Design, synthesis and biological evaluation of 7-(aryl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline derivatives as potential Hsp90 inhibitors and anticancer agents

Publication date: Available online 2 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Sina Omid Malayeri, Khalil Abnous, Atefeh Arab, Maryam Akaberi, Soghra Mehri, Afshin Zarghi, Razieh Ghodsi
A new series of quinoline analogues was designed and synthesized as Hsp90 inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against three human cancer cell lines including MCF-7 (human breast cancer cells), DU145 (human prostate cancer cell lines), and A549 (adenocarcinomic human alveolar basal epithelial cells). Some of our compounds (13a-13f) showed significant cytotoxic activity on MCF-7 cells. The most potent anti-proliferative compounds were also tested against Her2, a client protein of Hsp90. Compound 13d that demonstrated the highest antiproliferative activity in the series, was found the most potent one for both Her2 protein degradation and Hsp70 protein induction as well. Molecular modeling studies displayed possible mode of interaction between this compound and N-terminal ATP-binding site of Hsp90.

Graphical abstract

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An unusual cause of cutaneous ulceration

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A recently changed, long-standing nodule on the chest wall

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Value of ultrasonography findings for nail psoriasis before and after adalimumab administration

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Pigmented fungiform papillae of the tongue: the first case in an Italian woman

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How do carers and children with eczema choose their emollient?

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Reflectance confocal microscopy as a noninvasive diagnostic tool for naevoid basal cell carcinoma syndrome management

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A bluish nodule with rapid enlargement: a diagnostic challenge

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Rate of positive diagnosis of skin cancer and its stage in two-week wait referrals in England according to age

Summary

Background

The incidence of skin cancer is increasing. The two-week wait conversion rate (TWWCR) is the percentage of urgent suspected skin cancer referrals that are confirmed as cancer.

Aims

To examine the relationships between different epidemiological factors and TWWCR for malignant melanoma (MM) and cutaneous squamous cell carcinoma (SCC).

Methods

We extracted data from the National Cancer Data Repository (NCDR) and National Cancer Waiting Times Monitoring Dataset between 2009 and 2010 for MM and SCC in England. We conducted partial correlation and stepwise multiple regression analysis on TWWCR, age, incidence, detection rate, tumour thickness (MM only), percentage MM/SCC and social deprivation. We also looked at the two-week wait referral rate (TWWRR) and incidence rate with respect to age.

Results

TWWCR was significantly correlated with age when partial correlation was used to control for the factors described above for MM (P < 0.05) and SCC (P < 0.001). Stepwise regression of these factors returned only age as significant in the final model for MM (P < 0.001) and SCC (P < 0.01). Incidence of MM and SCC increased with age. TWWRR also increase with age, but with higher rate in younger people relative to their incidence.

Conclusions

Age is a predictor of TWWCR independent of the other factors measured, including thickness and incidence. This may be explained by the higher number of referrals for younger patients despite the lower incidence of skin cancer in this group. This may reflect a more appropriate rate of referral in order to achieve earlier diagnosis and better outcomes.

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Delayed allergic dermatitis presenting as a keloid-like reaction caused by sting from an Indo-Pacific Portuguese man-o’-war (Physalia utriculus)

Summary

Cnidarian envenomations are common occurrences in the tropics that can affect holidaymakers. The cutaneous reactions are classified as immediate or delayed types. Delayed allergic reactions are persistently recurring dermatitis, which can occur within 1–4 weeks from the initial sting, and may last for several months. Hypertrophic scar-like or keloid-like reactions are rare, and are believed to be a type IV hypersensitivity reaction to sequestered antigens from stinging filaments. We report an unusual case of delayed allergic dermatitis with keloid-like presentation caused by Physalia utriculus.

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Psoriasis and metabolic syndrome in children: current data

Summary

Background

The prevalence of cardiovascular and metabolic disorders in paediatric patients with psoriasis is not well established.

Aim

To conduct a meta-analysis of previously published studies dealing with the occurrence of metabolic disorders in children with psoriasis.

Methods

Data from 7 studies with a total of 965 children with psoriasis were analysed using a random effects model.

Results

Prevalence of metabolic syndrome (MetS) was significantly higher in patients with psoriasis than in healthy controls (HCs). In most studies, significantly decreased levels of high-density lipoprotein (HDL) cholesterol were found in children with psoriasis. Mean level of HDL cholesterol in patients with psoriasis was 2.05 mg/dL lower than in HCs. Patients with psoriasis and HCs did not differ significantly in their mean triglyceride levels, although the difference was at a threshold of statistical significance. Mean level of fasting glucose in children with psoriasis was 5.75 mg/dL higher than in HCs (P < 0.01). The two groups did not differ significantly in mean waist circumference or in systolic and diastolic arterial pressures.

Conclusions

Decreased levels of HDL cholesterol and increased concentrations of fasting glucose may represent very early stages of MetS in children with psoriasis. However, a large population-based study is needed to establish the relationship between psoriasis and MetS in children, including the environmental, genetic and immunological factors leading to their co-occurrence.

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Salicylism from topical wart paint: a novel report

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Early recognition and detection of juvenile psoriatic arthritis: a call for a standardized approach to screening

Summary

Background

National Institute for Health and Care Excellence (NICE) guidelines recommend annual screening for psoriatic arthritis (PsA) in all patients with psoriasis. Currently, no validated assessment tools have been recommended for screening for juvenile PsA (JPsA).

Aim

To determine dermatologists' practice when assessing children's joints and explore the challenges dermatologists experience when looking for joint disease, in order to inform future strategies to improve early detection of arthritis.

Methods

Structured telephone interviews were undertaken with dermatologists identified through the British Society of Paediatric Dermatology. Percentages for binary and categorized responses were calculated. Thematic content analysis was used to generate a set of core themes across the interview data.

Results

Of the 41 consultant dermatologists contacted, 23 agreed to be interviewed. Of these, 78% (18/23) reported they routinely ask about joint disease. Only 13% (3/23) routinely examine the joints of children with psoriasis. Overall, assessment for JPsA lacked a structured, evidence-based approach. The average confidence rating for assessing joint disease was low (score of 3). The two key barriers described for detecting arthritis were a lack of experience and training, and subtle or difficult to detect signs. The two main suggestions for improving detection were the introduction of an assessment tool/guideline and increased clinical experience and training.

Conclusion

There is a clear need for dermatologists to use a standardized approach for screening and to increase their confidence in paediatric musculoskeletal examination. In this article, we provide guidance on screening for psoriatic arthritis in children based on our clinical experience.

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Neural alterations in ADHD children as indicated by voxel-based cortical thickness and morphometry analysis

Publication date: Available online 2 January 2017
Source:Brain and Development
Author(s): Uttam Kumar, Amit Arya, Vivek Agarwal
PurposeNeuroimaging studies provide vital information related to the neurobiology of ADHD, but there still exists a wide gap in relevant information. The present study aimed to elucidate the neuroanatomical alteration in Attention deficit hyperactivity disorder (ADHD) children/adolescents.MethodsVoxel-based cortical thickness (VBCT) and voxel-based morphometry (VBM) was performed to examine neuroanatomic distinctions in 18 children/adolescents aged 7.5–13years diagnosed with DSM-IV TR as ADHD (non-medicated). They were compared with 18 healthy matched controls.ResultsVBCT findings in ADHD children/adolescents revealed reduced cortical thickness in the left superior frontal, left orbito-frontal and left dorsal anterior cingulate cortex. VBM findings confirmed decreased gray matter volume in the left orbito frontal, left middle frontal/dorsolateral prefrontal, left middle temporal and left cerebellum in comparison to control group. A decrease in white matter volume was also observed in the left inferior frontal and left calcarine of ADHD children/adolescents.ConclusionResults reflect possible abnormal neuroanatomical development patterns in ADHD children.



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Principal Strain Vascular Elastography: Simulation and Preliminary Clinical Evaluation

Publication date: Available online 2 January 2017
Source:Ultrasound in Medicine & Biology
Author(s): Rohit Nayak, Steven Huntzicker, Jacques Ohayon, Nancy Carson, Vikram Dogra, Giovanni Schifitto, Marvin M. Doyley
It is difficult to produce reliable polar strain elastograms (radial and circumferential) because the center of the carotid artery is typically unknown. Principal strain imaging can overcome this limitation, but suboptimal lateral displacement estimates make this an impractical approach for visualizing mechanical properties within the carotid artery. We hypothesized that compounded plane wave imaging can minimize this problem. To test this hypothesis, we performed (i) simulations with vessels of varying morphology and mechanical behavior (i.e., isotropic and transversely isotropic), and (ii) a pilot study with 10 healthy volunteers. The accuracy of principal and polar strain (computed using knowledge of the precise vessel center) elastograms varied between 7% and 17%. In both types of elastograms, strain concentrated at the junction between the fibrous cap and the vessel wall, and the strain magnitude decreased with increasing fibrous cap thickness. Elastograms of healthy volunteers were consistent with those of transversely isotropic homogeneous vessels; they were spatially asymmetric, a trend that was common to both principal and polar strains. No significant differences were observed in the mean strain recovered from principal and polar strains (p > 0.05). This investigation indicates that principal strain elastograms measured with compounding plane wave imaging overcome the problems incurred when polar strain elastograms are computed with imprecise estimates of the vessel center.



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Glutamatergic modulation of noradrenaline release in the rat median preoptic area

Publication date: Available online 2 January 2017
Source:Brain Research Bulletin
Author(s): Makoto Takahashi, Yasushi Hayashi, Junichi Tanaka
The present study was carried out to investigate whether glutamatergic receptor mechanisms modulate the release of noradrenaline (NA) in the region of the median preoptic nucleus (MnPO) using intracerebral microdialysis techniques in freely moving rats. Perfusion of N-methyl-D-asparatate (NMDA, 10 and 50μM) through the microdialysis probe significantly enhanced dialysate NA concentration in the region of the MnPO. Local perfusion of the NMDA antagonist dizocilpine (MK801, 10 and 50μM) did not change the basal release of NA in the MnPO area. MK801 (10μM) administered together with NMDA antagonized the stimulant effect of NMDA (50μM). Perfusion of the non-NMDA agonist quisqualic acid (QA, 10 and 50μM) or kainic acid (KA, 10 and 50μM) significantly increased the NA release in the MnPO area. Perfusion of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 and 50μM) had no effect on the NA release. CNQX (10μM) administered together with either QA (50μM) or KA (50μM) in the MnPO area prevented the stimulant effect of the agonists on the NA release. Nonhypotensive hypovolemia following subcutaneous injections of polyethylene glycol (PEG, 30%, 5ml) significantly elevated the NA level in the MnPO area. The PEG-induced elevation in the NA release was attenuated by perfusion of either MK801 (10μM) or CNQX (10μM). The present results suggest that glutamatergic synaptic inputs may act to enhance the release of NA in the MnPO area through both NMDA and non-NMDA receptors, and imply that these glutamatergic receptor mechanisms may be involved in the noradrenergic reguratory system for the body fluid balance.



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Effect of Prosthechea karwinskii (Orchidaceae) on obesity and dyslipidemia in Wistar rats

Publication date: Available online 2 January 2017
Source:Alexandria Journal of Medicine
Author(s): Alejandra Rojas-Olivos, Rodolfo Solano-Gómez, Alfonso Alexander-Aguilera, Manuel Jiménez-Estrada, Stefan Zilli-Hernández, Luicita Lagunez-Rivera
BackgroundProsthechea karwinskii is an endemic Mexican orchid, it's currently used as decorative element and in the traditional medicine to treat diabetes and some problems related to inflammatory processes.AimTo determine antioxidant activity index (AAI) and to validate by the first time and through an rat model the hydroalcoholic extract obtained from Prosthechea karwinskii, a plant used in traditional medicine for treat conditions relate to the metabolic syndrome.MethodsFor in vivo assays 25 weaned male Wistar rats were divided into a control group (CG; n=5) and a Metabolic Syndrome group (MS; n=20). The rats of the latter were induced to MS with 40% sucrose in the drink water during 13weeks. After MS induction this group was subdivided into 4 groups: MS group (n=5) received sucrose, and three groups receiving 200mg/kg of body weight of each extract pseudobulb (P, n=5), leaf (L, n=5), and flower (F, n=5). All treatments were followed for 13days. Blood was collected at the end of the study to measure glucose, cholesterol and triglycerides. AAI were measured in the extracts by the method of DPPH. The results were analyzed using MINITAB 16.1.0, and the statistical significance was determined by ANOVA and a Tukey's test (P<0.05).ResultsLeaves (L) extract had highest values in AAI, followed by flowers (F) and pseudobulb (P) extracts. Leaves extract had highest reducing effect on glucose level, while flower extract had highest reducing effect on the cholesterol and triglycerides levels.ConclusionsThe P. karwinskii extracts evaluated here reduces the glycemic and lipidemic parameters in Wistar rats with MS induced. These effects may be attributed to the high antioxidant capacity of the extracts.



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Toxic effects of formalin-treated cadaver on medical students, staff members, and workers in the Alexandria Faculty of Medicine

Publication date: Available online 2 January 2017
Source:Alexandria Journal of Medicine
Author(s): Noha Selim Mohamed Elshaer, Madiha Awad Elsayed Mahmoud
BackgroundFormaldehyde can be toxic, allergenic and carcinogenic. Evaporation of formaldehyde from formalin-treated cadavers in the anatomy dissection rooms can produce high exposure. This study was conducted to assess acute and chronic toxic effects of formalin-treated cadavers on medical students, staff members, and workers at the Anatomy department in the Alexandria Faculty of Medicine (AFM).MethodsA cross sectional approach was adopted to investigate medical students (n=454). Staff members and workers at the Anatomy department (n=16), and unexposed staff members and workers in the AFM (n=19) were included in the study. Medical students filled self-administered predesigned questionnaire. Formalin-exposed and unexposed staff members filled a questionnaire and a Complete Blood Count was done for them.ResultsThe most frequently reported symptoms by medical students were unpleasant smell (91.2%), itching in the eyes (81.3%), and excessive lacrimation (76.1%). Majority of them reported duration of relief within one hour (>80%), and more than two thirds reported wearing laboratory coats and hand gloves. Formalin-exposed staff reported symptoms of skin disorders as drying (75%), eczema (68.8%), and allergic contact dermatitis (87.5%), besides, eye irritation (68.8%), respiratory tract irritation (93.8%), and work-related bronchial asthma (53.3%). The mean RBCs and platelets counts were significantly lower among formalin-exposed staff (4.08±0.65×10⁶/ul and 237,375±71745.73/ul respectively) compared with unexposed staff (4.95±0.50×10⁶/ul and 280473.68±54456.27/ul respectively). WBCs count was abnormal (low or high) among formalin-exposed staff members (6.2%, and 18.8% respectively), while all unexposed staff had normal WBCs counts.ConclusionThe research highlighted the irritating action of formalin on medical students, and chronic toxic effects on staff members. This necessitates re-evaluation of the concentration of formalin, proper ventilation and assessment of working practices in the dissecting rooms at the Anatomy department.



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Investigating resting-state functional connectivity in the cervical spinal cord at 3T

Publication date: 15 February 2017
Source:NeuroImage, Volume 147
Author(s): Falk Eippert, Yazhuo Kong, Anderson M. Winkler, Jesper L. Andersson, Jürgen Finsterbusch, Christian Büchel, Jonathan C.W. Brooks, Irene Tracey
The study of spontaneous fluctuations in the blood-oxygen-level-dependent (BOLD) signal has recently been extended from the brain to the spinal cord. Two ultra-high field functional magnetic resonance imaging (fMRI) studies in humans have provided evidence for reproducible resting-state connectivity between the dorsal horns as well as between the ventral horns, and a study in non-human primates has shown that these resting-state signals are impacted by spinal cord injury. As these studies were carried out at ultra-high field strengths using region-of-interest (ROI) based analyses, we investigated whether such resting-state signals could also be observed at the clinically more prevalent field strength of 3T. In a reanalysis of a sample of 20 healthy human participants who underwent a resting-state fMRI acquisition of the cervical spinal cord, we were able to observe significant dorsal horn connectivity as well as ventral horn connectivity, but no consistent effects for connectivity between dorsal and ventral horns, thus replicating the human 7T results. These effects were not only observable when averaging along the acquired length of the spinal cord, but also when we examined each of the acquired spinal segments separately, which showed similar patterns of connectivity. Finally, we investigated the robustness of these resting-state signals against variations in the analysis pipeline by varying the type of ROI creation, temporal filtering, nuisance regression and connectivity metric. We observed that – apart from the effects of band-pass filtering – ventral horn connectivity showed excellent robustness, whereas dorsal horn connectivity showed moderate robustness. Together, our results provide evidence that spinal cord resting-state connectivity is a robust and spatially consistent phenomenon that could be a valuable tool for investigating the effects of pathology, disease progression, and treatment response in neurological conditions with a spinal component, such as spinal cord injury.



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Reviewer acknowledgment

Publication date: January 2017
Source:Free Radical Biology and Medicine, Volume 102





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Formation and repair of oxidatively generated damage in cellular DNA

Publication date: Available online 2 January 2017
Source:Free Radical Biology and Medicine
Author(s): Jean Cadet, Kelvin J.A. Davies, Marisa HG Medeiros, Paolo Di Mascio, J. Richard Wagner
In this review article, emphasis is placed on the critical survey of available data concerning modified nucleobase and 2-deoxyribose products that have been identified in cellular DNA following exposure to a wide variety of oxidizing species and agents including, hydroxyl radical, one-electron oxidants, singlet oxygen, hypochlorous acid and ten-eleven translocation enzymes. In addition, information is provided about the generation of secondary oxidation products of 8-oxo-7,8-dihydroguanine and nucleobase addition products with reactive aldehydes arising from the decomposition of lipid peroxides. It is worth noting that the different classes of oxidatively generated DNA damage that consist of single lesions, intra- and interstrand cross-links were unambiguously assigned and quantitatively detected on the basis of accurate measurements involving in most cases high performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry. The reported data clearly show that the frequency of DNA lesions generated upon severe oxidizing conditions, including exposure to ionizing radiation is low, at best a few modifications per 10⁶ normal bases. Application of accurate analytical measurement methods has also allowed the determination of repair kinetics of several well-defined lesions in cellular DNA that however concerns so far only a restricted number of cases.

Graphical abstract

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Editorial Board

Publication date: January 2017
Source:Free Radical Biology and Medicine, Volume 102





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1,4-Naphthoquinone activates the HSP90/HSF1 pathway through the S-arylation of HSP90 in A431 cells: Negative regulation of the redox signal transduction pathway by persulfides/polysulfides

Publication date: Available online 31 December 2016
Source:Free Radical Biology and Medicine
Author(s): Yumi Abiko, Liang Sha, Yasuhiro Shinkai, Takamitsu Unoki, Nho Cong Luong, Yukihiro Tsuchiya, Yasuo Watanabe, Reiko Hirose, Takaaki Akaike, Yoshito Kumagai
The current consensus is that environmental electrophiles activate redox signal transduction pathways through covalent modification of sensor proteins with reactive thiol groups at low concentrations, while they cause cell damage at higher concentrations. We previously exposed human carcinoma A431 cells to the atmospheric electrophile 1,4-naphthoquinone (1,4-NQ) and found that heat shock protein 90 (HSP90), a negative regulator of heat shock factor 1 (HSF1), was a target of 1,4-NQ. In the study presented here, we determined whether 1,4-NQ activates HSF1. We also examined whether such redox signaling could be regulated by nucleophilic sulfur species. Exposure of A431 cells to 1,4-NQ covalently modified cellular HSP90, resulting in repression of the association between HSF1 with HSP90, thereby enhancing HSF1 translocation into the nuclei. Liquid chromatography-tandem mass spectrometry analysis with recombinant HSP90 revealed that the modifications site were Cys412 and Cys564. We found that HSF1 activation mediated by 1,4-NQ upregulated downstream genes, such as HSPA6. HSF1 knockdown accelerated 1,4-NQ-mediated cytotoxicity in the cells. While simultaneous treatment with reactive persulfide and polysulfide, Na2S2 and Na2S4, blocked 1,4-NQ-dependent protein modification and HSF1 activation in A431 cells, the knockdown of Cys persulfide producing enzymes cystathionine β-synthase (CBS) and/or cystathionine γ-lyase (CSE) enhanced these phenomena. 1,4-NQ-thiol adduct and 1,4-NQ-S-1,4-NQ adduct were produced during the enzymatic reaction of recombinant CSE in the presence of 1,4-NQ. The results suggest that activation of the HSP90–HSF1 signal transduction pathway mediated by 1,4-NQ protects cells against 1,4-NQ and that per/polysulfides can diminish the reactivity of 1,4-NQ by forming sulfur adducts.

Graphical abstract

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Adsorption and interlayer diffusion controlled growth and unique surface patterned growth of polyelectrolyte multilayers

Publication date: 27 January 2017
Source:Polymer, Volume 109
Author(s): Jing Yu, Brooke M. Meharg, Ilsoon Lee
In this work, extremely high molecular weight (Mw) poly(allylamine hydrochloride) (PAH, 900K g/mol) and poly(acrylic acid) (PAA, 225 K g/mol) were selected to amplify the difference in the growth of multilayers in comparison with low Mw PAA (15K g/mol) and PAH (15K g/mol). By varying the pH conditions, the PAH/PAA multilayers were fabricated via the layer-by-layer (LbL) assembly in both linear and exponential growth regimes. In the linear growth regime with interlayer diffusion suppressed, high Mw polyelectrolytes with low charge density could slow down the adsorption step, leading to the decrease of thickness compared to low Mw polyelectrolytes when the deposition time was limited. However, the effect of Mw could be reversed by increasing the deposition time, for the adsorption of low Mw polyelectrolyte reached equilibrium, while the adsorption of high Mw polyelectrolyte continued. The larger coil size of high Mw polyelectrolyte could enable the surpassing of multilayer thickness compared with low Mw polyelectrolyte. In the exponential growth regime, besides the slow adsorption, the application of high Mw polyelectrolytes further suppressed the interlayer diffusion, leading to the decrease of multilayer thickness regardless of deposition time. We further studied the effects of deposition time, Mw of polyelectrolytes, and the number of bilayers on the surface morphology in the exponential growth regime. Surface roughness significantly increased with the application of high Mw PAA and the increase in deposition time. For the first time, the unique LbL film growth patterns of islet, ring and cantaloupe skin-like structures that consecutively formed on the surface of polyelectrolyte multilayers were reported by tuning the above parameters.

Graphical abstract

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1,4-Phenylenediamine based covalent triazine framework as an electro catalyst

Publication date: 27 January 2017
Source:Polymer, Volume 109
Author(s): Sivalingam Gopi, Murugavel Kathiresan
Herein, we report the synthesis of 1,4-phenylenediamine based covalent triazine framework (CTF) by reacting cyanuric chloride with 1,4-phenylenediamine under basic conditions. The as synthesized polymeric framework was characterized by solid state ¹³C-CPMAS and ¹⁵N NMR, FT-IR, Raman, SEM, TEM, UV-Vis and N2 sorption isotherm. Commercially available glassy carbon electrode is modified with the as synthesized polymer and its electro catalytic activity towards the reduction of nitrobenzene and oxygen evolution reaction (OER) is studied. Performance of the bare CTF material resembles the performance of commercial GC (glassy carbon) electrode.

Graphical abstract

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Fabrication and properties of poly(tetrafluoroethylene) nanofibres via sea-island spinning

Publication date: 27 January 2017
Source:Polymer, Volume 109
Author(s): Zhifei Zhang, Wei Tu, Ton Peijs, Cees W.M. Bastiaansen
Polytetrafluoroethylene (PTFE) has some unique properties such as high hydrophobicity and high resistance to elevated temperatures, chemicals and solvents which make it of interest for fibres and textiles. However, PTFE normally decomposes before melting, meaning that it cannot be readily melt-spun into fibres. In addition, PTFE is insoluble in all common organic solvents, prohibiting its use in common solution spinning methods such as dry, wet or electrospinning. Here we aim to develop an easy and environmentally friendly alternative for the production of PTFE nanofibres, using a modified island-in-the-sea solution spinning process. For this, first a dispersion of a PTFE homopolymer, PVA and water are compounded to create a blend of PTFE particles in a PVA solution. After the solid-state drawing of this blend and removal of the PVA, we are able to collect PTFE nanofibres with finest diameters of around 50 nm and lengths up to 15 μm. The effects of blend composition, morphology and drawing on PTFE fibre formation and properties are studied and discussed.

Graphical abstract

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NMR studies of water dynamics during sol-to-gel transition of poly (N-isopropylacrylamide) in concentrated aqueous solution

Publication date: 27 January 2017
Source:Polymer, Volume 109
Author(s): Shunsuke Kametani, Sokei Sekine, Takahiro Ohkubo, Tomohiro Hirano, Koichi Ute, H.N. Cheng, Tetsuo Asakura
The focus of this work was on the significant changes in the water dynamics of aqueous poly (N-isopropylacrylamide) (PNIPAM) solution during sol-to-gel transition. Through the use of NMR (particularly two-dimensional ²H NMR T1-T2 relaxation) and rheology, we were able to show that below 34° C fast exchange occurs among free water and water molecules adsorbed on the surface of PNIPAM molecules. At 34° C, PNIPAM becomes aggregated; most of the water molecules are trapped in the PNIPAM aggregates, where water molecules with different dynamics are found. Above 34° C, PNIPAM molecules aggregate further to form a gel network; the free bulk water then becomes dominant at this stage. On the basis of these observations, a model where water molecules interact with PNIPAM in different ways during the transition was proposed. We believe that our experimental approach provides new information and fresh perspectives on the sol-to-gel transition of PNIPAM.

Graphical abstract

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Melting and recrystallization kinetics of poly(butylene terephthalate)

Publication date: 27 January 2017
Source:Polymer, Volume 109
Author(s): Yoshitomo Furushima, Sadanori Kumazawa, Hideyuki Umetsu, Akihiko Toda, Evgeny Zhuravlev, Christoph Schick
Melting of original crystals and their recrystallization during heating were successfully separated for isothermally crystallized poly(butylene terephthalate) (PBT). The corresponding kinetics was determined and quantitatively discussed for a wide range of heating rates (0.1–100,000 K s^-1) using fast-scanning chip calorimetry (FSC) and differential scanning calorimetry (DSC). The double melting peaks observed on the FSC curves are assigned to the melting of original crystals (low-temperature peak) and recrystallized and/or reorganized crystals (high-temperature peak). Heating rate dependence of the degree of recrystallization has been evaluated and the kinetics was discussed on the basis of Ozawa's method. Compared with the melt-crystallization and cold-crystallization, recrystallization kinetics is the fastest process. This is because many crystal remnants, which do not transform into the isotropic melt, act as athermal nuclei, and accelerate recrystallization.

Graphical abstract

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Chamomile (Matricaria recutita L.) decoction extract inhibits in vitro intestinal glucose absorption and attenuates high fat diet-induced lipotoxicity and oxidative stress

Publication date: March 2017
Source:Biomedicine & Pharmacotherapy, Volume 87
Author(s): Mohamed-Amine Jabri, Mohsen Sakly, Lamjed Marzouki, Hichem Sebai
The present study aimed to investigate the inhibitory effect of chamomile decoction extract (CDE) on intestinal glucose absorption as well as its protective role against high fat diet (HFD)-induced obesity and lipotoxicity in rats. We used the Ussing chamber system to investigate the effect of CDE on intestinal transport of glucose. Male Wistar rats were fed HFD for six weeks to provoke obesity. CDE (100mg/kg, b.w. p.o.) has been per orally administered to HFD fed rats. Ex vivo, we found that CDE significantly and dose-dependently increased intestinal absorption of glucose. In vivo, HFD increased the body, liver and kidney weights, while CDE treatment showed a significant protective effects. High fat diet induced also a lipid profiles disorder and a disturbances in kidney and liver function parameters. Moreover liver and kidney lipotoxicity is accompanied by an oxidative stress status characterized by increased lipoperoxidation, depletion of antioxidant enzymes activity and non-enzymatic antioxidant (-SH groups and GSH) levels as well as increased levels of free iron, hydrogen peroxide (H2O2) and calcium. However, treatment with CDE alleviated all the deleterious effects of HFD feed. These findings suggest that chamomile decoction extract can be used as functional beverage against obesity, hyperglycemia and hyperlipidemia.



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Synergistic effects of acarbose and an Oroxylum indicum seed extract in streptozotocin and high-fat-diet induced prediabetic mice

Publication date: March 2017
Source:Biomedicine & Pharmacotherapy, Volume 87
Author(s): Wenlong Sun, Yuanbin Sang, Bowei Zhang, Xiaoxia Yu, Qinmin Xu, Zhilong Xiu, Yuesheng Dong
Prediabetes is defined as blood glucose levels above normal but below diabetes thresholds, and up to 70% of individuals with prediabetes will eventually develop diabetes if left untreated. Acarbose, the first FDA approved anti-prediabetes agent, has some disadvantages, such as reducing the risk of diabetes by only 36%, side effects and limited effects on complications. The aim of this study is to develop a new agent to treat prediabetes and to investigate the anti-prediabetes effects and mechanisms of acarbose and an Oroxylum indicum seed extract (OISE) in prediabetic mice. The combined drugs can reduce the dose of acarbose by 80% and reduce the risk of diabetes by 75%, which is one fold higher than acarbose monotherapy. The combined drugs showed synergistic anti-prediabetes effects and could be effective in preventing the complications of prediabetes. The combined drugs could improve glucose tolerance, improve lipid metabolism and reduce oxidative stress and tissue damage. For the mechanisms, the combined drugs can reduce synergistically postprandial hyperglycaemia by inhibiting α-glucosidase. Furthermore, baicalein in OISE was demonstrated to be a major component in reducing oxidative stress and chrysin was the primary compound that activated PPARγ.



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Capparis spinosa leaves extract: Source of bioantioxidants with nephroprotective and hepatoprotective effects

Publication date: March 2017
Source:Biomedicine & Pharmacotherapy, Volume 87
Author(s): Nizar Tlili, Anouar Feriani, Ezzeddine Saadoui, Nizar Nasri, Abdelhamid Khaldi
Capparis spinosa, Capparidaceae, is largely distributed all over the Mediterranean Basin and is traditionally used to treat many illnesses, such as liver and kidney diseases. The aim of the current study was to explore the antioxidant, nephroprotective and hepatoprotective effects of methanolic extract of Capparis spinosa leaves (MECS) associated with its phytochemical content. The levels of total phenolics, flavonoids and condensed tannins were 23.37mgGAE/g, 9.05mgQE/g and 9.35mgTAE/g, respectively. HPLC analysis revealed nine compounds, namely rutin, resveratrol, coumarin, epicatechin, luteolin, catechin, kaempferol, vanillic acid and gallic acid. The MECS showed interesting antioxidant capacity. The MECS-treatment significantly reduced the increased plasma levels of creatinine, urea and uric acid, reduced the elevated MDA levels, significantly reduced the antioxidant enzyme activities and restored the kidney damage, provoked by cisplatin-treatment. Furthermore, MECS-treatment significantly prevented the increase in serum ALT, AST and LDH levels in acute liver damage induced by CCl4, decreased the amount of hepatic malondialdehyde (MDA) formation and elevated the activities of SOD, CAT and GPx, and restored liver injury. This study supports the traditionally use of C. spinosa to cure kidney and liver diseases. The obtained results highlighted the possible use of C. spinosa as a source of phytochemical with important biological advantages.



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Propofol inhibits LPS-induced apoptosis in lung epithelial cell line, BEAS-2B

Publication date: March 2017
Source:Biomedicine & Pharmacotherapy, Volume 87
Author(s): Xiang Lv, Xuhui Zhou, Jia Yan, Jue Jiang, Hong Jiang
Lipopolysaccharide (LPS) plays an important role in lung endothelial apoptosis which is crucial for lung fibrogenesis in ARDS progression. Reactive oxygen species (ROS) has been reported to be involved in LPS-induced lung epithelial cell apoptosis. Propofol is a commonly used intravenous anesthetic agent in clinic and it could attenuate LPS-induced epithelial cells oxidation and apoptosis. However, the mechanisms are still obscure. In this study, we examined whether and how propofol attenuates LPS-induced oxidation and apoptosis in BEAS-2B cells. Compared with control group, LPS up-regulated Pin-1, phosphatase A2 (PP2A) expression, induced p66^Shc-Ser³⁶ phosphorylation, and facilitated p66^Shc mitochondrial translocation, thus leading to superoxide anion (O2⁻) generation, mitochondrial cytochrome c release, active caspase 3 over-expression and cell viability inhibition. Importantly, propofol was shown to down-regulate LPS-induced PP2A expression, limit p66^Shc mitochondrial translocation, decrease O2⁻ generation, inhibit mitochondrial cytochrome c release, reduce active caspase 3 expression, and recover cells viability, while propofol had no effects on LPS-induced Pin-1 expression and p66^Shc-Ser³⁶ phosphorylation. Moreover, the protective effects of propofol on LPS-induced BEAS-2B cells apoptosis were similar to that of calyculin A, which is an inhibitor of PP2A. We also found that FTY720, which is an activator of PP2A, can effectively reverse the protective function of propofol. Our data illustrated that propofol could alleviate LPS-induced BEAS-2B cells oxidation and apoptosis through down-regulating PP2A expression, limiting p66^Shc-Ser³⁶ dephosphorylation and p66^Shc mitochondrial translocation, decreasing O2⁻ generation, mitochondrial cytochrome c release, activating caspase 3 expression.



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Epiisopiloturine hydrochloride, an imidazole alkaloid isolated from Pilocarpus microphyllus leaves, protects against naproxen-induced gastrointestinal damage in rats

Publication date: March 2017
Source:Biomedicine & Pharmacotherapy, Volume 87
Author(s): Lucas A.D. Nicolau, Nathalia S. Carvalho, Dvison M. Pacífico, Larisse T. Lucetti, Karoline S. Aragão, Leiz M.C. Véras, Marcellus H.L.P. Souza, José R.S.A. Leite, Jand Venes R. Medeiros
ObjectiveThis study aimed to investigate the protective effect of epiisopiloturine hydrochloride (EPI), an imidazole alkaloid, on NAP-induced gastrointestinal damage in rats.MethodsInitially, rats were pretreated with 0.5% carboxymethylcellulose (vehicle) or EPI (3, 10 and 30mg/kg, p.o. or i.p., groups 3–5, respectively) twice daily, for 2days. After 1h, NAP (80mg/kg, p.o.) was given. The control group received only vehicle (group 1) or vehicle+naproxen (group 2). Rats were euthanized on 2nd day, 4h after NAP treatment. Stomachs lesions were measured. Samples were collected for histological evaluation and glutathione (GSH), malonyldialdehyde (MDA), myeloperoxidase (MPO), and cytokines levels. Moreover, gastric mucosal blood flow (GMBF) was evaluated.ResultsEPI pretreatment prevented NAP-induced macro and microscopic gastric damage with a maximal effect at 10mg/kg. Histological analysis revealed that EPI decreased scores of damage caused by NAP. EPI reduced MPO (3.4±0.3U/mg of gastric tissue) and inhibited changes in MDA (70.4±8.3mg/g of gastric tissue) and GSH (246.2±26.4mg/g of gastric tissue). NAP increased TNF-α levels, and this effect was reduced by EPI pretreatment. Furthermore, EPI increased GMBF by 15% compared with the control group.ConclusionOur data show that EPI protects against NAP-induced gastric and intestinal damage by reducing pro-inflammatory cytokines, reducing oxidative stress, and increasing GMBF.

Graphical abstract

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Neonatal anesthetic neurotoxicity: Insight into the molecular mechanisms of long-term neurocognitive deficits

Publication date: March 2017
Source:Biomedicine & Pharmacotherapy, Volume 87
Author(s): Deshui Yu, Linji Li, Weiguo Yuan
Mounting animal studies have demonstrated that almost all the clinically used general anesthetics could induce widespread neuroapoptosis in the immature brain. Alarmingly, some published findings have reported long-term neurocognitive deficits in response to early anesthesia exposure which deeply stresses the potential seriousness of developmental anesthetic neurotoxicity. However, the connection between anesthesia induced neuroapoptosis and subsequent neurocognitive deficits remains controversial. It should be noted that developmental anesthesia related neurotoxicity is not limited to neuroapoptosis. Early anesthesia exposure caused transient suppression of neurogenesis, ultrastructural abnormalities in synapse and alteration in the development of neuronal networks also could contribute to the long-term neurocognitive dysfunction. Understanding the mechanisms of developmental anesthetic neurotoxicity, especially by which anesthesia impairs brain function months after exposure, may lead to development of rational preventive and therapeutic strategies. The focus of present review is on some of those potential mechanisms that have been proposed for anesthesia induced cognitive decline.



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Climatological analysis of aerosol optical properties over East Africa observed from space-borne sensors during 2001–2015

Publication date: March 2017
Source:Atmospheric Environment, Volume 152
Author(s): Richard Boiyo, K. Raghavendra Kumar, Tianliang Zhao, Yansong Bao
The present study is aimed at analyzing spatial and temporal characteristics of aerosols retrieved from MODerate resolution Imaging Spectroradiometer (MODIS) and Ozone Monitoring Instrument (OMI) sensors over East Africa (EA). Data spanning for a period of 15 years during 2001–2015 was used to investigate aerosol optical depth (AOD550), Ångstrom exponent (AE470-660) and absorption aerosol Index (AAI) over EA and selected locations within EA. Validation results of MODIS-Terra versus the Aerosol Robotic NETwork (AERONET) AOD550 revealed that the former underestimated aerosol loading over the studied regions due to uncertainties in surface reflectance. The annual mean AOD550, AAI, and AE470-660 were found to be 0.20 ± 0.01, 0.81 ± 0.03, and 1.39 ± 0.01, respectively with peak values observed during the local dry seasons. The spatial seasonal distributions of mean AOD550 suggested high (low) values during the local dry (wet) periods. The high AOD values found along the borders of southwest of Uganda were attributed to smoke particles; while higher (lower) values of AE470-660 (AAI) dominated most parts of the study domain. Low AOD (0.1–0.2) centers were located in high-altitude regions with relatively high vegetation cover over western and central parts of Kenya, and central and northern parts of Tanzania. Furthermore, latitudinal and longitudinal gradients in AOD550 showed a "southern low and northern high" and a "western low and eastern high" profile, respectively during JJA, as other seasons showed heterogeneous variations. Trend analysis revealed a general increase in AOD and AAI and a decrease in AE; while impact factors significantly affected AOD distribution over EA. HYSPLIT back trajectory analyses revealed diverse transport pathways originated from the Arabian Deserts, central Africa, and southwest of Indian Ocean along with locally produced aerosols during different seasons.

Graphical abstract

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Ghrelin modulates gene and protein expression of digestive enzymes in the intestine and hepatopancreas of goldfish (Carassius auratus) via the GHS-R1a: Possible roles of PLC/PKC and AC/PKA intracellular signaling pathways

Publication date: 15 February 2017
Source:Molecular and Cellular Endocrinology, Volume 442
Author(s): Ayelén Melisa Blanco, Juan Ignacio Bertucci, Aída Sánchez-Bretaño, María Jesús Delgado, Ana Isabel Valenciano, Suraj Unniappan
Ghrelin, a multifunctional gut-brain hormone, is involved in the regulation of gastric functions in mammals. This study aimed to determine whether ghrelin modulates digestive enzymes in goldfish (Carassius auratus). Immunofluorescence microscopy found colocalization of ghrelin, GHS-R1a and the digestive enzymes sucrase-isomaltase, aminopeptidase A, trypsin and lipoprotein lipase in intestinal and hepatopancreatic cells. In vitro ghrelin treatment in intestinal and hepatopancreas explant culture led to a concentration- and time-dependent modulation (mainly stimulatory) of most of the digestive enzymes tested. The ghrelin-induced upregulations of digestive enzyme expression were all abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6, and most of them by the phospholipase C inhibitor U73122 or the protein kinase A inhibitor H89. This indicates that ghrelin effects on digestive enzymes are mediated by GHS-R1a, partly by triggering the PLC/PKC and AC/PKA intracellular signaling pathways. These data suggest a role for ghrelin on digestive processes in fish.



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Response to letter commenting on: Prognostic relevance of morphological classification models for myelodysplastic syndromes in an era of the revised International Prognostic Scoring System

Publication date: Available online 2 January 2017
Source:European Journal of Cancer
Author(s): M.F. van Spronsen, B.I. Witte, G.J. Ossenkoppele, T.M. Westers, A.A. van de Loosdrecht




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Association between the diagnosis-to-treatment interval and overall survival in Taiwanese patients with oral cavity squamous cell carcinoma

Publication date: February 2017
Source:European Journal of Cancer, Volume 72
Author(s): Chun-Ta Liao, Hsin-Ni Chen, Yu-Wen Wen, Shu Ru Lee, Shu-Hang Ng, Tsang-Wu Liu, Sen-Tien Tsai, Ming-Hsui Tsai, Jin-Ching Lin, Pei-Jen Lou, Cheng Ping Wang, Pen-Yuan Chu, Yi-Shing Leu, Kuo-Yang Tsai, Shyuang-Der Terng, Tsung-Ming Chen, Cheng-Hsu Wang, Chih-Yen Chien, Wen-Cheng Chen, Li-Yu Lee, Chien-Yu Lin, Hung-Ming Wang, Chih-Hung Lin, Tuan-Jen Fang, Shiang-Fu Huang, Chung-Jan Kang, Kai-Ping Chang, Lan Yan Yang, Tzu-Chen Yen
BackgroundTo investigate the association between the diagnosis-to-treatment interval (DTI) and overall survival (OS) in patients with oral cavity squamous cell carcinoma (OSCC).MethodsA total of 18,677 patients with first primary OSCC identified in the Taiwanese Cancer Registry Database between 2004 and 2010 were examined. The effect of DTI on 5-year OS rates was investigated with multivariate Cox regression analysis. After the identification of the optimal cutoff for DTI based on the 5-year OS rates, DTI was classified in the following 20-day groups: ≤20 days (57% of the study patients), 21–45 days (34%), 46–90 days (6%) and ≥91 days (3%). In additional exploratory analyses, DTI was reclassified in the following 30-day interval groups: ≤30 days (81% of the study patients), 31–60 days (14%), 61–90 days (2%) and ≥91 days (3%).ResultsMultivariate analyses identified DTI (≤20 days versus other subgroups), sex (female versus male), age (<65 versus ≥65 years), clinical stage (p-stage I versus p-stage II, III, IV) and treatment modality (initial surgery versus initial non-surgery) as independent prognostic factors for 5-year OS. Compared with a DTI ≤20 days, the DTI categories ≥91 days (hazard ratio [HR]: 1.28, P < 0.001), 46–90 days (HR: 1.25, P < 0.001) and 21–45 days (HR: 1.07, P = 0.007) were independently associated with a higher risk of 5-year mortality. Similar results were obtained for DTI ≤30 days groups.ConclusionsDTI is independently associated with 5-year OS in OSCC patients. A DTI longer than 30 days or even 20 days may potentially decrease survival.



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Sandblasting may damage the surface of composite CAD–CAM blocks

Publication date: Available online 2 January 2017
Source:Dental Materials
Author(s): Kumiko Yoshihara, Noriyuki Nagaoka, Yukinori Maruo, Goro Nishigawa, Masao Irie, Yasuhiro Yoshida, Bart Van Meerbeek
ObjectiveCAD–CAM blocks to fabricate semi-direct and indirect restorations are available in different sorts of ceramics as well as composite. In order to bond restorations prepared out of composite blocks into tooth cavities, it is recommended to gently sandblast the surface prior to the application of a primer/adhesive. Today, the effect of sandblasting composite block surfaces has not thoroughly been investigated. In this study, the ultra-structure of composite CAD–CAM blocks was investigated with special attention to the effect of sandblasting on the surface topography and of silanization on the bonding performance.MethodsFive different composite CAD–CAM blocks were involved. We correlatively investigated their structural and chemical composition using X-ray diffraction (XRD), energy dispersion spectroscopy (EDS), scanning electron microscopy (SEM) and (scanning) transmission electron microscopy ((S)TEM). The effect of sandblasting was also imaged in cross-section and at the interface with composite cement. Finally, we measured the shear bond strength to the sandblasted block surface with and without silanization.ResultsAll composite blocks revealed a different ultra-structure. Sandblasting increased surface roughness and resulted in an irregular surface with some filler exposure. Sandblasting also damaged the surface. When the sandblasted composite blocks were silanized, superior bonding receptiveness in terms of higher bond strength was achieved except for Shofu Block HC.SignificanceSandblasting followed by silanization improved the bond strength to composite CAD–CAM blocks. However, sandblasting may also damage the composite CAD–CAM block surface. For the composite CAD–CAM block Shofu Block HC, the damage was so severe that silanization did not improve bond strength.



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Role of postoperative radiotherapy in the management of malignant pleural mesothelioma

Abstract

Introduction

This study assessed the prognostic impact of postoperative radiotherapy in patients with surgically resected malignant pleural mesothelioma (MPM).

Methods

MPM patients diagnosed between 2000 and 2013 were identified from the SEER (Surveillance, Epidemiology, and End Results) database. A propensity-matched analysis was performed considering baseline characteristics (age, gender, race, histology, TNM stage, and type of surgery).

Results

A total of 2166 patients were identified. The median age was 60 years (range 25–85 years), and 469 patients received postoperative radiotherapy. Both before and after propensity score matching, overall survival (P < 0.0001 and P = 0.012, respectively) was better in the postoperative radiotherapy group. When the overall survival was stratified by histology, postoperative radiotherapy did not improve the survival in sarcomatoid histology patients both before and after matching (P = 0.424 and P = 0.281, respectively). In multivariate analysis of the matched population, not receiving postoperative radiotherapy did not correlate with worse survival (hazard ratio: 1.175; P = 0.12). Factors associated with worse survival include sarcomatoid histology, nodal positivity, and age ≥70.

Conclusion

Evidence from this analysis is insufficient on its own to routinely recommend postoperative radiotherapy for surgically resected MPM. However, large-scale prospective clinical trials are warranted to further evaluate this intervention in nonsarcomatoid histology.

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Cosmetic changes following surgery and accelerated partial breast irradiation using HDR interstitial brachytherapy

Abstract

Background

Patients with early-stage breast cancer can benefit from adjuvant accelerated partial breast irradiation (APBI) following breast-conserving surgery (BCS). This work reports on cosmetic results following APBI using multicatheter high-dose-rate interstitial brachytherapy (HDR-IBT).

Patients and methods

Between 2006 and 2014, 114 patients received adjuvant APBI using multicatheter HDR-IBT. For each patient, two photographs were analyzed: the first was taken after surgery (baseline image) and the second at the last follow-up visit. Cosmesis was assessed by a multigender multidisciplinary team using the Harvard Breast Cosmesis Scale. Dose–volume histogram (DVH) parameters and the observed cosmetic results were investigated for potential correlations.

Results

The median follow-up period was 3.5 years (range 0.6–8.5 years). The final cosmetic scores were 30% excellent, 52% good, 14.5% fair, and 3.5% poor. Comparing the baseline and follow-up photographs, 59.6% of patients had the same score, 36% had a better final score, and 4.4% had a worse final score. Only lower target dose nonuniformity ratio (DNR) values (0.3 vs. 0.26; p = 0.009) were significantly associated with improved cosmetic outcome vs. same/worse cosmesis.

Conclusion

APBI using multicatheter HDR-IBT adjuvant to BCS results in favorable final cosmesis. Deterioration in breast cosmesis occurs in less than 5% of patients. The final breast cosmetic outcome in patients treated with BCS and APBI using multicatheter HDR-IBT is influenced primarily by the cosmetic result of the surgery. A lower DNR value is significantly associated with a better cosmetic outcome.

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Radiotherapy in desmoid tumors

Abstract

Background

Desmoid tumors (aggressive fibromatosis) are rare soft tissue tumors which frequently recur after surgery. Desmoid tumors arise from musculoaponeurotic tissue in the extremities, head and neck, abdominal wall, or intra-abdominally. Our aim was to examine the outcome of radiotherapy of desmoid tumors in a single institution series.

Patients and methods

We evaluated 41 patients with desmoid tumors treated with 49 radiotherapies between 1987 and 2012. Radiologic images for response evaluation were reassessed and responses to treatment registered according to RECIST criteria 1.1. For patients with local failures radiation dose distribution was determined in each local failure volume using image co-registration. Recurrences were classified as in-target, marginal, or out-of-target. Prognostic factors for radiotherapy treatment failure were evaluated.

Results

Radiotherapy doses varied from 20–63 Gy (median 50 Gy) with a median fraction size of 2 Gy. The objective response rate to definitive radiotherapy was 55% (12/22 patients). Median time to response was 14 months. A statistically significant dose-response relation for definitive and postoperative radiotherapy was observed both in univariate (p-value 0.002) and in multivariate analysis (p-value 0.02) adjusted for potential confounding factors. Surgery before radiotherapy or surgical margin had no significant effect on time to progression. Nine of 11 (82%) local failures were classified as marginal and two of 11 (18%) in-target. None of the recurrences occurred totally out-of-target.

Conclusions

Radiotherapy is a valuable option for treating desmoid tumors. Radiotherapy dose appears to be significantly associated to local control.

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Analysis of pharmaceutical adulterants in plant food supplements by UHPLC-MS/MS

Publication date: 1 March 2017
Source:European Journal of Pharmaceutical Sciences, Volume 99
Author(s): Paula Paíga, Manuela J.E. Rodrigues, Manuela Correia, Joana S. Amaral, M. Beatriz P.P. Oliveira, Cristina Delerue-Matos
A method based on the Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) extraction and ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was successfully developed and validated for the analysis of 26 pharmaceutical compounds belonging to different therapeutic classes (anorexics, stimulants, anxiolytics, antidepressants and laxatives), which are all prone to be illegally added into weight-loss plant food supplements (PFS) for their pharmacological activity. Internal standard calibration with six isotopically labelled compounds rendered good linearity in the range of 5 to 1000μg/l, depending on the compound, and good sensitivity with limits of quantification in the range of 0.02–9.80μg/l. Recoveries were assessed for all the 16 samples analysed and were found between 70% and 120% for over 90% of the analytes. The average recovery value was 90.8%, for the different studied matrices (liquids, liquid ampoules, tablets and capsules), with RSD values lower than 10% for all forms. The changes introduced to the QuEChERS procedure maintained the good performance characteristics of the extraction method while preserving the chromatographic system for the introduction of unwanted matrix compounds. Synephrine was the only compound detected and quantified in one sample, but at a very low concentration (768μg/l) and its presence may be due to the plant extracts used in the formulation, as synephrine is known to be a natural constituent of Citrus aurantium amara. Despite none of the 16 evaluated samples were found to be adulterated by the illegal addition of the drugs included in this work, the developed methodology can be very useful for monitoring the adulteration of weight-loss PFS.

Graphical abstract

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A Devotion to Never Feeling Satisfied: New JACC Content Avenues

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Platelet Reactivity: Journey to the End of the Night

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Anterior T-Wave Inversion Does Not Convey Short-Term Sudden Death Risk: Inverted Is the New Normal

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Evolution of Prognosis in Left-Sided Infective Endocarditis: A Propensity Score Analysis of 2 Decades

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Alcohol Abuse and Cardiac Disease

AbstractBackground

Understanding the relationship between alcohol abuse, a common and theoretically modifiable condition, and the most common cause of death in the world, cardiovascular disease, may inform potential prevention strategies.

Objectives

The study sought to investigate the associations among alcohol abuse and atrial fibrillation (AF), myocardial infarction (MI), and congestive heart failure (CHF).

Methods

Using the Healthcare Cost and Utilization Project database, we performed a longitudinal analysis of California residents ≥21 years of age who received ambulatory surgery, emergency, or inpatient medical care in California between 2005 and 2009. We determined the risk of an alcohol abuse diagnosis on incident AF, MI, and CHF. Patient characteristics modifying the associations and population-attributable risks were determined.

Results

Among 14,727,591 patients, 268,084 (1.8%) had alcohol abuse. After multivariable adjustment, alcohol abuse was associated with an increased risk of incident AF (hazard ratio [HR]: 2.14; 95% confidence interval [CI]: 2.08 to 2.19; p < 0.0001), MI (HR: 1.45; 95% CI: 1.40 to 1.51; p < 0.0001), and CHF (HR: 2.34; 95% CI: 2.29 to 2.39; p < 0.0001). In interaction analyses, individuals without conventional risk factors for cardiovascular disease exhibited a disproportionately enhanced risk of each outcome. The population-attributable risk of alcohol abuse on each outcome was of similar magnitude to other well-recognized modifiable risk factors.

Conclusions

Alcohol abuse increased the risk of AF, MI, and CHF to a similar degree as other well-established risk factors. Those without traditional cardiovascular risk factors are disproportionately prone to these cardiac diseases in the setting of alcohol abuse. Thus, efforts to mitigate alcohol abuse might result in meaningful reductions of cardiovascular disease.

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Anterior T-Wave Inversion in Young White Athletes and Nonathletes: Prevalence and Significance

AbstractBackground

Anterior T-wave inversion (ATWI) on electrocardiography (ECG) in young white adults raises the possibility of cardiomyopathy, specifically arrhythmogenic right ventricular cardiomyopathy (ARVC). Whereas the 2010 European consensus recommendations for ECG interpretation in young athletes state that ATWI beyond lead V₁ warrants further investigation, the prevalence and significance of ATWI have never been reported in a large population of asymptomatic whites.

Objectives

This study investigated the prevalence and significance of ATWI in a large cohort of young, white adults including athletes.

Methods

Individuals 16 to 35 years of age (n = 14,646), including 4,720 females (32%) and 2,958 athletes (20%), were evaluated by using a health questionnaire, physical examination, and 12-lead ECG. ATWI was defined as T-wave inversion in ≥2 contiguous anterior leads (V₁ to V₄).

Results

ATWI was detected in 338 individuals (2.3%) and was more common in women than in men (4.3% vs. 1.4%, respectively; p < 0.0001) and more common among athletes than in nonathletes (3.5% vs. 2.0%, respectively; p < 0.0001). T-wave inversion was predominantly confined to leads V₁ to V₂ (77%). Only 1.2% of women and 0.2% of men exhibited ATWI beyond V₂. No one with ATWI fulfilled diagnostic criteria for ARVC after further evaluation. During a mean follow-up of 23.1 ± 12.2 months none of the individuals with ATWI experienced an adverse event.

Conclusions

ATWI confined to leads V₁ to V₂ is a normal variant or physiological phenomenon in asymptomatic white individuals without a relevant family history. ATWI beyond V₂ is rare, particularly in men, and may warrant investigation.

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Alcohol Consumption and Cardiac Disease: Where Are We Now?

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HIV Infection and Heart Failure Outcomes in Women

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Clinical Implications of Focal Intimal Disruption in Patients With Type B Intramural Hematoma

AbstractBackground

Focal intimal disruption (FID) has been described in >20% of type B intramural hematomas (IMH), with unclear prognosis and management.

Objectives

This study aimed to evaluate the short- and long-term evolution of medically treated patients with type B IMH with and without FID.

Methods

There were 107 consecutive patients with acute type B IMH were included prospectively in a multicenter protocol of clinical and imaging follow-up. FID was defined as an intimal disruption with contrast material-filled outpouching from the aorta lumen with a communicating orifice of >3 mm.

Results

There were 43 patients (40%) who developed an FID with larger basal maximum aortic diameter and hematoma thickness. Patients with acute FID had a higher risk of aorta-related events than those without FID (hazard ratio: 24.43; 95% confidence interval: 7.65 to 78.04; p < 0.001). Of the 94 discharged patients, 33 (35%) developed an FID within the first 6 months of follow-up: 19 evolved with mild (<1 mm/year), 8 with moderate (1 to 2 mm/year), and 6 with severe (>2 mm/year) aortic enlargement. Chronic FID was not associated with aorta-related events (hazard ratio: 0.98; 95% confidence interval: 0.22 to 4.34; p = 0.987).

Conclusions

The development of FID in the acute phase of type B IMH has a poor prognosis owing to the high risk of aortic rupture. In the chronic phase, most FIDs evolve with slow aortic dilation and without complications. Although acute FIDs should be treated early and invasively, lesions developing in the subacute-chronic phase can be managed with medical treatment and close imaging surveillance.

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Reply: High-Output Heart Failure: With or Without Obesity

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Instructions For Authors

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Long-Term Mortality After Coronary Revascularization in Nondiabetic Patients With Multivessel Disease

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Intramural Hematoma: When Does a Sheep Become a Wolf?

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Cardiovascular Medicine and Society: The Pregnant Cardiologist

Abstract

Women are a consistent minority in the field of cardiology, with concerns regarding balancing career and parenting responsibilities often cited as a contributing factor to this under-representation. To investigate the impact that a career in cardiology may have on the family planning decisions of female cardiologists, the Women in Cardiology section of the American College of Cardiology conducted a voluntary anonymous survey. The following perspective highlights lessons learned from the survey, and potential solutions to the issues surrounding maternity leave, radiation exposure during pregnancy, and breastfeeding accommodations raised by these data. Given that most female cardiologists are pregnant at some point during their careers, particularly during the vulnerable periods of training and early career, improving the experience of pregnancy and early parenthood for all cardiologists may secure the best possible candidates to the field of cardiology.

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Transposition of the Great Arteries in the Developing World: Surgery and Outcomes

AbstractBackground

Little has been published regarding surgery for transposition of the great arteries (TGA) in the developing world.

Objectives

This study sought to identify patient characteristics, surgical interventions, institutional characteristics, risk factors for mortality, and outcomes among patients undergoing surgery for TGA in this setting.

Methods

Developing world congenital heart surgical programs submitted de-identified data to a novel international collaborative database as part of a quality improvement project. We conducted a retrospective cohort study that included all cases of TGA with intact ventricular septum and TGA with ventricular septal defect performed from 2010 to 2013. Demographic, surgical, and institutional characteristics and their associations with in-hospital mortality were identified.

Results

There were 778 TGA operations performed at 26 centers, 480 (62%) for TGA with intact ventricular septum and 298 (38%) for TGA with ventricular septal defect. Most (80%) were single-stage arterial switch operations, but 20% were atrial baffling procedures (atrial switch operation) or 2-stage repairs (pulmonary artery band followed by arterial switch operation). Age at operation was >30 days in one-half of the cases and did not vary significantly with operation type. Survival was 85% and did not significantly vary with age at operation or operation type. Preceding septostomy was infrequently reported (16%) and was not associated with surgical mortality. Mortality was associated with lower World Health Organization weight/body mass index-for-age percentile and lower institutional volume of TGA repair.

Conclusions

Surgical repair of TGA performed in the developing world is associated with an early survival of 85%. Type of surgical repair and age at operation varied considerably, but no associations with mortality were identified. In contrast, poor nutrition and small surgical volume were most strongly associated with mortality. Multicenter collaborative quality improvement efforts may benefit patients with TGA in the developing world.

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The Evolution of the Fellows-in-Training and Early Career Professionals Page: Past, Present, and Future

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Surgery for TGA in Developing Countries: The End of the Beginning

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Electromagnetic Interference in Cardiac Implantable Electronic Devices: Is the Use of Smartphones Safe?

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Proenkephalin, Renal Dysfunction, and Prognosis in Patients With Acute Heart Failure: A GREAT Network Study

AbstractBackground

Proenkephalin A (PENK) and its receptors are widely distributed. Enkephalins are cardiodepressive and difficult to measure directly. PENK is a stable surrogate analyte of labile enkephalins that is correlated inversely with renal function. Cardiorenal syndrome is common in acute heart failure (HF) and portends poor prognosis.

Objectives

This study assessed the prognostic value of PENK in acute HF, by identifying levels that may be useful in clinical decisions, and evaluated its utility for predicting cardiorenal syndrome.

Methods

This multicenter study measured PENK in 1,908 patients with acute HF (1,186 male; mean age 75.66 ± 11.74 years). The primary endpoint was 1-year all-cause mortality; secondary endpoints were in-hospital mortality, all-cause mortality or HF rehospitalization within 1 year, and in-hospital worsening renal function, defined as a rise in plasma creatinine ≥26.5 μmol/l or 50% higher than the admission value within 5 days of presentation.

Results

During 1-year follow-up, 518 patients died. Measures of renal function were the major determinants of PENK levels. PENK independently predicted worsening renal function (odds ratio: 1.58; 95% confidence interval [CI]: 1.24 to 2.00; p < 0.0005) with a model receiver-operating characteristic area of 0.69. PENK was associated with the degree of worsening renal function. Multivariable Cox regression models showed that PENK level was an independent predictor of 1-year mortality (p < 0.0005) and 1-year death and/or HF (hazard ratio: 1.27; 95% CI: 1.10 to 1.45; p = 0.001). PENK levels independently predicted outcomes at 3 or 6 months and were independent predictors of in-hospital mortality, predominantly down-classifying risk in survivors when added to clinical scores; levels <133.3 pmol/l and >211.3 pmol/l detected low-risk and high-risk patients, respectively.

Conclusions

PENK levels reflect cardiorenal status in acute HF and are prognostic for worsening renal function and in-hospital mortality as well as mortality during follow-up.

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High-Output Heart Failure: With or Without Obesity

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Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator–controlled VOYAGE 2 trial

Publication date: Available online 2 January 2017
Source:Journal of the American Academy of Dermatology
Author(s): Kristian Reich, April W. Armstrong, Peter Foley, Michael Song, Yasmine Wasfi, Bruce Randazzo, Shu Li, Y.-K. Shen, Kenneth B. Gordon
BackgroundPhase II data suggested that guselkumab, an anti-interleukin-23 monoclonal antibody, was efficacious in psoriasis.ObjectiveWe sought to assess efficacy and safety of guselkumab in moderate to severe psoriasis versus placebo and adalimumab, including interrupted treatment and switching adalimumab nonresponders to guselkumab.MethodsPatients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 496); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20; n = 248); or adalimumab (80 mg week 0, then 40 mg week 1, and every 2 weeks through week 23; n = 248). At week 28, guselkumab 90% or greater improvement in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 90) responders were rerandomized to guselkumab or placebo with guselkumab after loss of response. Placebo→guselkumab responders and adalimumab responders received placebo, then guselkumab after loss of response. Nonresponders received guselkumab.ResultsAt week 16, more patients receiving guselkumab achieved an Investigator Global Assessment (IGA) score 0/1 (cleared/minimal) (84.1% vs 8.5%) and PASI 90 (70.0% vs 2.4%) versus placebo (coprimary end points). Guselkumab was superior to adalimumab at week 16 (IGA score 0/1, 75% or greater improvement in PASI score from baseline, and PASI 90) and week 24 (IGA score 0/1 and 0, PASI 90, 100% improvement in PASI score from baseline) (P < .001). From weeks 28 to 48, better persistence of response was observed in guselkumab maintenance versus withdrawal groups (P < .001). Of adalimumab nonresponders who switched to guselkumab, 66.1% achieved PASI 90 at week 48. Guselkumab improved patient-reported outcomes. Adverse events were comparable among groups.LimitationsOne-year follow-up limits retreatment data.ConclusionsGuselkumab is a highly effective, well-tolerated, maintenance therapy, including in adalimumab nonresponders.



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Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator–controlled VOYAGE 1 trial

Publication date: Available online 2 January 2017
Source:Journal of the American Academy of Dermatology
Author(s): Andrew Blauvelt, Kim A. Papp, Christopher E.M. Griffiths, Bruce Randazzo, Yasmine Wasfi, Yaung-Kaung Shen, Shu Li, Alexa B. Kimball
BackgroundGuselkumab, an interleukin-23 blocker, was superior to adalimumab in treating moderate to severe psoriasis in a phase II trial.ObjectivesWe sought to compare efficacy and safety of guselkumab with adalimumab and placebo in patients with psoriasis treated for 1 year.MethodsPatients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 329); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20, then every 8 weeks; n = 174); or adalimumab (80 mg week 0, 40 mg week 1, then 40 mg every 2 weeks through week 47; n = 334). Physician-reported outcomes (Investigator Global Assessment, Psoriasis Area and Severity Index [PASI]), patient-reported outcomes (Dermatology Life Quality Index, Psoriasis Symptoms and Signs Diary), and safety were evaluated through week 48.ResultsGuselkumab was superior (P < .001) to placebo at week 16 (85.1% vs 6.9% [Investigator Global Assessment score of 0/1 (cleared/minimal)] and 73.3% vs 2.9% [90% or greater improvement in PASI score from baseline (PASI 90)]). Guselkumab was also superior (P < .001) to adalimumab for Investigator Global Assessment 0/1 and PASI 90 at week 16 (85.1% vs 65.9% and 73.3% vs 49.7%), week 24 (84.2% vs 61.7% and 80.2% vs 53.0%), and week 48 (80.5% vs 55.4% and 76.3% vs 47.9%). Furthermore, guselkumab significantly improved patient-reported outcomes through week 48. Adverse event rates were comparable between treatments.LimitationsAnalyses were limited to 48 weeks.ConclusionsGuselkumab demonstrated superior efficacy compared with adalimumab and was well tolerated in patients with psoriasis through 1 year.



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Toxicity evaluation of magnetic hyperthermia induced by remote actuation of magnetic nanoparticles in 3D micrometastasic tumor tissue analogs for triple negative breast cancer

Publication date: March 2017
Source:Biomaterials, Volume 120
Author(s): Nathanael A. Stocke, Pallavi Sethi, Amar Jyoti, Ryan Chan, Susanne M. Arnold, J. Zach. Hilt, Meenakshi Upreti
Magnetic hyperthermia as a treatment modality is acquiring increased recognition for loco-regional therapy of primary and metastatic lung malignancies by pulmonary delivery of magnetic nanoparticles (MNP). The unique characteristic of magnetic nanoparticles to induce localized hyperthermia in the presence of an alternating magnetic field (AMF) allows for preferential killing of cells at the tumor site. In this study we demonstrate the effect of hyperthermia induced by low and high dose of MNP under the influence of an AMF using 3D tumor tissue analogs (TTA) representing the micrometastatic, perfusion independent stage of triple negative breast cancer (TNBC) that infiltrates the lungs. While application of inhalable magnetic nanocomposite microparticles or magnetic nanocomposites (MnMs) to the micrometastatic TNBC model comprised of TTA generated from cancer and stromal cells, showed no measureable adverse effects in the absence of AMF-exposure, magnetic hyperthermia generated under the influence of an AMF in TTA incubated in a high concentration of MNP (1 mg/mL) caused significant increase in cellular death/damage with mechanical disintegration and release of cell debris indicating the potential of these inhalable composites as a promising approach for thermal treatment of diseased lungs. The novelty and significance of this study lies in the development of methods to evaluate in vitro the application of inhalable composites containing MNPs in thermal therapy using a physiologically relevant metastatic TNBC model representative of the microenvironmental characteristics in secondary lung malignancies.

Graphical abstract

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Ultrasound-assisted synthesis of nano-structured Zinc(II)-based metal-organic frameworks as precursors for the synthesis of ZnO nano-structures

Publication date: July 2017
Source:Ultrasonics Sonochemistry, Volume 37
Author(s): Fahime Bigdeli, Hosein Ghasempour, Alireza Azhdari Tehrani, Ali Morsali, Hassan Hosseini-Monfared
A 3D, porous Zn(II)-based metal–organic framework {[Zn2(oba)2(4-bpmn)]·(DMF)1.5}n (TMU-21), (4-bpmn=N,N′-Bis-pyridin-4-ylmethylene-naphtalene-1,5-diamine, H2oba=4,4′-oxybis(benzoic acid)) with nano-rods morphology under ultrasonic irradiation at ambient temperature and atmospheric pressure was prepared and characterized by scanning electron microscopy. Sonication time and concentration of initial reagents effects on the size and morphology of nano-structured MOFs were studied. Also {[Zn2(oba)2(4-bpmn)] (TMU-21) and {[Zn2(oba)2(4-bpmb)] (TMU-6), 4-bpmb=N,N'-(1,4-phenylene)bis(1-(pyridin-4-yl)methanimine) were easily prepared by mechanochemical synthesis. Nanostructures of Zinc(II) oxide were obtained by calcination of these compounds and their de-solvated analogue as activated MOFs, at 550°C under air atmosphere. As a result of that, different Nanostructures of Zinc(II) oxide were obtained. The ZnO nanoparticles were characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and FT-IR spectroscopy.



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Oxidative stress biomarkers, cholinesterase activity and biotransformation enzymes in the liver of dice snake (Natrix tessellata Laurenti) during pre-hibernation and post-hibernation: A possible correlation with heavy metals in the environment

Publication date: April 2017
Source:Ecotoxicology and Environmental Safety, Volume 138
Author(s): Jelena Gavrić, Marko Anđelković, Ljiljana Tomović, Marko Prokić, Svetlana Despotović, Branka Gavrilović, Tijana Radovanović, Slavica Borković-Mitić, Slađan Pavlović, Zorica Saičić
We investigated in the liver of dice snakes during pre- and post-hibernation changes in the following antioxidant parameters: total, manganese and copper zinc containing superoxide dismutases (Tot SOD, MnSOD, CuZn SOD, respectively), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and the concentrations of total glutathione (GSH) and sulfhydryl groups (–SH). In addition, we examined the expression of phase I biotransformation enzyme cytochrome P4501A (CYP1A) and the activity of phase II biotransformation enzyme glutathioneS-transferase (GST), the level of lipid peroxidation (by measuring the thiobarbituric acid-reactive substances (TBARS)), cholinesterase activity (ChE) and metallothionein expression (MT). We also measured the concentrations of heavy metals, including Al, Cd, As, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb and Zn in the water and snake liver during both periods. During the post-hibernation period, the activities of Tot SOD, CuZn SOD and GST and the concentration of GSH were significantly decreased, while GSH-Px and GR activities, the concentrations of –SH groups and TBARS were significantly increased. The activities of Mn SOD, CAT and ChE, and the relative amounts of CYP1A and MT did not significantly change during the investigated periods. The observed differences in the examined parameters probably represent adaptive physiological responses to sudden changes in tissue oxygenation during arousal from hibernation. Our findings also indicate that the accumulated metals modulated the responses of the examined parameters during the investigated periods.



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One-step fabrication of biomimetic superhydrophobic surface by electrodeposition on magnesium alloy and its corrosion inhibition

Publication date: 1 April 2017
Source:Journal of Colloid and Interface Science, Volume 491
Author(s): Yan Liu, Jingze Xue, Dan Luo, Huiyuan Wang, Xu Gong, Zhiwu Han, Luquan Ren
A facile, rapid and one-step electrodeposition process has been employed to construct a superhydrophobic surface with micro/nano scale structure on a Mg-Sn-Zn (TZ51) alloy, which is expected to be applied as a biodegradable biomedical implant materials. By changing the electrodeposition time, the maximum contact angle of the droplet was observed as high as 160.4°±0.7°. The characteristics of the as-prepared surface were conducted by field emission scanning electron microscopy (FE-SEM), X-ray photoelectron spectroscopy (XPS) and Fourier-transform infrared spectroscopy (FT-IR). Besides, the anti-corrosion performance of the coatings in stimulated body fluid (SBF) solution were investigated by electrochemical measurement. The results demonstrated that the anti-corrosion property of superhydrophobic surface was greatly improved. This method show beneficial effects on the wettability and corrosion behavior, and therefore provides a efficient route to mitigate the undesirable rapid corrosion of magnesium alloy in favor of application for clinical field.

Graphical abstract

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Cardiovascular comorbidities in acromegaly: an update on their diagnosis and management

Abstract

Comorbidities related to the cardiovascular system are one of the most prevalent in patients with acromegaly, and contribute to an increased risk of morbidity and all-cause mortality. Specifically, hypertension, cardiomyopathy, heart valve disease, arrhythmias, atherosclerosis, coronary artery disease, and cardiac dysfunction may be frequent findings. Although the underlying physiopathology for each comorbidity may not be fully elucidated, uncontrolled growth hormone/insulin-like growth factor 1 excess, age, prolonged disease duration, and coexistence of other cardio-vascular risk factors are significant influencing variables. A simple diagnostic approach to screen for the presence of these comorbidities may allow prompt treatment and arrest the progression of cardiac abnormalities. In this article, we revise the most prevalent cardiovascular comorbidities and their pathophysiology in acromegalic patients, and we address some recommendations for their prompt diagnosis, management and treatment. Strengths and pitfalls of different diagnostic techniques that are currently being used and how different treatments can affect these complications will be further discussed.

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Does parathyroid hormone control bone quality?

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TSH increment and the risk of incident type 2 diabetes mellitus in euthyroid subjects

Abstract

Purpose

Thyroid function is known to influence glucose metabolism, and thyroid-stimulating hormone is the most useful parameter in screening for thyroid dysfunction.

Therefore, the aim of this study was to investigate the incidence of type 2 diabetes according to baseline thyroid-stimulating hormone level and thyroid-stimulating hormone change in euthyroid subjects.

Methods

We identified and enrolled 17,061 euthyroid subjects without diabetes among participants who had undergone consecutive thyroid function tests between 2006 and 2012 as a part of yearly health check-up program. Thyroid-stimulating hormone changes were determined by subtracting baseline thyroid-stimulating hormone level from thyroid-stimulating hormone level at 1 year before diagnosis of diabetes or at the end of follow-up in subjects who did not develope diabetes.

Results

During 84,595 person-years of follow-up, there were 956 new cases of type 2 diabetes. Cox proportional hazards models showed the risk of incident type 2 diabetes was significantly increased with each 1 μIU/mL increment in TSH after adjustment for multiple confounding factors (hazard ratio = 1.13, 95% confidence interval: 1.07–1.20, P < 0.001). Compared with individuals in the lowest tertile (−4.08 to 0.34 μIU/mL), those in the highest thyroid-stimulating hormone change tertile (0.41–10.84 μIU/mL) were at greater risk for incident type 2 diabetes (hazard ratio = 1.25, 95% confidence interval: 1.05–1.48, P for trend = 0.011). However, baseline thyroid-stimulating hormone level and tertile were not associated with the risk for diabetes.

Conclusions

Prominent increase in thyroid-stimulating hormone concentration can be an additional risk factor for the development of type 2 diabetes in euthyroid subjects.

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Handling limited datasets with neural networks in medical applications: a small-data approach

Publication date: Available online 2 January 2017
Source:Artificial Intelligence in Medicine
Author(s): Torgyn Shaikhina, Natalia A. Khovanova
MotivationSingle-centre studies in medical domain are often characterised by limited samples due to the complexity and high costs of patient data collection. Machine learning methods for regression modelling of small datasets (less than 10 observations per predictor variable) remain scarce. Our work bridges this gap by developing a novel framework for application of artificial neural networks (NNs) for regression tasks involving small medical datasets.MethodsIn order to address the sporadic fluctuations and validation issues that appear in regression NNs trained on small datasets, the method of multiple runs and surrogate data analysis were proposed in this work. The approach was compared to the state-of-the-art ensemble NNs; the effect of dataset size on NN performance was also investigated.ResultsThe proposed framework was applied for the prediction of compressive strength (CS) of femoral trabecular bone in patients suffering from severe osteoarthritis. The NN model was able to estimate the CS of osteoarthritic trabecular bone from its structural and biological properties with a standard error of 0.85MPa. When evaluated on independent test samples, the NN achieved accuracy of 98.3%, outperforming an ensemble NN model by 11%. We reproduce this result on CS data of another porous solid (concrete) and demonstrate that the proposed framework allows for an NN modelled with as few as 56 samples to generalise on 300 independent test samples with 86.5% accuracy, which is comparable to the performance of an NN developed with 18 times larger dataset (1030 samples).ConclusionThe significance of this work is two-fold: the practical application allows for non-destructive prediction of bone fracture risk, while the novel methodology extends beyond the task considered in this study and provides a general framework for application of regression NNs to medical problems characterised by limited dataset sizes.



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Pathogenic conversion of regulatory B10 cells into osteoclast-priming cells in rheumatoid arthritis

Publication date: January 2017
Source:Journal of Autoimmunity, Volume 76
Author(s): Fanlei Hu, Hongjiang Liu, Xu Liu, Xia Zhang, Liling Xu, Huaqun Zhu, Yingni Li, Lianjie Shi, Limin Ren, Jian Zhang, Zhanguo Li, Yuan Jia
Regulatory B10 cells were functionally impaired in rheumatoid arthritis (RA), yet the mechanisms were unclear. B cells are recently recognized as important participants in osteoclastogenesis by producing RANKL. In this study, we investigated whether regulatory B10 cells could convert into RANKL-producing cells, thus impairing their immunosuppressive functions in RA and exacerbating the disease progression. Our results showed that human regulatory B10 cells could ectopically express RANKL. Under RA circumstance, RANKL-producing B10 cells expanded dramatically, partially induced by TNF-α. The frequencies of these cells were positively correlated with RA patient disease activities and tender joint counts, but negatively correlated with the frequencies of regulatory B10 cells. Strikingly, RANKL-producing B10 cells from RA patients, but not healthy individuals significantly promoted osteoclast differentiation and bone erosion in a paracrine and cell-cell contact-dependent manner. Moreover, these pathogenic RANKL-producing B10 cells declined while regulatory IL-10-producing B10 cells increased in RA patients with disease remission after therapy. Collectively, these results showed that in RA, regulatory B10 cells demonstrated the potential of converting into RANKL-producing cells, thus exacerbating osteoclast formation, bone destruction and disease progression. Modulating the status of B10 cells might provide novel therapeutic strategies for RA.



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Editorial Board

Publication date: January 2017
Source:Journal of Autoimmunity, Volume 76





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GEC-ESTRO/ACROP recommendations for performing bladder-sparing treatment with brachytherapy for muscle-invasive bladder carcinoma

Publication date: Available online 31 December 2016
Source:Radiotherapy and Oncology
Author(s): Bradley R. Pieters, Elzbieta van der Steen-Banasik, Geert A. Smits, Marisol De Brabandere, Alberto Bossi, Erik Van Limbergen
The standard treatment for muscle-invasive bladder cancer (MIBC) is a radical cystectomy with pelvic lymph node dissection with or without neoadjuvant chemotherapy. In selected cases a bladder sparing approach is possible, for example a limited surgical excision combined with external beam radiotherapy and brachytherapy. To perform brachytherapy flexible catheters have to be implanted in the bladder wall. The implantation is done either by the open retropubic approach or the endoscopic surgical approach. The largest experience for brachytherapy is with low-dose rate and pulsed-dose rate, although some short-term experience with high-dose rate is also reported.The main advantage for this technique is the conservation of bladder function, with comparable local control rates as for cystectomy series in selected cases.The GEC-ESTRO/ACROP (Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology / Advisory Committee on Radiation Oncology Practice) recommendations to perform bladder implantations and brachytherapy as a treatment option for MIBC are described.



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PCNA dependent cellular activities tolerate dramatic perturbations in PCNA client interactions

Publication date: Available online 31 December 2016
Source:DNA Repair
Author(s): Rosemary H.C. Wilson, Antonio J. Biasutto, Lihao Wang, Roman Fischer, Emma L. Baple, Andrew H. Crosby, Erika J. Mancini, Catherine M. Green
Proliferating cell nuclear antigen (PCNA) is an essential cofactor for DNA replication and repair, recruiting multiple proteins to their sites of action. We examined the effects of the PCNA^S228I mutation that causes PCNA-associated DNA repair disorder (PARD). Cells from individuals affected by PARD are sensitive to the PCNA inhibitors T3 and T2AA, showing that the S228I mutation has consequences for undamaged cells. Analysis of the binding between PCNA and PCNA-interacting proteins (PIPs) shows that the S228I change dramatically impairs the majority of these interactions, including that of Cdt1, DNMT1, PolD3 and PolD4. In contrast p21 largely retains the ability to bind PCNA^S228I. This property is conferred by the p21 PIP box sequence itself, which is both necessary and sufficient for PCNA^S228I binding. Ubiquitination of PCNA is unaffected by the S228I change, which indirectly alters the structure of the inter-domain connecting loop. Despite the dramatic in vitro effects of the PARD mutation on PIP-degron binding, there are only minor alterations to the stability of p21 and Cdt1 in cells from affected individuals. Overall our data suggests that reduced affinity of PCNA^S228I for specific clients causes subtle cellular defects in undamaged cells which likely contribute to the etiology of PARD.



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Ethnobiological treatments of neurological conditions in the Chota Nagpur Plateau, India

Publication date: 23 February 2017
Source:Journal of Ethnopharmacology, Volume 198
Author(s): Abhijit Dey, Partha Gorai, Anuradha Mukherjee, Raghunath Dhan, Biplob Kumar Modak
Ethnopharmacological relevanceWorld Health Organization (WHO) has recognized the contribution of traditional medicine in the primary health care system. WHO also considers neurological disorders as one of the prime concern to the public health. Inadequate and inaccessible health facilities in the rural and underprivileged areas have forced the various tribal and non-tribal communities to use ethno-phyto and ethno-zoo therapeutics against different ailments. Chota Nagpur Plateau, India is one of the richest in India in terms of plant and animal diversity, and houses a number of indigenous communities often practising their own ethnobiological medicines. These undocumented indigenous treasure must be preserved and could be utilized in discovering lead compounds against human ailments including neuroprotective and psychoactive disorders.Materials and methodsA number of ethnobiological surveys were carried out during 2012–2015 in the three districts of the Bengal part of Manbhum region, Chota Nagpur Plateau via conducting open and semi-structured interviews among the traditional medicine men (65:59 males and 6 females aged between 22 and 85 years). This dataset was statistically analysed by calculating seven quantitative indexes such as use value (UV), informants' consensus factor (ICF), fidelity level (FL), relative importance (RI), cultural importance index (CII), index of agreement on remedies (IAR) and cultural agreement index (CAI).ResultsSixty five traditional medicine men (TMM) reported 47 traditional formulations involving 58 plant species and 17 animal species used against 13 neurological and psychological disorders and as pro-cognitives. Fabaceae was represented by the highest number of medicinal plant species (9 species) whereas herbs (48%) and roots (28%) represented the most common plant habit and plant part, respectively. Quantitative ethnobiology revealed the frequency and coherence of ethnomedicinal reports. The plant Piper nigrum (1.35) and the animal, Spilostethus hospes (0.50) showed the highest UV. Among the ethnobotanicals, maximum RI value was noted for Hemidesmus indicus (0.91) and IAR was found to be maximum (1.00) for 8 plant species. Among the ethnozoologicals, Spilostethus hospes (0.67) displayed maximum RI value whereas Axis axis (2.32) displayed maximum CAI value.ConclusionTMM possessed knowledge on preparations, dose dependence, administration, safety, possible toxicity and side effects of using traditional formulations. TMM practising age old traditional therapeutics serve as alternative medical option for the underprivileged rural ethnic people in these remote areas of the country.

Graphical abstract

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Memory consolidation of socially relevant stimuli during sleep in healthy children and children with attention-deficit/hyperactivity disorder and oppositional defiant disorder: What you can see in their eyes

Publication date: Available online 31 December 2016
Source:Biological Psychology
Author(s): Alexander Prehn-Kristensen, Ina Molzow, Alexandra Förster, Nadine Siebenhühner, Maxime Gesch, Christian D. Wiesner, Lioba Baving
Children with attention-deficit/hyperactivity disorder (ADHD) display deficits in sleep-dependent memory consolidation, and being comorbid with oppositional defiant disorder (ODD), results in deficits in face processing. The aim of the present study was to investigate the role of sleep in recognizing faces in children with ADHD+ODD. Sixteen healthy children and 16 children diagnosed with ADHD+ODD participated in a sleep and a wake condition. During encoding (sleep condition at 8 p.m.; wake condition at 8 a.m.) pictures of faces were rated according to their emotional content; the retrieval session (12h after encoding session) contained a recognition task including pupillometry. Pupillometry and behavioral data revealed that healthy children benefited from sleep compared to wake with respect to face picture recognition; in contrast recognition performance in patients with ADHD+ODD was not improved after sleep compared to wake. It is discussed whether in patients with ADHD+ODD social stimuli are preferentially consolidated during daytime.



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Turn-on fluorescence detection of ascorbic acid with gold nanolcusters

Publication date: 1 April 2017
Source:Talanta, Volume 165
Author(s): Huijie Meng, Dongqin Yang, Yifeng Tu, Jilin Yan
In this report, a sensitive fluorescent detection of ascorbic acid was developed with protein-stabilized gold nanoclusters. The fluorescence signal from the gold nanoclusters could be effectively quenched by elemental iodine. This kind of quenching could be inhibited by ascorbic acid through a corresponding reduction process, thus a turn-on response toward ascorbic acid was obtained. The validity and performances of the detection scheme were evaluated. The fluorescence responses were linearly related to ascorbic acid in the concentration range 0.1–10μM, and the method was capable of detecting ascorbic acid down to 22nM. The high performances of the developed scheme greatly simplified the sample preparation step, and the method was successfully applied for real sample analyses.

Graphical abstract

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Preparation of a poly(styrene-co-DPHA-co-EDMA) monolith and its application for the separation of small molecules and biomacromolecules by HPLC

Publication date: 1 April 2017
Source:Talanta, Volume 165
Author(s): Xixi Wang, Xueying Li, Xiaoya Jiang, Peipei Dong, Haiyan Liu, Ligai Bai, Hongyuan Yan
A high performance liquid chromatography (HPLC) monolithic column was prepared by redox polymerization of styrene, dipentaerythritol hexaacrylate (DPHA) and ethylene glycol dimethacrylate (EDMA) in a porogen system of n-propanol/PEG400. The monolith was characterized by scanning electron microscopy (SEM), mercury intrusion porosimetry (MIP) and the results indicated that the monolith had a stable and homogeneous structure. The porosity of the monolithic column was 75.86% and average pore diameter was 2.1µm. Several alkylbenzenes and anilines were used to evaluate the column performance in terms of hydrophobicity. Then the column was applied to separate small molecules including phytosterol and BSA tryptic digest. Finally, five standard proteins, egg white and plasma were separated respectively and high separation capacity of protein was obtained.

Graphical abstract

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Optimization of high-resolution continuum source graphite furnace atomic absorption spectrometry for direct analysis of selected trace elements in whole blood samples

Publication date: 1 April 2017
Source:Talanta, Volume 165
Author(s): Magdalena Wójciak-Kosior, Wojciech Szwerc, Maciej Strzemski, Zoltan Wichłacz, Jan Sawicki, Ryszard Kocjan, Michał Latalski, Ireneusz Sowa
Trace analysis plays an important role in medicine for diagnosis of various disorders; however, the appropriate sample preparation is required mostly including mineralization. Although graphite furnace atomic absorption spectrometry (GF AAS) allows the investigation of biological samples such as blood, serum, and plasma without this step, it is rarely used for direct analysis because the residues of the rich organic matrix inside the furnace are difficult to remove and this may cause spectral/matrix interferences and decrease the lifetime of the graphite tube. In our work, the procedure for determination of Se, Cr, Mn, Co, Ni, Cd and Pb with the use of the high resolution continuum source GF-AAS technique in whole blood samples with minimum sample pre-treatment was elaborated. The pyrolysis and atomization temperature as well as the time of signal integration were optimized to obtain the highest intensity and repeatability of the analytical signal. Moreover, due to the apparatus modification, an additional step was added in the for graphite furnace temperature program with minimal argon flow and maximal flow of air during pyrolysis stage to increase the oxidative condition for better matrix removal.The accuracy and precision of the optimized method was verified using certified reference material (CRM) Seronorm Trace Elements Whole Blood L-1 and the developed method was applied for trace analysis of blood samples from volunteer patients of the Orthopedics Department.

Graphical abstract

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Understanding Tumor-Antigen Presentation in the New Era of Cancer Immunotherapy

For more than a century, scientists have tried to exploit the anti-tumoral potential of the immune system to treat cancer. However, clinical success was traditionally limited. Consequently, classical anti-neoplastic treatments such as surgery, radiotherapy, and chemotherapy used to be the first line of treatment. Fortunately, this scenario is changing, particularly with the identification of immune checkpoint inhibitors. Now more than ever, it becomes essential to understand how cancer cells modulate the immune system. In this review, we summarize main mechanisms of antigen presentation in the tumor microenvironment, a main event in the establishment of anti-tumor immunity. Specifically, we focus on recent progress in mechanisms involved in tumor antigen presentation, as well as on strategies cancer cells develop to favor immune suppressive and immune tolerant enironments. In addition, we briefly discuss current therapeutic approaches to overcome tumor immune evasion.

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Development of Medical Images in Differentiating Benign from Malignant Thyroid Nodules

As the increasing incidence of thyroid nodules has been recently reported, differential diagnosis between malignancy and benign nodules plays a critical role for determination of therapy plans, but is still a challenge for clinicians. Because of uncertain results of fine needle aspiration (FNA) cytology in some cases, medical images give great noninvasive contribution to differential diagnosis of thyroid nodules. This review of current literature focused on the development of various image modalities on thyroid nodules, in order to supply essentials to clinicians for making pretreatment determination. When ultrasonography is recognized as a routine tool for detecting and differentiating thyroid nodules, improved accuracy has been found when it is combined with FNA. The newly-developed modalities of elastography and contrast enhanced ultrasonography could be used for evaluating the nodule stiffness and vascularity, respectively. Although not recommended as the first-line tool in the managment guideline, scintigraphy supplies supplementary information of the indeterminate nodules after FNA, especially in follicular thyroid nodules. Computed tomography( CT)-detected calcification and its patterns have been regarded to be important sign related to malignancy. Apparent diffusion coefficient ratios on diffusion-weighted magnetic resonance image( MRI) are detected significantly lower in malignant nodules than those in benign ones. CT and MRI are also preferred to demonstrating the surrounding anatomic structures and lymph nodes. The role of PET and PET/CT in the assessment of nodules has been increased, while SUVmax is attractive with a cutoff value about 6.0. In conclusion, with their respective functions, the medical image modalities could supply much helpful information for differential diagnosis of thyroid nodules.

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