bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid Detection, by PCR and Reverse Hybridization, of Mutations in the
Helicobacter pylori
23S rRNA Gene, Associated with Macrolide Resistance
Authors: van Doorn Leen-Jan , Debets-Ossenkopp Yvette J. , Marais Armelle , Sanna Ricardo , Mégraud Francis , Kusters Johannes G. , Quint Wim G. V.
Published: October 2018

A PCR-based reverse hybridization system (research prototype kit INNO-LiPA for
H. pylori
resistance) was developed and evaluated for simultaneous detection of 23S ribosomal DNA point mutations, associated with macrolide resistance in
Helicobacter pylori
. Fifty-seven
H. pylori
strains (51 natural, 6 laboratory-derived artificial, 52 resistant, and 5 susceptible strains) were tested by PCR-LiPA (detecting mutations A2115→G, G2141→A, A2142→G, A2142→C, A2143→G, A2143→C, and A2143→T), DNA sequencing, restriction fragment length polymorphism, and/or hybridization to oligonucleotide probes. Results were highly concordant, but PCR-LiPA appears to be more sensitive for the simultaneous detection of multiple mutants.
Sensitivity of Amoxicillin-Resistant
Helicobacter pylori
to Other Penicillins
Authors: Dore Maria P. , Graham David Y. , Sepulveda Antonia R. , Realdi Giuseppe , Osato Michael S.
Published: October 2018

The sensitivities to penicillins and to a penicillin and β-lactamase inhibitor combination agent were determined for
Helicobacter pylori
strains that were sensitive, moderately resistant, or highly resistant to amoxicillin. All strains were resistant to nafcillin and oxacillin. Moderately resistant strains showed an intermediate zone of inhibition to ticarcillin, mezlocillin, piperacillin, and amoxicillin-clavulanic acid. High-level resistance was associated with the smallest zone size for all penicillins tested.
Activities of Trovafloxacin Compared with Those of Other Fluoroquinolones against Purified Topoisomerases and
gyrA
and
grlA
Mutants of
Staphylococcus aureus
Authors: Gootz Thomas D. , Zaniewski Richard P. , Haskell Suzanne L. , Kaczmarek Frank S. , Maurice Alison E.
Published: October 2018

Frequencies of mutation to resistance with trovafloxacin and four other quinolones were determined with quinolone-susceptible
Staphylococcus aureus
RN4220 by a direct plating method. First-step mutants were selected less frequently with trovafloxacin (1.1 × 10
−10
at 2 to 4× the MIC) than with levofloxacin or ciprofloxacin (3.0 × 10
−7
to 3.0 × 10
−8
at 2 to 4× the MIC). Mutants with a change in GrlA (Ser80→Phe or Tyr) were most commonly selected with trovafloxacin, ciprofloxacin, levofloxacin, or pefloxacin. First-step mutants were difficult to select with sparfloxacin; however, second-step mutants with mutations in
gyrA
were easily selected when a preexisting mutation in
grlA
was present. Against 29
S. aureus
clinical isolates with known mutations in
gyrA
and/or
grlA
, trovafloxacin was the most active quinolone tested (MIC at which 50% of isolates are inhibited [MIC
50
] and MIC
90
, 1 and 4 μg/ml, respectively); in comparison, MIC
50
s and MIC
90
s were 32 and 128, 16 and 32, 8 and 32, and 128 and 256 μg/ml for ciprofloxacin, sparfloxacin, levofloxacin, and pefloxacin, respectively. Strains with a mutation in
grlA
only were generally susceptible to all of the quinolones tested. For mutants with changes in both
grlA
and
gyrA
MICs were higher and were generally above the susceptibility breakpoint for ciprofloxacin, sparfloxacin, levofloxacin, and pefloxacin. Addition of reserpine (20 μg/ml) lowered the MICs only of ciprofloxacin fourfold or more for 18 of 29 clinical strains. Topoisomerase IV and DNA gyrase genes were cloned from
S. aureus
RN4220 and from two mutants with changes in GrlA (Ser80→Phe and Glu84→Lys). The enzymes were overexpressed in
Escherichia coli
GI724, purified, and used in DNA catalytic and cleavage assays that measured the relative potency of each quinolone. Trovafloxacin was at least five times more potent than ciprofloxacin, sparfloxacin, levofloxacin, or pefloxacin in stimulating topoisomerase IV-mediated DNA cleavage. While all of the quinolones were less potent in cleavage assays with the altered topoisomerase IV, trovafloxacin retained its greater potency relative to those of the other quinolones tested. The greater intrinsic potency of trovafloxacin against the lethal topoisomerase IV target in
S. aureus
contributes to its improved potency against clinical strains of
S. aureus
that are resistant to other quinolones.
Nonnucleoside Pyrrolopyrimidines with a Unique Mechanism of Action against Human Cytomegalovirus
Authors: Jacobson Jennie G. , Renau Thomas E. , Nassiri M. Reza , Sweier Dominica G. , Breitenbach Julie M. , Townsend Leroy B. , Drach John C.
Published: October 2018

Based upon a prior study which evaluated a series of nonnucleoside pyrrolo[2,3-
d
]pyrimidines as inhibitors of human cytomegalovirus (HCMV), we have selected three active analogs for detailed study. In an HCMV plaque-reduction assay, compounds 828, 951, and 1028 had 50% inhibitory concentrations (IC
50
s) of 0.4 to 1.0 μM. Similar results were obtained when 828 and 951 were examined by HCMV enzyme-linked immunosorbent assay (IC
50
s = 1.9 and 0.4 μM, respectively) and when 828 was tested in a viral DNA-DNA hybridization assay (IC
50
= 1.3 μM). In yield-reduction assays with a low multiplicity of infection (MOI), all three compounds caused multiple log
10
reductions in virus titer, and the activities of these compounds were comparable to the activity of ganciclovir (GCV; IC
90
= 0.2 μM). In contrast to the reduction of viral titers by GCV, the reduction of viral titers by 828, 951, and 1028 decreased with increasing MOI. Cytotoxicity in human foreskin fibroblasts and KB cells ranged from 32 to >100 μM. In addition, 828 (the only compound tested) was less toxic against human bone marrow progenitor cells than GCV. Time-of-addition and time-of-removal studies established that the three pyrrolopyrimidines inhibited HCMV replication before GCV had an effect on viral DNA synthesis but after viral adsorption. Compound 828 was equally effective against GCV-sensitive and GCV-resistant HCMV clinical isolates. Combination studies with 828 and GCV showed that the effects of the two compounds on HCMV were additive but not synergistic. Taken together, the data indicate that these pyrrolopyrimidines target a viral protein that is required in an MOI-dependent manner and that is expressed early in the HCMV replication cycle.
Gastric Penetration of Amoxicillin in a Human
Helicobacter pylori
-Infected Xenograft Model
Authors: Lozniewski Alain , Duprez Adrien , Renault Corinne , Muhale Filipe , Conroy Marie-Christine , Weber Michele , Le Faou Alain , Jehl Francois
Published: October 2018

The delivery of antibiotics into
Helicobacter pylori
-infected human stomachs is still poorly understood. Human embryonic gastric xenografts in nude mice have recently been proposed as a new model for the study of
H. pylori
infection. Using this model, we compared the penetration of amoxicillin, after intraperitoneal administration of a dose of 20 mg/kg of body weight, into the gastric mucosae of infected and uninfected xenografts. The concentrations of this drug in serum and superficial gastric mucosae were determined at 20 min and 1 and 3 h after injection. Ten mice with
H. pylori
-infected grafts (
n
= 5) or uninfected grafts (
n
= 5) were studied. Mucosal samples were obtained by cryomicrotomy. The concentrations in serum were similar to those obtained in the serum of humans after oral administration of 1 g of amoxicillin. The mean area under the tissue concentration-versus-time curve from 0 to 3 h obtained for mice with infected grafts was significantly higher than that obtained for the animals with uninfected grafts (
P
= 0.01). These results suggest that the penetration of amoxicillin into the superficial gastric mucosa may be substantially increased in the case of
H. pylori
infection. Thus, human xenografts in nude mice represent a new, well-standardized model for investigation of systemic delivery of drugs into
H. pylori
-infected gastric mucosa.
Acyclovir Is Phosphorylated by the Human Cytomegalovirus UL97 Protein
Authors: Talarico Christine L. , Burnette Thimysta C. , Miller Wayne H. , Smith Sheila L. , Davis Michelle G. , Stanat Sylvia C. , Ng Teresa I. , He Zuwen , Coen Donald M. , Roizman Bernard , Biron Karen K.
Published: October 2018

Acyclovir (ACV) has shown efficacy in the prophylactic suppression of human cytomegalovirus (HCMV) reactivation in immunocompromised renal transplant patients without the toxicity associated with ganciclovir (GCV). The HCMV UL97 gene product, a protein kinase, is responsible for the phosphorylation of GCV in HCMV-infected cells. This report provides evidence for the phosphorylation of ACV by UL97. Anabolism studies with the HCMV wild-type strain AD169 and with recombinant mutants derived from marker transfer experiments performed by using mutant UL97 DNA from both clinical isolates and a laboratory-derived strain resistant to GCV showed that mutations in the UL97 gene cripple the ability of recombinant virus-infected cells to anabolize both GCV and ACV. These mutant UL97 recombinant viruses were less susceptible to both GCV and ACV than was the wild-type strain. A recombinant herpes simplex virus type 1 strain, in which the thymidine kinase gene is deleted and the UL13 gene is replaced with the HCMV UL97 gene, was able to induce the phosphorylation of ACV in infected cells. Finally, purified UL97 phosphorylated both GCV and ACV to their monophosphates. Our results indicate that UL97 promotes the selective activity of ACV against HCMV.
Antagonism of Azole Activity againstCandida albicansfollowing Induction of Multidrug Resistance Genes by Selected Antimicrobial Agents
Authors: Henry Karl W. , Cruz M. Cristina , Katiyar Santosh K. , Edlind Thomas D.
Published: October 2018

Antifungal azoles (e.g., fluconazole) are widely used for prophylaxis or treatment ofCandida albicansinfections in immunocompromised individuals, such as those with AIDS. These individuals are frequently treated with a variety of additional antimicrobial agents. Potential interactions between three azoles and 16 unrelated drugs (antiviral, antibacterial, antifungal, and antiprotozoal agents) were examined in vitro. Two compounds, tested at concentrations achievable in serum, demonstrated an antagonistic effect on azole activity againstC. albicans. At fluconazole concentrations two to four times the 50% inhibitory concentration,C. albicansgrowth (relative to treatment with fluconazole alone) increased 3- to 18-fold in the presence of albendazole (2 μg/ml) or sulfadiazine (50 μg/ml). Antagonism (3- to 78-fold) of ketoconazole and itraconazole activity by these compounds was also observed. Since azole resistance has been correlated with overexpression of genes encoding efflux proteins, we hypothesized that antagonism results from drug-induced overexpression of these same genes. Indeed, brief incubation ofC. albicanswith albendazole or sulfadiazine resulted in a 3-to->10-fold increase in RNAs encoding multidrug transporter Cdr1p or Cdr2p. Zidovudine, trimethoprim, and isoniazid, which were not antagonistic with azoles, did not induce these RNAs. Fluphenazine, a known substrate for Cdr1p and Cdr2p, strongly induced their RNAs and, consistent with our hypothesis, strongly antagonized azole activity. Finally, antagonism was shown to require a functional Cdr1p. The possibility that azole activity againstC. albicansis antagonized in vivo as well as in vitro in the presence of albendazole and sulfadiazine warrants investigation. Drug-induced overexpression of efflux proteins represents a new and potentially general mechanism for drug antagonism.
Evaluation of Low-Dose, Extended-Interval Clindamycin Regimens against
Staphylococcus aureus
and
Streptococcus pneumoniae
Using a Dynamic In Vitro Model of Infection
Authors: Lewis Russell E. , Klepser Michael E. , Ernst Erika J. , Lund Brian C. , Biedenbach Douglas J. , Jones Ronald N.
Published: October 2018

We have previously described the activity of low-dose clindamycin in extended-interval dosing regimens by determination of bactericidal titer in serum. In this study, we used a one-compartment in vitro dynamic infection model to compare the pharmacodynamics of clindamycin in three intravenous-dosing regimens (600 mg every 8 h [q8h], 300 mg q8h, and 300 mg q12h) against three clinical isolates of
Staphylococcus aureus
and two clinical isolates of
Streptococcus pneumoniae
. Test organisms were added to the central compartment of the model to yield a starting inoculum of 10
6
CFU/ml. Clindamycin was injected as a bolus into the central compartment at appropriate times over 48 h to simulate the q8h or q12h dosing regimens. Drug-free culture medium was then pumped through the system to mimic a half-life of 2.4 h. At predetermined time points during the experiment, samples were removed from the central compartments for colony count determination and drug concentration analysis. The rates of killing did not significantly differ among the three clindamycin dosing regimens against either
S. aureus
or
S. pneumoniae
(
P
= 0.88 or 0.998, respectively). Likewise, no significant differences in activities were detected among the three regimens against staphylococci (
P
= 0.677 and 0.667) or pneumococci (
P
= 0.88 and 0.99). Against an
S. aureus
isolate exhibiting inducible macrolide-lincosamide-streptogramin B resistance, none of the three clindamycin regimens prevented regrowth of the resistance phenotype in the model. In this model, clindamycin administered at a low dose in an extended-interval regimen (300 mg q12h) exhibited antibacterial activity equivalent to that of the 300- or 600-mg-q8h regimen.
Quinupristin-Dalfopristin Is Active against
Toxoplasma gondii
Authors: Khan Anis A. , Slifer Teri R. , Araujo Fausto G. , Remington Jack S.
Published: October 2018

Synercid and each of its components (quinupristin and dalfopristin) were examined for their activities against
Toxoplasma gondii
. In vitro, intracellular replication of tachyzoites was inhibited by synercid and each of its two components. The 50% inhibitory concentrations of synercid, quinupristin, and dalfopristin were 1.6, 2.7, and 6.3 μg/ml, respectively. Thus, synercid was markedly more active than its components. Treatment of acutely infected mice with 100 or 200 mg of synercid per kg of body weight per day administered intraperitoneally for 10 days resulted in survival of 50% (
P
= 0.0002) and 100% (
P
< 0.0001) of infected mice, respectively, whereas all control mice died by day 18. In contrast, treatment with 200 mg of either quinupristin and dalfopristin per kg per day alone resulted in only 20% survival; treatment with 50 mg of either drug per kg per day resulted only in the prolongation of time to death. These results suggest that synercid may be useful for treatment of toxoplasmosis in humans.
Role of Permeability in the Activities of β-Lactams against Gram-Negative Bacteria Which Produce a Group 3 β-Lactamase
Authors: Matsumura Naoki , Minami Shinzaburo , Watanabe Yasuo , Iyobe Shizuko , Mitsuhashi Susumu
Published: October 2018

The production of a group 3 β-lactamase permitted
Escherichia coli
to raise the MICs of ceftazidime, cefpirome, and meropenem greatly but those of imipenem and piperacillin only slightly. The ratios of maximum rate of hydrolysis to

K
m

of ceftazidime, cefpirome, and piperacillin were lower than those of meropenem and imipenem for the group 3 β-lactamase. The permeability coefficients for piperacillin and meropenem were higher than those for ceftazidime and cefpirome. Imipenem had the highest permeability coefficient.
Activity of Pleconaril against Enteroviruses
Authors: Pevear Daniel C. , Tull Tina M. , Seipel Martin E. , Groarke James M.
Published: October 2018

The activity of pleconaril in cell culture against prototypic enterovirus strains and 215 clinical isolates of the most commonly isolated enterovirus serotypes was examined. The latter viruses were isolated by the Centers for Disease Control and Prevention during the 1970s and 1980s from clinically ill subjects. Pleconaril at a concentration of ≤0.03 μM inhibited the replication of 50% of all clinical isolates tested. Ninety percent of the isolates were inhibited at a drug concentration of ≤0.18 μM. The most sensitive serotype, echovirus serotype 11, was also the most prevalent enterovirus in the United States from 1970 to 1983. Pleconaril was further tested for oral activity in three animal models of lethal enterovirus infection: coxsackievirus serotype A9 infection in suckling mice, coxsackievirus serotype A21 strain Kenny infection in weanling mice, and coxsackievirus serotype B3 strain M infection in adult mice. Treatment with pleconaril increased the survival rate in all three models for both prophylactic and therapeutic dosing regimens. Moreover, pleconaril dramatically reduced virus levels in target tissues of coxsackievirus serotype B3 strain M-infected animals. Pleconaril represents a promising new drug candidate for potential use in the treatment of human enteroviral infections.
Introduction of a
norA
Promoter Region Mutation into the Chromosome of a Fluoroquinolone-Susceptible Strain of
Staphylococcus aureus
Using Plasmid Integration
Authors: Kaatz Glenn W. , Seo Susan M. , Foster Timothy J.
Published: October 2018

It has been postulated that a mutation 11 bp 3′ to the −10 motif of the
norA
promoter is involved in the increased expression of the gene observed in some strains of
Staphylococcus aureus
exhibiting efflux-related fluoroquinolone resistance. Introduction of this mutation into the chromosome of a fluoroquinolone-susceptible strain by plasmid integration resulted in the minimum inhibitory concentrations of NorA substrates being increased, fluoroquinolone uptake being reduced, and
norA
expression being enhanced. Diffuse hybridization of
norA
and integrating vector probes at a similar molecular weight range, higher than that of the
norA
transcript, was observed in the integrant, suggesting the possibility of a plasmid-based promoter contributing to
norA
expression. The ratio of the quantity of this transcript, which was also observed in the parent strain of the integrant, to the quantity of primary
norA
transcript was 0.14, demonstrating that it was unlikely that this mRNA species contributed significantly to the results observed. It is more likely that the introduced promoter region mutation does affect the expression of
norA.
Immunomodulation of Pneumococcal Pulmonary Infection with

N
G

-Monomethyl-
l
-Arginine
Authors: Bergeron Yves , Ouellet Nathalie , Simard Marie , Olivier Martin , Bergeron Michel G.
Published: October 2018

It has recently become apparent that inflammatory reactions including nitric oxide (NO) release contribute to the outcome of pulmonary infections. To investigate the effect of

N
G

-monomethyl-
l
-arginine (L-NMMA), a NO synthase inhibitor, on the pathogenesis of pneumococcal pneumonia, we inoculated CD
1
Swiss mice with 10
7
CFU of
Streptococcus pneumoniae
. Treatment with two daily subcutaneous injections of 3 mg of L-NMMA per kg of body weight (over a 5-day period) reproducibly delayed mortality, as the number of surviving mice 72, 84, and 96 h after infection was increased by 16.8% (
P
< 0.05), 25.0% (
P
< 0.005), and 11.5% (
P
< 0.05), respectively. In fact, the following chronology of events was noted in L-NMMA-treated infected animals, compared to the untreated infected controls. (i) At 12 to 24 h after infection, larger amounts of leukotriene B
4
in bronchoalveolar lavage (BAL) fluid associated with greater neutrophilia in lung tissue and alveolar spaces and more persistent release of tumor necrosis factor alpha, interleukin-1 alpha (IL-1α), and IL-6 were observed. (ii) At 24 to 72 h, there was better preservation of lung ultrastructure, including reduction of edema in the interstitium and protection of alveolar spaces, despite identical bacterial growth in lungs, in L-NMMA-treated infected animals than in untreated animals. (iii) At 72 to 96 h, the death rate was delayed, despite the absence of antibiotic therapy. In our experiment, partial blockade of NO release was achieved. These data indicate that NO plays an important role in the induction of tissue injury and death during pneumococcal pneumonia and that L-NMMA is helpful for host protection.
Relationship between Pyrazinamide Resistance, Loss of Pyrazinamidase Activity, and Mutations in the
pncA
Locus in Multidrug-Resistant Clinical Isolates of
Mycobacterium tuberculosis
Authors: Mestdagh M. , Fonteyne P. A. , Realini L. , Rossau R. , Jannes G. , Mijs W. , De Smet K. A. L. , Portaels F. , Van den Eeckhout E.
Published: October 2018

Sixty-two
Mycobacterium tuberculosis
isolates were tested for pyrazinamidase activity, and their pyrazinamide susceptibility was determined by the radiometric method. Sequencing of
pncA
genes in the 23 resistant strains revealed mutations in 16 pyrazinamidase-negative strains, 11 of which had not been previously described. Six isolates containing wild-type
pncA
might possess alternative resistance mechanisms.
Identification of Antinorovirus Genes in Human Cells Using Genome-Wide CRISPR Activation Screening
Authors: Orchard Robert C. , Sullender Meagan E. , Dunlap Bria F. , Balce Dale R. , Doench John G. , Virgin Herbert W.
Published: October 2018

Norovirus is one of the leading causes of food-borne illness worldwide. Despite its prevalence, our understanding of norovirus biology is limited due to the difficulty in growing human norovirus
in vitro
and a lack of an animal model. Murine norovirus (MNoV) is a model norovirus system because MNoV replicates robustly in cell culture and in mice. To identify host genes that can restrict norovirus replication when overexpressed, we performed genome-wide CRISPR activation screens to induce gene overexpression at the native locus through recruitment of transcriptional activators to individual gene promoters. We found 49 genes that could block murine norovirus replication in human cells. Several of these genes are associated with classical immune signaling pathways, while many of the molecules we identified have not been previously associated with antiviral activity. Our data are a resource for those studying noroviruses, and we provide a robust approach to identify novel antiviral genes.
Structure of the Recombinant
Neisseria gonorrhoeae
Adhesin Complex Protein (rNg-ACP) and Generation of Murine Antibodies with Bactericidal Activity against Gonococci
Authors: Almonacid-Mendoza Hannia Liliana , Humbert María Victoria , Dijokaite Aiste , Cleary David W. , Soo Yiwen , Hung Miao-Chiu , Orr Christian M. , Machelett Moritz M. , Tews Ivo , Christodoulides Myron
Published: October 2018

Neisseria gonorrhoeae
(gonococcus [Ng]) is the causative organism of the sexually transmitted disease gonorrhoea, and the organism is listed by the World Health Organization as a high-priority pathogen for research and development of new control measures, including vaccines. In this study, we demonstrated that the
N. gonorrhoeae
adhesin complex protein (Ng-ACP) was conserved and expressed by 50 gonococcal strains and that recombinant proteins induced antibodies in mice that killed the bacteria
in vitro
. We determined the structure of Ng-ACP by X-ray crystallography and investigated structural conservation with
Neisseria meningitidis
ACP and MliC/PliC proteins from other bacteria which act as inhibitors of the human innate defense molecule lysozyme. These findings are important and suggest that Ng-ACP could provide a potential dual target for tackling gonococcal infections.
Cerebral fat embolism syndrome (FES): similar cases with different outcomes
Authors: Jorgensen Alexis , Bashir Azhar , Satpathy Jibanananda
Published: October 2018

Fat embolism syndrome (FES) is a rare multisystem, clinical syndrome occurring in 0.9%–2.2% of long-bone fractures. The severity of FES can vary from subclinical with mild respiratory changes and haematological aberrations to a fulminant state characterised by sudden onset of severe respiratory and neurological impairment. Here we present two patients with cerebral FES secondary to femur fracture. Both patients exhibited profound neurological impairment with varied outcomes. Our cases highlight the importance of a high clinical suspicion of FES in patients with long-bone fractures and neurological deterioration. We recommend early plate osteosynthesis to prevent additional emboli in patients with FES and situational placement of intracranial pressure monitoring. Finally, cerebral FES has low mortality even in a patient with tentorial herniation and fixed, dilated pupils.
Lady with ‘lobster claw’ feet
Authors: Aman Amani , Darby Louis , Rahmani Muhammad Javaid Hameed
Published: October 2018

A 94-year-old woman admitted with confusion secondary to a urinary tract infection exhibited deformities in all four limbs that were present from birth. Her appearance was suggestive of split hand/split foot malformation a rare congenital condition that affects the central rays of the distal limb portion. She had no syndromic features and had lived without support or assistance of her daily activities. A keen knitter, she regularly knitted for her three grandchildren, all of which, along with her son, were unaffected by this condition.
Palliative care clinicians and online education in India: a survey
Authors: Kiss-Lane Tayler , Spruijt Odette , Day Thomas , Lam Vivian , Ramchandran Kavitha J , Chan Sandy , Hsin Gary , Vallath Nandini , Bhatnagar Sushma , Rajagopal MR , Lorenz Karl A
Published: October 2018

Background

Whether online resources can facilitate spread of palliative care knowledge and skills in India is an urgent question given few providers and a large, ageing population.

Objectives

We surveyed needs and feasibility regarding e-learning.

Methods

Indian, Australian and North American palliative care experts developed an electronic survey using Qualtrics, emailed to all registrants of the 2017 Indian Association of Palliative Care (IAPC) conference and distributed during the conference.

Results

Of 60 respondents (66% men, 60% doctors), most worked in hospitals and had oncology backgrounds, and 35% were from Kerala and Tamil Nadu. Most (90.9%) received palliative care training in India or overseas with 41% trained in a Trivandrum Institute of Palliative Sciences residential course (4–6 weeks). 17% completed the IAPC essential certificate and 22% had undertaken various distance learning courses. Interest in online training was substantial for most aspects of palliative care.

Conclusion

There was a high level of interest and reported feasibility in taking a case-based online course. This pilot survey provides support for online case-based education in India, particularly among physicians.
The rebirth of medical paternalism: An NHS Trust v Y
Authors: Foster Charles
Published: October 2018

Over the last quarter of a century, English medical law has taken an increasingly firm stand against medical paternalism. This is exemplified by cases such as Bolitho v City and Hackney Health Authority, Chester v Afshar, and Montgomery v Lanarkshire Health Board. In relation to decision-making on behalf of incapacitous adults, the actuating principle of the Mental Capacity Act 2005 is respect for patient autonomy. The only lawful acts in relation to an incapacitous person are acts which are in the best interests of that person. The 2005 Act requires a holistic assessment of best interests. Best interests are wider than ‘medical best interests’. The 2018 judgment of the Supreme Court in An NHS Trust v Y (which concerned the question of whether a court needed to authorise the withdrawal of life-sustaining clinically administered nutrition/hydration (CANH) from patients in prolonged disorders of consciousness (PDOC)) risks reviving medical paternalism. The judgment, in its uncritical endorsement of guidelines from various medical organisations, may lend inappropriate authority to medical judgments of best interests and silence or render impotent non-medical contributions to the debate about best interests—so frustrating the 2005 Act. To minimise these dangers, a system of meditation should be instituted whenever it is proposed to withdraw (at least) life-sustaining CANH from (at least) patients with PDOC, and there needs to be a guarantee of access to the courts for families, carers and others who wish to challenge medical conclusions about withdrawal. This would entail proper public funding for such challenges.
Faddeev–Jackiw approach of noncommutative space–time electromagnetic theories
Authors: Abreu Everton M. C. , Fernandes Rafael L. , Mendes Albert C. R. , Neto Jorge Ananias , de Paula Rodrigo M.
Published: October 2018

The interest in higher derivatives field theories has its origin mainly in their influence concerning the renormalization properties of physical models and to remove ultraviolet divergences. The noncommutative Podolsky theory is a constrained system that cannot be directly quantized by the canonical way. In this work, we have used the Faddeev–Jackiw method in order to obtain the Dirac brackets of the NC space–time Maxwell, Proca and Podolsky theories.
Reliability Analysis of High Gain Integrated DC–DC Topologies for Xenon Lamp Applications
Authors: Navamani Divya , Vijayakumar K. , Manoraj Jason
Published: October 2018

Emerging switched-mode power supplies incorporated applications demand reliable, less volume and high efficient dc–dc converters. The persistent usage of the dc–dc converters in various applications makes their reliability a significant concern. Hence, this paper deals with a family of non-isolated high gain integrated dc–dc converter topologies derived from a quadratic converter. The reliability analysis is carried out using electronic equipment reliability handbook, MIL-HDBK-217F. For the first time, reliability prediction is done based on the working environment of the power electronic equipments. We developed the reliability prediction for the converters used in the lighting application such as automotive headlamp and aircraft landing lights. The mean time to failure for both the environment is calculated. The reliability comparison is carried out for the proposed topologies and the most reliable converter is chosen. Also, all the converter topologies are simulated using nL5 simulator to confirm their theoretical results. Finally, a laboratory prototype for 40 W with input voltage of 12 V is implemented for the most reliable topology to validate the steady-state analysis.
Interpolating the Schwarzschild and de Sitter metrics
Authors: Halilsoy M. , Mazharimousavi S. Habib
Published: October 2018

The binary potential technique of interpolation (by [M. Riesz, Acta Math. 81 (1949) 1]) is applied to some well-known metrics of general relativity. These include Schwarzschild, de Sitter and [Formula: see text]-dimensional BTZ spacetimes. In particular, the Schwarzschild–de Sitter solution is analyzed in some detail with a finite range parameter. Reasoning by the high level of nonlinearity and absence of a superposition law necessitates searching for alternative approaches. We propose the method of interpolation between different spacetimes as one such possibility paving the way toward controling the two-metric system by a common parameter.
The Sato-Tate distribution in thin families of elliptic curves over high degree extensions of finite fields
Authors: Shparlinski Igor E.
Published: October 2018

Over the last two decades, there has been a wave of activity establishing the Sato-Tate kind of distribution in various families of elliptic curves over prime fields. Typically the goal here is to prove this for families which are as thin as possible. We consider a function field analogue of this question, that is, for high degree extensions of a finite field where new effects allow us to study families, which are much thinner that those typically investigated over prime fields.
Modular invariants and isogenies
Authors: Pazuki Fabien
Published: October 2018

We provide explicit bounds on the difference of heights of the [Formula: see text]-invariants of isogenous elliptic curves defined over [Formula: see text]. The first one is reminiscent of a classical estimate for the Faltings height of isogenous abelian varieties, which is indeed used in the proof. We also use an explicit version of Silverman’s inequality and isogeny estimates by Gaudron and Rémond. We give applications in the study of Vélu’s formulas and of modular polynomials.
Mycofluidics: The Fluid Mechanics of Fungal Adaptation
Authors: Roper Marcus , Seminara Agnese
Published: October 2018

Fungi are the dark matter of biology, typically leading cryptic lives, buried in soil or inside of plants or other organisms, and emerging into the light only when they build their elegantly engineered fruiting bodies. Ecological success across so many niches has required that they solve many challenging fluid mechanical problems of growth, dispersal, and transport of fluids across networks. Study of fungal life histories by fluid mechanicians has shown their exquisite capability for engineering and revealed new organizing ideas for understanding fungal diversity.
Toward a Better Understanding of Assessment Centers: A Conceptual Review
Authors: Kleinmann Martin , Ingold Pia V.
Published: October 2018

Assessment centers (ACs) are employed for selecting and developing employees and leaders. They are interpersonal at their core because they consist of interactive exercises. Minding this perspective, this review focuses on the role of the assessee, the assessor, and the AC design, as well as their interplay in the interpersonal situation of the AC. Therefore, it addresses which conceptual perspectives have increased our understanding of ACs in this context. Building on this, we review relevant empirical findings. On this basis, the review contributes to an empirically driven understanding of the interpersonal nature of ACs and provides directions for practice and future research avenues on this topic as well as on technology in ACs and cross-cultural applications.
Finite-Time Stabilization for Stochastic Inertial Neural Networks with Time-Delay via Nonlinear Delay Controller
Authors: Li Deyi , Wang Yuanyuan , Chen Guici , Zhu Shasha
Published: October 2018

This paper pays close attention to the problem of finite-time stabilization related to stochastic inertial neural networks with or without time-delay. By establishing proper Lyapunov-Krasovskii functional and making use of matrix inequalities, some sufficient conditions on finite-time stabilization are obtained and the stochastic settling-time function is also estimated. Furthermore, in order to achieve the finite-time stabilization, both delayed and nondelayed nonlinear feedback controllers are designed, respectively, in terms of solutions to a set of linear matrix inequalities (LMIs). Finally, a numerical example is provided to demonstrate the correction of the theoretical results and the effectiveness of the proposed control design method.
The Single-Server Queue with the Dropping Function and Infinite Buffer
Authors: Chydzinski Andrzej , Barczyk Marek , Samociuk Dominik
Published: October 2018

We present an analysis of queues with the dropping function and infinite buffer. In such queues, the arriving packet (job, customer, etc.) can be dropped with the probability which is a function of the queue size. Currently, the main application area of the dropping function is active queue management in routers, but it is applicable also in many other queueing systems. So far, queues with the dropping function have been analyzed with finite buffers only, which led to complicated, computationally demanding formulas. Assuming infinite buffers enabled us herein to obtain formulas in compact, easy to use forms. Moreover, a model with the infinite buffer can often be used as a good approximation of the real queue, in which the buffer is large. We start with noticing that the classic stability condition, ρ<1, cannot be used for queues with the dropping function and infinite buffer. For this reason, we prove a few new, easy to use conditions, which guarantee system stability or instability. Then we prove several theorems on popular performance characteristics, including the queue size, busy period, loss ratio, output rate, and system response time. Additionally, we derive a special, very important characteristic called the burst ratio, which may influence severely the quality of real-time multimedia transmissions. All the theorems are illustrated with numerical examples, demonstrating in particular how the system stability may be tested and how the shape of the dropping function may affect different performance characteristics.
Anemia among Women Attending Antenatal Care at the University of Gondar Comprehensive Specialized Referral Hospital, Northwest Ethiopia, 2017
Authors: Worku Takele Wubet , Tariku Amare , Wagnew Shiferaw Fasil , Demsie Amare , Alemu Wondale Getinet , Zelalem Anlay Degefaye
Published: October 2018

Background. In Ethiopia, prenatal anemia is a major public health concern affecting both the health of the woman and babies. The World Health Organization recommends to conduct repeated prevalence studies concerning prenatal anemia . However, there is no recent evidence on the magnitude of the prenatal anemia. Therefore, the aim of this study was to determine the prevalence and the associated factors of prenatal anemia among women attending the Antenatal Care Clinic at the University of Gondar Referral Hospital.Methods. A facility-based cross-sectional quantitative study was conducted among 362 participants from June 03-July 08, 2017, at the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. The systematic random sampling technique was employed. Structured interviewer administered questionnaire was used. Human Immunodeficiency Virus (HIV) screening was conducted. Nutritional status of the participants was assessed. Blood sample was collected by capillary tube . Intestinal parasite was examined by stool wet mount test. HIV serostatus was detected. Anemia was defined as hemoglobin concentration below 11 g/dl. The multivariable logistic regression model was employed to identify associated factors and to control the possible effects of confounders.Result. The prevalence of anemia was 22.2% (95% CI: 18.11, 27.1%). The highest odds of anemia were observed among pregnant women with family size of >five [AOR = 3 (95% CI: 1.03, 8.65)], unprotected water source users, [AOR = 4.09 (95% CI: 1.75, 9.55)], HIV infected [AOR = 2.94(95% CI: 1.37, 6.35)], and multigravida women [AOR = 3.5 (95% CI: 1.35, 9.17)].Conclusion and Recommendations. The prevalence of anemia among pregnant women attending the University of Gondar Referral Hospital was a moderate public health problem. Unprotected water source, large family size, Human Immunodeficiency Virus infection, and repeated pregnancies were factors that predicted anemia. Thus, prevention of Human Immunodeficiency Virus infection, family planning utilization, and accessing pure water are recommended.
Irisin a Novel Metabolic Biomarker: Present Knowledge and Future Directions
Authors: Martinez Munoz Ilse Yessabel , Camarillo Romero Eneida del Socorro , Garduno Garcia Jose de Jesus
Published: October 2018

The rising prevalence of chronic diseases such as type 2 diabetes and cardiovascular diseases owing to fat mass excess has been described. In recent years, muscle function/dysfunction has become relevant in metabolic homeostasis. Irisin was described as an exercise-induced myokine. It is the product of type I membrane protein cleavage encoded by the fibronectin type III domain containing 5 (FNDC5) gene. The main beneficial function attributable to irisin is the change of subcutaneous and visceral adipose tissue into brown adipose tissue, with a consequential increase in thermogenesis. Irisin has also been described as a hormone that may have a key role in glucose homeostasis. The way the association of type 2 diabetes with obesity occurs is not fully understood. In recent years, the possible pathways through which irisin could interact with other organs such as the brain or bone have been described. The present paper intends to review the new findings and possible new directions in irisin research.
Pre-Reducing Process Kinetics to Recover Metals from Nickel Leach Waste Using Chelating Resins
Authors: Botelho Junior Amilton Barbosa , Dreisinger David Bruce , Espinosa Denise Crocce Romano , Tenório Jorge Alberto Soares
Published: October 2018

The main problem of the separation process from nickel mining using the ion exchange technique is the presence of iron, which precipitates in pH above 2.00 and causes coprecipitation of copper and cobalt. Chelating resins have the main advantage of being selected for a specific metal present in solution. Studies have been developed to increase the efficiency of metals recovery using chemical reduction and the ion exchange process to recover metals. The aim of this work was to use sodium sulfite as a reducing agent to convert Fe(III) to Fe(II). Chelating resins Lewatit® TP 207, selective for copper, and Lewatit® TP 220, selective for nickel and cobalt, were studied. Batch experiments were performed to study the effect of pH with and without sodium sulfite. Results indicated that the industrial process has increased efficiency when the reducing process is applied.
A Multimodal Molecular Imaging Study Evaluates Pharmacological Alteration of the Tumor Microenvironment to Improve Radiation Response
Authors: Takakusagi Yoichi , Naz Sarwat , Takakusagi Kaori , Ishima Masahiro , Murata Hiroshi , Ohta Keisuke , Miura Masahiko , Sugawara Fumio , Sakaguchi Kengo , Kishimoto Shun , Munasinghe Jeeva P. , Mitchell James B. , Krishna Murali C.
Published: October 2018

Hypoxic zones in solid tumors contribute to radioresistance, and pharmacologic agents that increase tumor oxygenation prior to radiation, including antiangiogenic drugs, can enhance treatment response to radiotherapy. Although such strategies have been applied, imaging assessments of tumor oxygenation to identify an optimum time window for radiotherapy have not been fully explored. In this study, we investigated the effects of α-sulfoquinovosylacyl-1,3-propanediol (SQAP or CG-0321; a synthetic derivative of an antiangiogenic agent) on the tumor microenvironment in terms of oxygen partial pressure (pO2), oxyhemoglobin saturation (sO2), blood perfusion, and microvessel density using electron paramagnetic resonance imaging, photoacoustic imaging, dynamic contrast–enhanced MRI with Gd-DTPA injection, and T2*-weighted imaging with ultrasmall superparamagnetic iron oxide (USPIO) contrast. SCCVII and A549 tumors were grown by injecting tumor cells into the hind legs of mice. Five days of daily radiation (2 Gy) combined with intravenous injection of SQAP (2 mg/kg) 30 minutes prior to irradiation significantly delayed growth of tumor xenografts. Three days of daily treatment improved tumor oxygenation and decreased tumor microvascular density on T2*-weighted images with USPIO, suggesting vascular normalization. Acute effects of SQAP on tumor oxygenation were examined by pO2, sO2, and Gd-DTPA contrast-enhanced imaging. SQAP treatment improved perfusion and tumor pO2 (ΔpO2: 3.1 ± 1.0 mmHg) and was accompanied by decreased sO2 (20%–30% decrease) in SCCVII implants 20–30 minutes after SQAP administration. These results provide evidence that SQAP transiently enhanced tumor oxygenation by facilitating oxygen dissociation from oxyhemoglobin and improving tumor perfusion. Therefore, SQAP-mediated sensitization to radiation in vivo can be attributed to increased tumor oxygenation.

Significance:

A multimodal molecular imaging study evaluates pharmacological alteration of the tumor microenvironment to improve radiation response.
Near-Infrared Dye-Labeled Anti-Prostate Stem Cell Antigen Minibody Enables Real-Time Fluorescence Imaging and Targeted Surgery in Translational Mouse Models
Authors: Zhang Mo , Kobayashi Naoko , Zettlitz Kirstin A. , Kono Evelyn A. , Yamashiro Joyce M. , Tsai Wen-Ting K. , Jiang Ziyue K. , Tran Chau P. , Wang Chung , Guan Johnny , Wu Anna M. , Reiter Robert E.
Published: October 2018

Purpose:

The inability to intraoperatively distinguish primary tumor, as well as lymphatic spread, increases the probability of positive surgical margins, tumor recurrence, and surgical toxicity. The goal of this study was to develop a tumor-specific optical probe for real-time fluorescence-guided surgery.

Experimental Design:

A humanized antibody fragment against PSCA (A11 minibody, A11 Mb) was conjugated with a near-infrared fluorophore, IRDye800CW. The integrity and binding of the probe to PSCA were confirmed by gel electrophoresis, size-exclusion chromatography, and flow cytometry, respectively. The ability of the probe to detect tumor-infiltrated lymph nodes and metastatic lesions was evaluated in 2 xenograft models, as well as in transgenic mice expressing human PSCA (hPSCA). An invasive intramuscular model was utilized to evaluate the efficacy of the A11 Mb-IRDye800CW-guided surgery.

Results:

A11 Mb was successfully conjugated with IRDye800CW and retained specific binding to PSCA. In vivo imaging showed maximal signal-to-background ratios at 48 hours. The A11 Mb-IRDye800CW specifically detected PSCA-positive primary tumors, tumor-infiltrated lymph nodes, and distant metastases with high contrast. Fluorescence guidance facilitated more complete tumor resection, reduced tumor recurrence, and improved overall survival, compared with conventional white light surgery. The probe successfully identified primary orthotopic tumors and metastatic lesions in hPSCA transgenic mice.

Conclusions:

Real-time fluorescence image–guided surgery with A11 Mb-IRDye800CW enabled detection of lymph node metastases and positive surgical margins, facilitated more complete tumor removal, and improved survival, compared with white light surgery. These results may be translatable into clinical practice to improve surgical and patient outcomes.
ODM-203, a Selective Inhibitor of FGFR and VEGFR, Shows Strong Antitumor Activity, and Induces Antitumor Immunity
Authors: Holmström Tim H. , Moilanen Anu-Maarit , Ikonen Tarja , Björkman Mari L. , Linnanen Tero , Wohlfahrt Gerd , Karlsson Stefan , Oksala Riikka , Korjamo Timo , Samajdar Susanta , Rajagopalan Srinivasan , Chelur Shekar , Narayanan Kishore , Ramachandra Raghuveer K. , Mani Jiju , Nair Rashmi , Gowda Nagaraj , Anthony Thomas , Dhodheri Samiulla , Mukherjee Subhendu , Ujjinamatada Ravi K. , Srinivas Nanduri , Ramachandra Murali , Kallio Pekka J.
Published: October 2018

Alterations in the gene encoding for the FGFR and upregulation of the VEGFR are found often in cancer, which correlate with disease progression and unfavorable survival. In addition, FGFR and VEGFR signaling synergistically promote tumor angiogenesis, and activation of FGFR signaling has been described as functional compensatory angiogenic signal following development of resistance to VEGFR inhibition. Several selective small-molecule FGFR kinase inhibitors are currently in clinical development. ODM-203 is a novel, selective, and equipotent inhibitor of the FGFR and VEGFR families. In this report we show that ODM-203 inhibits FGFR and VEGFR family kinases selectively and with equal potency in the low nanomolar range (IC50 6–35 nmol/L) in biochemical assays. In cellular assays, ODM-203 inhibits VEGFR-induced tube formation (IC50 33 nmol/L) with similar potency as it inhibits proliferation in FGFR-dependent cell lines (IC50 50–150 nmol/L). In vivo, ODM-203 shows strong antitumor activity in both FGFR-dependent xenograft models and in an angiogenic xenograft model at similar well-tolerated doses. In addition, ODM-203 inhibits metastatic tumor growth in a highly angiogenesis-dependent kidney capsule syngenic model. Interestingly, potent antitumor activity in the subcutaneous syngenic model correlated well with immune modulation in the tumor microenvironment as indicated by marked decrease in the expression of immune check points PD-1 and PD-L1 on CD8 T cells and NK cells, and increased activation of CD8 T cells. In summary, ODM-203 shows equipotent activity for both FGFR and VEGFR kinase families and antitumor activity in both FGFR and angigogenesis models.