudomonas aeruginosastrains expressing different antimicrobial resistance phenotypes. Only thenfxBmutant demonstrated increased susceptibility to complement compared with that for the wild-type strain. This increment was due to the overexpression of MexCD-OprJ, which led to increased C3 opsonization and a reduced ability to infect the lungs of mice. Our results show that the acquisition of antibiotic resistance may alter the interplay ofP. aeruginosawith the host immune system.
Resurrecting Inactive Antimicrobial Peptides from the Lipopolysaccharide Trap
Authors: Mohanram Harini , Bhattacharjya Surajit 
Published: January 2014

ABSTRACT
Host defense antimicrobial peptides (AMPs) are a promising source of antibiotics for the treatment of multiple-drug-resistant pathogens. Lipopolysaccharide (LPS), the major component of the outer leaflet of the outer membrane of Gram-negative bacteria, functions as a permeability barrier against a variety of molecules, including AMPs. Further, LPS or endotoxin is the causative agent of sepsis killing 100,000 people per year in the United States alone. LPS can restrict the activity of AMPs inducing aggregations at the outer membrane, as observed for frog AMPs, temporins, and also in model AMPs. Aggregated AMPs, “trapped” by the outer membrane, are unable to traverse the cell wall, causing their inactivation. In this work, we show that these inactive AMPs can overcome LPS-induced aggregations while conjugated with a short LPS binding β-boomerang peptide motif and become highly bactericidal. The generated hybrid peptides exhibit activity against Gram-negative and Gram-positive bacteria in high-salt conditions and detoxify endotoxin. Structural and biophysical studies establish the mechanism of action of these peptides in LPS outer membrane. Most importantly, this study provides a new concept for the development of a potent broad-spectrum antibiotic with efficient outer membrane disruption as the mode of action.
Ruxolitinib and Tofacitinib Are Potent and Selective Inhibitors of HIV-1 Replication and Virus ReactivationIn Vitro
Authors: Gavegnano Christina , Detorio Mervi , Montero Catherine , Bosque Alberto , Planelles Vicente , Schinazi Raymond F. 
Published: January 2014

ABSTRACTThe JAK-STAT pathway is activated in both macrophages and lymphocytes upon human immunodeficiency virus type 1 (HIV-1) infection and thus represents an attractive cellular target to achieve HIV suppression and reduced inflammation, which may impact virus sanctuaries. Ruxolitinib and tofacitinib are JAK1/2 inhibitors that are FDA approved for rheumatoid arthritis and myelofibrosis, respectively, but their therapeutic application for treatment of HIV infection was unexplored. Both drugs demonstrated submicromolar inhibition of infection with HIV-1, HIV-2, and a simian-human immunodeficiency virus, RT-SHIV, across primary human or rhesus macaque lymphocytes and macrophages, with no apparent significant cytotoxicity at 2 to 3 logs above the median effective antiviral concentration. Combination of tofacitinib and ruxolitinib increased the efficacy by 53- to 161-fold versus that observed for monotherapy, respectively, and each drug applied alone to primary human lymphocytes displayed similar efficacy against HIV-1 containing various polymerase substitutions. Both drugs inhibited virus replication in lymphocytes stimulated with phytohemagglutinin (PHA) plus interleukin-2 (IL-2), but not PHA alone, and inhibited reactivation of latent HIV-1 at low-micromolar concentrations across the J-Lat T cell latency model and in primary human central memory lymphocytes. Thus, targeted inhibition of JAK provided a selective, potent, and novel mechanism to inhibit HIV-1 replication in lymphocytes and macrophages, replication of drug-resistant HIV-1, and reactivation of latent HIV-1 and has the potential to reset the immunologic milieu in HIV-infected individuals.
Protection of Mice against Shiga Toxin 2 (Stx2)-Associated Damage by Maternal Immunization with a Brucella Lumazine Synthase-Stx2 B Subunit Chimera
Authors: Mejias María Pilar , Cabrera Gabriel , Fernández-Brando Romina Jimena , Baschkier Ariela , Ghersi Giselle , Abrey-Recalde Maria Jimena , Miliwebsky Elizabeth , Meiss Roberto , Goldbaum Fernando , Zylberman Vanesa , Rivas Marta , Palermo Marina Sandra 
Published: January 2014

ABSTRACTHemolytic-uremic syndrome (HUS) is defined as the triad of anemia, thrombocytopenia, and acute kidney injury. Enterohemorrhagic Shiga toxin (Stx)-producingEscherichia coli(EHEC), which causes a prodromal hemorrhagic enteritis, remains the most common etiology of the typical or epidemic form of HUS. Because no licensed vaccine or effective therapy is presently available for human use, we recently developed a novel immunogen based on the B subunit of Shiga toxin 2 (Stx2B) and the enzyme lumazine synthase fromBrucellaspp. (BLS) (BLS-Stx2B). The aim of this study was to analyze maternal immunization with BLS-Stx2B as a possible approach for transferring anti-Stx2 protection to the offspring. BALB/c female mice were immunized with BLS-Stx2B before mating. Both dams and pups presented comparable titers of anti-Stx2B antibodies in sera and fecal extracts. Moreover, pups were totally protected against a lethal dose of systemic Stx2 injection up to 2 to 3 months postpartum. In addition, pups were resistant to an oral challenge with an Stx2-producing EHEC strain at weaning and did not develop any symptomatology associated with Stx2 toxicity. Fostering experiments demonstrated that anti-Stx2B neutralizing IgG antibodies were transmitted through breast-feeding. Pups that survived the EHEC infection due to maternally transferred immunity prolonged an active and specific immune response that protected them against a subsequent challenge with intravenous Stx2. Our study shows that maternal immunization with BLS-Stx2B was very effective at promoting the transfer of specific antibodies, and suggests that preexposure of adult females to this immunogen could protect their offspring during the early phase of life.
Hidden in Plain Sight: Chlamydial Gastrointestinal Infection and Its Relevance to Persistence in Human Genital Infection
Authors: Rank Roger G. , Yeruva Laxmi 
Published: January 2014

ABSTRACTAlthough the concept of persistence in chlamydial infections has been recognized for about 80 years, there is still very little known about the mechanism by which this occurs. In this review, we revisit an old paradigm, long known to chlamydiologists and veterinarians, that in virtually all hosts of chlamydiae, including mammals and birds, chlamydiae reside in the gastrointestinal tract for long periods of time in the absence of clinical disease. Thus, if gastrointestinal infection occurs in most hosts, then it is very likely that gastrointestinal infection occurs in humans as well. We demonstrate that gastrointestinal infection does indeed occur in humans and propose that this anatomical site is the source of persistent infection in humans. The data in ruminants and animal models demonstrate that the immune system is unable to clear chlamydiae from the gut, so they can remain indefinitely, with continual shedding in feces. Clearly, many women become reinfected from an untreated partner; however, we propose that women, cured of genital infection, remain at risk for autoinoculation from the lower gastrointestinal tract. Moreover, there are substantial data demonstrating treatment failure of chlamydial infections, particularly with azithromycin. New data in the mouse model have shown that azithromycin is far less effective against chlamydial gastrointestinal infection than against genital infections. Therefore, it is possible that women cured of genital infection by antibiotics remain infected in the gastrointestinal tract and can become reinfected by autoinoculation from that site.