The Role of PI3K/Akt and ERK in Neurodegenerative Disorders

Abstract

Disruption of Akt and Erk-mediated signal transduction significantly contributes in the pathogenesis of various neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's diseases, Huntington's disease, and many others. These regulatory proteins serve as the regulator of cell survival, motility, transcription, metabolism, and progression of the cell cycle. Therefore, targeting Akt and Erk pathway has been proposed as a reasonable approach to suppress ND progression. This review has emphasized on involvement of Akt/Erk cascade in the neurodegeneration. Akt has been reported to regulate neuronal toxicity through its various substrates like FOXos, GSK3β, and caspase-9 etc. Akt is also involved with PI3K in signaling pathway to mediate neuronal survival. ERK is another kinase which also regulates proliferation, differentiation, and survival of the neural cell. There has also been much progress in developing a therapeutic molecule targeting Akt and Erk signaling. Therefore, improved understanding of the molecular mechanism behind the regulatory aspect of Akt and Erk networks can make strong impact on exploration of the neurodegenerative disease pathogenesis.

http://bit.ly/2BcLvCz

Reply to the Letter to the Editor of Fei Jia et al. concerning “Comparison of combined anterior–posterior approach versus posterior-only approach in neuromuscular scoliosis: a systematic review and meta-analysis” by Shao ZX, et al. [Eur Spine J; (2018) 27(9): 2213–2222]

http://bit.ly/2sYmZAj

TiO 2 nanotube arrays modified with nanoparticles of platinum group metals (Pt, Pd, Ru): enhancement on photoelectrochemical performance

Abstract

Highly ordered TiO₂ nanotube arrays (TiO₂ NTs) were synthesized by anodization method using a titanium foil and further modified with nanoparticles (Ø = 2~10 nm) of three platinum group metals (that is, platinum, palladium, and ruthenium) through potentiostatic pulsed electrodeposition method to obtain the composite material. Compared with pure TiO₂ NTs, all the three composite samples (M-TiO₂ NTs, M = Pt, Pd, Ru) showed different enhancement effects on the light responses, as well as different photoelectrochemical performances. In this study, the performance of M-TiO₂ NTs, which worked as photoanode and cathode, was investigated. Ru-TiO₂ exhibited the best degradation yield (~ 85.8%) when applied as photoanode under visible light illumination, which indicated the platinum group metal could also be induced under visible irradiation, not just served as the co-catalyst. M-TiO₂ NTs as cathode were evaluated under the hydrogen evolution reaction (HER). The three M-TiO₂ NT electrodes showed an improved efficiency over pure TiO₂ NTs, while Pt-TiO₂ NTs performed even better (without any sacrificial agent) with higher Faradic efficiency than platinum electrode in the photoelectrocatalytic hydrogen production, which could be explained by the uniform and fine metal nanoparticles on the surface of TiO₂ NTs to offer abundant active sites for the reaction.

Graphical abstract

In this paper, TiO2 nanotube arrays loaded with nanoparticles of platinum group metals have been explored on their enhancement of photoelectrocatalytic activity. Platinum group metals served as co-catalyst in the surface of TiO2 nanotubes and show great variations in different reactions.

http://bit.ly/2Gds9Ap

Verification of image quality and quantification in whole-body positron emission tomography with continuous bed motion

Abstract

Objective

Whole-body dynamic imaging using positron emission tomography (PET) facilitates the quantification of tracer kinetics. It is potentially valuable for the differential diagnosis of tumors and for the evaluation of therapeutic efficacy. In whole-body dynamic PET with continuous bed motion (CBM) (WBDCBM-PET), the pass number and bed velocity are key considerations. In the present study, we aimed to investigate the effect of a combination of pass number and bed velocity on the quantitative accuracy and quality of WBDCBM-PET images.

Methods

In this study, WBDCBM-PET imaging was performed at a body phantom using seven bed velocity settings in combination with pass numbers. The resulting image quality was evaluated. For comparing different acquisition settings, the dynamic index (DI) was obtained using the following formula: [P/S], where P represents the pass number, and S represents the bed velocity (mm/s). The following physical parameters were evaluated: noise equivalent count at phantom (NEC_phantom), percent background variability (N_10 mm), percent contrast of the 10 mm hot sphere (Q_{H, 10 mm}), the Q_{H, 10 mm}/N_10 mm ratio, and the maximum standardized uptake value (SUV_max). Furthermore, visual evaluation was performed.

Results

The NEC_phantom was equivalent for the same DI settings regardless of the bed velocity. The N_10 mm exhibited an inverse correlation (r < − 0.89) with the DI. Q_H,10 mm was not affected by DI, and a correlation between Q_H,10 mm/N_10 mm ratio and DI was found at all the velocities (r > 0.93). The SUV_max of the spheres was not influenced by the DI. The coefficient of variations caused by bed velocity decreased in larger spheres. There was no significant difference between the bed velocities on visual evaluation.

Conclusion

The quantitative accuracy and image quality achieved with WBDCBM-PET was comparable to that achieved with non-dynamic CBM, regardless of the pass number and bed velocity used during imaging for a given acquisition time.

http://bit.ly/2G2JvAQ

The impact of body mass index on perioperative outcomes after robotic liver resection

Abstract

High body mass index (BMI) is associated with other multiple comorbidities such as non-alcoholic fatty liver disease, steatohepatitis, liver cirrhosis, and cardiopulmonary diseases, which can impact the perioperative outcomes following liver resection. We aimed to study the impact of BMI on perioperative outcomes after robotic liver resection. All the patients undergoing robotic liver resection between 2013 and 2017 were prospectively followed. The patients were divided into three groups (BMI < 25, BMI 25–35, BMI > 35 kg/m²) for illustrative purposes. Demographic and perioperative outcome data were compared. Data are presented as median (mean ± SD). Thirty-eight patients underwent robotic hepatectomy, 73% were women, age was 58 (57 ± 17.6) years, and ASA class was 3 (3 ± 0.5). Indications for surgery were neoplastic lesions in 34 patients (89%), hemangioma in two patients (6%), fibrous mass in one patient (2.5%), and focal nodular hyperplasia in one patient (2.5%). 32% of the patients underwent right or left hemihepatectomy, 21% underwent sectionectomy, 5% underwent central hepatectomy and the reminder underwent non-anatomical liver resection. Operative time was 261 (254.6 ± 94.3) min. Estimated blood loss was 175 (276 ± 294.8) ml. Length of hospital stay was 3 (5 ± 4.9) days. By regression analysis of the three BMI groups, estimated blood loss, rate of postoperative complication, rate of conversion, need for transfusion, length of ICU stay, and length of hospital stay did not have a significant relationship with BMI. A total of five patients (13%) experience complications. Four patients had complications that were nonspecific to liver resection, including acute renal injury, respiratory failure, and enterocutaneous fistula. One patient had bile leak, treated with ERCP stenting. No mortality was seen in this study. Obesity should not dissuade surgeons from utilizing minimally invasive robotic approach for liver resection. Robotic technique is a safe and feasible in patients with high BMI. The impact of BMI on outcomes is insignificant.

http://bit.ly/2MJUMGG

MiR-5571-3p and miR-135b-5p, derived from analyses of microRNA profile sequencing, correlate with increased disease risk and activity of rheumatoid arthritis

Abstract

Objectives

This study aimed to investigate microRNA (miRNA) expression profiles in synovium tissues of rheumatoid arthritis (RA) patients by RNA sequencing and to evaluate the values of dysregulated miRNAs in RA diagnosis and monitoring.

Methods

Thirty RA patients who underwent knee arthroscopy and 30 controls with knee trauma who underwent surgery were consecutively recruited, and synovium tissue samples of both groups were obtained during surgeries. In the exploration part, miRNA and mRNA expression profiles of 3 RA samples and 3 control samples were detected using RNA sequencing then followed by bioinformatic analyses. In the validation part, 5 candidate miRNA levels were detected by quantitative polymerase chain reaction (qPCR) in 30 RA patients and 30 control patients.

Results

In the exploration part, 78 miRNAs and 1582 mRNAs were upregulated while 40 miRNAs and 1295 mRNAs were downregulated in synovium tissue samples of RA patients compared with those of controls. Furthermore, enrichment analyses revealed that these dysregulated miRNAs and mRNAs were mainly implicated in immune activities and inflammatory diseases such as leukocyte migration, complement activation, and RA. In the validation part, qPCR assay revealed that miR-5571-3p and miR-135b-5p expressions were increased in RA patients compared with those in controls and disclosed good predictive values for RA risk with high area under the curves (AUCs). Besides, both miR-5571-3p and miR-135b-5p levels were positively correlated with disease activity and inflammation level of RA.

Conclusions

Analyses of miRNA expression profiles by sequencing indicate that miR-5571-3p and miR-135b-5p correlate with increased RA risk and activity.

http://bit.ly/2G2oZjx

A novel WDR62 missense mutation in microcephaly with abnormal cortical architecture and review of the literature

Abstract

Autosomal recessive primary microcephaly (MCPH) is a group of rare neurodevelopmental diseases with severe microcephaly at birth. One type of the disorder, MCPH2, is caused by biallelic mutations in the WDR62 gene, which encodes the WD repeat–containing protein 62. Patients with WDR62 mutation may have a wide range of malformations of cortical development in addition to congenital microcephaly. We describe two patients, a boy and a girl, with severe congenital microcephaly, global developmental delay, epilepsy, and failure to thrive. MRI showed hemispherical asymmetry, diffuse pachygyria, thick gray matter, indistinct gray-white matter junction, and corpus callosum and white matter hypoplasia. Whole exome sequencing revealed the same novel homozygous missense mutation, c.668T>C, p.Phe223Ser in exon 6 of the WDR62 gene. The healthy parents were heterozygous for this mutation. The mutation affects a highly conserved region in one of the WD repeats of the WDR62 protein. Haplotype analysis showed genetic relatedness between the families of the patients. Our findings expand the spectrum of mutations randomly distributed in the WDR62 gene. A review is also provided of the brain malformations described in WDR62 mutations in association with congenital microcephaly.

http://bit.ly/2CZFqct

Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines

Summary

The latex from Euphorbia tirucalli is used in Brazil as a folk medicine for several diseases, including cancer. Recently, we showed a cytotoxic activity of E. tirucalli euphol in a wide range of cancer cell lines. Moreover, we showed that euphol inhibits proliferation, motility and colony formation in pancreatic cancer cells, induces autophagy and sensitizes glioblastoma cells to temozolomide cytotoxicity. Herein, we report in vitro activity of three semi-synthetic ingenol compounds derived from E. tirucalli, IngA (ingenol-3-trans-cinnamate), IngB (ingenol-3-hexanoate) and IngC (ingenol-3-dodecanoate), against a large panel of human cancer cell lines. Antineoplastic effects of the three semi-synthetic compounds were assessed using MTS assays on 70 cancer cell lines from a wide array of solid tumors. Additionally, their antitumor potential was compared with known compounds of the same class, namely ingenol-3-angelate (Picato®) and ingenol 3,20-dibenzoate and in combination with standard chemotherapeutic agents. We observed that IngA, B, and C exhibited dose-dependent cytotoxic effects. Amongst the semi-synthetic compounds, IngC displayed the best activity across the tumor cell lines. In comparison with ingenol-3-angelate and ingenol 3,20-dibenzoate, IngC showed a mean of 6.6 and 3.6-fold higher efficacy, respectively, against esophageal cancer cell lines. Besides, IngC sensitized esophageal cancer cells to paclitaxel treatment. In conclusion, the semi-synthetic ingenol compounds, in particular, IngC, demonstrated a potent antitumor activity on all cancer cell lines evaluated. Although the underlying mechanisms of action of IngC are not elucidated, our results provide insights for further studies suggesting IngC as a putative therapy for cancer treatment.

http://bit.ly/2MHZULh

Transgenic versus conventional corn: fate of fumonisins during industrial dry milling

Abstract

The aim of this study was to compare the fate of fumonisins in transgenic and non-transgenic corn during industrial dry milling. For this purpose, whole corn samples and their fractions (germ, pericarp, endosperm, corn meal, and grits) were collected from one of the major Brazilian milling plants, totaling 480 samples. There was no significant difference (p > 0.05) between mean fumonisin (FB₁ + FB₂) levels in transgenic (1130 μg/kg) and non-transgenic (920 μg/kg) whole corn. However, in non-transgenic germ, endosperm and corn meal fraction fumonisin levels were higher (2940 μg/kg, 250 μg/kg and 190 μg/kg, respectively) than in transgenic fractions (2180 μg/kg, 130 μg/kg and 85.0 μg/kg, respectively). Furthermore, the highest percentages of fumonisins were distributed in the germ, corresponding to about 87 and 76% of the total fumonisins present in the whole corn from non-transgenic and transgenic hybrids, respectively. Concerning the endosperm from non-transgenic and transgenic corn, approximately, 23% and 13% of the total fumonisins were retained after the dry milling. Further processing in corn meal (300 to 420 μm particle size) and grits (590 to 1190 μm) decreased the percentages of remaining fumonisins to 4% and 2% (transgenic) and 10% and 3% (non-transgenic corn), respectively. These results suggested that fumonisin concentration was higher in outer and inner non-transgenic fractions when compared to transgenic ones and that the fate of fumonisins during the industrial dry milling could be affected by the transgenic status. However, it was not possible to conclude that the difference was exclusively due to this variable.

http://bit.ly/2SgBT3s

First report of Fusarium foetens as a mycotoxin producer

Abstract

Fusarium foetens, a pathogen of Begonia plants, has been recently described as a new fungal species. This Fusarium species causes a destructive vascular wilt disease which leads to the death of the plant. Moreover, Fusarium species are known to produce a huge variety of secondary metabolites such as mycotoxins and phytotoxins. Here, we studied the toxicogenic profile of one F. foetens strain, isolated from maize, employing two methods based on the use of ultra-performance liquid chromatography coupled to mass spectrometry-ion trap-time of flight detection. The mycotoxins beauvericin and fusaric acid were detected in a pure culture of F. foetens. In addition, four fusaric acid analogs (10,11-dihidroxyfusaric acid, hydroxyfusaric acid, dehydrofusaric acid, and a hydroxylated unsaturated fusaric acid analog) were tentatively identified on the basis of their accurate mass and fragmentation patterns. Therefore, these preliminary data indicate that F. foetens isolated from maize is able to produce Fusarium mycotoxins including beauvericin and fusaric acid.

http://bit.ly/2GeP2U6

Modified ingenol semi-synthetic derivatives from Euphorbia tirucalli induce cytotoxicity on a large panel of human cancer cell lines

Summary

The latex from Euphorbia tirucalli is used in Brazil as a folk medicine for several diseases, including cancer. Recently, we showed a cytotoxic activity of E. tirucalli euphol in a wide range of cancer cell lines. Moreover, we showed that euphol inhibits proliferation, motility and colony formation in pancreatic cancer cells, induces autophagy and sensitizes glioblastoma cells to temozolomide cytotoxicity. Herein, we report in vitro activity of three semi-synthetic ingenol compounds derived from E. tirucalli, IngA (ingenol-3-trans-cinnamate), IngB (ingenol-3-hexanoate) and IngC (ingenol-3-dodecanoate), against a large panel of human cancer cell lines. Antineoplastic effects of the three semi-synthetic compounds were assessed using MTS assays on 70 cancer cell lines from a wide array of solid tumors. Additionally, their antitumor potential was compared with known compounds of the same class, namely ingenol-3-angelate (Picato®) and ingenol 3,20-dibenzoate and in combination with standard chemotherapeutic agents. We observed that IngA, B, and C exhibited dose-dependent cytotoxic effects. Amongst the semi-synthetic compounds, IngC displayed the best activity across the tumor cell lines. In comparison with ingenol-3-angelate and ingenol 3,20-dibenzoate, IngC showed a mean of 6.6 and 3.6-fold higher efficacy, respectively, against esophageal cancer cell lines. Besides, IngC sensitized esophageal cancer cells to paclitaxel treatment. In conclusion, the semi-synthetic ingenol compounds, in particular, IngC, demonstrated a potent antitumor activity on all cancer cell lines evaluated. Although the underlying mechanisms of action of IngC are not elucidated, our results provide insights for further studies suggesting IngC as a putative therapy for cancer treatment.

http://bit.ly/2MHZULh

De-Hankelization of singular spectrum analysis matrices via L 1 norm criterion

Abstract

This paper proposes to employ the L₁ norm criterion to perform the de-Hankelization in the singular spectrum analysis (SSA). In particular, the represented values of the off-diagonals in the two-dimensional SSA matrices are found via minimizing the L₁ norm errors of the vectors defining as the absolute differences between the off-diagonal vectors and the vectors with all their elements being the represented values. This results to reduce the total number of the large-valued elements in the error vectors. Also, this paper guarantees to achieve the exact perfect reconstruction of the original signal. As the formulated problem is a standard linear programming problem, the solution could be efficiently found via the simplex method. The computer numerical simulations verify the results.

http://bit.ly/2S1RQv3

Pediatric nodular fasciitis at the roof of the optic canal causing decreased vision: case report and review of the literature

Abstract

We present a 3-year-old girl with decreased visual acuity of the left eye. Radiological studies revealed a mass lesion at the roof of the left optic canal with bony erosion, which compressed the left optic nerve. Gross total resection of the mass and decompression of the optic canal were performed. Histopathological study was consistent with nodular fasciitis. This is the first report of nodular fasciitis at the roof of the optic canal in a young child. Nodular fasciitis compressing the optic nerve should be included in differential diagnoses of optic neuropathy in young children.

http://bit.ly/2UxjKeV

Antibacterial effects of iron oxide (Fe 3 O 4 ) nanoparticles: distinguishing concentration-dependent effects with different bacterial cells growth and membrane-associated mechanisms

Abstract

Nowadays, the influence of nanoparticles (NPs) on microorganisms attracts a great deal of attention as an alternative to antibiotics. Iron oxide (Fe₃O₄) NPs' effects on Gram-negative Escherichia coli BW 25113 and Gram-positive Enterococcus hirae ATCC 9790 growth and membrane-associated mechanisms have been investigated in this study. Growth specific rate of E. coli was decreased, indicating the bactericidal effect of Fe₃O₄ NPs. This inhibitory effect of NPs had a concentration-dependent manner. The reactive oxygen species together with superoxide radicals and singlet oxygen formed by Fe₃O₄ NPs could be the inhibition cause. Fe₃O₄ NPs showed opposite effects on E. hirae: the growth stimulation or inhibition was observed depending on NPs concentration used. Addition of NPs altered redox potential kinetics and inhibited H₂ yield in E. coli; no change in intracellular pH was determined. Fe₃O₄ NPs decreased H⁺-fluxes through bacterial membrane more in E. coli than in E. hirae even in the presence of DCCD and increased ATPase activity more in E. hirae than in E. coli. Our results showed that the Fe₃O₄ NPs demonstrate differentiating effects on Gram-negative and Gram-positive bacteria likely due to the differences in bacterial cell wall structure and metabolic peculiarities. Fe₃O₄ NPs of different concentrations have no hemolytic (cytotoxic) activity against erythrocytes. Therefore, they can be proposed as antibacterial agents in biomedicine, biotechnology, and pharmaceutics.

http://bit.ly/2t2uztG

Enhanced production and identification of antioxidants in in vitro cultures of the cacti Mammillaria candida and Turbinicarpus laui

Abstract

Cacti are an important source of metabolites but present limitations for their commercial exploitation, like slow growth and a decrease of wild populations. An alternative to obtain their biocompounds without affecting the natural environment are the in vitro culture techniques. We established in vitro cultures from Mammillaria candida Scheidweiler and Turbinicarpus laui Glass and Foster and used different stresses to increase metabolites and antioxidant activity. The cultures were exposed to 1.25% polyethylene glycol to induce a moderate drought stress, 50 g L⁻¹ sucrose to generate an osmotic stress, chitosan (1.25 to 5 mg mL⁻¹) to simulate a biotic attack, or to UV light. Chitosan was the best elicitor improving 1.5 times the concentration of phenolics, 9 to 10 times the content of flavonoids and betalains, and 16% the antioxidant activity in M. candida suspensions. In T. laui suspensions, this elicitor duplicates the flavonoids content and antioxidant activity. The antioxidant levels in elicited suspensions increased 5 to 10 times in relation to plant tubercles. Eleven compounds were identified in M. candida suspensions being digalloyl rhamnoside and epicatequin gallate the most abundant; in the T. laui suspensions, 16 compounds were detected and the most abundant were 17-decarboxi neobetanin and derivatives of luteolin. Thus, cacti in vitro culture is an efficient system to obtain high level of metabolites of biological interest.

http://bit.ly/2MKQEWI

Apatinib, a novel VEGFR inhibitor plus docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR: a phase I trial

Summary

Background This phase I trial was primarily conducted to determine the maximum tolerated dose (MTD) of apatinib combined with docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR who have failed to first-line platinum-based chemotherapy, and to evaluate the safety and tolerability of apatinib plus docetaxel. Methods This was a single-center, open-label, dose-escalating phase I trial. The study used a standard 3 + 3 dose escalation design with the primary aim of determining the MTD. Twelve patients with advanced lung adenocarcinoma were enrolled, the primary endpoint was safety. Two doses of apatinib, 250 mg/day (level 1) and 500 mg/day (level 2), were evaluated in combination with 60 mg/m² doxetacel every 3 weeks. Six patients have been treated at levels 1 and 2, respectively. Optimal dose of apatinib was determined by dose-limiting toxicity (DLT). Results Six patients have been treated at levels 1 and 2. At level 1, one of six patients experienced grade 3 acneiform rash as DLTs. At level 2, two patients experienced grade 3 hypertension and one experienced grade 3 nasal bleeding. MTD and recommended dose for phase II study was 250 mg/day. Most frequent adverse events of any grade were bilirubin elevation, hypertension, alanine aminotransferase elevation, transglutaminase elevation, hand foot syndrome and fatigue. The median progression-free survival was 2.76 month. Moreover, three patients had developed progressive disease and the mean duration of response was 2.79 months. Conclusion Apatinib plus docetaxel was well tolerated and showed promising efficacy in advanced lung adenocarcinoma. This combination therapy may represent a potent therapeutic option for advanced lung adenocarcinoma patients with wild-type EGFR.

http://bit.ly/2UyJHuN

Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo

Summary

We generated a nitric oxide (NO)-releasing derivative of the anti-HIV protease inhibitor lopinavir by linking the NO moiety to the parental drug. We investigated the effects of lopinavir and its derivative lopinavir-NO on melanoma cell lines in vitro and in vivo. Lopinavir-NO exhibited a twofold stronger anticancer action than lopinavir in vitro. These results were successfully translated into syngeneic models of melanoma in vivo, where a significant reduction in tumour volume was observed only in animals treated with lopinavir-NO. Both lopinavir and lopinavir-NO inhibited cell proliferation and induced the trans-differentiation of melanoma cells to Schwann-like cells. In melanoma cancer cell lines, both lopinavir and lopinavir-NO induced morphological changes, minor apoptosis and reactive oxygen species (ROS) production. However, caspase activation and autophagy were detected only in B16 cells, indicating a cell line-specific treatment response. Lopinavir-NO released NO intracellularly, and NO neutralization restored cell viability. Treatment with lopinavir-NO induced only a transient activation of Akt and inhibition of P70S6 kinase. The results of this study identify lopinavir-NO as a promising candidate for further clinical trials in melanoma and possibly other solid tumours.

http://bit.ly/2sZ68NO

Bispecific anti-CD3 x anti-B7-H3 antibody mediates T cell cytotoxic ability to human melanoma in vitro and in vivo

Summary

Inhibition of the B7-H3 immune checkpoint is reported to limit the tumor growth of B7-H3⁺ tumors. In this study, we demonstrated B7-H3 expression in human melanoma cells, including a primary culture and several cell lines. Furthermore, we investigated whether B7-H3 could serve as a target for T cell-mediated immunotherapy against melanoma. The cytotoxic capacity of activated T cells (ATCs) armed with an anti-CD3 x anti-B7-H3 bispecific antibody (B7-H3Bi-Ab) to melanoma cells was measured using a bioluminescent signal through a luciferase reporter on tumor cells. In contrast to unarmed ATCs, B7-H3Bi-Ab-armed ATCs exhibited increased cytotoxicity against melanoma cells at effector/target ratios from 1:1 to 20:1. Moreover, B7-H3Bi-Ab-armed ATCs secreted more interferin-gamma (IFN-γ), accompanied by higher levels of activating marker CD69 and CD25 expression. Infusion of B7-H3Bi-Ab-armed ATCs suppressed melanoma growth in a xenograft mouse model. Taken together, our results indicate that B7-H3Bi-Ab-armed ATCs may be a promising approach to immunotherapy for melanoma patients.

http://bit.ly/2UyJAPT

Evaluation des Zungengrunds bei OSAS unter elektrischer Stimulationstherapie des N. hypoglossus

Zusammenfassung

Hintergrund

Die nächtliche elektrische Stimulationstherapie des Nervus hypoglossus von Patienten mit obstruktivem Schlafapnoesyndrom (OSAS) ist eine vergleichsweise junge Therapieform. Verlaufsdaten zu Auswirkungen auf die Zungengrundmorphologie unter langfristiger Stimulationstherapie liegen nicht vor.

Fragestellung

Im Rahmen dieser Studie erfolgte die sonografische Evaluation der Zunge bei Patienten mit OSAS vor und nach der Implantation eines Hypoglossusstimulationssystems. Ziel war es, die Durchführbarkeit der Methode zu zeigen sowie erste Hinweise auf Veränderungen der Zungengrundmorphologie unter Therapie zu erhalten.

Material und Methoden

Bei sieben Patienten mit OSAS (m = 5, w = 2, 60,14 ± 12,5 J, Zeit unter Stimulationstherapie 296,43 ± 92,04 Tage) wurden vor und 12 Monate nach Implantation eines einseitigen Stimulationssystems des N. hypoglossus (ImThera Aura 6000™) mittels Ultraschall (GE Vivid S6, 4 MHz, Konvexsonde) die Zunge und der Zungengrund vermessen.

Ergebnisse

12 Monate nach Implantation hatte sich die gemessene Distanz zwischen beiden Aa. linguales an ihrer Eintrittsstelle in den Zungengrund verringert (MW vor Implantation 3,844 ± 0,397 cm; MW nach 12 Monaten 3,591 ± 0,302; p = 0,037). Alle anderen Parameter wiesen keine statistisch auffällige Veränderung auf.

Diskussion

Ultraschall kann ein sinnvolles Hilfsmittel bei der Evaluation von Patienten mit OSAS sein. Die klinische Bedeutung der beobachteten Messwerte ist noch unklar. Eine langfristige Verkleinerung des Zungengrunddurchmessers durch die Stimulationstherapie scheint möglich zu sein.

http://bit.ly/2GdZ6g2

Apatinib, a novel VEGFR inhibitor plus docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR: a phase I trial

Summary

Background This phase I trial was primarily conducted to determine the maximum tolerated dose (MTD) of apatinib combined with docetaxel in advanced lung adenocarcinoma patients with wild-type EGFR who have failed to first-line platinum-based chemotherapy, and to evaluate the safety and tolerability of apatinib plus docetaxel. Methods This was a single-center, open-label, dose-escalating phase I trial. The study used a standard 3 + 3 dose escalation design with the primary aim of determining the MTD. Twelve patients with advanced lung adenocarcinoma were enrolled, the primary endpoint was safety. Two doses of apatinib, 250 mg/day (level 1) and 500 mg/day (level 2), were evaluated in combination with 60 mg/m² doxetacel every 3 weeks. Six patients have been treated at levels 1 and 2, respectively. Optimal dose of apatinib was determined by dose-limiting toxicity (DLT). Results Six patients have been treated at levels 1 and 2. At level 1, one of six patients experienced grade 3 acneiform rash as DLTs. At level 2, two patients experienced grade 3 hypertension and one experienced grade 3 nasal bleeding. MTD and recommended dose for phase II study was 250 mg/day. Most frequent adverse events of any grade were bilirubin elevation, hypertension, alanine aminotransferase elevation, transglutaminase elevation, hand foot syndrome and fatigue. The median progression-free survival was 2.76 month. Moreover, three patients had developed progressive disease and the mean duration of response was 2.79 months. Conclusion Apatinib plus docetaxel was well tolerated and showed promising efficacy in advanced lung adenocarcinoma. This combination therapy may represent a potent therapeutic option for advanced lung adenocarcinoma patients with wild-type EGFR.

http://bit.ly/2UyJHuN

Lopinavir-NO, a nitric oxide-releasing HIV protease inhibitor, suppresses the growth of melanoma cells in vitro and in vivo

Summary

We generated a nitric oxide (NO)-releasing derivative of the anti-HIV protease inhibitor lopinavir by linking the NO moiety to the parental drug. We investigated the effects of lopinavir and its derivative lopinavir-NO on melanoma cell lines in vitro and in vivo. Lopinavir-NO exhibited a twofold stronger anticancer action than lopinavir in vitro. These results were successfully translated into syngeneic models of melanoma in vivo, where a significant reduction in tumour volume was observed only in animals treated with lopinavir-NO. Both lopinavir and lopinavir-NO inhibited cell proliferation and induced the trans-differentiation of melanoma cells to Schwann-like cells. In melanoma cancer cell lines, both lopinavir and lopinavir-NO induced morphological changes, minor apoptosis and reactive oxygen species (ROS) production. However, caspase activation and autophagy were detected only in B16 cells, indicating a cell line-specific treatment response. Lopinavir-NO released NO intracellularly, and NO neutralization restored cell viability. Treatment with lopinavir-NO induced only a transient activation of Akt and inhibition of P70S6 kinase. The results of this study identify lopinavir-NO as a promising candidate for further clinical trials in melanoma and possibly other solid tumours.

http://bit.ly/2sZ68NO

Bispecific anti-CD3 x anti-B7-H3 antibody mediates T cell cytotoxic ability to human melanoma in vitro and in vivo

Summary

Inhibition of the B7-H3 immune checkpoint is reported to limit the tumor growth of B7-H3⁺ tumors. In this study, we demonstrated B7-H3 expression in human melanoma cells, including a primary culture and several cell lines. Furthermore, we investigated whether B7-H3 could serve as a target for T cell-mediated immunotherapy against melanoma. The cytotoxic capacity of activated T cells (ATCs) armed with an anti-CD3 x anti-B7-H3 bispecific antibody (B7-H3Bi-Ab) to melanoma cells was measured using a bioluminescent signal through a luciferase reporter on tumor cells. In contrast to unarmed ATCs, B7-H3Bi-Ab-armed ATCs exhibited increased cytotoxicity against melanoma cells at effector/target ratios from 1:1 to 20:1. Moreover, B7-H3Bi-Ab-armed ATCs secreted more interferin-gamma (IFN-γ), accompanied by higher levels of activating marker CD69 and CD25 expression. Infusion of B7-H3Bi-Ab-armed ATCs suppressed melanoma growth in a xenograft mouse model. Taken together, our results indicate that B7-H3Bi-Ab-armed ATCs may be a promising approach to immunotherapy for melanoma patients.

http://bit.ly/2UyJAPT

Quality Assurance in Interventional Radiology: Post-procedural Care

Abstract

Purpose of Review

To review best practices to improve the quality of patient service in the field of interventional radiology after performing the procedure.

Recent Findings

The aim of this paper is to highlight aspects of post-procedural care such as effective communication, post-procedural management of the patient, handling of obtained specimens, post-procedural follow-up, tracking outcomes, and education to assist the interventionalist in providing comprehensive quality post-procedural care.

Summary

Post-procedural communication, follow-up, and outcome tracking are essential elements in the quality assurance of an Interventional Radiology service.

http://bit.ly/2HK9izo

Quality Assurance in Interventional Radiology: Preprocedural Care

Abstract

Purpose of Review

To review best practices to improve the quality of patient service in the field of interventional radiology prior to performing the procedure.

Recent Findings

We highlight a checklist of elements that have a potential for improvement and contribution to overall quality of patient care from the time of taking the consult, until the time of the procedure. Our check list includes establishing appropriateness of the procedure, reducing waiting times, patient-centered care, patient education, shared decision making, establishing expectations, informed consent, managing the patient's medication list, preprocedure diet, prevention of CIN, prevention of contrast reactions, pain control and sedation, and coagulation status and hemostasis risk. Several consensus guidelines are referenced in this chapter. However, individual patients and clinical scenario vary and determine which guideline to follow or modify based in clinical judgment.

Summary

The clinic is a key component of success in any Interventional Radiology practice, as it provides the space for consultation, patient education, and preprocedural planning.

http://bit.ly/2t0AY8N

The role of lamin A/C in mesenchymal stem cell differentiation

Abstract

Lamin A/C is the major architectural protein of cell nucleus in charge of the nuclear mechanosensing. By integrating extracellular mechanical and biochemical signals, lamin A/C regulates multiple intracellular events including mesenchymal stem cell (MSC) fate determination. Herein, we review the recent findings about the effects and mechanisms of lamin A/C in governing MSC lineage commitment, with a special focus on osteogenesis and adipogenesis. Better understanding of MSC differentiation regulated by lamin A/C could provide insights into pathogenesis of age-related osteoporosis.

http://bit.ly/2BbxVPK

Benefits of rhythm control and rate control in recent‐onset atrial fibrillation. the hermes‐af study

Abstract

Background

Although rhythm control has failed to demonstrate long‐term benefits over rate control in long‐standing episodes of atrial fibrillation (AF), there is little evidence concerning recent‐onset ones. We analyzed the benefits of rhythm and rate control in terms of symptoms alleviation and need for hospital admission in patients with recent‐onset AF.

Methods

This was a multicentre, observational, cross‐sectional study with prospective standardized data collection carried out in 124 Emergency Departments. Clinical variables, treatment effectiveness and outcomes (control of symptoms, final disposition) were analyzed in stable patients with recent‐onset AF consulting for AF‐related symptoms.

Results

Of 421 patients included, rhythm control was chosen in 352 patients (83.6%), global effectiveness of 84%. Rate control was performed in 69 patients (16.4%), and was achieved in 67 (97%) of them. Control of symptoms was achieved in 396 (94.1%) patients, and was associated with a heart rate after treatment ≤110 beats per minute (odds ratio [OR] 14.346, 95% confidence interval [CI] 3.90‐52.70, p<0.001) and a rhythm control strategy (OR 2.78, 95% CI 1.02‐7.61, p=0.046). Sixty patients (14.2%) were admitted: discharge was associated with a rhythm control strategy (OR 0.44, 95% CI 1.22‐4.76, p=0.031) and admission was associated with a heart rate >110 bpm after treatment (OR 0.03, 95% CI 0.008‐0.13, p<0.001) and acute heart failure (OR 9.45, 95% CI 2.91‐30.65, p<0.001).

Conclusion

In our study, recent‐onset AF patients in whom rhythm control was attempted in the Emergency Department had a high rate of symptoms’ alleviation and a reduced rate of hospital admissions.

This article is protected by copyright. All rights reserved.

from Emergency Medicine via xlomafota13 on Inoreader http://bit.ly/2Bc7NnZ

The perceptual flow of phonetic information

Abstract

Over a long and distinguished career, Randy Diehl has elucidated the brain mechanisms underlying spoken language processing. The present study touches on two of Randy's central interests, phonetic features and Bayesian statistics. How does the brain go from sound to meaning? Traditional approaches to the study of speech intelligibility and word recognition are unlikely to provide a definitive answer. A finer-grained, Bayesian-inspired approach may help. In this study, listeners identified 11 Danish consonants spoken in a Consonant + Vowel + [l] environment. Each syllable was filtered so that only a portion of the original audio spectrum was presented. Three-quarter-octave bands of speech, centered at 750, 1,500, and 3,000 Hz, were presented individually and in combination. The conditional, posterior probabilities associated with decoding the phonetic-features Voicing, Manner, and Place of Articulation were computed from confusion matrices to delineate the perceptual flow of phonetic information processing. Analysis of the conditional probabilities associated with both correct and incorrect feature decoding suggest that Manner of articulation is linked to the decoding of Voicing (but not vice-versa), and that decoding of Place of articulation is associated with decoding of Manner of articulation (but not the converse). Such feature-decoding asymmetries may reflect processing strategies in which the decoding of lower-level features, such as Voicing and Manner, is leveraged to enhance the recognition of more complex linguistic elements (e.g., phonetic segments, syllables, and words), especially in adverse listening conditions. Such asymmetric feature decoding patterns are consistent with a hierarchical, perceptual flow model of phonetic processing.

http://bit.ly/2Soyb81

HDAC2-mediated upregulation of IL-6 triggers the migration of osteosarcoma cells

Abstract

Understanding the mechanisms of advanced metastasis in osteosarcoma (OS) cell is important for the targeted treatment and drug development. Emerging evidence shows that epigenetic factors such as histone deacetylases (HDACs) are involved in the progression and chemoresistance of OS, while their roles are largely unknown. Our data showed that the expression of HDAC2, while not HDAC1, 4, or 8, was significantly increased in OS cells and tissues. OS patients with increased expression of HDAC2 showed reduced overall survival with p value of 0.0001. Targeted inhibition of HDAC2 suppressed the in vitro migration and invasion of OS cells. Our data showed that the inhibition of HDAC2 can decrease the expression and transcription of interleukin-6 (IL-6) in OS cells. Overexpression of IL-6 can reverse si-HDAC2-induced suppression of cell migration. Mechanistical studies showed that inhibition of HDAC2 decreased the phosphorylation and nuclear accumulation of p65, the key factor of NF-κB complex responsible for the transcription of IL-6. This was due to that HDAC2 can activate the transcription of IKK-β in OS cells. Collectively, our data showed that HDAC2-activated NF-κB can increase the expression of IL-6 in OS cells, which resulted in the promotion of cell migration. It suggested that targeted inhibition of HDAC2/NF-κB/IL-6 might be a potential approach for OS therapy.

http://bit.ly/2G1LKnZ

Surgical Anatomy of the Lumbar Plexus (2018) Editors: R.Shane Tubbs, Marios Loukas, Amgad S. Hanna, Rod J. Oskouian 220 pp, 130 illustrations, Hardback ISBN: 9781626238893 Thieme Publishers New York/Stuttgart.

http://bit.ly/2TpZFan

The evolution of structure and performance in copolyether-ester fibers with different heat-treatment process

Abstract

The changes in performance characteristics, such as tenacity and elastic recovery, of copolyether-ester fibers were compared for different post-heat treatments (with or without tension). The differences in the mechanical behaviour were linked to changes in the microstructure which are obtained from wide angle X-ray scattering (WAXS), small X-ray scattering (SAXS) and birefringence techniques. The obtained results showed that the performance of the fibers is strongly dependent on the heat-treatment conditions. The treatment with tension proved to be an effective and viable approach for comprehensively improving the performance characteristics of the fibers, such as tenacity, elasticity and stability. A clear distinction is observed for the treatment without tension, which increases the elasticity but lowers the tenacity of the fibers. Heat treatments without tension lead to small crystal formations and partial crystal fusion between some small crystalline regions within the fibers. The lower molecular orientation during this process leads to the loss of tenacity. When heat treated with tension, a small amount of amorphous hard segments began to crystallize under the tensile stress, resulting in larger phase separation, and part of the amorphous region became oriented, improving the tenacity and elastic recovery of the fibers.

http://bit.ly/2ShaZbt

p38 MAPK Inhibitor (SB203580) and Metformin Reduces Aortic Protein Carbonyl and Inflammation in Non-obese Type 2 Diabetic Rats

Abstract

Microvascular and macrovascular diseases are the main causes of morbidity in type 2 diabetes patients through chronic hyperglycaemic condition via oxidative stress and inflammation. Reactive oxygen species (ROS) activate p38 MAPK phosphorylation and inflammation which enhances protein modification by carbonylation. The use of metformin and a p38 MAPK inhibitor is hypothesised to reduce ROS production and inflammation but effects of metformin and p38 MAPK inhibitor (SB203580) on ROS production and inflammation in vascular type 2 diabetes mellitus non-obese (T2DM) have not been investigated. The Goto-Kakizaki rat T2DM model was divided into three groups as T2DM, T2DM treated with 15 mg/kg bw metformin and T2DM treated with 2 mg/kg bw SB203580 for 4 weeks. Rat aortas were isolated and protein carbonyl (PC) contents were measured by spectrophotometric DNPH assay. Aortic IL-1ß level was determined by ELISA. Results showed that aortic PC contents in the T2DM group were significantly higher than in non-diabetic rats. Treatment with metformin or SB203580 significantly reduced PC contents while only metformin significantly reduced IL-1ß levels. Findings indicated that metformin reduced ROS production and inflammation in diabetic vessels and possibly reduce vascular complications in non-obese T2DM.

http://bit.ly/2G0htpF

Bazedoxifene protects cerebral autoregulation after traumatic brain injury and attenuates impairments in blood–brain barrier damage: involvement of anti-inflammatory pathways by blocking MAPK signaling

Abstract

Objective

Traumatic brain injury (TBI) is a significant cause of death and long-term deficits in motor and cognitive functions for which there are currently no effective chemotherapeutic drugs. Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM) and has been investigated as a treatment for postmenopausal osteoporosis. It is generally safe and well tolerated, with favorable endometrial and breast safety profiles. Recent findings have shown that SERMs may have therapeutic benefits; however, the role of BZA in the treatment of TBI and its molecular and cellular mechanisms remain poorly understood. The aim of the present study was to examine the neuroprotective effects of BZA on early TBI in rats and to explore the underlying mechanisms of these effects.

Materials and methods

TBI was induced using a modified weight-drop method. Neurological deficits were evaluated according to the neurological severity score (NSS). Morris water maze and open-field behavioral tests were used to test cognitive functions. Brain edema was measured by brain water content, and impairments in the blood–brain barrier (BBB) were evaluated by expression analysis of tight junction-associated proteins, such as occludin and zonula occludens-1 (ZO-1). Neuronal injury was assessed by hematoxylin and eosin (H&E) staining. LC–MS/MS analysis was performed to determine the ability of BZA to cross the BBB.

Results

Our results indicated that BZA attenuated the impaired cognitive functions and the increased BBB permeability of rats subjected to TBI through activation of inflammatory cascades. In vivo experiments further revealed that BZA provided this neuroprotection by suppressing TBI-induced activation of the MAPK/NF-κB signaling pathway. Thus, mechanically, the anti-inflammatory effects of BZA in TBI may be partially mediated by blocking the MAPK signaling pathway.

Conclusions

These findings suggest that BZA might attenuate neurological deficits and BBB damage to protect against TBI by blocking the MAPK/NF-κB signaling pathway.

http://bit.ly/2TnfdvB

The Effect of Stimulus Polarity on the Relation Between Pitch Ranking and ECAP Spread of Excitation in Cochlear Implant Users

Abstract

Although modern cochlear implants (CIs) use cathodic-leading symmetrical biphasic pulses to stimulate the auditory nerve, a growing body of evidence suggests that anodic-leading pulses may be more effective. The positive polarity has been shown to produce larger electrically evoked compound action potential (ECAP) amplitudes, steeper slope of the amplitude growth function, and broader spread of excitation (SOE) patterns. Polarity has also been shown to influence pitch perception. It remains unclear how polarity affects the relation between physiological SOE and psychophysical pitch perception. Using a within-subject design, we examined the correlation between performance on a pitch-ranking task and spatial separation between SOE patterns for anodic and cathodic-leading symmetric biphasic pulses for 14 CI ears. Overall, there was no effect of polarity on either ECAP SOE patterns, pitch ranking performance, or the relation between the two. This result is likely due the use of symmetric biphasic pulses, which may have reduced the size of the effect previously observed for pseudomonophasic pulses. Further research is needed to determine if a pseudomonophasic stimulus might further improve the relation between physiology and pitch perception.

http://bit.ly/2TpFoBN

Dried blood spot testing for estimation of renal function and analysis of metformin and sitagliptin concentrations in diabetic patients: a cross-sectional study

Abstract

Purpose

Dried blot spot (DBS) analysis of drugs or clinical parameters offers many advantages. We investigated the feasibility of using DBS for analysis of anti-diabetic drugs concomitantly with the estimated creatinine clearance (Cl_crea).

Methods

The cross-sectional study involved physicians in an enabling analysis with 70 diabetic patients and community pharmacists in a field investigation with 84 participants. All 154 DBS samples were analyzed for creatinine, metformin, and sitagliptin.

Results

The diabetic patients revealed of a wide range of age (32–88 years), BMI values (19.8–54.7 kg/m²), and extent of polypharmacotherapy (1–21 drugs). A correlation factor to convert capillary blood creatinine from DBS into plasma concentrations was determined. Patients' Cl_crea ranged from 21.6–155.9 mL/min. The results indicated statistically significant correlations (p < 0.05) between the use of two or three particular drug classes (diuretics, NSAIDs, renin-angiotensin system blockers) and a decreased renal function. DBS concentrations of metformin ranged between 0.23–4.99 μg/mL. The estimated elimination half-life (t ½) of metformin was 11.9 h in patients with a Cl_Crea higher than 60 mL/min and 18.5 h for diabetics with lower Cl_Crea. Sitagliptin capillary blood concentrations ranged between 11.12–995.6 ng/mL. Calculated t ½ of sitagliptin were 8.4 h and 13.0 h in patients with a Cl_Crea above and below 60 mL/min, respectively.

Conclusions

DBS allow for the analysis of concentrations of predominantly renally eliminated drugs and community pharmacists can provide a valuable contribution to DBS sampling.

http://bit.ly/2G538ID

Frequency of functional gastrointestinal disorders in children with familial Mediterranean fever

Abstract

Introduction

Familial Mediterranean fever (FMF) is characterized by self-limiting fever episodes usually accompanied by serositis, arthralgia, and arthritis. Functional gastrointestinal disorders (FGIDs) are diseases in which brain-gut axis and low-grade inflammation take part in pathogenesis. We aimed to study the FGIDs frequencies and possible risk factors for FGIDs in children with FMF.

Method

This case-control study included 103 children with FMF followed up between July 2016 and July 2018 and 100 healthy controls. Age, gender, disease characteristics, and MEFV gene results were recorded retrospectively. Laboratory parameters were obtained at the time of study enrollment. Diagnosis of FGIDs was assessed with Rome IV criteria.

Results

The mean age at study enrollment was 12.58 ± 3.79 and 9.71 ± 3.59 years in FMF and healthy control groups, respectively. Overall FGID frequency was 39.8% (n = 41) in FMF patients and 19% (n = 19) in the control group. Functional dyspepsia and irritable bowel syndrome (particularly constipation predominant subtype) rates were statistically higher in the FMF group. In detail, genotype, age at onset, symptoms, colchicine duration, and colchicine responses did not differ between FMF patients in regard to having FGIDs.

Conclusions

This study showed that children with FMF may predispose to pain predominant FGIDs. We also suggest that FGIDs should be considered in FMF patients suffering recurrent abdominal pain episodes unaccompanied by APR elevation, which can be also named as incomplete FMF attacks.

http://bit.ly/2DNTjfP

Down-regulation of miR-377 suppresses high glucose and hypoxia-induced angiogenesis and inflammation in human retinal endothelial cells by direct up-regulation of target gene SIRT1

Abstract

Diabetic retinopathy (DR) is one of the common microvascular complications of diabetes mellitus, which is the main cause of blindness in diabetic patients. Angiogenesis plays an important role in retinal detachment and retinal microvascular inflammation throughout the whole development of DR. This study aimed to investigate the regulatory effect and the potential mechanism of miR-377 on high glucose and hypoxia-induced angiogenesis and inflammation in human retinal endothelial cells, and found that the miR-377 level was significantly increased after high glucose and hypoxia-mimetic agent to simulate the DR milieu. Moreover, miR-377 was confirmed to directly decrease target SIRT1 gene, further aggravated proliferation, cell cycle transition, migration and angiogenesis, pro-inflammatory molecules release induced by high glucose and hypoxia in vitro. Conversely, down-regulation of miR-377 enhanced expression of SIRT1 and in turn alleviated high glucose and hypoxia-induced angiogenesis and inflammation in vitro. Additionally, Western blot results showed that down-regulation of miR-377 restrained high glucose and hypoxia-induced protein expressions of p-IκBα, nuclear P65 and p-P65. Conversely, up-regulation of miR-377 presented opposite results. Conclusively, down-regulation of miR-377 could partially suppress high glucose and hypoxia-induced angiogenic functions, restrain pro-inflammatory cytokines release, and its mechanism may though inhibition of NF-κB pathway by direct up-regulation of target gene SIRT1 expression. Our study suggests that miR-377 may be used as a potential novel target for prevention strategy for DR.

http://bit.ly/2RwbMkk

Physical and Chemical Compatibility of Extended-Release Triamcinolone Acetonide (TA-ER) with Common Local Anesthetics

Abstract

Introduction

Intra-articular (IA) corticosteroids are used extensively for the treatment of patients with knee osteoarthritis pain. In clinical practice, local anesthetics are frequently combined with corticosteroids prior to IA injection to provide rapid-onset analgesia. From this common practice there is no evidence to suggest that the addition of local anesthetics to corticosteroid preparations, including triamcinolone acetonide (TA), alters the physical properties or efficacy of the corticosteroid. Triamcinolone acetonide extended-release (TA-ER, formerly FX006) is a novel, microsphere-based TA formulation that demonstrated analgesic efficacy in phase 2 and 3 randomized controlled trials.

Methods

The current study assessed the compatibility of TA-ER and lidocaine, ropivacaine, and/or bupivacaine in vitro. The TA-ER and local anesthetic mixtures were assayed for changes in syringeability, pH, particle size, percentage free drug, purity, and appearance compared with TA-ER alone.

Results

By these measures, the combination of local anesthetics with TA-ER did not negatively impact the chemical or physical properties of TA-ER when compared to TA-ER controls.

Conclusion

These results demonstrate that lidocaine, bupivacaine, and ropivacaine are physically and chemically compatible with TA-ER, suggesting that local anesthetic solutions can be added to TA-ER preparations in clinical practice without adversely affecting TA-ER in vitro product characteristics.

Funding

Flexion Therapeutics, Inc.

http://bit.ly/2sWyclb

Comment on: “Equity in Physical Activity: A Misguided Goal”

http://bit.ly/2Uw7MlT

Reply to Williams et al.: Comment on: “Equity in Physical Activity: A Misguided Goal”

http://bit.ly/2DNFDBr

Musculoskeletal pains and cardiovascular autonomic function in the general Northern Finnish population

Abstract

Background

Heart rate variability (HRV) and baroreflex sensitivity (BRS) measurements provide means for the objective assessment of cardiovascular autonomic function. As previous studies have associated chronic pain with abnormal autonomic function, we aimed to characterize the relationship between the number of musculoskeletal pain sites (NPS), pain intensity, and cardiovascular autonomic function among the population-based Northern Finland Birth Cohort 1966.

Methods

At the age of 46, cohort members self-reported their musculoskeletal pains (enabling the determination of NPS [0–8] and pain intensity [Numerical Rating Scale, NRS, 0–10]) and underwent clinical assessments of cardiovascular autonomic function in seated and standing positions (HRV variables: heart rate [HR] and root mean square of successive differences in beat-to-beat intervals [rMSSD] for the entire cohort; BRS variables: low-frequency systolic blood pressure variability [SBPV] and cross-spectral baroreflex sensitivity [BRS] for those attending the examination in Oulu, Finland). Extensive confounder data were also collected (body mass index, physical activity, smoking, Hopkins Symptom Checklist-25, comorbidities, and medications). The full samples included 4186 and 2031 individuals (HRV and BRS samples, respectively). Three subanalyses focused on individuals with intense and frequent pain, individuals with symptoms of depression and anxiety, and the relationship between pain intensity and autonomic parameters.

Results

Linear regression models showed varying associations between NPS, pain intensity, and cardiovascular autonomic parameters. However, after all adjustments NPS was only associated with one outcome among women (BRS, standing: beta = − 0.015, p = 0.048) and two among men (HR, seated: beta = − 0.902, p = 0.003; HR, standing: beta = − 0.843, p = 0.014). Pain intensity was not associated with any outcome after full adjustments. Significant sex*pain interactions were found in the data.

Conclusions

Our data suggest that musculoskeletal pain has, at most, a limited independent association with cardiovascular autonomic function. Future studies should carefully account for the potential confounders and sex interactions that this study revealed.

http://bit.ly/2G0r5Rg

Distal femoral reconstruction following failed total knee arthroplasty is accompanied with risk for complication and reduced joint function

Abstract

Background

Substantial bone loss following failed total knee arthroplasty (TKA) represents a major challenge in revision arthroplasty, that can require distal femoral reconstruction (DFR). In this study, we aimed to assess the clinical outcome and the complication frequencies of individuals who underwent DFR with modular megaprostheses. Additionally, we aimed to compare functional outcome measures after DFR in these sophisticated cases to an age-matched control group of total knee prostheses to quantify the potential loss of function.

Methods

A retrospective chart review of 30 consecutive patients after DFR from 1997 to 2017 with a mean age of 74.38 years (± 10.1) was performed. Complications were classified according to the Henderson classification. Knee Society Score (KSS) was calculated and range of motion (ROM) was assessed.

Results

Thirteen (43.3%) patients had at least one complication requiring revision surgery. Revision-free survival was 74.8% at one year, 62.5% at three and 40.9% at 10 years post-op. Soft-tissue failure complications were found in three (10.0%) patients, aseptic loosening in four (13.3%) patients, structural failure in one (3.3%) patient and infection in eight (26.6%) patients. Of those with infection, five (16.6%) experienced ongoing prosthetic joint infection and three (10.0%) developed new infection after distal femur reconstruction. Patients with DFR achieved 69.3% of KSS pain score, 23.1% KSS function score and 76.2% of ROM compared to patients with primary TKA.

Conclusions

DFR after failed TKA represents a treatment procedure with high risk for complication in this particular group. Despite the prospect of rapid postoperative mobilization, reduced functionality, range of motion and mobilization have to be considered when choosing this treatment option.

http://bit.ly/2GeYTte

Evaluation of health-related quality of life after total hip arthroplasty: a case-control study in the Iranian population

Abstract

Background

As the total hip arthroplasty (THA) mainly aims to improve the quality of life of the patients, study of health-related quality of life (HRQoL) after THA has attracted much attention. Yet, the results considerably vary between studies. Here, we evaluate the HRQoL of the patient after THA, for the first time in the Iranian population.

Methods

In a case-control study, HRQoL was assessed in 217 patients after THA and compared with a matched reference population. The 36-item short-form health survey (SF-36) was used for the evaluation of HRQoL. A multiple linear regression model was used to investigate the influence of sociodemographic and clinical characteristics of the patients on the HRQOL.

Results

The mean follow-up of the patients was 27 ± 18 months. The mean total SF-36 score was 41.4 ± 22.2 in the case and 67.3 ± 26.6 in the control group (p = 0.001). The mean physical component score, but not the mental component score, was significantly lower in the patient group (p = 0.001). Except for the vitality and emotional role, all other SF-36 subscales were significantly lower in the case group. Male sex (B = 4.52, p = 0.023), number of comorbidities (B = − 4.82, p = 0.011), body mass index (B = − 1.18, p = 0.044), number of post-operative complications (B = − 6.57, p = 0.001), and adherence to physiotherapy protocol (B = 2.09, p = 0.014) were associated with HRQoL after THA.

Conclusion

Although THA is considered as one of the most successful orthopedic practices, it is associated with remarkable reduced HRQoL in Iranian population when compared with the reference population. A variety of patients-associated factors influence the HRQoL after THA.

http://bit.ly/2FZhnOV

Analysis of patellofemoral arthrokinematic motion quality in open and closed kinetic chains using vibroarthrography

Abstract

Background

Knee movements performed in open (OKC) and closed (CKC) kinetic chains generate various patterns of muscle activities and especially distinct contact stresses in the patellofemoral joint (PFJ). In contrast to these features, the arthrokinematic motion quality (AMQ) of the PFJ has not been compared between mentioned conditions. In this study we performed vibroarthrographic analysis of AMQ in movements performed in OKC and CKC, in healthy subjects and individuals with chondromalacia patellae, to assess which of the test conditions is more efficient in differentiation between healthy and deteriorated joints. Moreover, our analysis will broaden the knowledge related to behavior of normal and pathological synovial joints during motion with and without weight bearing. It is an essential issue, due to the recently observed significant interest in comparing potential benefits and limitations of CKC and OKC exercises as they relate to lower extremity rehabilitation.

Methods

100 subjects (62 healthy controls and 38 subjects with PFJ chondromalacia) were enrolled. During repeated knee flexion/extension motions performed in OKC (in a sitting position) and CKC (sit-to-stand movements), the vibroarthrographic signals were collected using an accelerometer and described by variability (VMS), amplitude (R4), and spectral power in 50–250 Hz (P1) and 250–450 Hz (P2) bands.

Results

Significant differences in VMS [V], R4 [V], P1 [V²/Hz] and P2 [V²/Hz] between OKC and CKC were found (0.0001, 0.969. 0.800 0.041 vs 0.013, 3.973, 6.790, 0.768, respectively, P < 0.001). Moreover, in both analyzed load-related conditions the subjects with chondromalacia were characterized by significantly higher values of all parameters, when compared to controls (P < 0.001), with effect size values over 0.6.

Conclusions

We showed that motion of the physiological, unloaded PFJ articular surfaces in OKC is nearly vibrationless, which corresponds with optimal AMQ of PFJ, while loaded movements in CKC are characterized by a higher vibroacoustic emission level. Moreover, chondral lesions should be considered as an increased friction-related, aggravating factor of AMQ, which is critical in CKC movements under load. Nonetheless, OKC and CKC conditions are characterized by large effect sizes, and provide an efficient test frame for differentiating physiological knees and joints with chondral lesions.

http://bit.ly/2GcpXZT

Biomechanics following skip-level cervical disc arthroplasty versus skip-level cervical discectomy and fusion: a finite element-based study

Abstract

Background

Moderately increased motion at the intermediate segment (IS) after skip-level fusion may accelerate disc degeneration. However, limited biomechanical data are available that examine the effects on the IS following cervical disc arthroplasty (CDA). The purpose of this study is to investigate the biomechanical changes in the IS of the cervical spine after skip-level fusion or skip-level arthroplasty.

Methods

A finite element model of a healthy cervical spine (C2-C7) was constructed. Two surgical models were developed: (1) skip-level fusion at C3/4 and C5/6 and (2) skip-level arthroplasty at C3/4 and C5/6. A 75-N follower load and 1.0-N·m moments were applied to the top of the C2 vertebra to produce flexion, extension, lateral bending and axial rotation in the intact model. The end-points in each direction corresponding to the intact model were applied to the surgical models under displacement-control protocols.

Results

The ranges of motion (ROMs) of the fusion model were markedly decreased at the operated levels, while the corresponding ROMs of the arthroplasty model were similar to those of the intact spine in all directions. In the fusion model, the ROMs of the IS (C4/5) were markedly increased in all directions. The ROMs in the arthroplasty model were similar to those in the intact spine, and the ROMs of untreated segments were evenly increased. In the fusion model, the intradiscal pressure and facet contact force at were C4/5 remarkably increased and unevenly distributed among the unfused segments. In the arthroplasty model, the IS did not experience additive stress.

Conclusion

The IS does not experience additive ROM or stress in the intervertebral disc or facet joints after skip-level arthroplasty, which has fewer biomechanical effects on the IS than does skip-level fusion. This study provides a biomechanical rationale for arthroplasty in treating patients with skip-level cervical degenerative disc disease.

http://bit.ly/2G197xV

Mitteilungen der DGMKG

http://bit.ly/2GcmJpf

Die operative Behandlung von Lippen-Kiefer-Gaumen-Spalten – eine interdisziplinäre Aufgabe

http://bit.ly/2G2Mjh6

Synthesis of rGO/TiO 2 /PEDOT nanocomposites, supercapacitor device performances and equivalent electrical circuit models

Abstract

A new nanocomposite electrode incorporating poly(3,4-ethylenedioxythiophene) (PEDOT) within the nanocomposite film of the reduced graphene oxide / Titanium dioxide (TiO₂) was synthesized to be used in supercapacitor devices. We used constant EDOT monomer for in-situ polymerization and different initial monomer concentration ratio of [rGO]_o/[TiO₂]_o = 1/1, ½ and 1/5. The obtained nanocomposites were examined by FTIR-ATR, UV-vis, SEM-EDX, TGA-DTA, BET surface areas and pore distribution, XRD, TEM, AFM, CV, GCD and EIS analyses. The results showed that graphene oxide was successfully reduced to rGO by means of the microwave-assisted method. It was confirmed by the increases in the specific capacitance of (C_sp = 652 F/g) at 1 mV/s for the rGO/TiO₂/PEDOT nanocomposite at [rGO]_o/[TiO₂]_o = 1/5. This was related to the pore size (~33.50 nm) of the material for rGO/TiO₂/PEDOT at [rGO]_o/[TiO₂]_o = 1/5 obtained from BET analysis. The other C_sp values were 475.33 F/g for [rGO]_o/[TiO₂]_o = 1/2, 114.09 F/g for rGO/PEDOT and 48.02 F/g for [rGO]_o/[TiO₂]_o = 1/1. Equivalent circuit model of R_ct(C_dlR_ct) was analyzed via ZSimpWin and TINA programmes. A facile and inexpensive approach for a ternary nanocomposite synthesis of rGO/TiO₂/PEDOT was presented for future supercapacitor applications.

Graphical abstract

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http://bit.ly/2Uyi8lo

Missed opportunities: the absence of climate change in media coverage of forest fire events in Alberta

Abstract

Extreme weather events that may be associated with climate change drivers offer valuable opportunities for public discussion of climate change. Such events tend to draw a high level of public attention, and they represent acute and personal impacts of climate change, unlike most climate-related information to which members of the public are exposed. Media coverage of such extreme events, however, appears to avoid linking such events to climate change. In one of few media analyses of the inclusion of climate change discussion in coverage of extreme events that are linked to climate change, we provide the results of an analysis of media coverage of climate-related threats to forests, including in particular forest fires in the Province of Alberta. This is a region in which forests, which are threatened by the impacts of climate change, are an important contributor to the regional economy, livelihoods, and lifestyles. Newspaper articles were collected from Alberta's two largest regional papers, the Edmonton Journal and the Calgary Herald. Our findings show that coverage of forest issues in the media is dominated by fires, while discussion of pest outbreaks and forest sustainability are far less prevalent. While climate change is a topic that is covered in these newspapers as frequently as forest-related issues, there is very little overlap in this coverage and the articles that do discuss both forests and climate change are not associated with extreme events. In subsequent thematic analysis, we find that forest fire coverage tends to be restricted to discussion of single themes, particularly, risk or the economy, while avoiding discussion of multiple themes and their interactions. Mention of the causes of climate change is rare in coverage of either of these forest-related issues. Possible explanations for avoidance of climate change discussion in forest fire media coverage are discussed.

http://bit.ly/2MMyHaA

Development of conditional cell lysis mutants of Saccharomyces cerevisiae as production hosts by modulating OCH1 and CHS3 expression

Abstract

The traditional yeast Saccharomyces cerevisiae has been widely used as a host for the production of recombinant proteins and metabolites with industrial potential. However, its thick and rigid cell wall presents problems for the effective recovery of products. In this study, we modulated the expression of ScOCH1, encoding the α-1,6-mannosyltransferase responsible for outer chain biosynthesis of N-glycans, and ScCHS3, encoding the chitin synthase III required for synthesis of the majority of cell wall chitin, by exploiting the repressible ScMET3 promoter. The conditional single mutants P_MET3-OCH1 and P_MET3-CHS3 and the double mutant P_MET3-OCH1/P_MET3-CHS3 showed comparable growth to the wild-type strain under normal conditions but exhibited increased sensitivity to temperature and cell wall-disturbing agents in the presence of methionine. Such conditional growth defects were fully recovered by supplementation with 1 M sorbitol. The osmotic lysis of the conditional mutants cultivated with methionine was sufficient to release the intracellularly expressed recombinant protein, nodavirus capsid protein, with up to 60% efficiency, compared to lysis by glass bead breakage. These mutant strains also showed approximately three-fold-enhanced secretion of a recombinant extracellular glycoprotein, Saccharomycopsis fibuligera β-glucosidase, with markedly reduced hypermannosylation, particularly in the P_MET3-OCH1 mutants. Furthermore, a substantial increase of extracellular glutathione production, up to four-fold, was achieved with the conditional mutant yeast cells. Together, our data support that the conditional cell wall lysis mutants constructed based on the modulation of ScOCH1 and ScCHS3 expression would likely be useful hosts for the improved recovery of proteins and metabolites with industrial application.

http://bit.ly/2S0ttOl

Correction to: Achieving Glycaemic Control with Concentrated Insulin in Patients with Type 2 Diabetes

Page 7, Section 4.1, third paragraph, which previously read:

http://bit.ly/2BeCZTA

l -Ornithine l -Aspartate (LOLA) for Hepatic Encephalopathy in Cirrhosis: Results of Randomized Controlled Trials and Meta-Analyses

Abstract

This manuscript represents an appraisal of the evidence in support of l-ornithine-l-aspartate (LOLA) for the management and treatment of hepatic encephalopathy (HE) in cirrhosis. Meta-analyses of randomized controlled trials (RCTs) conducted over the last two decades generally reveal evidence of benefit of LOLA in a range of clinical presentations. This included improvement of mental state grade in overt HE (OHE) assessed by West Haven criteria as well as in minimal HE (MHE) assessed by psychometric testing where the oral formulation of LOLA was determined to be particularly effective. However, concerns over study quality were noted in one meta-analysis. Nevertheless, the concomitant lowering of fasting blood ammonia was reported in all RCTs using this endpoint. Network meta-analyses showed that LOLA appears to be comparable (or superior) in efficacy to non-absorbable disaccharides or probiotics. Emerging evidence from single RCTs show efficacy of LOLA for the treatment of post-transjugular intrahepatic portosystemic shunt (TIPSS) HE as well as for secondary HE prophylaxis. These findings provide support for the use of LOLA in the treatment of HE and future trials should focus on the use of LOLA for prophylaxis.

http://bit.ly/2UBuIQX

Hepatic Encephalopathy: Definition, Clinical Grading and Diagnostic Principles

Abstract

In general, hepatic encephalopathy (HE) is defined as a brain dysfunction caused by liver insufficiency and/or portal-systemic blood shunting. This article relates to the so-called type C HE: that is, HE in patients with liver cirrhosis. It manifests as a wide spectrum of neurological or psychiatric abnormalities, ranging from subclinical alterations, detectable only by neuropsychological or neurophysiological assessment, to coma. Several scales have been developed for grading the extent of HE. The most often used is the West Haven criteria (WHC), which differentiate between four grades of clinically overt HE. Patients with liver cirrhosis without clinically overt symptoms of HE but neuropsychological or neurophysiological findings indicating brain dysfunction are considered to have minimal hepatic encephalopathy (MHE). For simplification, some experts suggest differentiating between covert HE (MHE plus grade I HE according to WHC) and overt HE (WHC grades II–IV). Diagnosis of both MHE and overt HE is hampered by the fact that none of the symptoms of HE or the findings in the various diagnostic measures applied are specific. Thus, a diagnosis of HE or MHE can only be made after exclusion of other possible causes of brain dysfunction.

http://bit.ly/2DMSW4Z

l -Ornithine l -Aspartate (LOLA) as a Novel Approach for Therapy of Non-alcoholic Fatty Liver Disease

Abstract

l-ornithine l-aspartate (LOLA) has been known as an effective ammonia-lowering agent for more than 50 years with good evidence in hepatic encephalopathy. Administration of LOLA removes ammonia via two distinct mechanisms: by synthesis of urea and by the synthesis of glutamine via the enzyme glutamine synthetase. While LOLA has been used in cirrhosis and acute liver injury settings, it is less clear if LOLA could be used in non-alcoholic fatty liver disease (NAFLD). NAFLD and the progressive form non-alcoholic steatohepatitis (NASH) are currently the leading causes of chronic liver disease worldwide, with roughly 25% of the world population affected by NAFLD. Consequences of NASH are end-stage liver disease and cardiovascular morbidity and mortality. As the basis for NAFLD is excess calorie uptake and excess adipose tissue mass, the conservative therapeutic approach is weight loss by intense lifestyle change. However, no pharmacological treatment options are currently approved. LOLA is being investigated as a pharmacological tool to ameliorate liver injury in NAFLD on the basis that it lowers liver ammonia concentrations and supplies anti-oxidative glutamine and glutathione. Indirect hepatoprotective effects currently under investigation could also be beneficial.

http://bit.ly/2UBuERd

Impact of Hepatic Encephalopathy in Cirrhosis on Quality-of-Life Issues

Abstract

Hepatic encephalopathy (HE) has a major impact on health-related quality of life (HRQOL) in patients, which has clinical and psychosocial consequences. HRQOL in cirrhosis has been measured by generic and liver-specific instruments, with most studies indicating a negative impact of HE. HRQOL abnormalities span daily functioning, sleep–wake cycle changes, and the ability to work. Of these, sleep–wake cycle changes have a major effect on HRQOL, which remains challenging to treat. The personal effect of HRQOL is modulated by the presence of HE, the etiology of cirrhosis, and cognitive reserve. Patients with higher cognitive reserve are able to tolerate HE and its impact on HRQOL better than those with a poor cognitive reserve. The impact of HRQOL impairment is felt by patients (higher mortality and poor daily functioning), as well as by caregivers and families. Caregivers of patients with HE bear a major financial and psychological burden, which may affect their personal health and longevity.

http://bit.ly/2DKowAq

Pharmacokinetic and Pharmacodynamic Properties of l -Ornithine l -Aspartate (LOLA) in Hepatic Encephalopathy

Abstract

l-Ornithine l-aspartate (LOLA), a stable salt of l-ornithine and l-aspartate, readily dissociates into its constituent amino acids that are readily absorbed by active transport, distributed, and metabolized. l-ornithine serves as an intermediary in the urea cycle in periportal hepatocytes in the liver and as an activator of carbamoyl phosphate synthetase, and, like l-aspartate, by transamination to glutamate via glutamine synthetase in perivenous hepatocytes as well as by skeletal muscle and brain. By way of these metabolic pathways, both amino acids participate in reactions whereby the ammonia molecule is incorporated into urea and glutamine and it is the nature, cellular, and biological location of these pathways that underpins the application of LOLA as an effective ammonia-lowering strategy widely used for the management and treatment of hepatic encephalopathy. These metabolic pathways were elucidated based upon studies in experimental animals and were confirmed by studies in patients with severe liver diseases. More recent studies suggest that LOLA may have additional direct hepatoprotective properties. Moreover, its use may result in improvements in skeletal muscle function in cirrhosis.

http://bit.ly/2UBuysP

Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology

Abstract

Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, 'Parkinsonism in cirrhosis'. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.

http://bit.ly/2DNVL5N

l -Ornithine l -Aspartate (LOLA) for the Treatment of Hepatic Encephalopathy in Cirrhosis: Novel Insights and Translation to the Clinic

http://bit.ly/2UwTSQx

Lactate Dehydrogenase Predicts Early Hematoma Expansion and Poor Outcomes in Intracerebral Hemorrhage Patients

Abstract

This study aimed to investigate whether serum lactate dehydrogenase (LDH) levels predicted hematoma expansion and poor outcomes in intracerebral hemorrhage (ICH) patients. The differentially expressed proteins between patients with and without hematoma expansion were screened using proteomic analysis. Then the critical value of the target protein was determined by retrospectively analyzing the data from a derivation cohort. A prospective study on the validation cohort of three clinical centers was performed to investigate the association between the target protein and hematoma expansion and poor outcomes (modified Rankin Scale > 3) at 90 days by using univariate and multivariate logistic regression analyses. Among the 41 differentially expressed proteins, LDH A chain was upregulated, which is one of the two main subunits of LDH protein. Considering that it was easy to determine serum LDH levels, LDH was selected as the target protein. In the derivation cohort, LDH ≥ 220 U/L was selected as the critical value to predict hematoma expansion by using receiver operating characteristic analysis. A total of 366 ICH patients were enrolled in the validation cohort and LDH ≥ 220 U/L was positive in 127 patients (34.7%). The multivariate logistic regression analysis demonstrated LDH levels and LDH ≥ 220 U/L independently predicted hematoma expansion (p < 0.001) and poor outcomes (p < 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of LDH ≥ 220 U/L for hematoma expansion and poor outcome prediction were 79.1%, 80.0%, 56.7%, 92.1%, and 79.8% and 53.3%, 78.2%, 63.0%, 70.7%, and 68.0%, respectively. In conclusion, LDH is a reliable predictor for early hematoma expansion and poor outcomes in patients with ICH.

http://bit.ly/2MHVtjN

Comparison of different conditions for DNA extraction in sputum - a pilot study

Abstract

Background

The analysis of microbiome in respiratory samples is a topic of great interest in chronic respiratory diseases. The method used to prepare sputum samples for microbiome analysis is very heterogeneous. The selection of the most suitable methodology for DNA extraction is fundamental to have the most representative data. The objective of this study was to compare different conditions for DNA extraction from sputum in adult patients with bronchiectasis.

Methods

Five sputum samples from bronchiectasis patients were collected at the Policlinico Hospital in Milan, Italy. Eighteen conditions for DNA extraction were compared, including two enzyme-based (Roche and Zymo) and one beads-based (Mobio) technique. These techniques were tested with/without Dithiothreitol (DTT) and with/without lysostaphin (0.18 and 0.36 mg/mL) step. DNA was quantified, tested using Real-time PCR for 16S rDNA and S. aureus and, then, microbiome was evaluated.

Results

Although 16S rDNA was similarly detected across all the different techniques, Roche kit gave the highest DNA yield. The lowest Ct values for Real-time PCR for S. aureus was identified when lysostaphin was added. Considering genera from microbiome, alpha diversity indices did not show any significant differences between techniques, while relative abundances were more similar in presence of DTT.

Conclusions

None of the conditions emerged to be superior to the others even if enzyme-based kits seem to be needed in order to have a higher extraction yield.

http://bit.ly/2sYNgP1

Clinical spectrum of Lyme disease

Abstract

Lyme disease (borreliosis) is one of the most common vector-borne diseases worldwide. Its incidence and geographic expansion has been steadily increasing in the last decades. Lyme disease is caused by Borrelia burgdorferi sensu lato, a heterogeneous group of which three genospecies have been systematically associated to Lyme disease: B. burgdorferi sensu stricto Borrelia afzelii and Borrelia garinii. Geographical distribution and clinical manifestations vary according to the species involved. Lyme disease clinical manifestations may be divided into three stages. Early localized stage is characterized by erythema migrans in the tick bite site. Early disseminated stage may present multiple erythema migrans lesions, borrelial lymphocytoma, lyme neuroborreliosis, carditis, or arthritis. The late disseminated stage manifests with acordermatitis chronica atrophicans, lyme arthritis, and neurological symptoms. Diagnosis is challenging due to the varied clinical manifestations it may present and usually involves a two-step serological approach. In the current review, we present a thorough revision of the clinical manifestations Lyme disease may present. Additionally, history, microbiology, diagnosis, post-treatment Lyme disease syndrome, treatment, and prognosis are discussed.

http://bit.ly/2DMp34M

Left-sided infective endocarditis caused by Streptococcus agalactiae : rare and serious

Abstract

A comparative study of the behaviour of left-sided infective endocarditis (left-sided IE) due to Streptococcus agalactiae (GBS) with left-sided IE caused by Staphylococcus aureus (SA). A prospective, multicentre cohort study in eight public hospitals in Spain, from January 1984 to December 2015; comparative analysis and factors associated with mortality. In total, there were 1754 episodes of left-sided IE; 41 (2.3%) caused by GBS vs. 344 (19.6%) due to SA, definitive IE 39 vs. 324 cases, males, 25 vs. 213, respectively. There were no differences in age or comorbidity, and healthcare-associated acquirement was 10% vs. 43%, p 0.001. Transthoracic echocardiogram (TTE) was performed in 95% vs. 96.8% and a transesophageal echocardiogram (TEE) in 61% vs. 56%. Vegetations were detected in 80% and measured > 1 cm in a similar proportion. It affected native valves in 85.4% vs. 82.6% and late prosthetic valve in 14.6% vs. 9.6%. The course was acute in both groups. There were more skin manifestations in SA left-sided IE, 7.3% vs. 32%, p 0.001. Both groups had similar complications, but in SA, there was more renal failure, 24% vs. 45%, p 0.010. Surgical risk and operated patients were similar. Mortality was proportionally higher in the SA group, without significance 29% vs. 43% (150), p 0.09. Heart failure, septic shock and neurological deterioration conditioned mortality: HR 1.96, 1.69 and 1.37 (CI 95% 1.40–2.73; 1.19–2.39 and 0.99–1.88 respectively) and to a lesser degree SA as aetiology agent and age. Left-sided IE caused by GBS is similar in severity to left-sided IE caused by SA.

http://bit.ly/2UxWQEu

Pathogenic significance of hemorrhagic pneumonia in hematologic malignancy patients with Stenotrophomonas maltophilia bacteremia: clinical and microbiological analysis

Abstract

Hemorrhagic pneumonia (HP) is known as the clinical manifestation of Stenotrophomonas maltophilia infection, while catheter-related blood stream infection (CRBSI) is the common clinical presentation of S. maltophilia bacteremia (SMB). The purpose of this study is to evaluate the risk factors for mortality in hematologic malignancy patients with SMB and to analyze clinical and microbiological characteristics of HP associated with SMB and CRBSI. SMB cases of patients with a hematologic malignancy were collected from 2006 through 2016. The overall 30-day mortality rate and mortality risk factors were assessed. The expression of major virulence-associated genes from S. maltophilia isolates, which included genes encoding type-1 fimbriae (smf-1), proteases (StmPr1 and StmPr2), and esterase (Smlt3773), from the blood of patients with HP and CRBSI was investigated. The phenotypic and genotypic traits were also compared. A total of 118 cases of SMB were included. The overall 30-day mortality rate was 61.0%. A multivariable analysis showed that HP was the most important risk factor for mortality (adjusted OR = 106.41; 95% CI = 5.18–2184.55). Although no statistical significance was observed in microbiological analysis, isolates from HP have a trend toward a higher protease activity (93.8% vs. 73.3%, P = 0.172). Clinical analysis showed that thrombocytopenia (P = 0.037) and prolonged neutropenia (P = 0.043) were significant factors associated with HP. Our data, which includes hematologic malignancy patients with SMB, suggest that HP is the significant risk factor for mortality and that the unique characteristics of patients and microbes contribute to the pathogenesis.

http://bit.ly/2DLjFih

A global priority list of the TOp TEn resistant Microorganisms (TOTEM) study at intensive care: a prioritization exercise based on multi-criteria decision analysis

Abstract

The World Health Organization (WHO) proposed a global priority pathogen list (PPL) of multidrug-resistant (MDR) bacteria. Our current objective was to provide global expert ranking of the most serious MDR bacteria present at intensive care units (ICU) that have become a threat in clinical practice. A proposal addressing a PPL for ICU, arising from the WHO Global PPL, was developed. Based on the supporting data, the pathogens were grouped in three priority tiers: critical, high, and medium. A multi-criteria decision analysis (MCDA) was used to identify the priority tiers. After MCDA, mortality, treatability, and cost of therapy were of highest concern (scores of 19/20, 19/20, and 15/20, respectively) while dealing with PPL, followed by healthcare burden and resistance prevalence. Carbapenem-resistant (CR) Acinetobacter baumannii, carbapenemase-expressing Klebsiella pneumoniae (KPC), and MDR Pseudomonas aeruginosa were identified as critical organisms. High-risk organisms were represented by CR Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and extended-spectrum beta-lactamase (ESBL) Enterobacteriaceae. Finally, ESBL Serratia marcescens, vancomycin-resistant Enterococci, and TMP-SMX-resistant Stenotrophomonas maltophilia were identified as medium priority. We conclude that education, investigation, funding, and development of new antimicrobials for ICU organisms should focus on carbapenem-resistant Gram-negative organisms.

http://bit.ly/2UtixW3

Herpes zoster and the risks of osteoporosis and fracture: a nationwide cohort study

Abstract

This study aimed to investigate the association between herpes zoster (HZ) and the risks of osteoporosis and fracture. We conducted a nationwide retrospective cohort study using the National Health Insurance Research Database of Taiwan. The study enrolled 63,786 patients: 31,893 diagnosed with HZ between 2000 and 2012 were included in the HZ cohort, and 31,893 matched controls without HZ were included in the non-HZ cohort, with 1:1 exact matching for age, sex, and index year. Hazard ratios (HRs) were calculated for the risks of osteoporosis and fracture according to the HZ status using the Cox proportional hazards regression models. During a mean follow-up period of 6.0 years, 5597 and 4639 patients in the HZ and non-HZ cohorts, respectively, developed osteoporosis or fractures (incidence rate: 29.8 vs. 23.8 per 1000 person-years). HZ diagnosis was significantly associated with an elevated risk of developing osteoporosis or fracture (adjusted HR [aHR] = 1.20, p < 0.001). On analyses for each individual event, the HZ cohort had significantly increased risks for all events, including osteoporosis (aHR = 1.32, p < 0.001), hip fracture (aHR = 1.34, p < 0.001), vertebral fracture (aHR = 1.38, p < 0.001), and other fractures (aHR = 1.10, p < 0.001) compared with the non-HZ cohort. Patients with postherpetic neuralgia had especially higher risks of osteoporosis and fracture. Age- and sex-stratified analyses also revealed similar patterns. In conclusion, HZ was independently associated with an increased risk of osteoporosis and fracture. Further studies are required to investigate its underlying mechanisms.

http://bit.ly/2DLosQG

Presence of Toxoplasma gondii infection in brain as a potential cause of risky behavior: a report of 102 autopsy cases

Abstract

Toxoplasmosis was linked to impairment in brain function, encompassing a wide range of behavioral and neuropsychiatric changes. Currently, the precise localization of Toxoplasma gondii in the human brain is limited and the parasite DNA was not found in population-based screening of autopsy cases. The aim of proposed study was to identify the presence of parasite DNA within the brain and its association with risky behavior and alcohol consumption in postmortem examination. Preliminarily, 102 cases with certain circumstances of death at time of forensic autopsy was included. Due to high risk of bias, the females were excluded from the analysis and final study group consists 97 cases divided into three groups: risky behavior, inconclusively risky behavior, and control group. The obtained tissue samples for Nested PCR covered four regions of the brain: symmetric left/right and anterior/posterior horns of lateral ventricles comprising lining ependyma and hippocampus. The second type of material comprised blood evaluated for antibodies prevalence using ELISA and alcohol concentration using HS-GC-FID. Analysis demonstrated 16.5% prevalence concerning the parasite DNA presence in examined brain tissue samples without specific distribution and association with age at death or days after death until an autopsy was performed. Results have shown correlation between occurrence of risky behavior leading to death and higher proportions of positive parasite DNA presence within the brain. Correlation was not observed between parasite DNA presence and excessive alcohol consumption. Conducted screening demonstrated correlation between parasite DNA presence in the brain with risky behavior and provided new information on possible effects of latent toxoplasmosis.

http://bit.ly/2UwIl3K

Iclaprim activity against wild-type and corresponding thymidine kinase–deficient Staphylococcus aureus in a mouse protection model

Abstract

The in vitro and in vivo antimicrobial activities of dihydrofolate reductase (DHFR) inhibitors are inhibited in the presence of free thymidine in the growth milieu and in rodent efficacy models. However, for thymidine kinase (TK) deficient mutant bacteria, the presence of free thymidine does not impact the activity of DHFR inhibitors, and these mutants were used to assess the in vivo efficacy of the DHFR inhibitor, iclaprim. The efficacies of iclaprim, trimethoprim, and vancomycin were evaluated in a systemic mouse infection model. Female CD-1 mice were infected intraperitoneally (IP) with wild-type Staphylococcus aureus ATCC 25923 (MSSA) or AW 6 (MRSA) or their corresponding isogenic TK-deficient mutant S. aureus strains AH 1246 and AH 1252. Iclaprim showed potent antibacterial activity against both the TK-deficient mutant S. aureus strains, with PD₅₀ values of 1.8 and < 0.5 mg/kg, respectively, for strains AH 1246 and AH 1252. In contrast, poor antibacterial activity was observed against corresponding wild-type (TK competent) S. aureus strains, with PD₅₀ values of 10.8 and 2.2 mg/kg, respectively, for strains ATCC 25923 and AW 6. This study confirms that thymidine plays an important antagonistic role when determining the efficacy of DHFR inhibitors in vivo. This is the first study to show that iclaprim is active against TK-deficient S. aureus strains in a systemic mouse infection model, and that TK-deficient mutants may be used to evaluate iclaprim's activity in rodent models in vivo.

http://bit.ly/2DKbFOL

Sociodemographic and clinical factors associated with acceptance of outpatient parenteral antibiotic therapy in a Singapore tertiary hospital from 2014 to 2017

Abstract

Outpatient parenteral antibiotic therapy (OPAT) can facilitate early discharge; however, not all offered OPAT can accept. We assessed factors associated with acceptance of OPAT in a large Asian tertiary hospital cohort. From 2014 to 2017, we reviewed all referrals to Singapore General Hospital's (SGH) Outpatient Parenteral Antibiotic Therapy (OPAT) service. We compared differences in sociodemographic and clinical factors between patients who opted for OPAT and those who declined, using chi-square test for univariate analysis and logistic regression for multivariate analysis. From 2014 to 2017, a total of 1406 OPAT referrals were made. Of these, 95.9% (1349/1406) were deemed suitable for OPAT. Amongst those suitable, 90.0% (1213/1349) accepted OPAT treatment. On multivariate analysis, being independently ambulant (aOR = 3.46, 95%CI = 2.21–5.37) was independently associated with higher odds of acceptance for OPAT; whereas, patients with peripheral vascular disease had lower odds of accepting OPAT (aOR = 0.32, 95%CI = 0.16–0.62). Lower socioeconomic status (SES) was closely associated with rejection of OPAT, with markers of both individual-level SES (subsidized ward class) and area-level SES (staying in a public rental flat) being independently associated with lower odds of OPAT preference. Distance and travel time were not associated with OPAT acceptance. The top reasons for rejecting OPAT were lack of caregiver (n = 35), mobility issues (n = 24), financial issues (n = 24), and difficulty caring for the line (n = 21). Comorbidities, mobility, and financial issues are important factors to consider when determining suitability for OPAT. More can be done to improve accessibility of OPAT amongst lower-income patients and those staying in lower-SES areas.

http://bit.ly/2UpH4vg

Non-Typhi, non-Paratyphi Salmonella -related hospitalisations in Spain: trends, clinical aspects, risk factors for worse prognosis and hospital costs

Abstract

This study reviews non-typhoid Salmonella (NTS)-related hospitalisations at National level in Spain between 2010 and 2015. NTS hospitalisations were obtained from the National Registry of Hospitalisations. A descriptive analysis of the hospitalisations was performed, including hospitalisation rates (HR) and case-fatality rates (CFR%) calculation. For those with NTS as Main Diagnosis logistic regression were used to estimate the relationship between the different factors and death outcome. 21,660 registered NTS-related hospitalisations were described (88.8% with Salmonella coded as Main Diagnosis). Average HR_2010–2015 was 7.7 (range, 7.3 to 8.1) hospitalisations/100,000 population. Those with NTS infections as Secondary Diagnosis were on average (p < 0.001) older (47.9 vs. 36.5 years), presented worse Charlson Comorbidity Index (2.1 vs. 1.2), higher CFR% (4.8% vs. 0.7%), spent more days hospitalised (15.1 vs. 5.8 days), and generated more costs (6173 vs. 4272 euros/per hospitalisation) than those with NTS as Main Diagnosis. For those with NTS as Main Diagnosis increased risk of death was related to being > 64 years old (OR = 20.99; p < 0.001); presenting septicaemia (OR = 15.82; p < 0.001) or localised infections (OR = 3.98; p = 0.061); Charlson Comorbidity Index > 3 (OR = 4.57; p < 0.001); a non-HIV co-infection (OR = 1.80; p = 0.013); other risk factors (OR = 5.70; p < 0.001); bowel perforation (OR = 70.30; p < 0.001); or acute renal failure (OR = 1.95; p = 0.001). In those with Salmonella as Main Diagnosis, among all complications, bowel perforation presented the strongest association with death outcome. Clinical practice guidelines can help to identify patients at risk of bowel perforation to reduce the fatality of the disease.

http://bit.ly/2DKbymj

How to measure quantitative antibiotic use in order to support antimicrobial stewardship in acute care hospitals: a retrospective observational study

Abstract

A cornerstone of antimicrobial stewardship programs (ASPs) is monitoring quantitative antibiotic use. Frequently used metrics are defined daily dose (DDD) and days of therapy (DOT). The purpose of this study was (1) to explore for the hospital setting the possibilities of quantitative data retrieval on the level of medical specialty and (2) to describe factors affecting the usability and interpretation of these quantitative metrics. We performed a retrospective observational study, measuring overall systemic antibiotic use at specialty level over a 1-year period, from December 1st 2014 to December 1st 2015, in one university and 13 non-university hospitals in the Netherlands. We distinguished surgical and non-surgical adult specialties. The association between DDDs, calculated from aggregated dispensing data, and DOTs, calculated from patient-level prescription data, was explored descriptively and related to organizational factors, data sources (prescription versus dispensing data), data registration, and data extraction. Twelve hospitals were able to extract dispensing data (DDD), three of which on the level of medical specialty; 13 hospitals were able to extract prescription data (DOT), 11 of which by medical specialty. A large variation in quantitative antibiotic use was found between hospitals and the correlation between DDDs and DOTs at specialty level was low. Differences between hospitals related to organizational factors, data sources, data registration, and data extraction procedures likely contributed to the variation in quantitative use and the low correlation between DDDs and DOTs. The differences in healthcare organization, data sources, data registration, and data extraction procedures contributed to the variation in reported quantitative use between hospitals. Uniform registration and extraction procedures are necessary for appropriate measurement and interpretation and benchmarking of quantitative antibiotic use.

http://bit.ly/2UzwuSB