Publication date: Available online 10 February 2018
Source:Injury
Author(s): Young-Kyun Lee, Byung-Ho Yoon, Ji Sup Hwang, Yong-Han Cha, Ki-Choul Kim, Kyung-Hoi Koo
BackgroundBasicervical femur neck fracture (FNF) is a rare type of fracture, and is associated with increased risk of fixation failure due to its inherent instability. The purpose of this study was (1) to investigate the incidence of fixation failure and (2) to determine risk factors for fixation failure in basicervical FNF after internal fixation.MethodsTo identify basicervical FNF with a minimum of 12 months follow-up, we retrospectively reviewed records of 3217 patients who underwent hip fracture surgery from May 2003 to March 2016. Among the identified 77 patients with basicervical FNF, 69 patients were followed up for at least 12 months. We evaluated the rate of collapse of fracture site and reoperation due to fixation failure. We performed a multivariable analysis to determine risk factors associated with fracture site collapse and fixation failure.ResultsAmong the 69 patients with basicervical FNF, 17 (24.6%) showed collapse of fracture site, and 6 (8.6%) underwent conversion to arthroplasty because of fixation failure. In the multivariable analysis, use of extramedullary plating with a sliding hip screw was an independent significant risk factor for both collapse of fracture site (odds ratio 6.84; 95% confidence interval 1.91–24.5, p = 0.003) and fixation failure (odds ratio 12.2; 95% confidence interval 1.08–137.7, p = 0.042).ConclusionsBasicervical FNF treated with extramedullary plate with a sliding hip screw is more likely to fail than that treated with intramedullary nail with a helical blade. Our results suggested that intramedullary nail with a helical blade is more recommended for basicervical FNF compared with extramedullary plate with a sliding hip screw.Level of evidenceIII, Retrospective cohort study.
http://ift.tt/2nPLJsw
Παρασκευή 9 Φεβρουαρίου 2018
Risk factors of fixation failure in basicervical femoral neck fracture: Which device is optimal for fixation?
Chest ultrasonography for the emergency diagnosis of traumatic pneumothorax and haemothorax: A systematic review and meta-analysis
Publication date: Available online 8 February 2018
Source:Injury
Author(s): Leonardo Jönck Staub, Roberta Rodolfo Mazzali Biscaro, Erikson Kaszubowski, Rosemeri Maurici
ObjectiveTo assess the diagnostic of the chest ultrasonography for the emergency diagnosis of traumatic pneumothorax and haemothorax in adults.Study designSystematic review and meta-analysis.MethodsPubMed, EMBASE, Scopus, Web of Science and LILACS (up to 2016) were systematically searched for prospective studies on the diagnostic accuracy of ultrasonography for pneumothorax and haemothorax in adult trauma patients. The references of other systematic reviews and the included studies were checked for further articles. The characteristics and results of the studies were extracted using a standardised form, and their methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Primary analysis was performed considering each hemithorax as an independent unit, while secondary analysis considered each patient. The global diagnostic accuracy of the chest ultrasonography was estimated using the Rutter–Gatsonis hierarchical summary ROC method. Moreover, Reitsma's bivariate model was used to estimate the sensitivity, specificity, positive likelihood ratio (LR + ) and negative likelihood ratio (LR–) of each sonographic sign. This review was previously registered (PROSPERO CRD42016048085).ResultsNineteen studies were included in the review, 17 assessing pneumothorax and 5 assessing haemothorax. The reference standard was always chest tomography, alone or in parallel with chest radiography and observation of the chest tube. The overall methodological quality of the studies was low. The diagnostic accuracy of chest ultrasonography had an area under the curve (AUC) of 0.979 for pneumothorax (Fig). The absence of lung sliding and comet-tail artefacts was the most reported sonographic sign of pneumothorax, with a sensitivity of 0.81 (95% confidence interval [95%CI], 0.71–0.88), specificity of 0.98 (95%CI, 0.97–0.99), LR+ of 67.9 (95%CI, 26.3–148) and LR– of 0.18 (95%CI, 0.11–0.29). An echo-poor or anechoic area in the pleural space was the only sonographic sign for haemothorax, with a sensitivity of 0.60 (95%CI, 0.31–0.86), specificity of 0.98 (95%CI, 0.94–0.99), LR+ of 37.5 (95%CI, 5.26–207.5), LR– of 0.40 (95%CI, 0.17–0.72) and AUC of 0.953.ConclusionNotwithstanding the limitations of the included studies, this systematic review and meta-analysis suggested that chest ultrasonography is an accurate tool for the diagnostic assessment of traumatic pneumothorax and haemothorax in adults.
http://ift.tt/2o0ioLo
Trajectory of physical activity after hip fracture: an analysis of community-dwelling individuals from the English Longitudinal Study of Ageing
Publication date: Available online 10 February 2018
Source:Injury
Author(s): Tariq Aboelmagd, Jack R. Dainty, Alex MacGregor, Toby O. Smith
INTRODUCTIONTo analyse physical activity participation in a community-dwelling people in England with hip fracture the interval prior to fracture, in the fracture recovery period, and a minimum of two years post-fracture.MATERIALS AND METHOds215 individuals were identified from the English Longitudinal Study of Ageing cohort (2002-2014) who sustained a hip fracture following a fall and for whom data were available on physical activity participation relating to the period pre-fracture, within-fracture recovery phase and post-fracture (minimum of two years). Physical activity was assessed using the validated ELSA physical activity questionnaire. Prevalence of 'low' physical activity participation was calculated and multi-level modelling analyses were performed to explore physical activity trajectories over the follow-up phase, and whether age, depression, gender and frailty were associated with physical activity participation.RESULTSPrevalence of low physical activity participation within two years prior to hip fracture was 16.7% (95% Confidence Intervals (CI): 11.6% to 21.8%). This increased at the final follow-up phase to 21.3% (95% CI: 15.1% to 27.6%). This was not a statistically significant change (P = 0.100). Age (P = 0.005) and frailty (P < 0.001) were statistically significant explanatory variables (P = 0.005) where older age and greater frailty equated to lower physical activity participation. Neither gender (P = 0.288) nor depression (P = 0.121) were significant explanatory variables.CONCLUSIONPhysical activity levels do not significantly change between pre-fracture to a minimum of two years post-hip fracture for community-dwelling individuals. This contrasts with previous reports of reduced mobility post-hip fracture, suggesting that 'physical activity' and 'mobility' should be considered as separate outcomes in this population.
http://ift.tt/2nRKrNH
Temozolomide–perillyl alcohol conjugate downregulates O6-methylguanin DNA methltransferase via inducing ubiquitination-dependent proteolysis in non-small cell lung cancer
Temozolomide–perillyl alcohol conjugate downregulates O6-methylguanin DNA methltransferase via inducing ubiquitination-dependent proteolysis in non-small cell lung cancer
Temozolomide–perillyl alcohol conjugate downregulates O<sup>6</sup>-methylguanin DNA methltransferase via inducing ubiquitination-dependent proteolysis in non-small cell lung cancer, Published online: 09 February 2018; doi:10.1038/s41419-017-0193-2
Temozolomide–perillyl alcohol conjugate downregulates O6-methylguanin DNA methltransferase via inducing ubiquitination-dependent proteolysis in non-small cell lung cancerhttp://ift.tt/2ESqSMv
Loss of function mutations in EPHB4 are responsible for vein of Galen aneurysmal malformation
http://ift.tt/2H5SMFp
Therapeutic efficacy of microtube-embedded chondroitinase ABC in a canine clinical model of spinal cord injury
http://ift.tt/2G0eU2Q
The functional network signature of heterogeneity in freezing of gait
http://ift.tt/2H5RZEr
Bone loss at implants and teeth in the same inter-proximal unit: A radiographic study
Abstract
Objective
This study was performed to determine whether the distance between an implant and a tooth present in an inter-proximal unit influenced the amount of marginal bone loss that occurred at the two facing (adjacent) surfaces.
Materials and methods
One hundred and eighty patients with a total of 278 inter-proximal units were included. Radiographs of implants that also included adjacent (facing) natural tooth/teeth were digitalized, and various linear measurements were performed using a software program. The marginal bone level and the bone level change that had occurred during a mean of 5.8 years were assessed as well as distance between the implant and the adjacent tooth/teeth.
Results
The mean amount of additional marginal bone loss that took place during the observation period was about 0.4 mm at both implants and adjacent tooth surfaces. The horizontal distance between an implant and the facing tooth did not influence the amount of marginal bone loss that had occurred. In most inter-proximal units, more advanced bone loss (>1 mm, >2 mm) had ensued either at the implant or at the facing tooth surface. Advanced additional bone loss occurred at both the implant and the tooth in only about 3% of the examined subjects.
Conclusion
Bone loss at implants and teeth appears to be a site-specific phenomenon and not dependent on the inter-proximal distance.
http://ift.tt/2EW8nH6
Breast cancer subtype and survival by parity and time since last birth
Abstract
Background
Pregnancy affects breast cancer risk but how it affects the subtype and prognosis remain controversial. We studied the effect of parity and time since last birth on breast cancer subtype and outcome.
Patients and methods
We conducted a retrospective multivariate cohort study including all premenopausal women with early breast cancer aged ≤ 50 years (N = 1306) at diagnosis at the University Hospitals Leuven (Jan. 2000–Dec. 2009). Primary study endpoints were the breast cancer subtype, disease-free survival, and distant disease-free survival by parity and time since last birth. Statistical methods used were baseline-category logits models and Cox proportional hazard models. Multivariable models were used to correct for possible confounders.
Results
Breast cancer subtypes did not differ between nulliparous (N = 266) and parous women (N = 1040) but subtypes differed significantly in parous women by time since last birth (p < 0.001). Tumors within 5 years of last birth were proportionally more likely triple negative and HER-2 like, even when corrected for age at diagnosis. After a mean follow-up period of 10 years, parous women had a better disease-free survival compared to nulliparous women (HR 0.733; CI 0.560–0.961; p = 0.025, HR 0.738; CI 0.559–0.974; p = 0.032 before and after correction for known prognostic factors, respectively). In parous women, a longer time since last birth was correlated with a longer disease-free survival compared to patients with a recent pregnancy (HR 0.976; CI 0.957–0.996; p = 0.018). However, after correction, this association completely disappeared (HR 1.010; CI 0.982–1.040; p = 0.480).
Conclusion
We observed a better disease-free survival for parous than nulliparous women. The influence of recent birth on disease-free survival is probably due to tumor and patient characteristics, as recent birth is associated with more aggressive subtypes.
http://ift.tt/2nXi53R
Development of a nomogram for the estimation of long-term adherence to clozapine therapy using neutrophil fluorescence
Aims
Previously, we have reported an association between clozapine use and elevated FL3 neutrophil fluorescence, a flow-cytometric parameter for cell viability. Here, we developed and evaluated a PK/PD model relating FL3-fluorescence to clozapine exposure and derived a nomogram for estimation of long-term adherence.
Methods
Data from 27 patients initiating clozapine were analyzed using non-linear mixed effects modelling. A previously described PK model for clozapine was coupled to a FL3 fluorescence model. For this an effect compartment with clozapine concentrations as input and a first order decay rate as output was linked with an Emax model to FL3-fluorescence. FL3-fluorescence was simulated for clozapine doses of 50, 150 and 400 mg daily (N=10.000) to establish the nomogram. Finally, true simulated adherence (% of daily doses taken over 100 days) was compared to nomogram estimated adherence to evaluate the performance of the nomogram.
Results
The half-life of FL3-fluorescence was estimated at 228 hours (coefficient of variation 35%).. Median absolute prediction errors (PE) of the nomogram in case of fully random adherence for 50, 150 and 400 mg ranged from -0.193% to -0.525%. The nomogram performed slightly worse in case of non-random adherence (median PE up to 5.19%), but still clinically acceptable. Compliance patterns containing longer drug holidays revealed that the nomogram adequately estimates compliance over approximately the last 3 weeks prior to FL3-measurement.
Conclusion
Our nomogram could provide information regarding long-term adherence based on prescribed clozapine dose and FL3-fluorescence. Future studies should further explore the clinical value of this biomarker and nomogram.
http://ift.tt/2ExfMik
The challenges of fertility preservation in cancer patients: an interview with Michael Grynberg
Future Oncology, Ahead of Print.
http://ift.tt/2Ef0qQ2
FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer
Future Oncology, Ahead of Print.
http://ift.tt/2CaEJe1
Hydration requirements with emetogenic chemotherapy: granisetron extended-release subcutaneous versus palonosetron
Future Oncology, Ahead of Print.
http://ift.tt/2EhhtAS
A multiparametric analysis combining DCE-MRI- and IVIM -derived parameters to improve differentiation of parotid tumors: a pilot study
Future Oncology, Ahead of Print.
http://ift.tt/2CaWzOa
Drought Sensitivity of Norway Spruce at the Species' Warmest Fringe: Quantitative and Molecular Analysis Reveals High Genetic Variation Among and Within Provenances
Norway spruce (Picea abies) is by far the most important timber species in Europe, but its outstanding role in future forests is jeopardized by its high sensitivity to drought. We analyzed drought response of Norway spruce at the warmest fringe of its natural range. Based on a 35-year old provenance experiment we tested for genetic variation among and within seed provenances across consecutively occurring strong drought events using dendroclimatic time series. Moreover, we tested for associations between 1,700 variable SNPs and traits related to drought response, wood characteristics and climate-growth relationships. We found significant adaptive genetic variation among provenances originating from the species' Alpine, Central and Southeastern European range. Genetic variation between individuals varied significantly among provenances explaining up to 44% of the phenotypic variation in drought response. Varying phenotypic correlations between drought response and wood traits confirmed differences in selection intensity among seed provenances. Significant associations were found between 29 SNPs and traits related to drought, climate-growth relationships and wood properties which explained between 11 and 43% of trait variation, though 12 of them were due to single individuals having extreme phenotypes of the respective trait. The majority of these SNPs are located within exons of genes and the most important ones are preferentially expressed in cambium and xylem expansion layers. Phenotype-genotype associations were stronger if only provenances with significant quantitative genetic variation in drought response were considered. The present study confirms the high adaptive variation of Norway spruce in Central and Southeastern Europe and demonstrates how quantitative genetic, dendroclimatic and genomic data can be linked to understand the genetic basis of adaptation to climate extremes in trees.
http://ift.tt/2sk1SLD
Platelets enhance Multiple Myeloma progression via IL-1{beta} upregulation
Purpose: Tumor cell-platelet interactions contribute to tumor progression and metastasis in solid tumors. However, the role of platelets in hematological malignancies is not clear. We investigated the association of platelet activation status with clinical stages in multiple myeloma (MM) patients and explored the role of platelets in MM progression. Experimental Design: Platelets were obtained from healthy donors and MM patients. We examined platelet activation status in MM patients by flow cytometry and transmission electron microscopy. We also observed the enriched pathways that are involved with platelet activation in RNA sequencing of platelets. MM cell lines were used to assess the effect of platelets on MM cell proliferation in vitro and their engraftment in vivo. RNA sequencing of MM cell lines was performed to explore molecular mechanisms underlying MM cell-platelet interaction and a CRISPR/Cas9 knockout approach was used for validation. Results: Platelets from MM patients were highly activated with disease progression. RNA sequencing of platelets revealed that genes involved in platelets were enriched in patients with smoldering MM (SMM) or MM. Platelets promoted MM cell proliferation in vitro and contributed to tumor engraftment in bone marrow in vivo. RNA sequencing revealed that IL-1β was upregulated in MM cell lines co-cultured with platelets, whereas IL-1β knockout in MM cell lines abrogated the effects of platelets on MM cell proliferation and engraftment in vivo. Conclusions: Platelets from MM patients were highly activated with disease progression. IL-1β is critical to platelet-mediated MM progression and might be a potential target for MM treatment.
http://ift.tt/2Evlb9l
Pan-cancer molecular classes transcending tumor lineage across 32 cancer types, multiple data platforms, and over 10,000 cases
Purpose: The Cancer Genome Atlas data resources represent an opportunity to explore commonalities across cancer types involving multiple molecular levels, but tumor lineage and histology can represent a barrier in moving beyond differences related to cancer type. Experimental Design: On the basis of gene expression data, we classified 10224 cancers, representing 32 major types, into ten molecular-based "classes." Molecular patterns representing tissue or histologic dominant effects were first removed computationally, with the resulting classes representing emergent themes across tumor lineages. Results: Key differences involving mRNAs, miRNAs, proteins, and DNA methylation underscored the pan-cancer classes. One class expressing neuroendocrine and cancer-testis antigen markers represented ~4% of cancers surveyed. Basal-like breast cancers segregated into an exclusive class, distinct from all other cancers. Immune checkpoint pathway markers and molecular signatures of immune infiltrates were most strongly manifested within a class representing ~13% of cancers. Pathway-level differences involving hypoxia, NRF2-ARE, Wnt, and Notch were manifested in two additional classes enriched for mesenchymal markers and miR-200 silencing. Conclusions: All pan-cancer molecular classes uncovered here, with the important exception of the basal-like breast cancer class, involve a wide range of cancer types and would facilitate understanding the molecular underpinnings of cancers beyond tissue-oriented domains. Numerous biological processes associated with cancer in the laboratory setting were found here to be coordinately manifested across large subsets of human cancers. The number of cancers manifesting features of neuroendocrine tumors may be much higher than previously thought, which disease is known to occur in many different tissues.
http://ift.tt/2sfQhwM
Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multi-kinase inhibition
Purpose: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits SMARCA4 and SMARCA2. A great need exists for effective targeted therapies for SCCOHT. Experimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two patient-derived xenograft (PDX) models and one cell line xenograft model of SCCOHT. Results: The receptor tyrosine kinase (RTK) family was enriched in siRNA screen hits with FGFRs and PDGFRs being overlapping hits between drug and siRNA screens. Of multiple potent drug classes in SCCOHT cell lines, RTK inhibitors were only one of two classes with selectivity in SCCOHT relative to three SWI/SNF-wild-type ovarian cancer cell lines. We further identified ponatinib as the most effective clinically approved RTK inhibitor. Re-expression of SMARCA4 was shown to confer a 1.7-fold increase in resistance to ponatinib. Subsequent proteomic assessment of ponatinib target modulation in SCCOHT cell models confirmed inhibition of nine known ponatinib target kinases alongside 77 non-canonical ponatinib targets in SCCOHT. Finally, ponatinib delayed tumor doubling time four-fold in SCCOHT-1 xenografts while reducing final tumor volumes in SCCOHT PDX models by 58.6% and 42.5%. Conclusion: Ponatinib is an effective agent for SMARCA4-mutant SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted.
http://ift.tt/2EyTwEH
Targeting HSF1: a prime integrator of proteotoxic stress response in myeloma
The HSF1 transcription factor is an integrator of the cellular stress response and its expression has demonstrated poor prognosis in multiple myeloma. Novel anti-HSF1 small molecule inhibitors CCT251236 and KRIB11 demonstrate in vitro and in vivo anti-myeloma activity, representing a novel approach for targeting the heat shock response in myeloma.
http://ift.tt/2simVhv
Multiplatform next-generation sequencing identifies novel RNA molecules and transcript isoforms of the endogenous retrovirus isolated from cultured cells
http://ift.tt/2so0309
Neural synchronization: average strength vs. temporal patterning
Excessively strong neural synchrony may contribute to the symptoms of different neurological and neuropsychiatric disorders (Uhlhaas and Singer, 2006). Thus, hypokinetic symptoms of Parkinson's disease are associated with elevated beta-band synchrony (Kühn et al., 2009), however this association is not very consistent (Stein and Bar-Gad, 2013). One possible explanation is that this elevated synchrony is very intermittent (Park et al., 2010).
http://ift.tt/2EwYlOU
Use of Appropriate Surveillance for Patients With Non-Dysplastic Barrett’s Esophagus
Barrett's Esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Guidelines recommend that patients with nondysplastic BE (NDBE) undergo surveillance endoscopy every 3–5 years. We aimed to identify factors associated with surveillance endoscopy of patients with NDBE and identify trends in appropriate surveillance endoscopy of NDBE at a large tertiary care center.
http://ift.tt/2EUCVZQ
Association of 1p/19q codeletion and Radiation Necrosis in Adult Cranial Gliomas after Proton or Photon Therapy
To analyze the incidence and risk factors of clinically significant radiation necrosis (cRN) in adult cranial oligodendrogliomas and astrocytomas treated with proton or photon therapy.
http://ift.tt/2BPxY5w
Prospective trial using internal pair-production positron emission tomography to establish the Yttrium-90 radioembolization dose required for response of hepatocellular carcinoma
Yttrium-90 (90Y) internal pair-production PET can quantify the radiation dose delivered to hepatic tumors after radioembolization. This study prospectively assessed the threshold dose for objective response of hepatocellular carcinoma (HCC).
http://ift.tt/2BkBsw4
Oncolytic Virus Therapy: Using Tumor-Targeting Viruses to Treat Cancer
A small but growing number of patients with cancer are being treated with oncolytic viruses, which infect and kill tumor cells. But research now suggests that these treatments also work against cancer by spurring an immune response.
http://ift.tt/2sjSgQK
Patient-Centered Care in Renal Medicine: Five Strategies to Meet the Challenge
There is growing interest in patient-centered care, defined by the Institute of Medicine as "care that is respectful of and responsive to individual patient preferences, needs, and values." Although generally accepted as uncontroversial, the notion of "centering" care on our patients is in fact quite revolutionary. Because medical teaching, research, and practice have traditionally been organized around diseases and organ systems rather than patients, making care more patient centered would require no less than a paradigm shift in how we practice medicine.
http://ift.tt/2nPgwFH
Clinical, Social, and Genetic Factors Associated with Obesity at 12 Months of Age
To examine genomic, social, and clinical risk factors of ≥85 weight for length percentile (WFLP) at 12 months.
http://ift.tt/2EhvXNq
Remote photoplethysmography with constrained ICA using periodicity and chrominance constraints
Remote photoplethysmography (rPPG) has been in the forefront recently for measuring cardiac pulse rates from live or recorded videos. It finds advantages in scenarios requiring remote monitoring, such as medic...
http://ift.tt/2smZzY2
Assessment of fluid responsiveness in spontaneously breathing patients: a systematic review of literature
Patients who increase stoke volume or cardiac index more than 10 or 15% after a fluid challenge are usually considered fluid responders. Assessment of fluid responsiveness prior to volume expansion is critical...
http://ift.tt/2BNQpHR
Acute kidney injury in major abdominal surgery: incidence, risk factors, pathogenesis and outcomes
Acute kidney injury (AKI) is a common complication in patients undergoing major abdominal surgery. Various recent studies using modern standardized classifications for AKI reported a variable incidence of AKI ...
http://ift.tt/2Bk1boh
Delayed cerebral thrombosis complicating pneumococcal meningitis: an autopsy study
Delayed cerebral thrombosis (DCT) is a devastating cerebrovascular complication in patients with excellent initial recovery of pneumococcal meningitis. The aetiology is unknown, but direct bacterial invasion, ...
http://ift.tt/2BPJhuK
Resistance analysis of genotype 3 HCV indicates subtypes inherently resistant to NS5A inhibitors
Abstract
Background and aims: HCV genotype-3 (gt3) is highly prevalent globally, with non-gt3a subtypes common in Southeast Asia. Resistance-associated substitutions (RASs) have been shown to play a role in treatment failure. However, the role of RASs in gt3 is not well understood. We report the prevalence of RASs in a cohort of directly acting antivirals (DAA) treatment-naïve gt3 infected patients, including those with rarer subtypes and evaluate the effect of these RAS on DAAs in-vitro.
Methods: Baseline samples from 496 gt3 patients enrolled in the BOSON clinical trial were analysed by next-generation sequencing after probe-based enrichment for HCV. Whole viral genomes were analysed for the presence of RASs to approved DAAs. The resistance phenotype of RASs in combination to daclatasvir, velpatasvir, pibrentasvir, elbasvir and sofosbuvir was measured using the S52 ΔN gt3a replicon model.
Results: The NS5A A30K and Y93H substitutions were the most common at 8.8% (n=44) and 12.2% (n=61) respectively and showed a 10-fold and 11-fold increase in EC50 for daclatasvir compared to the unmodified replicon. Paired RASs (A30K + L31M and A30K + Y93H) were identified in 18 patients (9 of each pair); these combinations were shown to be highly resistant to daclatasvir, velpatasvir, elbasvir and pibrentasvir. The A30K + L31M combination was found in all gt3b and gt3g samples.
Conclusion: Our study reveals high frequencies of RASs to NS5A Inhibitors in gt3 HCV. The paired A30K + L31M substitutions occur in all patients with gt3b and gt3g virus. In vitro analysis suggests that these subtypes may be inherently resistant to all approved NS5A Inhibitors for gt3 HCV. This article is protected by copyright. All rights reserved.
http://ift.tt/2ErMD8b
Assessment of GeneXpert GxAlert platform for multi-drug resistant tuberculosis diagnosis and patients’ linkage to care in Tanzania
The gap between patients diagnosed with multi-drug resistant tuberculosis (MDR-TB) and enrolment in treatment is one of the major challenges in tuberculosis control programmes. A 4-year (2013–2016) retrospecti...
http://ift.tt/2EdF4hV
Clinical effect of a dentifrice containing three kinds of bactericidal ingredients on periodontal disease: a pilot study in patients undergoing supportive periodontal therapy
This study aimed to evaluate clinically the effect of a novel dentifrice containing three kinds of bactericidal ingredients on periodontal disease.
http://ift.tt/2ERol56
Transcriptomic response in Acropora muricata under acute temperature stress follows preconditioned seasonal temperature fluctuations
Global climate change has resulted in the decline of health and condition of various coral reefs worldwide. Here, we describe expression profiles of Acropora muricata collected during opposing seasons in Otsuki, ...
http://ift.tt/2EcyBDX
Children with oedema recover better than those with severe wasting in outpatient therapeutic program at Boloso Sore district, Southwest Ethiopia
Severely undernourished young children clinically present with a typical nutritional oedema or none-oedematous. However, research evidence is limited on how these types predict treatment outcomes in Ethiopia. ...
http://ift.tt/2EQWUIA
Patient delay in seeking tuberculosis diagnosis and associated factors in Hadiya Zone, Southern Ethiopia
To assess patient delay in seeking tuberculosis diagnosis and associated factors in Hadiya Zone, Southern Ethiopia.
http://ift.tt/2EeLyNH
Preparation, Purification, and Use of Fatty Acid-containing Liposomes
http://ift.tt/2nOGU2B
Improving the conditioning of the optimization criterion in acoustic multi-channel equalization using shorter reshaping filters
In acoustic multi-channel equalization techniques, such as complete multi-channel equalization based on the multiple-input/output inverse theorem (MINT), relaxed multi-channel least-squares (RMCLS), and partia...
http://ift.tt/2nW1RrP
Efficacy comparison of transcervical video-assisted mediastinoscopic lymphadenectomy combined with left transthoracic esophagectomy versus right transthoracic esophagectomy for esophageal cancer treatment
Abstract
Background
This study aimed to propose a new surgical strategy, i.e., the transcervical video-assisted mediastinoscopic lymphadenectomy (VAMLA) with esophagectomy via the left transthoracic approach for patients with esophageal cancer (EC), and to compare the outcomes with those of esophagectomy via the right thoracic approach.
Methods
From December 2014 to March 2016, 49 cases were enrolled in this non-randomized concurrent control study. Twenty-eight patients with EC who underwent transcervical VAMLA with esophagectomy via the left transthoracic approach were assigned into the study group, while 21 EC patients undergoing esophagectomy via the right transthoracic approach during the same period were enrolled into the control group. Operative outcomes including operative time, the numbers of removed lymph nodes, intraoperative blood loss, the length of hospital stay, and postoperative complications in both groups were evaluated and compared.
Results
There were no significant differences in the baseline profiles between the two groups, and all patients in the two groups successfully underwent the surgery. There was a significant difference between transcervical VAMLA with esophagectomy via the left thoracic approach and esophagectomy via the right thoracic approach with regard to the number of all dissected lymph nodes [(29.0 ± 8.7) vs. (17.8 ± 8.1), p < 0.05], dissected superior mediastinal lymph nodes [(11.2 ± 5.0) vs. (3.7 ± 2.9), p < 0.05], and dissected in the recurrent laryngeal nerve lymph nodes [(5.6 ± 3.5) vs. (2.3 ± 2.1), p < 0.05]. No significant differences were observed in the operative time, intraoperative blood loss, length of postoperative hospital stay, number of dissected abdominal lymph nodes, postoperative pulmonary complications (pneumonia and atelectasis), anastomotic fistula, chylothorax, and vocal cord paralysis (p > 0.05).
Conclusion
Transcervical VAMLA combined with esophagectomy via the left thoracic approach appears technically feasible and safe and shows advantages in the number of dissected superior mediastinal lymph nodes, suggesting that it may serve as a new treatment option for patients with esophageal carcinoma.
http://ift.tt/2sqRPo7
Cholangiocyte-derived exosomal long noncoding RNA H19 promotes cholestatic liver injury in mouse and human
Abstract
Cholestatic liver injury is an important clinical problem with limited understanding of disease pathologies. Exosomes are small extracellular vesicles released by a variety of cells including cholangiocytes. Exosome-mediated cell-cell communication can modulate various cellular functions by transferring a variety of intracellular components to target cells. Our recent studies indicate that the long non-coding RNA H19 is mainly expressed in cholangiocytes and its aberrant expression is associated with significant down-regulation of small heterodimer partner (SHP) in hepatocytes and cholestatic liver injury in multidrug resistance 2 knockout (Mdr2-/-) mice. However, how cholangiocyte-derived H19 suppresses SHP in hepatocytes remains unknown. Here, we report that cholangiocyte-derived exosomes mediate transfer of H19 into hepatocytes and promote cholestatic injury. The hepatic H19 level is correlated with the severity of cholestatic injury in both fibrotic mouse models, including Mdr2-/- mice, a well-characterized model of primary sclerosing cholangitis (PSC), or carbon-tetrachloride (CCl4)-induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually upregulated during disease progression in Mdr2-/- mice and cirrhotic patients. The H19-carrying exosomes from the primary cholangiocytes of wild type (WT) mice suppress SHP expression in hepatocytes, but not the exosomes from the cholangiocytes of H19-/- mice. Furthermore, overexpression of H19 significantly suppressed SHP expression at both transcriptional and post-transcriptional levels. Importantly, transplant of H19-carrying serum exosomes of old fibrotic Mdr2-/- mice significantly promoted liver fibrosis in young Mdr2-/- mice. Conclusion: Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal-H19 represents a novel non-invasive biomarker and potential therapeutic target for cholestatic diseases. This article is protected by copyright. All rights reserved.
http://ift.tt/2C9gs82
Rationale, design, and methodology of a trial evaluating three models of care for HCV treatment among injection drug users on opioid agonist therapy
People who inject drugs (PWID) constitute 60% of the approximately 5 million people in the U.S. infected with hepatitis C virus (HCV). Treatment of PWID is complex due to addiction, mental illness, poverty, ho...
http://ift.tt/2sgzwSs
Role of Purinergic Receptor P2Y1 in Spatiotemporal Ca2+ Dynamics in Astrocytes
Fine processes of astrocytes enwrap synapses and are well positioned to sense neuronal information via synaptic transmission. In rodents, astrocyte processes sense synaptic transmission via Gq-protein coupled receptors (GqPCR), including the P2Y1 receptor (P2Y1R), to generate Ca2+ signals. Astrocytes display numerous spontaneous microdomain Ca2+ signals; however, it is not clear whether such signals are due to local synaptic transmission and/or in what timeframe astrocytes sense local synaptic transmission. To ask whether GqPCRs mediate microdomain Ca2+ signals, we engineered mice (both sexes) to specifically overexpress P2Y1Rs in astrocytes, and we visualized Ca2+ signals via a genetically encoded Ca2+ indicator, GCaMP6f, in astrocytes from adult mice. Astrocytes overexpressing P2Y1Rs showed significantly larger Ca2+ signals in response to exogenously applied ligand and to repetitive electrical stimulation of axons compared with controls. However, we found no evidence of increased microdomain Ca2+ signals. Instead, Ca2+ waves appeared and propagated to occupy areas that were up to 80-fold larger than microdomain Ca2+ signals. These Ca2+ waves accounted for only 2% of total Ca2+ events, but they were 1.9-fold larger and 2.9-fold longer in duration than microdomain Ca2+ signals at processes. Ca2+ waves did not require action potentials for their generation and occurred in a probenecid-sensitive manner, indicating that the endogenous ligand for P2Y1R is elevated independently of synaptic transmission. Our data suggest that spontaneous microdomain Ca2+ signals occur independently of P2Y1R activation and that astrocytes may not encode neuronal information in response to synaptic transmission at a point source of neurotransmitter release.
SIGNIFICANCE STATEMENT Astrocytes are thought to enwrap synapses with their processes to receive neuronal information via Gq-protein coupled receptors (GqPCRs). Astrocyte processes display numerous microdomain Ca2+ signals that occur spontaneously. To determine whether GqPCRs play a role in microdomain Ca2+ signals and the timeframe in which astrocytes sense neuronal information, we engineered mice whose astrocytes specifically overexpress the P2Y1 receptor, a major GqPCR in astrocytes. We found that overexpression of P2Y1 receptors in astrocytes did not increase microdomain Ca2+ signals in astrocyte processes but caused Ca2+ wavelike signals. Our data indicate that spontaneous microdomain Ca2+ signals do not require activation of P2Y1 receptors.
http://ift.tt/2Edh4iU
The Stress-Induced Transcription Factor NR4A1 Adjusts Mitochondrial Function and Synapse Number in Prefrontal Cortex
The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry is vulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the buildup of chronic stress. Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial, and behavioral outcomes, we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number in PFC. NR4A1 acted as a transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling, AMP-activated protein kinase activation, and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role in the regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant-negative approach, and knockout of Nr4a1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFC tissues of men and women, high levels of the transcriptionally active NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria and synaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions, constituting a pathological feature across disorders.
SIGNIFICANCE STATEMENT The bioenergetic cost of chronic stress is too high to be sustainable by pyramidal prefrontal neurons. Cellular checkpoints have evolved to adjust the responses of mitochondria and synapses to the buildup of chronic stress. NR4A1 plays such a role by controlling the energetic competence of mitochondria with respect to synapse number. As an immediate-early gene, Nr4a1 promotes neuronal plasticity, but sustained expression or activity can be detrimental. NR4A1 expression and activity is sustained by chronic stress in animal models and in human studies of neuropathologies sensitive to the buildup of chronic stress. Therefore, antagonism of NR4A1 is a promising avenue for preventing the regressive synaptic reorganization in cortical systems in the context of chronic stress.
http://ift.tt/2C8csET
Differentiation and Characterization of Excitatory and Inhibitory Synapses by Cryo-electron Tomography and Correlative Microscopy
As key functional units in neural circuits, different types of neuronal synapses play distinct roles in brain information processing, learning, and memory. Synaptic abnormalities are believed to underlie various neurological and psychiatric disorders. Here, by combining cryo-electron tomography and cryo-correlative light and electron microscopy, we distinguished intact excitatory and inhibitory synapses of cultured hippocampal neurons, and visualized the in situ 3D organization of synaptic organelles and macromolecules in their native state. Quantitative analyses of >100 synaptic tomograms reveal that excitatory synapses contain a mesh-like postsynaptic density (PSD) with thickness ranging from 20 to 50 nm. In contrast, the PSD in inhibitory synapses assumes a thin sheet-like structure ~12 nm from the postsynaptic membrane. On the presynaptic side, spherical synaptic vesicles (SVs) of 25–60 nm diameter and discus-shaped ellipsoidal SVs of various sizes coexist in both synaptic types, with more ellipsoidal ones in inhibitory synapses. High-resolution tomograms obtained using a Volta phase plate and electron filtering and counting reveal glutamate receptor-like and GABAA receptor-like structures that interact with putative scaffolding and adhesion molecules, reflecting details of receptor anchoring and PSD organization. These results provide an updated view of the ultrastructure of excitatory and inhibitory synapses, and demonstrate the potential of our approach to gain insight into the organizational principles of cellular architecture underlying distinct synaptic functions.
SIGNIFICANCE STATEMENT To understand functional properties of neuronal synapses, it is desirable to analyze their structure at molecular resolution. We have developed an integrative approach combining cryo-electron tomography and correlative fluorescence microscopy to visualize 3D ultrastructural features of intact excitatory and inhibitory synapses in their native state. Our approach shows that inhibitory synapses contain uniform thin sheet-like postsynaptic densities (PSDs), while excitatory synapses contain previously known mesh-like PSDs. We discovered "discus-shaped" ellipsoidal synaptic vesicles, and their distributions along with regular spherical vesicles in synaptic types are characterized. High-resolution tomograms further allowed identification of putative neurotransmitter receptors and their heterogeneous interaction with synaptic scaffolding proteins. The specificity and resolution of our approach enables precise in situ analysis of ultrastructural organization underlying distinct synaptic functions.
http://ift.tt/2C8vriw
An evaluation of E. coli in urinary tract infection in emergency department at KAMC in Riyadh, Saudi Arabia: retrospective study
Urinary tract infection (UTIS) is a common infectious disease in which level of antimicrobial resistance are alarming worldwide. Therefore, this study aims to describe the prevalence and the resistance pattern...
http://ift.tt/2BNpRqr
HeartStart MRx Defibrillator by Philips Electronics: Class I Recall - Defects in Gas Discharge Tubes May Cause Device Failure
Audience: Emergency Medicine, Risk Manager, Nursing [Posted 02/09/2018] ISSUE: Philips is recalling the HeartStart MRx Defibrillator due to a defect in the device's Gas Discharge Tube (GDT). The GDT has micro cracks which allows internal gasses to...
http://ift.tt/2nW2zVX
HeartStart MRx Defibrillator by Philips Electronics: Class I Recall - Defects in Gas Discharge Tubes May Cause Device Failure
Audience: Emergency Medicine, Risk Manager, Nursing [Posted 02/09/2018] ISSUE: Philips is recalling the HeartStart MRx Defibrillator due to a defect in the device's Gas Discharge Tube (GDT). The GDT has micro cracks which allows internal gasses to...
http://ift.tt/2nW2zVX
Bilateral deep brain stimulation of the subthalamic nucleus increases pointing error during memory-guided sequential reaching
Abstract
Deep brain stimulation of the subthalamic nucleus (STN DBS) significantly improves clinical motor symptoms, as well as intensive aspects of movement like velocity and amplitude in patients with Parkinson's disease (PD). However, the effects of bilateral STN DBS on integrative and coordinative aspects of motor control are equivocal. The aim of this study was to investigate the effects of bilateral STN DBS on integrative and coordinative aspects of movement using a memory-guided sequential reaching task. The primary outcomes were eye and finger velocity and end-point error. We expected that bilateral STN DBS would increase reaching velocity. More importantly, we hypothesized that bilateral STN DBS would increase eye and finger end-point error and this would not simply be the result of a speed accuracy trade-off. Ten patients with PD and bilaterally implanted subthalamic stimulators performed a memory-guided sequential reaching task under four stimulator conditions (DBS-OFF, DBS-LEFT, DBS-RIGHT, and DBS-BILATERAL) over 4 days. DBS-BILATERAL significantly increased eye velocity compared to DBS-OFF, DBS-LEFT, and DBS-RIGHT. It also increased finger velocity compared to DBS-OFF and DBS-RIGHT. DBS-BILATERAL did not change eye end-point error. The novel finding was that DBS-BILATERAL increased finger end-point error compared to DBS-OFF, DBS-LEFT, and DBS-RIGHT even after adjusting for differences in velocity. We conclude that bilateral STN DBS may facilitate basal ganglia–cortical networks that underlie intensive aspects of movement like velocity, but it may disrupt selective basal ganglia–cortical networks that underlie certain integrative and coordinative aspects of movement such as spatial accuracy.
http://ift.tt/2Erz5tp
Regulation of Lateral Hypothalamic Orexin Activity by Local GABAergic Neurons
Orexin (also known as hypocretin) neurons are considered a key component of the ascending arousal system. They are active during wakefulness, at which time they drive and maintain arousal, and are silent during sleep. Their activity is controlled by long-range inputs from many sources, as well as by more short-range inputs, including from presumptive GABAergic neurons in the lateral hypothalamus/perifornical region (LH/PF). To characterize local GABAergic input to orexin neurons, we used channelrhodopsin-2-assisted circuit mapping in brain slices. We expressed channelrhodopsin-2 in GABAergic neurons (Vgat+) in the LH/PF and recorded from genetically identified surrounding orexin neurons (LH/PFVgat -> Orx). We performed all experiments in mice of either sex. Photostimulation of LH/PF GABAergic neurons inhibited the firing of orexin neurons through the release of GABA, evoking GABAA-mediated IPSCs in orexin neurons. These photo-evoked IPSCs were maintained in the presence of TTX, indicating direct connectivity. Carbachol inhibited LH/PFVgat -> Orx input through muscarinic receptors. By contrast, application of orexin was without effect on LH/PFVgat -> Orx input, whereas dynorphin, another peptide produced by orexin neurons, inhibited LH/PFVgat -> Orx input through -opioid receptors. Our results demonstrate that orexin neurons are under inhibitory control by local GABAergic neurons and that this input is depressed by cholinergic signaling, unaffected by orexin and inhibited by dynorphin. We propose that local release of dynorphin may, via collaterals, provides a positive feedback to orexin neurons and that, during wakefulness, orexin neurons may be disinhibited by acetylcholine and by their own release of dynorphin.
SIGNIFICANCE STATEMENT The lateral hypothalamus contains important wake-promoting cell populations, including orexin-producing neurons. Intermingled with the orexin neurons, there are other cell populations that selectively discharge during nonrapid eye movement or rapid eye movement sleep. Some of these sleep-active neurons release GABA and are thought to inhibit wake-active neurons during rapid eye movement and nonrapid eye movement sleep. However, this hypothesis had not been tested. Here we show that orexin neurons are inhibited by a local GABAergic input. We propose that this local GABAergic input inhibits orexin neurons during sleep but that, during wakefulness, this input is depressed, possibly through cholinergically mediated disinhibition and/or by release of dynorphin from orexin neurons themselves.
http://ift.tt/2EfTMsG
Nonselective Wiring Accounts for Red-Green Opponency in Midget Ganglion Cells of the Primate Retina
In primate retina, "red-green" color coding is initiated when signals originating in long (L) and middle (M) wavelength-sensitive cone photoreceptors interact antagonistically. The center-surround receptive field of "midget" ganglion cells provides the neural substrate for L versus M cone-opponent interaction, but the underlying circuitry remains unsettled, centering around the longstanding question of whether specialized cone wiring is present. To address this question, we measured the strength, sign, and spatial tuning of L- and M-cone input to midget receptive fields in the peripheral retina of macaque primates of either sex. Consistent with previous work, cone opponency arose when one of the cone types showed a stronger connection to the receptive field center than to the surround. We implemented a difference-of-Gaussians spatial receptive field model, incorporating known biology of the midget circuit, to test whether physiological responses we observed in real cells could be captured entirely by anatomical nonselectivity. When this model sampled nonselectively from a realistic cone mosaic, it accurately reproduced key features of a cone-opponent receptive field structure, and predicted both the variability and strength of cone opponency across the retina. The model introduced here is consistent with abundant anatomical evidence for nonselective wiring, explains both local and global properties of the midget population, and supports a role in their multiplexing of spatial and color information. It provides a neural basis for human chromatic sensitivity across the visual field, as well as the maintenance of normal color vision despite significant variability in the relative number of L and M cones across individuals.
SIGNIFICANCE STATEMENT Red-green color vision is a hallmark of the human and nonhuman primate that starts in the retina with the presence of long (L)- and middle (M)-wavelength sensitive cone photoreceptor types. Understanding the underlying retinal mechanism for color opponency has focused on the broad question of whether this characteristic can emerge from nonselective wiring, or whether complex cone-type-specific wiring must be invoked. We provide experimental and modeling support for the hypothesis that nonselective connectivity is sufficient to produce the range of red-green color opponency observed in midget ganglion cells across the retina. Our nonselective model reproduces the diversity of physiological responses of midget cells while also accounting for systematic changes in color sensitivity across the visual field.
http://ift.tt/2Eflczb
The Role of Human Primary Motor Cortex in the Production of Skilled Finger Sequences
Human primary motor cortex (M1) is essential for producing dexterous hand movements. Although distinct subpopulations of neurons are activated during single-finger movements, it remains unknown whether M1 also represents sequences of multiple finger movements. Using novel multivariate functional magnetic resonance imaging (fMRI) analysis techniques and combining evidence from both 3T and 7T fMRI data, we found that after 5 d of intense practice, premotor and parietal areas encoded the different movement sequences. There was little or no evidence for a sequence representation in M1. Instead, activity patterns in M1 could be fully explained by a linear combination of patterns for the constituent individual finger movements, with the strongest weight on the first finger of the sequence. Using passive replay of sequences, we show that this first-finger effect is due to neuronal processes involved in the active execution, rather than to a hemodynamic nonlinearity. These results suggest that M1 receives increased input from areas with sequence representations at the initiation of a sequence, but that M1 activity itself relates to the execution of component finger presses only. These results improve our understanding of the representation of finger sequences in the human neocortex after short-term training and provide important methodological advances for the study of long-term skill development.
SIGNIFICANCE STATEMENT There is clear evidence that human primary motor cortex (M1) is essential for producing individuated finger movements, such as pressing a button. Over and above its involvement in movement execution, it is less clear whether M1 also plays a role in learning and controlling sequences of multiple finger movements, such as when playing the piano. Using cutting-edge multivariate fMRI analysis and carefully controlled experiments, we demonstrate here that, while premotor areas clearly show a sequence representation, activity patterns in M1 can be fully explained from the patterns for individual finger movements. The results provide important new insights into the interplay of M1 and premotor cortex for learning of sequential movements.
http://ift.tt/2Edy09g
Activity in the Ventral Medial Prefrontal Cortex Is Necessary for the Therapeutic Effects of Extinction in Rats
Poor response and high relapse rates remain problematic in the treatment of stress-related psychiatric disorders such as depression and post-traumatic stress disorder. Although mechanisms of pharmacotherapies are intensely studied, little is known about mechanisms of behavioral therapy that could inform improved treatments. We have previously demonstrated the therapeutic effects of extinction learning as a behavioral intervention modeling exposure therapy in rats. In the present study, we tested the hypothesis that activity in the ventral medial prefrontal cortex (vmPFC) during extinction is necessary for its therapeutic effects. The inhibitory Gi-coupled designer receptor exclusively activated by designer drug CaMKIIα-hM4Di was expressed in vmPFC before administering chronic unpredictable stress (CUS). vmPFC projection neurons were then inhibited during extinction treatment by administering clozapine-N-oxide. Coping behavior and cognitive flexibility were assessed 24 h later on the shock-probe defensive burying test and attentional set-shifting test, respectively. Replicating previous results, extinction reversed the CUS-induced deficits in coping behavior and cognitive flexibility. Inhibiting vmPFC during extinction blocked these therapeutic effects. Further, increasing vmPFC activity with the excitatory Gq-coupled designer receptor exclusively activated by designer drug hM3Dq 24 h before testing was sufficient to reverse the CUS-induced deficits. CUS reduced mPFC responsivity, assessed by measuring afferent-evoked field potentials in the mPFC, and this reduction was reversed by extinction treatment 24 h before testing. These results demonstrate the necessity of vmPFC activity in the therapeutic effects of extinction as a model of exposure therapy, and suggest that increased vmPFC activity induced by extinction is sufficient to produce lasting plastic changes that underlie its beneficial effects.
SIGNIFICANCE STATEMENT Stress-related psychiatric disorders remain poorly treated. Psychotherapies can be effective, but their mechanisms remain unknown, hindering progress toward improved treatment. We used a rat model of behavioral therapy to identify potential targets for enhancing treatment. Fear extinction as a therapeutic behavioral intervention reversed stress-induced cognitive dysfunction and passive coping in rats, modeling components of stress-related psychiatric disease. Extinction also reversed stress-induced attenuation of mPFC responsivity. The therapeutic effects were prevented by blocking activity of glutamatergic neurons in the mPFC during extinction, and were mimicked by inducing activity in lieu of extinction. Thus, activity and plasticity in the mPFC underlie the beneficial effects of extinction on cognitive flexibility and coping behavior compromised by stress, and could be targets to enhance behavioral therapy.
http://ift.tt/2EgIUeo
Cancers, Vol. 10, Pages 46: Liver Transplantation for Alcoholic Liver Disease and Hepatocellular Carcinoma
Cancers, Vol. 10, Pages 46: Liver Transplantation for Alcoholic Liver Disease and Hepatocellular Carcinoma
Cancers doi: 10.3390/cancers10020046
Authors: Patrizia Burra Alberto Zanetto Giacomo Germani
Hepatocellular carcinoma is one of the main important causes of cancer-related death and its mortality is increasingly worldwide. In Europe, alcohol abuse accounts for approximately half of all liver cancer cases and it will become the leading cause of hepatocellular carcinoma in the next future with the sharp decline of chronic viral hepatitis. The pathophysiology of alcohol-induced carcinogenesis involves acetaldehyde catabolism, oxidative stress and chronic liver inflammation. Genetic background plays also a significant role and specific patterns of gene mutations in alcohol-related hepatocellular carcinoma have been characterized. Survival is higher in patients who undergo specific surveillance programmes than in patients who do not. However, patients with alcohol cirrhosis present a significantly greater risk of liver decompensation than those with cirrhosis due to other aetiologies. Furthermore, the adherence to screening program can be suboptimal. Liver transplant for patients with Milan-in hepatocellular carcinoma represents the best possible treatment in case of tumour recurrence/progression despite loco-regional or surgical treatments. Long-term result after liver transplantation for alcohol related liver disease is good. However, cardiovascular disease and de novo malignancies can significantly hamper patients' survival and should be carefully considered by transplant team. In this review, we have focused on the evolution of alcohol-related hepatocellular carcinoma epidemiology and risk factors as well as on liver transplantation in alcoholic patients with and without hepatocellular carcinoma.
http://ift.tt/2ESzQsV
Cancers, Vol. 10, Pages 47: Bioapplications of Cell-SELEX-Generated Aptamers in Cancer Diagnostics, Therapeutics, Theranostics and Biomarker Discovery: A Comprehensive Review
Cancers, Vol. 10, Pages 47: Bioapplications of Cell-SELEX-Generated Aptamers in Cancer Diagnostics, Therapeutics, Theranostics and Biomarker Discovery: A Comprehensive Review
Cancers doi: 10.3390/cancers10020047
Authors: Xuehui Pang Cheng Cui Shuo Wan Ying Jiang Liangliang Zhang Lian Xia Long Li Xiaowei Li Weihong Tan
Currently, functional single-stranded oligonucleotide probes, termed aptamers, generated by an iterative technology, Systematic Evolution of Ligands by Exponential Enrichment (SELEX), are utilized to selectively target molecules or cells with high affinity. Aptamers hold considerable promise as multifunctional molecules or conjugates for challenging nanotechnologies or bioapplications now and in the future. In this review, we first describe recent endeavors to select aptamers towards live cancer cells via cell-SELEX. We then introduce several characteristic applications of selected aptamers, especially in imaging, drug delivery and therapy. In part, these advances have been made possible via synthesis of aptamer-based nanomaterials, which, by their sizes, shapes, and physicochemical properties, allow such aptamer-nanomaterial complexes to function as signal reporters or drug carriers. We also describe how these aptamer-based molecular tools contribute to cancer biomarker discovery through high-affinity recognition of membrane protein receptors.
http://ift.tt/2nYHJF8
Predicting drug-induced arrhythmias by multiscale modeling
Abstract
Drugs often have undesired side effects. In the heart, they can induce lethal arrhythmias such as torsades de pointes. The risk evaluation of a new compound is costly and can take a long time, which often hinders the development of new drugs. Here we establish a high resolution, multiscale computational model to quickly assess the cardiac toxicity of new and existing drugs. The input of the model is the drug-specific current block from single cell electrophysiology; the output is the spatio-temporal activation profile and the associated electrocardiogram. We demonstrate the potential of our model for a low risk drug, ranolazine, and a high risk drug, quinidine: For ranolazine, our model predicts a prolonged QT interval of 19.4% compared to baseline and a regular sinus rhythm at 60.15 beats per minute. For quinidine, our model predicts a prolonged QT interval of 78.4% and a spontaneous development of torsades de pointes both in the activation profile and in the electrocardiogram. Our model reveals the mechanisms by which electrophysiological abnormalities propagate across the spatio-temporal scales, from specific channel blockage, via altered single cell action potentials and prolonged QT intervals, to the spontaneous emergence of ventricular tachycardia in the form of torsades de pointes. Our model could have important implications for researchers, regulatory agencies, and pharmaceutical companies on rationalizing safe drug development and reducing the time-to-market of new drugs. This article is protected by copyright. All rights reserved.
http://ift.tt/2sqJ6ST
The impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on the rate of malignancy for atypia of undetermined significance subcategories
BACKGROUND
The recent revision in terminology, with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) replacing noninvasive follicular variant of papillary thyroid carcinoma, has reclassified the clinically indolent tumor as nonmalignant. The objective of this study was to evaluate the impact of this change on the rate of malignancy (ROM) for subcategories of an atypia of undetermined significance (AUS) diagnosis on fine-needle aspiration (FNA) cytology.
METHODS
Consecutive thyroid FNAs interpreted as AUS over a period of 4 years were retrospectively analyzed. The ROM for AUS subcategories, including atypia of undetermined significance with nuclear atypia (AUS-N), atypia of undetermined significance with a microfollicular pattern (AUS-F), atypia of undetermined significance with nuclear atypia and a microfollicular pattern (AUS-N/F), atypia of undetermined significance with Hürthle cells (AUS-H), and atypia of undetermined significance, not otherwise specified (AUS-NOS), were analyzed.
RESULTS
Of the 426 nodules interpreted as AUS, 244 were surgically excised. The incidence of NIFTP in each subcategory was as follows: 18% for AUS-N, 18% for AUS-F, 9% for AUS-N/F, 3% for AUS-H, and 0% for AUS-NOS. After the reclassification of NIFTP as nonmalignant, the ROM based on histologic follow-up significantly decreased from 43% to 26% for AUS-N (P < .001) and from 29% to 10% for AUS-F (P = .008). The ROM for AUS-N remained significantly higher than the ROM for AUS-F (P = .030).
CONCLUSIONS
A subset of resected AUS nodules can be reclassified as NIFTP, and that significantly decreases the ROM, especially for AUS-N and AUS-F. Nonetheless, AUS-N still harbors a substantially higher ROM than AUS-F. Cancer Cytopathol 2018. © 2018 American Cancer Society.
http://ift.tt/2BjVV3T
New Research From Clinical Psychological Science
Read about the latest articles published in Clinical Psychological Science:
Suzanne Penna
This book review discusses Neuropsychological Assessment in the Age of Evidence-Based Practice, edited by Stephen Bowden and published by the National Academy of Neuropsychology. As background, Penna describes neuropsychology's status as a leader in psychological assessment and suggests that neuropsychologists may find this book useful to keep up to date on methodological advancements in the field. The book is divided into three sections that describe the evidence behind neuropsychology practice, successful application of practice, and clinical application of evidence-based criteria. Penna cites the chapters covering psychometrics and statistics as the strongest of the book, and she concludes that neuropsychologists should find this book valuable in ensuring that the work they do is supported by the strongest available science.
Raegan Mazurka, Katherine E. Wynne-Edwards, and Kate L. Harkness
Clinical scientists have observed that depression is twice as likely to occur in women as it is in men, identifying reactivity to stress as one possible explanation for this pattern. To better understand the interaction between stress, depression, and biological sex, the researchers had depressed and nondepressed adolescent participants undergo the Trier Social Stress Test, which required them to prepare and deliver a speech and perform a difficult math task in front of strangers on short notice. Participants' levels of cortisol, a stress hormone, were measured via saliva throughout the experiment. Using two types of statistical analysis, the researchers found that the results converged on opposite patterns of cortisol response for girls and boys. Depressed girls showed reduced cortisol output during the stress test relative to nondepressed girls, whereas depressed boys showed a greater cortisol output under stress relative to nondepressed boys. The authors attribute this discrepancy to differences in hormones and cumulative stress exposure between girls and boys. They suggest that researchers should take sex into account when examining the relationship between stress and depression.
A Unique Safety Signal: Social-Support Figures Enhance Rather Than Protect from Fear Extinction
Erica A. Hornstein, Kate E. B. Haltom, Kanika Shirole, and Naomi I. Eisenberger
Clinical scientists often treat fear using exposure therapy, exposing the patient to fear-inducing cues without the aversive outcome, a process that ultimately extinguishes the fear response. Although some have theorized that the presence of a safety signal interferes with attempts to extinguish fear responses, the authors of this study hypothesized that a specific type of safety signal–an image of a social-support figure–might aid fear extinction. To study this, the authors measured participants' skin conductance responses (SCR) as they viewed images, some of which were paired or not paired with uncomfortable shocks. The participants learned to respond with fear when images paired with the shocks appeared; later, the images appeared again, accompanied by a picture of a personal social-support figure, a picture of a stranger, or no picture. The picture of a social-support figure inhibited participants' learned fear response, but the photo of the stranger did not, a pattern that appeared to hold up to 24 hours later. The authors discuss possible biological and social explanations for the findings and encourage additional work investigating the effects of social support.
http://ift.tt/2G2xjMu
Checkpoint inhibitors in triple-negative breast cancer (TNBC): Where to go from here
Advances in cancer immunotherapy and a growing body of research have focused on the role of the antitumor response in breast cancer. Triple-negative breast cancer (TNBC) is the most immunogenic breast cancer subtype, and there is strong evidence that tumor-infiltrating lymphocytes in TNBC have prognostic value and are associated with clinical outcome and improved survival. Evading antitumor immunity is a hallmark for the development and progression of cancer. Immunotherapy studies have focused on the role of the programmed cell death-1 (PD-1) receptor/programmed death-ligand 1 (PD-L1) pathway in maintaining immunosuppression in the tumor microenvironment. Blockade of the PD-1/PD-L1 axis has emerged as a promising therapeutic option to enhance antitumor immunity and is actively being investigated in TNBC, with encouraging results. In this article, the authors review the current literature on checkpoint inhibitors in TNBC with a focus on PD-1/PD-L1 antibodies and discuss combination strategies and novel approaches for improving antitumor immunity and clinical outcome. Cancer 2018. © 2018 American Cancer Society.
http://ift.tt/2Bk5Vdw
Allogeneic hematopoietic stem cell transplantation for relapsed follicular lymphoma: A combined analysis on behalf of the Lymphoma Working Party of the EBMT and the Lymphoma Committee of the CIBMTR
BACKGROUND
Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only potentially curative treatment option for relapsed follicular lymphoma (FL), yet questions remain about the optimal timing. This study analyzed long-term outcomes and associated factors among recipients of allo-HCT with FL.
METHODS
Patients with relapsed FL who underwent allo-HCT from 2001 to 2011 with a human leukocyte antigen (HLA)–matched donor were included. Outcome analyses for overall survival (OS), progression-free survival (PFS), transplant-related mortality (TRM), and disease relapse/progression were calculated. A multivariate analysis was performed to determine factors associated with outcomes, and a prognostic score for treatment failure was developed in a subset analysis of patients.
RESULTS
In all, 1567 patients with relapsed FL were included; the median follow-up was 55 months. The 5-year probabilities of OS and PFS were 61% and 52%, respectively. The 5-year cumulative incidences of disease progression/relapse and TRM were 29% and 19%, respectively. Chemoresistant disease, older age, heavy pretreatment, poor performance status (PS), and myeloablative protocols were predictors for worse survival. The prognostic score, using age, lines of prior therapy, disease status, and PS, stratified patients into 3 groups—low, intermediate, and high risk—with 5-year PFS rates of 68%, 53%, and 46%, respectively, and 5-year OS rates of 80%, 62%, and 50%, respectively.
CONCLUSIONS
Allo-HCT should be considered for patients with relapsed FL and available HLA-matched donors. Outcomes are better in earlier phases of the disease, and reduced-intensity conditioning should be preferred. The prognostic score presented here can assist in counseling patients and determining the time to proceed to transplantation. Cancer 2018. © 2018 American Cancer Society.
http://ift.tt/2BOe234
Cost-Effectiveness Thresholds: the Past, the Present and the Future
Abstract
Cost-effectiveness (CE) thresholds are being discussed more frequently and there have been many new developments in this area; however, there is a lack of understanding about what thresholds mean and their implications. This paper provides an overview of the CE threshold literature. First, the meaning of a CE threshold and the key assumptions involved (perfect divisibility, marginal increments in budget, etc.) are highlighted using a hypothetical example, and the use of historic/heuristic estimates of the threshold is noted along with their limitations. Recent endeavours to estimate the empirical value of the thresholds, both from the supply side and the demand side, are then presented. The impact on CE thresholds of future directions for the field, such as thresholds across sectors and the incorporation of multiple criteria beyond quality-adjusted life-years as a measure of 'value', are highlighted. Finally, a number of common issues and misconceptions associated with CE thresholds are addressed.
http://ift.tt/2ERUmdt
ICD-10 impact on ascertainment and accuracy of oral cleft cases as recorded by the Brazilian national live birth information system
We compared Brazilian oral cleft (OC) frequencies between the population-based Brazilian System of Live Birth (SINASC) and the hospital-based Latin American Collaborative Study of Congenital Malformations (ECLAMC), trying to understand the paucity of cleft of lip and palate (CLP) in the first system. SINASC uses the International Classification of Disease version 10 (ICD-10) for congenital defects coding, ECLAMC uses ICD-8 with modifications. In SINASC, the CLP frequency was 1.7 per 10,000 (95% confidence limits 1.7–1.8), cleft lip (CL) 1.6 (1.5–1.7), and cleft palate (CP) 2.0 (1.9–2.1). In ECLAMC, the CLP frequency was 10.4 per 10,000 (9.0–12.1), CL 5.5 (4.5–6.7), and CP 4.4. (4.5–6.7). In SINASC, only 33% of the oral clefts were CLP, versus 51% in ECLAMC. Part of this discrepancy may have been due to the relative excess of CP and CL cases. Although congenital defect frequencies are usually lower in population than in hospital-based registries, differences in the proportion of the main OC categories are not expected and are probably due to ICD-10 coding issues, such as lumping of unilateral CL and CL without other specifications. ICD-10 codes, whose deficiency for oral clefts is fully explained in the literature, lack modifiers for severity, or clinical subtypes. This paper shows the practical aspect of the ICD-10 system deficiency in capturing cleft lip and palate (CLP) subtypes, as demonstrated in SINASC covering three million births per year. Such errors are expected to occur in any registry that uses the ICD-10 coding system, and must be adjusted, given its relevance worldwide.
http://ift.tt/2FZrDCG
Hormonal factors and pancreatic cancer risk in women: The Malmö Diet and Cancer Study
Abstract
The incidence of pancreatic cancer is levelling between sexes. Smoking, high age and heredity are established risk factors, but evidence regarding the influence of hormonal factors is unclear. In this study, we investigated the associations of reproductive factors, use of oral contraceptives (OC) and hormone replacement therapy (HRT) with pancreatic cancer risk in the Malmö Diet and Cancer Study, a prospective, population-based cohort encompassing 17 035 women.
Up until December 31st 2015, 110 women were identified with incident pancreatic cancer through the Swedish Cancer Registry. Higher age at menarche was significantly associated with pancreatic cancer risk (age-adjusted [hazard ratio] HR=1.17; 95% confidence interval [CI] 1.04-1.32, and fully adjusted HR=1.17; 95% CI 1.04-1.32). Ever use of OC was not significantly associated with pancreatic cancer risk but ever use of HRT was significantly associated with a decreased risk of pancreatic cancer (age-adjusted HR=0.47, 95% CI 0.23-0.97, and fully adjusted HR=0.48, 95% CI 0.23-1.00), in particular use of estrogen-only regimen (age-adjusted HR=0.21; 95% CI 0.05-0.87 and fully adjusted HR=0.22; 95% CI 0.05-0.90). Age at menopause or first childbirth, parity, and breastfeeding history were not significantly associated with pancreatic cancer risk.
Collectively, these findings suggest a protective role of female hormones against pancreatic cancer. Further studies are needed, and potential modifying genetic factors and indirect hazardous effects of smoking should also be considered. This article is protected by copyright. All rights reserved.
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Three molecular pathways model colorectal carcinogenesis in Lynch syndrome
Abstract
Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR-deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR-deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome. This article is protected by copyright. All rights reserved.
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Current status of surgical incisions used in donors during living related liver transplantation – a nationwide survey in Japan
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Extracellular vesicles from human liver stem cells reduce injury in an ex vivo normothermic hypoxic rat liver perfusion model
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Identification of Anti-Trypanosoma cruzi Lead Compounds with Putative Immunomodulatory Activity [PublishAheadOfPrint]
In substitution for the current Chagas disease treatment with several relevant side effects, new therapeutic candidates have been extensively investigated. In this context, the balanced interaction between mediators of the host immune response seems to be a key element for therapeutic success, where a pro-inflammatory microenvironment modulated by IL-10 is shown to be relevant to potentiate anti-Trypanosoma cruzi drug activity. This study aimed to identify the potential immunomodulatory activity of the anti-T. cruzi K777, Pyronaridine (PYR) and Furazolidone (FUR) compounds in peripheral blood mononuclear cells (PBMC) from noninfected subjects (NI) and chronic Chagas disease patients (CD). Our results showed low cytotoxicity to PBMC populations, with CC50 = 13.1μM (K777); 9.0μM (PYR) and greater than 20μM (FUR). In addition, K777 showed no impact on the exposure index (EI) of phytohemagglutinin-stimulated leukocytes (PHA), while PYR and FUR treatments induced increased EI of monocytes and T lymphocytes at late stages of apoptosis in NI subjects. Moreover, K777 induced a more prominent pro-inflammatory response (TNF-α+CD8+/CD4+, IFN-+CD4+/CD8+ modulated by IL-10 (IL-10+CD4+T/CD8+T) in comparison with PYR (TNF-α+CD8+, IL-10+CD8+) and FUR (TNF-α+CD8+, IL-10+CD8+). Signature analysis of intracytoplasmic cytokines corroborated with the proinflammatory/modulated (K777) and pro-inflammatory (PYR and FUR) profiles previously found. In conclusion, K777 lead compound may induce beneficial changes in the immunological profile of patients presenting the chronic phase of Chagas disease and may contribute to a more effective therapy against the disease.
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Establishment and validation of Galleria mellonella as a novel model organism to study Mycobacterium abscessus infection, pathogenesis and treatment. [PublishAheadOfPrint]
Introduction: Treatment of Mycobacterium abscessus infections is extremely challenging due to its intrinsic resistance to most antibiotics, and research of pathogenesis is limited due to a lack of a practical in vivo model of infection.
Objectives: To establish a simple in-vivo model for M. abscessus infection, virulence, and drug testing in G. mellonella larvae.
Methods: We inoculated larvae with M. abscessus, and followed histopathology, CFU count and mortality with and without antibiotic treatment. We also constructed a luminescent, recombinant M. abscesssus, mDB158, and imaged infected larvae using IVIS®.
Results: M. abscessus proliferated and induced granulomatous-like responses in infected larvae leading to larval mortality. The G. mellonella model was further successfully validated by demonstration of the expected favorable antimicrobial effect of treatment with meropenem, and the superiority of combination treatment (meropenem and tigecycline) over single agents. We then used IVIS® imaging of larvae infected with luminescent M. abscessus, allowing live real-time assessment of bacterial load. We used this method to compare the antimicrobial effect of various antibiotics (meropemen, amikacin, linezolid, levofloxacin, etc.) on bacterial proliferation and larval survival. Meropenem and amikacin had the most favorable effect, correlating well with common clinical practice guidelines.
Conclusions: These findings suggest G. mellonella to be an excellent in vivo model for research of M. abscessus infection, pathogenesis and treatment. Luminescent M. abscessus and IVIS® imaging further facilitates this model. Results obtained in this model clearly substantiated common clinical practice, thus validating the model as a predictor of treatment efficacy and outcome.
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Time to Multidrug-Resistant Tuberculosis Treatment Initiation in Association with Treatment Outcomes in Shanghai, China [PublishAheadOfPrint]
In high TB-burden countries like China, the diagnosis of multidrug-resistant tuberculosis (MDR-TB) using conventional drug susceptibility testing (DST) takes months, making treatment delay inevitable. Poor outcomes of MDR-TB might be associated with delayed, even inappropriate treatment. The purpose of this study was to investigate the time to MDR-TB treatment initiation, and to assess the association between early treatment and treatment outcomes. Between April 2011 and December 2014, this population-based, retrospective cohort study collected the demographic and clinical characteristics, and the drug susceptibility profiles of all registered MDR-TB patients in Shanghai, China. Dates of TB and MDR-TB diagnoses, DST performing and treatment initiation were extracted to calculate the time to treatment. In total, 284 of 346 MDR-TB patients were eligible for analysis, and 68.3% (194/284) had favored outcomes. The median time to treatment initiation from TB diagnosis was 172 days among those with favored outcomes and 190 days among those with poor outcomes. Treatment initiated within 60 days after DST performing (OR 2.56, 95% CI 1.22-5.36) and empiric treatment (OR 2.09, 95% CI 1.01-4.32) were positively associated with favored outcomes. Substantial delays to MDR-TB treatment were observed when conventional DST was used. Early treatment predicted favored outcomes. Rapid diagnostic methods should be scaled up and, improvements should be made in patient management and information linkage to reduce treatment delay.
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Short proline-rich lipopeptide potentiates minocycline and rifampicin against multidrug- and extensively drug-resistant Pseudomonas aeruginosa. [PublishAheadOfPrint]
A series of 16 short proline-rich lipopeptides (SPRLPs) were constructed to mimic longer naturally-existing proline-rich antimicrobial peptides. Antibacterial assessment revealed that lipopeptides containing hexadecanoic acid (C16) possess optimal antibacterial activity relative to others with shorter lipid component. SPRLPs were further evaluated for their potential to serve as adjuvants in combination with existing antibiotics to enhance antibacterial activity against drug-resistant Pseudomonas aeruginosa. Out of sixteen prepared SPRLPs, C12-PRP was found to significantly potentiate the antibiotics minocycline and rifampicin against multidrug- and extensively drug-resistant (MDR/XDR) P. aeruginosa clinical isolates. This non-hemolytic C12-PRP is comprised of a heptapeptide sequence PRPRPRP-NH2 acylated to dodecanoic acid (C12) at the N-terminus. The adjuvant potency of C12-PRP was apparent by its ability to reduce the minimum inhibitory concentration of minocycline and rifampicin below their interpretative susceptibility breakpoints against MDR/XDR P. aeruginosa. An attempt to optimize C12-PRP through peptidomimetic modification was performed by replacing all L- to D-amino acids. C12-PRP demonstrated pliability to optimization as synergism with minocycline and rifampicin were retained. Moreover, C12-PRP displayed no cytotoxicity against human liver carcinoma HepG2 and human embryonic kidney HEK-293 cell lines. Thus, the SPRLP C12-PRP is a lead adjuvant candidate that warrants further optimization. Discovery of agents that are able to resuscitate activity of existing antibiotics against drug-resistant Gram-negative pathogens, especially P. aeruginosa are of great clinical interest.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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