bluuebunny/crossref_metadata_2025 huggingface dataset:
CCR2 upregulated on peripheral T cells in osteoarthritis but not in bone marrow
Authors: Arkestål Kurt , Mints Michael , Enocson Anders , Linton Ludvig , Marits Per , Glise Hans , Andersson John , Winqvist Ola
Published: October 2018

Osteoarthritis (OA) is a condition affecting millions of patients around the world, causing pain and disability and often resulting in joint replacement surgery. The aetiology of OA has long been attributed to mechanical wear mainly due to the increased prevalence of OA in load bearing joints among older patients. However, recent studies reveal a complex molecular disease causality in which inflammation, nutritional deficit and angiogenesis lead to the destruction of the joint structure. The aim of this study was to examine chemokine receptor expression in peripheral blood and bone marrow in OA patients. We devised a protocol for extracting healthy bone marrow from patients undergoing hip arthroplasty due to coxarthrosis. Flow cytometry was used to determine the expression of 18 chemokine receptors on CD4 and CD8 T cells from bone marrow and blood from 7 osteoarthritis patients and peripheral blood from 9 healthy controls. We found a significantly increased fraction of CCR2 expressing CD4 and CD8 T cell in peripheral blood compared to healthy controls. Also, there was a significant decrease in CXCR3 (Th1) (P < 0.01) expressing T cells in peripheral blood from OA patients. Finally, multivariate analysis was used to separate T cell profiles from healthy controls and OA patients and demonstrate that the divergence of chemokine receptor expression occurs in the mature T cell subsets. In conclusion, we find increased CCR2 expression in peripheral blood from OA patients that possibly may be targeted in future clinical studies.
Cell‐ and tissue‐specific epigenetic changes associated with chronic inflammation in insulin resistance and type 2 diabetes mellitus
Authors: Naidoo Velosha , Naidoo Merusha , Ghai Meenu
Published: October 2018

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycaemia, which can cause micro‐ and macrovascular complications. Chronic inflammation may be the cause and result of T2DM, and its related complications as an imbalance between pro‐ and anti‐inflammatory cytokines can affect immune functions. Apart from genetic changes occurring within the body resulting in inflammation in T2DM, epigenetic modifications can modify gene expression in response to environmental cues such as an unhealthy diet, lack of exercise and obesity. The most widely studied epigenetic modification, DNA methylation (DNAm), regulates gene expression and may manipulate inflammatory genes to increase or decrease inflammation associated with T2DM. This review explores the studies related to epigenetic changes, more specifically DNAm, associated with chronic inflammation in T2DM, at both the cell and tissue levels. Studying epigenetic alterations during inflammatory response, as a result of genetic and environmental signals, creates opportunities for the development of “early detection/relative risk” tests to aid in prevention of T2DM. Understanding inflammation in T2DM at the gene level in inflammation‐associated cells and tissues may provide further insight for the development of specific therapeutic targets for the disorder.
Elevated levels of interleukin‐33 are associated with allergic and eosinophilic asthma
Authors: Gasiuniene Edita , Janulaityte Ieva , Zemeckiene Zivile , Barkauskiene Diana , Sitkauskiene Brigita
Published: October 2018

IL‐33 is a recently discovered cytokine which plays an important role in asthma pathogenesis.

Aim

To evaluate serum IL‐33 in patients with asthma and healthy controls, and to evaluate the association of IL‐33 with different asthma phenotypes.

Methods

Patients with asthma (n = 115) and healthy subjects (n = 85) were included in the study. Subjects with asthma were divided into groups according to their phenotype: allergic/non‐allergic, eosinophilic/non‐eosinophilic, obese/non‐obese and severity according to GINA (mild, moderate and severe). The concentration of IL‐33 in serum was measured by standardized enzyme‐linked immunosorbent assay.

Results

The level of IL‐33 was significantly higher in patients with asthma when compared to healthy subjects (672.73 ± 104.47 pg/mL vs 268.52 ± 27.56 pg/mL, P < 0.05). IL‐33 was also higher in the allergic asthma group patients when compared to non‐allergic asthmatics (844.61 ± 152.08 pg/mL vs 369.56 ± 77.94 pg/mL, P < 0.05). There was a significantly higher serum IL‐33 level in the eosinophilic asthma group when compared to the group of non‐eosinophilic asthma patients (1001.10 ± 199.11 pg/mL vs 337.49 ± 72.68 pg/mL, P < 0.01). We did not find a significant difference in serum IL‐33 level between different asthma severity groups, obese and non‐obese asthmatics.

Conclusion

IL‐33 is increased in asthma patients, particularly in some phenotypes: allergic asthma and eosinophilic asthma.
Effects of capsaicin application on the skin during resting exposure to temperate and warm conditions
Authors: Botonis Petros G. , Miliotis Panagiotis G. , Kounalakis Stylianos N. , Koskolou Maria D. , Geladas Nickos D.
Published: October 2018

We investigated thermoregulatory and cardiovascular responses at rest in a temperate (20°C) and in a warm (30°C) environment (40% RH) without and with the application of capsaicin on the skin. We hypothesized that regardless of environmental temperature, capsaicin application would stimulate heat loss and concomitantly deactivate heat conservation mechanisms, thus resulting in rectal temperature (Tre) and mean blood pressure decline due to excitation of heat‐sensitive TRPV1. Ten male subjects were exposed, while seated, for 30 minutes to 20.8 ± 1.0°C or to 30.6 ± 1.1°C: without (NCA) and with (CA) application of capsaicin patches on the skin. Thermoregulatory (Tre, proximal‐distal skin temperature gradient) and cardiovascular variables (modelflow technique) as well as oxygen uptake were continuously measured. The area under the curve for Tre decline at 20°C was smaller in CA (−2.1 ± 1.3 a.u.) than in NCA (−0.6 ± 1.1 a.u., P < 0.01, r = 0.8). Likewise, at 30°C it was smaller in CA (−2.2 ± 2.1 a.u.) compared to NCA (−0.8 ± 2.0 a.u., P = 0.02, r = 0.7). Local vasomotor tone and oxygen uptake, were significantly lower by 36.7% ± 94.2% and 12.3% ± 12.3%, respectively, with capsaicin compared to NCA (P = 0.05 and P < 0.01, respectively). Additionally, in 30°C CA mean arterial pressure was lower by 10.7% ± 5.9%, 8.9% ± 5.9%, and 10.6% ± 7.0% compared to 30°C NCA, 20°C NCA, and 20°C CA, respectively (P < 0.01, P = 0.02, and P < 0.01, respectively, d = 1.4‐1.8). In conclusion, capsaicin application on the skin induced vasodilation and Tre decline. At 30°C CA, thermal responses were accompanied by arterial hypotension most likely due to the interactive effects of both stressors (warm environment and capsaicin) on cutaneous vascular regulation.
Effect of isavuconazole on tacrolimus and sirolimus serum concentrations in allogeneic hematopoietic stem cell transplant patients: A drug‐drug interaction study
Authors: Kieu Van , Jhangiani Kristi , Dadwal Sanjeet , Nakamura Ryotaro , Pon Doreen
Published: October 2018

Introduction

Isavuconazole, a triazole antifungal, is an inhibitor of cytochrome P450 3A4, which also metabolizes tacrolimus and sirolimus. In previous studies, isavuconazole administration increased tacrolimus and sirolimus area under the curve values by 2.3‐fold and 1.8‐fold, respectively, in healthy adults and tacrolimus concentration/dose (C/D) ratio by 1.3‐fold in solid organ transplant patients. We aimed to determine the magnitude of effect of isavuconazole administration on tacrolimus and sirolimus C/D ratios in allogeneic hematopoietic stem cell transplant (alloHSCT) patients.

Methods

A retrospective, single‐center, single‐arm study in adult alloHSCT patients who received at least 10 days of combination therapy with isavuconazole and tacrolimus and/or sirolimus as inpatients or outpatients was conducted. Tacrolimus and sirolimus trough serum concentrations were measured up to twice weekly for up to 4 weeks.

Results

Twenty‐two patients receiving tacrolimus and twenty patients receiving sirolimus met the inclusion criteria. The mean C/D ratio increased from baseline by 1.42‐fold for tacrolimus during week 1 (P = 0.002) and up to 1.56‐fold for sirolimus during week 2 (P = 0.02). For the remaining timepoints, tacrolimus and sirolimus C/D ratios were not statistically significantly different from baseline.

Conclusion

In alloHSCT patients, modest increases in tacrolimus and sirolimus C/D ratios from baseline were observed within the first 2 weeks after initiation of isavuconazole.
Donor‐derived strongyloidiasis after organ transplantation in Norway
Authors: Nordheim Espen , Olafsson Storrø Monica , Natvik Ane Kristine , Birkeland Kro Grete , Midtvedt Karsten , Varberg Reisæter Anna , Hagness Morten , Fevang Børre , Pettersen Frank O.
Published: October 2018

Strongyloides stercoralis is an intestinal helminth which in humans can cause asymptomatic chronic infection maintained for decades through its auto‐infective cycle. During solid organ transplantation, recipients may unintentionally receive an organ infected with strongyloides. This is a very rare complication but may have deadly outcome if not detected. We hereby report two transplant recipients whom developed Strongyloides hyperinfection syndrome after organ transplantation from the same deceased donor. Recipient 1 was kidney transplanted and presented at day 65 post engraftment with diarrhea and subsequent septicemia and gastric retention. Larvae were detected in gastric aspirate. Recipient 2 was simultaneously kidney and pancreas transplanted and presented at day 90 post engraftment also with gastric retention and septicemia. Larvae were demonstrated on duodenal biopsy and stool sample. The clinical course was complicated with severe duodenal bleedings, gastric retention, meningitis, and prolonged hospitalization. Retrospective testing of pre‐transplant donor serum was positive for Strongyloides stercoralis antibodies. As a result of disease severity and gastric retention albenazole was administered via a jejunal tube and ivermectin subcutaneously in both recipients. S stercoralis was successfully eradicated and the transplants ended up with unaffected graft function. Following these two cases, we started systematic screening of all deceased donors for serum Strongyloides IgG in October 2016. After having screened 150 utilized donors one tested positive for Strongyloides, which initiated prophylactic ivermectin treatment to organ recipients. No symptoms or disease developed. Our center will continue to screen all donors as prophylactic treatment may avert this potentially lethal complication in cases of donor‐derived Strongyloides infection.
International validation of harmonized definitions for complications of blood donations
Authors: Land Kevin J. , Townsend Mary , Goldman Mindy , Whitaker Barbee I. , Perez Gabriela E. , Wiersum‐Osselton Jo C.
Published: October 2018

BACKGROUND

In December 2014, a multinational collaboration of hemovigilance experts from the International Society of Blood Transfusion (ISBT), the International Hemovigilance Network, and AABB published harmonized definitions of complications related to blood donation titled “Standard for Surveillance of Complications Related to Blood Donation.” Both mandatory and optional terms were included. The definitions are endorsed by the Alliance of Blood Operators and the European Blood Alliance.

STUDY DESIGN AND METHODS

The objective of this study was to validate harmonized donor hemovigilance definitions with potential users. In June 2016, 30 real‐world cases were sent to potential users around the world along with the definitions, an answer sheet, and instructions on how to complete the validation exercise.

RESULTS

Overall, 54 responses from 25 countries were received, including over 400 comments. The results were presented for feedback at both ISBT and AABB meetings. Case diagnoses were consistent across most responders. Exceptions were rare adverse events, nonstandard presentations, or incomplete information. In general, the application of optional definitions, including severity grading and imputability, had the most variability.

CONCLUSION

The use of standardized terms in the donor setting serves to increase focus on donor safety, facilitate conversation, foster exchange of information, and frame questions for future research. Overall, the definitions provide adequate coverage of donor reactions; however, some terms require clarification. Severity grading and imputability and other optional terms need clear and objective definitions and instructions on when and how to use them. Additional feedback and final recommendations are summarized in this report.
Assessment of plasma lactate and core‐peripheral temperature gradient in association with stages of naturally occurring myxomatous mitral valve disease in dogs
Authors: Soares Felipe B. , Pereira‐Neto Gláucia B. , Rabelo Rodrigo C.
Published: October 2018

Objective

To evaluate plasma lactate concentrations and core‐peripheral temperature gradients as perfusion parameters in dogs with heart failure caused by myxomatous mitral valve disease (MMVD) and to determine whether the above perfusion parameters are correlated with disease stages.

Design

Prospective observational study.

Setting

University teaching hospital.

Animals

After excluding 129 dogs because of exclusion criteria, 7 dogs with heart failure classified as stage B2 and 10 dogs classified as stage C according to the American Heart Association (AHA)/American College of Cardiology (ACC) were included in the study. Six dogs without MMVD were evaluated as the control group.

Interventions

None.

Measurements and Main Results

Among the evaluated parameters, the plasma lactate concentrations were increased in stage C (median 3.70 mmol/L [33.3 mg/dL], interquartile range (IQR) 0.72 mmol/L [6.5 mg/dL]) compared with those in the control (median 2.80 mmol/L [25.2 mg/dL], IQR 0.8 mmol/L [7.2 mg/dL];P= 0.024) and stage B2 groups (median 2.70 mmol/L [24.3 mg/dL], IQR 1.8 mmol/L [16.2 mg/dL];P= 0.045). Significant differences were not observed in the core‐peripheral temperature gradients among the control, stage B2, and stage C dogs.

Conclusions

Dogs with structural heart disease as a result of MMVD may have occult tissue hypoperfusion in stage C that is demonstrated by hyperlactatemia.
Enhanced cracking in Si/B-doped Si0.70Ge0.30/Si heterostructures via hydrogen trapping effect
Authors: Wei Xing , Xue Zhongying , Chang Yongwei , Li Jiurong , Wang Gang , Chen Da , Guo Qinglei
Published: October 2018

Hydrogenation-induced cracking in Si/B-doped Si0.70Ge0.30/Si heterostructure with ultralow dose hydrogen implantation (3 × 1016/cm2) is demonstrated. The thickness of the Si0.70Ge0.30 interlayer, embedded between a 240 nm thick Si capping layer and the Si substrate, is 15 nm. After hydrogen implantation, long range H migration and trapping occurred in the Si0.70Ge0.30 interlayer are observed. Moreover, the crack is found to be closely correlated to the concentration of B atoms doped in the buried Si0.70Ge0.30 layer. With increasing B concentrations, the trapped H increases, leading to a smooth cracking confined in the Si0.70Ge0.30/Si interface, and fewer defects are found in the Si capping layer. In conjunction with plasma activation and wafer bonding, the as-transferred Si-on-insulator possesses a rather smooth surface (0.24 nm) and low threading dislocation density (4.4 × 105 cm−2).
Ab initio analysis of nucleation reactions during tungsten atomic layer deposition on Si(100) and W(110) substrates
Authors: King Mariah J. , Theofanis Patrick L. , Lemaire Paul C. , Santiso Erik E. , Parsons Gregory N.
Published: October 2018

Novel insight into the mechanisms that govern nucleation during tungsten atomic layer deposition is presented through a detailed analysis using density functional theory. Using the calculated energetics, the authors suggest the most probable series of reactions that lead to monolayer formation on desired growth surfaces, Si(100) and W(110), during sequential doses of WF6 and SiH4. From this analysis, they conclude that a relatively high-energy barrier exists for initial nucleation of WF6 on a silicon substrate; therefore, the system is limited to physical adsorption and is only capable of accessing nucleation pathways once the reaction barrier is energetically accessible. During early doses of WF6, the initial silicon surface acts as the reductant. Results from this half-reaction provide support for the noncoalesced growth of initial W layers since nucleation is shown to require a 2:1 ratio of silicon to WF6. In addition, the release of H2 is significantly favored over HF production leading to the formation of fluorine-contaminated silicon sites; etching of these sites is heavily supported by the absence of fluorine observed in experimentally deposited films as well as the high volatility of silicon-subfluorides. In the second half-reaction, SiH4 plays the multipurpose role of stripping fluorine atoms from W, displacing any adsorbed hydrogen atoms, and depositing a silicon-hydride layer. Saturation of the previously formed W layer with silicon-hydrides is a crucial step in depositing the consecutive layer since these surface species act as the reductants in the succeeding dose of WF6. The SiH4 half-reaction reaches a limit when all fluorine atoms are removed as silicon-subfluorides (SiFxHy) and tungsten sites are terminated with silicon-hydrides. The WF6 dose reaches a limit in early doses when the reductant, i.e., the surface, becomes blocked due to the formation of a planar network of fluorine-containing tungsten intermediates and in later cycles when the reductant, i.e., adsorbed silicon-hydrides, is etched entirely from the surface. Overall, the calculated energetics indicate that WFxHy, SiFx, and H2 molecules are the most probable by-products released during the ALD process. Results from this work contribute significantly to the fundamental understanding of atomic layer growth of tungsten using silicon species as reducing agents and may be used as a template for analyzing novel ALD processes.
Electrospun charge transport structures for hybrid perovskite solar cells
Authors: Murphy John P. , Brockway Molly C. , Andriolo Jessica M. , Skinner Jack L.
Published: October 2018

Hybrid perovskite solar cells are rapidly climbing in efficiency and are close to large-scale commercialization due to continued efforts in improving the opto-electronic properties and stability of hybrid perovskite materials. Improvements to the charge transport structures in hybrid perovskite solar cells allow for much higher charge extraction from perovskite solar cells, improving overall efficiency of solar cells utilizing electrospun charge transport structures. Electrospinning and postprocessing techniques were utilized to produce high surface area electron and hole transport structures for use in perovskite solar cells, and opto-electronic properties and surface/layer interactions were studied.
Streptococcus pneumoniae and Streptococcus pyogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system
Authors: Sutcliffe J , Tait-Kamradt A , Wondrack L
Published: October 2018

Macrolide-resistant Streptococcus pyogenes isolates from Finland, Australia, and the United Kingdom and, more recently, Streptococcus pneumoniae and S. pyogenes strains from the United States were shown to have an unusual resistance pattern to macrolides, lincosamides, and streptogramin B antibiotics. This pattern, referred to as M resistance, consists of susceptibility to clindamycin and streptogramin B antibiotics but resistance to 14- and 15-membered macrolides. An evaluation of the macrolide-lincosamide-streptogramin B resistance phenotypes among our streptococcal strains collected from 1993 to 1995 suggested that this unusual resistance pattern is not rare. Eighty-five percent (n = 66) of the S. pneumoniae and 75% (n = 28) of the S. pyogenes strains in our collection had an M phenotype. The mechanism of M resistance was not mediated by target modification, as isolated ribosomes from a pneumococcal strain bearing the M phenotype were fully sensitive to erythromycin. Further, the presence of an erm methylase was excluded with primers specific for an erm consensus sequence. However, results of studies that determined the uptake and incorporation of radiolabeled erythromycin into cells were consistent with the presence of a macrolide efflux determinant. The putative efflux determinant in streptococci seems to be distinct from the multicomponent macrolide efflux system in coagulase-negative staphylococci. The recognition of the prevalence of the M phenotype in streptococci has implications for sensitivity testing and may have an impact on the choice of antibiotic therapy in clinical practice.
Efficacy of single-dose ceftriaxone in experimental otitis media induced by penicillin- and cephalosporin-resistant Streptococcus pneumoniae
Authors: Barry B , Muffat-Joly M , Bauchet J , Faurisson F , Gehanno P , Pocidalo J J , Carbon C
Published: October 2018

We used a gerbil model of otitis media to assess the efficacy of single-dose ceftriaxone against three Streptococcus pneumoniae strains highly resistant to penicillin (MICs, 4 to 8 micrograms/ml) and with various susceptibilities to ceftriaxone (MICs, 0.5, 4, and 8 micrograms/ml). Middle ear infection was induced by bilateral transbullar challenge with 10(7) bacteria per ear. Antibiotic treatment was administered subcutaneously at 2 h postinfection. Infection status was checked 2 days later by counting the bacteria in middle ear and cerebrospinal fluid samples. With the cefriaxone-susceptible strain (MIC, 0.5 microgram/ml), we tested doses of 5 to 100 mg/kg of body weight. With a dose of 50 mg/kg, treatment outcome was equivalent to that with amoxicillin, which was used as a reference (25 mg/kg, two injections); no bacteria were recovered from 82% of the middle ear samples, and the rate of cerebrospinal fluid culture positivity was significantly reduced to 6%, relative to 59% for the untreated controls. Similar efficacy was obtained with a dose of 100 mg/kg against the two ceftriaxone-resistant strains. Pharmacokinetic study indicates that the values of the parameters in plasma after the administration of a dose of 100 mg/kg (peak level of total drug, 268 +/- 33 micrograms/ml; elimination half-life, 0.8 h; area under concentration-time curve, 488 micrograms.h.ml-1) were still suboptimal compared with the values of the parameters measured in pediatric patients after intravenous or intramuscular administration of a dose of 50 mg/kg. Our results indicate the efficacy of ceftriaxone against experimental cephalosporin-resistant pneumococcal otitis and provide a basis for the clinical use of single-dose ceftriaxone against pneumococcal otitis media.
Rapid, Transient Fluconazole Resistance in
Candida albicans
Is Associated with Increased mRNA Levels of
CDR
Authors: Marr Kieren A. , Lyons Christopher N. , Rustad Tiger , Bowden Raleigh A. , White Theodore C.
Published: October 2018

Fluconazole-resistant
Candida albicans
, a cause of recurrent oropharyngeal candidiasis in patients with human immunodeficiency virus infection, has recently emerged as a cause of candidiasis in patients receiving cancer chemotherapy and marrow transplantation (MT). In this study, we performed detailed molecular analyses of a series of
C. albicans
isolates from an MT patient who developed disseminated candidiasis caused by an azole-resistant strain 2 weeks after initiation of fluconazole prophylaxis (K. A. Marr, T. C. White, J. A. H. vanBurik, and R. A. Bowden, Clin. Infect. Dis. 25:908–910, 1997). DNA sequence analysis of the gene (
ERG11
) for the azole target enzyme, lanosterol demethylase, revealed no difference between sensitive and resistant isolates. A sterol biosynthesis assay revealed no difference in sterol intermediates between the sensitive and resistant isolates. Northern blotting, performed to quantify mRNA levels of genes encoding enzymes in the ergosterol biosynthesis pathway (
ERG7
,
ERG9
, and
ERG11
) and genes encoding efflux pumps (
MDR1
,
ABC1
,
YCF
, and
CDR
), revealed that azole resistance in this series is associated with increased mRNA levels for members of the ATP binding cassette (ABC) transporter superfamily,
CDR
genes. Serial growth of resistant isolates in azole-free media resulted in an increased susceptibility to azole drugs and corresponding decreased mRNA levels for the
CDR
genes. These results suggest that
C. albicans
can become transiently resistant to azole drugs rapidly after exposure to fluconazole, in association with increased expression of ABC transporter efflux pumps.
Evaluation of Antimicrobial and Lipopolysaccharide-Neutralizing Effects of a Synthetic CAP18 Fragment againstPseudomonas aeruginosain a Mouse Model
Authors: Sawa Teiji , Kurahashi Kiyoyasu , Ohara Maria , Gropper Michael A. , Doshi Vatsal , Larrick James W. , Wiener-Kronish Jeanine P.
Published: October 2018

CAP18 (cationic antimicrobial protein; 18 kDa) is a neutrophil-derived protein that can bind to and inhibit various activities of lipopolysaccharide (LPS). The 37 C-terminal amino acids of CAP18 make up the LPS-binding domain. A truncated 32-amino-acid C-terminal fragment of CAP18 had potent activity againstPseudomonas aeruginosain vitro. We studied the antimicrobial and LPS-neutralizing effects of this synthetic truncated CAP18 peptide (CAP18106–137) on lung injury in mice infected with cytotoxicP. aeruginosa. To determine its maximal effect, the CAP18106–137peptide was mixed with bacteria just prior to tracheal instillation, and lung injury was evaluated by determining the amount of leakage of an alveolar protein tracer (125I-albumin) into the circulation and by the quantification of lung edema. The lung injury caused by the instillation of 5 × 105CFU ofP. aeruginosawas significantly reduced by the concomitant instillation of CAP18106–137. However, the administration of CAP18106–137alone, without bacteria, induced lung edema, suggesting that it has some toxicity. Also, the peptide did not significantly reduce the number of bacteria that had been simultaneously instilled, nor did it significantly improve the survival of the infected mice. The addition of CAP18106–137to aztreonam along with the bacteria did decrease the level of antibiotic-induced release of inflammatory mediators including tumor necrosis factor alpha, interleukin-6, and nitric oxide and also improved the survival of the mice. Therefore, more investigations are needed to confirm the toxicities and the therapeutic benefits of CAP18106–137as an adjunctive therapy to antibiotics in the treatment of infections caused by gram-negative bacteria.
In Vitro Activity of Lumefantrine (Benflumetol) against Clinical Isolates of
Plasmodium falciparum
in Yaoundé, Cameroon
Authors: Basco Leonardo K. , Bickii Jean , Ringwald Pascal
Published: October 2018

The in vitro antimalarial activity of the new Chinese synthetic drug, lumefantrine, also known as benflumetol (a fluorene derivative belonging to the aminoalcohol class), was determined by an isotopic microtest against 61 fresh clinical isolates of
Plasmodium falciparum
and compared with that of other established antimalarial agents. The geometric mean 50% inhibitory concentration of lumefantrine was 11.9 nmol/liter (95% confidence intervals, 10.4 to 13.6 nmol/liter; range, 3.3 to 25.6 nmol/liter). The in vitro activities of lumefantrine against the chloroquine-sensitive and the chloroquine-resistant isolates did not differ (
P
> 0.05). There was a significant positive correlation of responses between lumefantrine and two other aminoalcohols studied, mefloquine (
r
= 0.688) and halofantrine (
r
= 0.677), and between lumefantrine and artesunate (
r
= 0.420), suggesting a potential for in vitro cross-resistance. Our data suggest high in vitro activity of lumefantrine, comparable to that of mefloquine, and are in agreement with the promising results of preliminary clinical trials.
Chemoprophylaxis of Influenza A Virus Infections, with Single Doses of Zanamivir, Demonstrates that Zanamivir Is Cleared Slowly from the Respiratory Tract
Authors: Fenton Robert J. , Morley Peter J. , Owens Ian J. , Gower David , Parry Simon , Crossman Lee , Wong Tony
Published: October 2018

Zanamivir (4-guanidino-2,4-dideoxy-2,3-dehydro-
N
-acetylneuraminic acid; Relenza; GG167) is a potent and highly specific neuraminidase (sialidase) inhibitor with inhibitory activity in vivo against both influenza A and B viruses. This compound has been extensively tested in both mouse and ferret models of influenza and has recently been approved for the treatment of influenza in Europe and Australasia. The compound markedly reduces the clinical course of disease in humans when given therapeutically by inhalation directly into the respiratory tract. In addition, experimental influenza infections in phase I clinical trials have shown the benefit of giving a single prophylactic dose of zanamivir in addition to a therapeutic regime. The studies reported here were designed to determine the persistence of zanamivir, as assessed by its antiviral activity in vivo, in the respiratory tracts of infected animals. We have shown that the prophylactic administration of zanamivir, when the drug is given in a single dose by the intranasal route, can significantly reduce lung virus titers in the mouse and can reduce both viral titers and symptoms in the ferret. Whole-body autoradiographical analyses of mice have indicated a long retention time for this compound in respiratory tract tissues when it is given in a single dose by the intranasal route. These results indicate that zanamivir may have clinical value as a prophylactic agent in protecting at-risk groups from influenza virus infection. In addition, these data may be useful in the design of prophylactic protocols for humans, in that the dosing schedule may only need to be intermittent to provide protection.
Safety and Single-Dose Pharmacokinetics of Abacavir (1592U89) in Human Immunodeficiency Virus Type 1-Infected Children
Authors: Hughes Walter , McDowell James A. , Shenep Jerry , Flynn Patricia , Kline Mark W. , Yogev Ram , Symonds William , Lou Yu , Hetherington Seth
Published: October 2018

Abacavir (formerly 1592U89) is a potent 2′-deoxyguanosine analog reverse transcriptase inhibitor that has been demonstrated to have a favorable safety profile in initial clinical trials with adults with human immunodeficiency virus (HIV) type 1 infection. A phase I study was conducted to evaluate the pharmacokinetics and safety of abacavir following the administration of two single oral doses (4 and 8 mg/kg of body weight) to 22 HIV-infected children ages 3 months to 13 years. Plasma was collected for analysis at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 5, and 8 h after the administration of each dose. Plasma abacavir concentrations were determined by high-performance liquid chromatography, and data were analyzed by noncompartmental methods. Abacavir was well tolerated by all subjects. The single abacavir-related adverse event was rash, which occurred in 2 of 22 subjects. After administration of the oral solution, abacavir was rapidly absorbed, with the time to the peak concentration in plasma occurring within 1.5 h postdosing. Pharmacokinetic parameter estimates were comparable among the different age groups for each dose level. The mean maximum concentration in plasma (
C
max
) and the mean area under the curve from time zero to infinity (AUC
0–∞
) increased by 16 and 45% more than predicted, respectively, as the abacavir dose was doubled from 4 to 8 mg/kg (
C
max
increased from 1.69 to 3.94 μg/ml, and AUC
0–∞
increased from 2.82 to 8.09 μg · h/ml). Abacavir was rapidly eliminated, with a mean elimination half-life of 0.98 to 1.13 h. The mean apparent clearance from plasma decreased from 27.35 to 18.88 ml/min/kg as the dose increased. Neither body surface area nor creatinine clearance were correlated with pharmacokinetic estimates at either dose. The extent of exposure to abacavir appears to be slightly lower in children than in adults, with the comparable unit doses being based on body weight. In conclusion, this study showed that abacavir is safe and well tolerated in children when it is administered as a single oral dose of 4 or 8 mg/kg.
Effects of the Hematoregulatory Peptide SK&F 107647 Alone and in Combination with Amphotericin B against Disseminated Candidiasis in Persistently Neutropenic Rabbits
Authors: Lyman Caron A. , Gonzalez Corina , Schneider Mark , Lee James , Walsh Thomas J.
Published: October 2018

The effects of the hematoregulatory peptide SK&F 107647 were examined in a persistently and profoundly neutropenic rabbit model of disseminated candidiasis in order to determine its potential to enhance resistance against infection and its role as an adjunct to conventional antifungal chemotherapy. In healthy animals, SK&F 107647 elicited a time-dependent increase in CD11b-positive monocytes and neutrophils. When administered to neutropenic rabbits infected with
Candida albicans
, no significant differences in the number of CFU per gram in any of the tissues tested compared with the number in untreated control rabbits were detected. However, when SK&F 107647 was administered in combination with low doses of amphotericin B, there was a significant reduction in organism burden in the lungs, liver, spleen, and kidneys compared with the burdens in the organs of untreated control animals and in the lungs and kidneys compared with the burdens in the lungs and kidneys of animals treated with amphotericin B alone. These data suggest a potential role for this peptide as adjunctive therapy in combination with conventional antifungal agents in the treatment of disseminated candidiasis in the setting of profound and persistent neutropenia.
A Simple
In Vitro
Gut Model for Studying the Interaction between Escherichia coli and the Intestinal Commensal Microbiota in Cecal Mucus
Authors: Mokszycki Matthew E. , Leatham-Jensen Mary , Steffensen Jon L. , Zhang Ying , Krogfelt Karen A. , Caldwell Matthew E. , Conway Tyrrell , Cohen Paul S.
Published: October 2018

Both commensal and pathogenic strains of
Escherichia coli
appear to colonize the mammalian intestine by interacting physically and metabolically with other members of the microbiota in the mucus layer that overlays the cecal and colonic epithelium. However, the use of animal models and the complexity of the mammalian gut make it difficult to isolate experimental variables that might dictate the interactions between
E. coli
and other members of the microbiota, such as those that are critical for successful colonization. Here, we describe a simple and relatively inexpensive
in vitro
gut model that largely mimics
in vivo
conditions and therefore can facilitate the manipulation of experimental variables for studying the interactions of
E. coli
with the intestinal microbiota.
The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S
Authors: Wenzel Michaela , Rautenbach Marina , Vosloo J. Arnold , Siersma Tjalling , Aisenbrey Christopher H. M. , Zaitseva Ekaterina , Laubscher Wikus E. , van Rensburg Wilma , Behrends Jan C. , Bechinger Burkhard , Hamoen Leendert W.
Published: October 2018

Cyclic β-sheet decapeptides, such as tyrocidines and gramicidin S, were among the first antibiotics in clinical application. Although they have been used for such a long time, there is virtually no resistance to them, which has led to a renewed interest in this peptide class. Both tyrocidines and gramicidin S are thought to disrupt the bacterial membrane. However, this knowledge is mainly derived from
in vitro
studies, and there is surprisingly little knowledge about how these long-established antibiotics kill bacteria. Our results shed new light on the antibacterial mechanism of β-sheet peptide antibiotics and explain why they are still so effective and why there is so little resistance to them.
Octopaminergic Signaling Mediates Neural Regulation of Innate Immunity in Caenorhabditis elegans
Authors: Sellegounder Durai , Yuan Chung-Hsiang , Wibisono Phillip , Liu Yiyong , Sun Jingru
Published: October 2018

Insufficient or excessive immune responses to pathogen infection are major causes of disease. Increasing evidence indicates that the nervous system regulates the immune system to help maintain immunological homeostasis. However, the precise mechanisms of this regulation are largely unknown. Here we show the existence of an octopaminergic immunoinhibitory pathway in
Caenorhabditis elegans
. Our study results indicate that this pathway is tonically active under normal conditions to maintain immunological homeostasis or suppress unwanted innate immune responses but downregulated upon pathogen infection to allow enhanced innate immunity. As excessive innate immune responses have been linked to human health conditions such as Crohn's disease, rheumatoid arthritis, atherosclerosis, diabetes, and Alzheimer's disease, elucidating octopaminergic neural regulation of innate immunity could be helpful in the development of new treatments for innate immune diseases.
Inducible Nitric Oxide Synthase Is a Key Host Factor forToxoplasmaGRA15-Dependent Disruption of the Gamma Interferon-Induced Antiparasitic Human Response
Authors: Bando Hironori , Lee Youngae , Sakaguchi Naoya , Pradipta Ariel , Ma Ji Su , Tanaka Shun , Cai Yihong , Liu Jianfa , Shen Jilong , Nishikawa Yoshifumi , Sasai Miwa , Yamamoto Masahiro
Published: October 2018

Toxoplasma,an important intracellular parasite of humans and animals, causes life-threatening toxoplasmosis in immunocompromised individuals. Gamma interferon (IFN-γ) is produced in the host to inhibit the proliferation of this parasite and eventually cause its death. Unlike mouse disease models, which involve well-characterized virulence strategies that are used byToxoplasmato suppress IFN-γ-dependent immunity, the strategies used byToxoplasmain humans remain unclear. Here, we show that GRA15, aToxoplasmaeffector protein, suppresses the IFN-γ-induced indole-2,3-dioxygenase 1-dependent antiparasite immune response in human cells. Because NLRP3-dependent production of IL-1β and nitric oxide (NO) inToxoplasma-infected human cells is involved in the GRA15-dependent virulence mechanism, blocking NO or IL-1β production in the host could represent a novel therapeutic approach for treating human toxoplasmosis.
WHONDRS: a Community Resource for Studying Dynamic River Corridors
Authors: Stegen James C. , Goldman Amy E.
Published: October 2018

The Worldwide Hydrobiogeochemistry Observation Network for Dynamic River Systems (WHONDRS) aims to galvanize a global community to provide the scientific basis for improved management of dynamic river corridors. WHONDRS is a global research consortium working to understand connections among dynamic hydrology, biogeochemistry, and microbiology in river corridors from local to global scales.
Prediction of school outcome after preterm birth: a cohort study
Authors: Odd David , Evans David , Emond Alan M
Published: October 2018

Objective

To identify if the educational trajectories of preterm infants differ from those of their term peers.

Design

This work is based on the Avon Longitudinal Study of Parents and Children (ALSPAC). Educational measures were categorised into 10 deciles to allow comparison of measures across time periods. Gestational age was categorised as preterm (23–36 weeks) or term (37–42 weeks). Multilevel mixed-effects linear regression models were derived to examine the trajectories of decile scores across the study period. Gestational group was added as an interaction term to assess if the trajectory between educational measures varied between preterm and term infants. Adjustment for possible confounders was performed.

Subjects

The final dataset contained information on 12 586 infants born alive at between 23 weeks and 42 weeks of gestation.

Main outcome measures

UK mandatory educational assessments (SATs) scores throughout educational journal (including final GCSE results at 16 years of age).

Results

Preterm infants had on average lower Key Stage (KS) scores than term children (−0.46 (−0.84 to −0.07)). However, on average, they gained on their term peers in each progressive measure (0.10 (0.01 to 0.19)), suggesting ‘catch up’ during the first few years at school. Preterm infants appeared to exhibit the increase in decile scores mostly between KS1 and KS2 (p=0.005) and little between KS2 and KS3 (p=0.182) or KS3 and KS4 (p=0.149).

Conclusions

This work further emphasises the importance of early schooling and environment in these infants and suggests that support, long after the premature birth, may have additional benefits.
Myasthenia gravis crisis coinciding with asthma exacerbation in a patient with recent heroin use: three causes of acute hypercarbic respiratory failure
Authors: Aktas Adem , Rojas Edward , Parikh Hardik A , Pergament Kathleen
Published: October 2018

A 57-year-old woman with a history of asthma, hypertension and substance abuse disorder was admitted to the medical intensive care unit with hypercapnic respiratory failure. After the history was obtained, patient admitted heroin use earlier that day. The initial physical examination revealed right eye ptosis, diplopia, fatigability of neck flexion and extension. She also presented with wheezing and a prolonged expiratory phase. Pupils were 4 mm, with sluggish response to light bilaterally. CT chest with contrast showed a large mediastinal mass. Three different processes coexisted in this patient: simultaneous occurrence of a myasthenia gravis crisis, asthma exacerbation and a component of heroin use. This case highlights a series of overlapping clinical features that could lead to potential confounding and misdiagnosis. Respiratory symptoms improved after initial treatment for asthma exacerbation, but ptosis, diplopia and fatigability of neck muscles persisted.
Pericardial sarcoma
Authors: Abdelnaby Mahmoud , Almaghraby Abdallah , Saleh Yehia , Abayazeed Rasha
Published: October 2018

Pericardial sarcomas are extremely rare aggressive neoplasms. Non-specific symptoms and incidental discovery are usually the rule. Multimodality imaging is extremely important for diagnosis and tissue characterisation of all cardiac masses. Despite treatment, pericardial sarcomas are considered extremely fatal. We encountered a 27-year-old female patient who presented to our facility with progressive dyspnoea. On examination, clinical signs of cardiac tamponade were appreciated, transthoracic echocardiography revealed a tamponading pericardial effusion and a large heterogeneous pericardial mass. Pericardiocentesis revealed haemorrhagic fluid. Subsequently, CT revealed a pericardial mass compressing the right atrium. Excision biopsy showed a well-circumscribed mass, and cut sections showed friable grey–white tissue with areas of haemorrhage and necrosis. Pathological examination confirmed the diagnosis of high-grade undifferentiated sarcoma of the pericardium. The patient was started on adjuvant chemotherapy and radiotherapy. Follow-up after 1 year showed no relapse.
Large mesenteric lymphangioma in an adult patient: an unusual presentation of a rare disease
Authors: Wall Kevin C , Schmitz Robin , Carney John M , Blazer III Dan G
Published: October 2018

Lymphangiomas are most commonly described as a small painless mass in the neck or a vesicular rash in an infant patient. Ninety per cent of cases are diagnosed before the age of 2. Treatment usually involves surgical resection. Intra-abdominal lymphangiomas and mesenteric lymphangiomas, as described in our case report, represent a rare pathology. The exact prevalence of this condition is unclear but it has been suggested in the literature that there have been as few as 820 cases since the 16th century. The clinical presentation is usually subacute and diagnosis made incidentally during a workup of chronic gastrointestinal symptoms. Acute abdominal symptoms, as in our case presentation, are unusual but may be explained by the mass effect of a large intra-abdominal lesion. Cross-sectional imaging is key in preoperative workup and operative planning. Complete surgical resection is recommended and curative in the majority of cases with a low risk of local recurrence.
Rare case of adult pancreatic haemangioma and literature review
Authors: Raymundo Selma Regina de Oliveira , Hussain Kassim Mohamede Kassim , Hussein Kassim Guzzon , Kuga Magali Lúcia
Published: October 2018

Pancreatic haemangiomas are benign vascular tumours very rare in adults. Twenty-two cases are described in the literature. The symptoms are non-specific, and therefore rarely clinically suspected, and the vast majority are incidental findings in imaging tests such as ultrasound, CT, angiography or MRI. They appear on CT as a cystic lesion with contrast enhancement in the arterial phase. We present the case of a 36-year-old male patient with no history of disease, referred with lumbar pain and suspected renal calculus after tomography showing hypervascular enhancement in the pancreatic body and infiltrative lesion (possible neuroendocrine neoplasia) on MRI and biliopancreatic echoendoscopy. He was submitted to laparotomy with subtotal pancreatectomy and splenectomy and satisfactory evolution.
Macular spatial distribution of preserved autofluorescence in patients with choroideremia
Authors: Hariri Amir H , Ip Michael S , Girach Aniz , Lam Byron L , Fischer M. Dominik , Sankila Eeva-Marja , Pennesi Mark Edward , Holz Frank G , Maclaren Robert E , Birch David G , Hoyng Carel B , MacDonald Ian M , Black Graeme C , Tsang Stephen H , Bressler Neil M , Stepien Kimberly E , Larsen Michael , Gorin Michael B , Meunier Isabelle , Webster Andrew R , Sadda SriniVas
Published: October 2018

Background/Aims

To better understand the pattern of degeneration progression in cases with choroideremia.

Methods

A cohort of genotypically confirmed choroideremia cases who underwent optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging was studied. Using HEYEX review software, the foveal centre was marked on FAF images under guidance of corresponding OCT images, followed by application of an ETDRS grid. The boundaries of preserved autofluorescence (AF) were manually segmented in each individual ETDRS subfield. The regional distribution of preserved AF was assessed by comparing its area among the various subfields.

Results

A total of 168 eyes from 84 choroideremia cases were enrolled. There was a statistically significant difference in the amount of preserved AF area between inner subfields as determined by one-way analysis of variance (F (3,668)=9.997, p<0.001) and also between outer subfields (F (3,668)=8.348, p<0.001). A Tukey posthoc test revealed that the preserved AF area in the nasal subfields in both the inner and outer subfields was significantly smaller compared with analogue subfields.

Conclusion

The asymmetric spatial distribution of preserved AF in choroideremia (corresponding to the stellate shaped nature of these regions) suggests that the progression of degeneration has directional preference.