bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular function of α7 nicotinic receptors as drug targets
Authors: Bouzat Cecilia , Lasala Matías , Nielsen Beatriz Elizabeth , Corradi Jeremías , Esandi María del Carmen 
Published: November 2017

AbstractNicotinic acetylcholine receptors (nAChRs) are pentameric ligand‐gated ion channels involved in many physiological and pathological processes. In vertebrates, there are seventeen different nAChR subunits that combine to yield a variety of receptors with different pharmacology, function, and localization. The homomeric α7 receptor is one of the most abundant nAChRs in the nervous system and it is also present in non‐neuronal cells. It plays important roles in cognition, memory, pain, neuroprotection, and inflammation. Its diverse physiological actions and associated disorders have made of α7 an attractive novel target for drug modulation. Potentiation of the α7 receptor has emerged as a novel therapeutic strategy for several neurological diseases, such as Alzheimer's and Parkinson's diseases, and inflammatory disorders. In contrast, increased α7 activity has been associated with cancer cell proliferation. The presence of different drug target sites offers a great potential for α7 modulation in different pathological contexts. In particular, compounds that target allosteric sites offer significant advantages over orthosteric agonists due to higher selectivity and a broader spectrum of degrees and mechanisms of modulation. Heterologous expression of α7, together with chaperone proteins, combined with patch clamp recordings have provided important advances in our knowledge of the molecular basis of α7 responses and their potential modulation for pathological processes. This review gives a synthetic view of α7 and its molecular function, focusing on how its unique activation and desensitization features can be modified by pharmacological agents. This fundamental information offers insights into therapeutic strategies.
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Pharmacokinetics and Drug-Drug Interactions of Lopinavir-Ritonavir Administered with First- and Second-Line Antituberculosis Drugs in HIV-Infected Children Treated for Multidrug-Resistant Tuberculosis
Authors: van der Laan Louvina E. , Garcia-Prats Anthony J. , Schaaf H. Simon , Tikiso Tjokosela , Wiesner Lubbe , de Kock Mine , Winckler Jana , Norman Jennifer , McIlleron Helen , Denti Paolo , Hesseling Anneke C. 
Published: November 2017

ABSTRACTLopinavir-ritonavir forms the backbone of current first-line antiretroviral regimens in young HIV-infected children. As multidrug-resistant (MDR) tuberculosis (TB) frequently occurs in young children in high-burden TB settings, it is important to identify potential interactions between MDR-TB treatment and lopinavir-ritonavir. We describe the pharmacokinetics of and potential drug-drug interactions between lopinavir-ritonavir and drugs routinely used for MDR-TB treatment in HIV-infected children. A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 with MDR-TB receiving treatment with combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin and 16 without TB) who were established on a lopinavir-ritonavir-containing antiretroviral regimen. One-compartment models with first-order absorption and elimination for both lopinavir and ritonavir were combined into an integrated model. The dynamic inhibitory effect of the ritonavir concentration on lopinavir clearance was described using a maximum inhibition model. Even after adjustment for the effect of body weight with allometric scaling, a large variability in lopinavir and ritonavir exposure, together with strong correlations between the pharmacokinetic parameters of lopinavir and ritonavir, was detected. MDR-TB treatment did not have a significant effect on the bioavailability, clearance, or absorption rate constants of lopinavir or ritonavir. Most children (81% of children with MDR-TB, 88% of controls) achieved therapeutic lopinavir trough concentrations (>1 mg/liter). The coadministration of lopinavir-ritonavir with drugs routinely used for the treatment of MDR-TB was found to have no significant effect on the key pharmacokinetic parameters of lopinavir or ritonavir. These findings should be considered in the context of the large interpatient variability found in the present study and the study's modest sample size.
Risk Factors and Outcomes Associated with Multidrug-Resistant Acinetobacter baumannii upon Intensive Care Unit Admission
Authors: Blanco Natalia , Harris Anthony D. , Rock Clare , Johnson J. Kristie , Pineles Lisa , Bonomo Robert A. , Srinivasan Arjun , Pettigrew Melinda M. , Thom Kerri A. 
Published: November 2017

ABSTRACT

Multidrug-resistant (MDR)
Acinetobacter baumannii
, associated with broad-spectrum antibiotic use, is an important nosocomial pathogen associated with morbidity and mortality. This study aimed to investigate the prevalence of MDR
A. baumannii
perirectal colonization among adult patients upon admission to the intensive care unit (ICU) over a 5-year period and to identify risk factors and outcomes associated with colonization. A retrospective cohort analysis of patients admitted to the medical intensive care unit (MICU) and surgical intensive care unit (SICU) at the University of Maryland Medical Center from May 2005 to September 2009 was performed using perirectal surveillance cultures on admission. Poisson and logistic models were performed to identify associated risk factors and outcomes. Four percent of the cohort were positive for MDR
A. baumannii
at ICU admission. Among patients admitted to the MICU, those positive for MDR
A. baumannii
at admission were more likely to be older, to have received antibiotics before ICU admission, and to have shorter length of stay in the hospital prior to ICU admission. Among patients admitted to the SICU, those colonized were more likely to have at least one previous admission to our hospital. Patients positive for MDR
A. baumannii
at ICU admission were 15.2 times more likely to develop a subsequent positive clinical culture for
A. baumannii
and 1.4 times more likely to die during the current hospitalization. Risk factors associated with MDR
A. baumannii
colonization differ by ICU type. Colonization acts as a marker of disease severity and of risk of developing a subsequent
Acinetobacter
infection and of dying during hospitalization. Therefore, active surveillance could guide empirical antibiotic selection and inform infection control practices.
Discovery of New Inhibitors of Toxoplasma gondii via the Pathogen Box
Authors: Spalenka Jérémy , Escotte-Binet Sandie , Bakiri Ali , Hubert Jane , Renault Jean-Hugues , Velard Frédéric , Duchateau Simon , Aubert Dominique , Huguenin Antoine , Villena Isabelle 
Published: November 2017

ABSTRACT

Toxoplasma gondii
is a cosmopolitan protozoan parasite which affects approximately 30% of the population worldwide. The drugs currently used against toxoplasmosis are few in number and show several limitations, such as drug intolerance, poor bioavailability, or drug resistance mechanism developed by the parasite. Thus, it is important to find new compounds able to inhibit parasite invasion or proliferation. In this study, the 400 compounds of the open-access Pathogen Box, provided by the Medicines for Malaria Venture (MMV) foundation, were screened for their anti-
Toxoplasma gondii
activity. A preliminary
in vitro
screening performed over 72 h by an enzyme-linked immunosorbent assay (ELISA) revealed 15 interesting compounds that were effective against
T. gondii
at 1 μM. Their cytotoxicity was estimated on Vero cells, and their 50% inhibitory concentrations (IC
50
) were further calculated. As a result, eight anti-
Toxoplasma gondii
compounds with an IC
50
of less than 2 μM and a selectivity index (SI) value of greater than 4 were identified. The most active was MMV675968, showing an IC
50
of 0.02 μM and a selectivity index value equal to 275. Two other compounds, MMV689480 and MMV687807, also showed a good activity against
T. gondii
, with IC
50
s of 0.10 μM (SI of 86.6) and 0.15 μM (SI of 11.3), respectively. Structure-activity relationships for the eight selected compounds also were discussed on the basis of fingerprinting similarity measurements using the Tanimoto method. The anti-
Toxoplasma gondii
compounds highlighted here represent potential candidates for the development of new drugs that could be used against toxoplasmosis.
Fungal Prophylaxis with a Gastro-Resistant Posaconazole Tablet for Patients with Hematological Malignancies in the POSANANTES Study
Authors: Peterlin Pierre , Chauvin Cécile , Le Gouill Steven , Pere Morgane , Dalichampt Marie , Guillaume Thierry , Garnier Alice , Paré Maxime , Le Bourgeois Amandine , Moreau Philippe , Chevallier Patrice , Deslandes Guillaume , Gastinne Thomas 
Published: November 2017

ABSTRACT

Posaconazole is an antifungal drug used in both prophylaxis and treatment of invasive fungal infections. Its oral formulation requires therapeutic drug monitoring. To overcome gastric acidity, a gastro-resistant posaconazole tablet has recently been developed. POSANANTES was a prospective noninterventional study that aimed to monitor plasma concentration trough level (
C
min
) of posaconazole tablets used prophylactically in patients with hematological malignancies. Fifty patients were included. Group A (
n
= 31) included patients receiving induction chemotherapy for myeloid malignancies, and group B (
n
= 19) included patients treated for graft-versus-host disease after allogeneic hematopoietic stem cells transplantation. In multivariate analysis, female sex, group B assignment, and evaluation of
C
min
at day 8 (versus any other day planned by the analysis) were associated with a higher
C
min
, while diarrhea was associated with a lower
C
min
(
P
< 0.05). Thirty-four percent (
n
= 17) of all included patients had to prematurely stop treatment, mainly in group A. In conclusion, this real-life prospective study showed good absorption of posaconazole tablets used for prophylaxis in patients with hematological malignancies, even though this strategy was somewhat limited due to the high number of patients in group A who had to stop their treatment in an untimely fashion.
CD101, a Novel Echinocandin, Possesses Potent Antibiofilm Activity against Early and Mature Candida albicans Biofilms
Authors: Chandra Jyotsna , Ghannoum Mahmoud A. 
Published: November 2017

ABSTRACT

Currently available echinocandins are generally effective against
Candida
biofilms, but the recent emergence of resistance has underscored the importance of developing new antifungal agents that are effective against biofilms. CD101 is a long-acting novel echinocandin with distinctive pharmacokinetic properties and improved stability and safety relative to other drugs in the same class. CD101 is currently being evaluated as a once-weekly intravenous (i.v.) infusion for the treatment of candidemia and invasive candidiasis. In this study, we determined (i) the effect of CD101 against early and mature phase biofilms formed by
C. albicans
in vitro
and (ii) the temporal effect of CD101 on the formation of biofilms using time-lapse microscopy (TLM). Early- or mature-phase biofilms were formed on silicone elastomer discs and were exposed to the test compounds for 24 h and quantified by measuring their metabolic activity. Separate batches were observed under a confocal microscope or used to capture TLM images from 0 to 16 h. Measurements of their metabolic activity showed that CD101 (0.25 or 1 μg/ml) significantly prevented adhesion-phase cells from developing into mature biofilms (
P
= 0.0062 or 0.0064, respectively) and eradicated preformed mature biofilms (
P
= 0.04 or 0.01, respectively) compared to those of untreated controls. Confocal microscopy showed significant reductions in biofilm thicknesses for both early and mature phases (
P
< 0.05). TLM showed that CD101 stopped the growth of adhesion- and early-phase biofilms within minutes. CD101-treated hyphae failed to grow into mature biofilms. These results suggest that CD101 may be effective in the prevention and treatment of biofilm-associated nosocomial infections.
Synthesis and Evaluation of Methyl 4-(7-Hydroxy-4,4,8-Trimethyl-3-Oxabicyclo[3.3.1]Nonan-2-yl)Benzoate as an Antileishmanial Agent and Its Synergistic Effect with Miltefosine
Authors: Bhalla Prachi , Sultana Sabera , Chiranjivi Adarsh Kumar , Saikia Anil K. , Dubey Vikash Kumar 
Published: November 2017

ABSTRACT
In our interest in oxabicyclic compounds as potent antileishmanial agents, the present work deals with the chemical synthesis of a new oxabicyclic derivative, methyl 4-(7-hydroxy-4,4,8-trimethyl-3-oxabicyclo[3.3.1]nonan-2-yl)benzoate (PS-207). This oxabicyclic derivative showed a good antileishmanial effect on the parasite, on both the promastigote and the amastigote. The mode of parasitic death from PS-207 seemed to be apoptosis-like. Interestingly, the combination of PS-207 with a low dose of miltefosine showed a synergistic effect against the parasite.
Nonpathogenic Colonization with Chlamydia in the Gastrointestinal Tract as Oral Vaccination for Inducing Transmucosal Protection
Authors: Wang Luying , Zhu Cuiming , Zhang Tianyuan , Tian Qi , Zhang Nu , Morrison Sandra , Morrison Richard , Xue Min , Zhong Guangming 
Published: November 2017

ABSTRACT

Chlamydia
has been detected in the gastrointestinal tracts of humans and animals. We now report that gastrointestinal
Chlamydia muridarum
is able to induce robust transmucosal protection in mice.
C. muridarum
colonization in the gastrointestinal tract correlated with both a shortened course of
C. muridarum
genital tract infection and stronger protection against subsequent genital tract challenge infection. Mice preinoculated intragastrically with
C. muridarum
became highly resistant to subsequent
C. muridarum
infection in the genital tract, resulting in prevention of pathology in the upper genital tract. The transmucosal protection in the genital tract was rapidly induced, durable, and dependent on major histocompatibility complex (MHC) class II antigen presentation but not MHC class I antigen presentation. Although a deficiency in CD4
+
T cells only partially reduced the transmucosal protection, depletion of CD4
+
T cells from B cell-deficient mice completely abolished the protection, suggesting a synergistic role of both CD4
+
T and B cells in the gastrointestinal
C. muridarum
-induced transmucosal immunity. However, the same protective immunity did not significantly affect
C. muridarum
colonization in the gastrointestinal tract. The long-lasting colonization with
C. muridarum
was restricted to the gastrointestinal tract and was nonpathogenic to either gastrointestinal or extragastrointestinal tissues. Furthermore, gastrointestinal
C. muridarum
did not alter the gut microbiota or the development of gut mucosal resident memory T cell responses to a nonchlamydial infection. Thus,
Chlamydia
may be developed into a safe and orally deliverable replicating vaccine for inducing transmucosal protection.
Head injury mechanisms in FIS World Cup alpine and freestyle skiers and snowboarders
Authors: Steenstrup Sophie Elspeth , Bakken Arnhild , Bere Tone , Patton Declan Alexander , Bahr Roald 
Published: November 2017

IntroductionHead injuries represent a concern in skiing and snowboarding, with traumatic brain injuries being the most common cause of death.AimTo describe the mechanisms of head and face injuries among World Cup alpine and freestyle skiers and snowboarders.MethodsWe performed a qualitative analysis of videos obtained of head and face injuries reported through the International Ski Federation Injury Surveillance System during 10 World Cup seasons (2006–2016). We analysed 57 head impact injury videos (alpine n=29, snowboard n=13, freestyle n=15), first independently and subsequently in a consensus meeting.ResultsDuring the crash sequence, most athletes (84%) impacted the snow with the skis or board first, followed by the upper or lower extremities, buttocks/pelvis, back and, finally, the head. Alpine skiers had sideways (45%) and backwards pitching falls (35%), with impacts to the rear (38%) and side (35%) of the helmet. Freestyle skiers and snowboarders had backwards pitching falls (snowboard 77%, freestyle 53%), mainly with impacts to the rear of the helmet (snowboard 69%, freestyle 40%). There were three helmet ejections among alpine skiers (10% of cases), and 41% of alpine skiing injuries occurred due to inappropriate gate contact prior to falling. Athletes had one (47%) or two (28%) head impacts, and the first impact was the most severe (71%). Head impacts were mainly on snow (83%) on a downward slope (63%).ConclusionThis study has identified several characteristics of the mechanisms of head injuries, which may be addressed to reduce risk.
Decisional needs assessment of patients with complex care needs in primary care: a participatory systematic mixed studies review protocol
Authors: Bujold Mathieu , Pluye Pierre , Légaré France , Haggerty Jeannie , Gore Genevieve C , Sherif Reem El , Poitras Marie-Ève , Beaulieu Marie-Claude , Beaulieu Marie-Dominique , Bush Paula L , Couturier Yves , Débarges Béatrice , Gagnon Justin , Giguère Anik , Grad Roland , Granikov Vera , Goulet Serge , Hudon Catherine , Kremer Bernardo , Kröger Edeltraut , Kudrina Irina , Lebouché Bertrand , Loignon Christine , Lussier Marie-Thérèse , Martello Cristiano , Nguyen Quynh , Pratt Rebekah , Rihoux Benoit , Rosenberg Ellen , Samson Isabelle , Senn Nicolas , Li Tang David , Tsujimoto Masashi , Vedel Isabelle , Ventelou Bruno , Wensing Michel 
Published: November 2017

IntroductionPatients with complex care needs (PCCNs) often suffer from combinations of multiple chronic conditions, mental health problems, drug interactions and social vulnerability, which can lead to healthcare services overuse, underuse or misuse. Typically, PCCNs face interactional issues and unmet decisional needs regarding possible options in a cascade of interrelated decisions involving different stakeholders (themselves, their families, their caregivers, their healthcare practitioners). Gaps in knowledge, values clarification and social support in situations where options need to be deliberated hamper effective decision support interventions. This review aims to (1) assess decisional needs of PCCNs from the perspective of stakeholders, (2) build a taxonomy of these decisional needs and (3) prioritise decisional needs with knowledge users (clinicians, patients and managers).Methods and analysisThis review will be based on the interprofessional shared decision making (IP-SDM) model and the Ottawa Decision Support Framework. Applying a participatory research approach, we will identify potentially relevant studies through a comprehensive literature search; select relevant ones using eligibility criteria inspired from our previous scoping review on PCCNs; appraise quality using the Mixed Methods Appraisal Tool; conduct a three-step synthesis (sequential exploratory mixed methods design) to build taxonomy of key decisional needs; and integrate these results with those of a parallel PCCNs’ qualitative decisional need assessment (semistructured interviews and focus group with stakeholders).Ethics and disseminationThis systematic review, together with the qualitative study (approved by the Centre Intégré Universitaire de Santé et Service Sociaux du Saguenay-Lac-Saint-Jean ethical committee), will produce a working taxonomy of key decisional needs (ontological contribution), to inform the subsequent user-centred design of a support tool for addressing PCCNs’ decisional needs (practical contribution). We will adapt the IP-SDM model, normally dealing with a single decision, for PCCNs who experience cascade of decisions involving different stakeholders (theoretical contribution). Knowledge users will facilitate dissemination of the results in the Canadian primary care network.PROSPERO registration numberCRD42015020558.
Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types
Authors: Lonez Caroline , Verma Bikash , Hendlisz Alain , Aftimos Philippe , Awada Ahmad , Van Den Neste Eric , Catala Gaetan , Machiels Jean-Pascal H , Piette Fanny , Brayer Jason B , Sallman David A , Kerre Tessa , Odunsi Kunle , Davila Marco L , Gilham David E , Lehmann Frédéric F 
Published: November 2017

IntroductionNKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3ζ signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning.Methods and analysisThis open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3×108, 1×109 and 3×109NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours.Ethics approval and disseminationEthical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals.Trial registration numberNCT03018405, EudraCT 2016-003312-12; Pre-result.