Bioassay-guided isolation of active principles from Nigerian medicinal plants identifies new trypanocides with low toxicity and no cross-resistance to diamidines and arsenicals

Publication date: 18 April 2017
Source:Journal of Ethnopharmacology, Volume 202
Author(s): Godwin Unekwuojo Ebiloma, John Ogbaji Igoli, Evangelos Katsoulis, Anne-Marie Donachie, Anthonius Eze, Alexander Ian Gray, Harry P. de Koning
Ethnopharmacological relevanceLeaves from the plant species studied herein are traditionally used in northern Nigeria against various protozoan infections. However, none of these herbal preparations have been standardized, nor have their toxicity to mammalian cells been investigated. In search of improved and non-toxic active antiprotozoal principles that are not cross-resistant with current anti-parasitics, we here report the results of the in vitro screening of extracts from seven selected medicinal plant species (Centrosema pubescens, Moringa oleifera, Tridax procumbens, Polyalthia longifolia, Newbouldia laevis, Eucalyptus maculate, Jathropha tanjorensis), used traditionally to treat kinetoplastid infections in Nigeria, and the isolation of their bioactive principles.Aim of the studyTo investigate the efficacies of medicinal plant extracts, and of compounds isolated therefrom, against kinetoplastid parasites, assess cross-resistance to existing chemotherapy, and assay their toxicity against mammalian cells in vitro.Material and methodsPlants were extracted with hexane, ethyl acetate and methanol. Active principles were isolated by bioassay-led fractionation, testing for trypanocidal activity, and identified using NMR and mass spectrometry. EC50 values for their activity against wild-type and multi-drug resistant Trypanosoma brucei were obtained using the viability indicator dye resazurin.ResultsSeven medicinal plants were evaluated for activity against selected kinetoplastid parasites. The result shows that crude extracts and isolated active compounds from Polyalthia longifolia and Eucalyptus maculata, in particular, display promising activity against drug-sensitive and multi-drug resistant Trypanosoma brucei. The EC50 value of a clerodane (16α-hydroxy-cleroda-3,13(14)-Z-dien-15,16-olide) isolated from Polyalthia longifolia was as low as 0.38µg/mL, while a triterpenoid (3β,13β-dihydroxy-urs-11-en-28-oic acid) isolated from Eucalyptus maculata displayed an EC50 of 1.58µg/mL. None of the isolated compounds displayed toxicity towards Human Embryonic Kidney cells at concentrations up to 400µg/mL. In addition, the isolated compounds were active against Leishmania mexicana, as well as against T. congolense.ConclusionWe have isolated a clerodane compound from Polyalthia longifolia that shows low toxicity, no cross-resistance with current treatments, and promising activity against both human-infective and veterinary Trypanosoma species.

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Antinociceptive and anti-inflammatory effects of the methanolic stem bark extract of Antrocaryon klaineanum Pierre (Anacardiaceae) in mice and rat

Publication date: 5 May 2017
Source:Journal of Ethnopharmacology, Volume 203
Author(s): Annie Laure Magne Fongang, Edwige Laure Nguemfo, Yolande Djouatsa Nangue, Calvin Bogning Zangueu, Yannick Fouokeng, Anatole Guy Blaise Azebaze, Eulogio José Llorent-Martínez, Maria Luisa Fernández-de Córdova, Alain Bertrand Dongmo, Wolfgang Vierling
Ethnopharmacological relevanceAntrocaryon klaineanum is used by traditional healers to treat many disorders including pain and inflammatory diseases. This study aimed to evaluate the analgesic and antiinflammatory activities of methanol extract of A. klaineanum in mice and rats.Materials and methodsReverse phase high-performance liquid chromatography (RP-HPLC) was performed to establish the chromatographic fingerprint and to identify various chemical components of the plant extract. The anti-nociceptive activity of methanol extract of A. klaineanum was assessed using the acetic acid-induced abdominal constriction model, formalin test, capsaicin and cinnamaldehyde induced-neurogenic pain and hot plate test. Anti-inflammatory activity was assessed on carrageenan-induced inflammation. Extract was administrated orally at 200, 400 and 600mg/kg.ResultsPhytochemical analysis indicated the presence of proanthocyanidins, phenolic acids and flavonoids. The results of anti-nociceptive and anti-inflammatory activities showed that methanol extract significantly (p<0.01) reduced the pain induced by acetic acid with an inhibition percentage of 45.49% (600mg/kg). In the formalin test, the extract also significantly (p<0.01) reduced linking time in both phase (neurogenic and inflammatory) of the test with inhibition percentage of 56.28% and 60.73% respectively at the dose of 600mg/kg. The methanol extract of A. klaineanum significantly (P<0.001) reduced neurogenic pain linking time induced by capsaicin and cinnamaldehyde by 82.54% and 75.94% at the highest dose (600mg/kg) respectively. More over the extract significantly increase the reaction time in hot plate test. In the inflammatory test, the plant extract significantly reduced the carrageen induced rat paw oedema from 30min to 6h with a maximum percentage inhibition of 89.88% (6h) at the dose of 600mg/kg.ConclusionThese results demonstrate that the methanol extract of A. klaineanum may possess analgesic and anti-inflammatory effects and provide support of the traditional use of this plant in the treatment of different pain and inflammatory conditions. Further investigation could reveal metabolites of the extract responsible for the observed effects.

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Comparison of Lamiaceae medicinal uses in eastern Morocco and eastern Andalusia and in Ibn al-Baytar's Compendium of Simple Medicaments (13th century CE)

Publication date: 18 April 2017
Source:Journal of Ethnopharmacology, Volume 202
Author(s): Asmae El-Gharbaoui, Guillermo Benítez, M. Reyes González-Tejero, Joaquín Molero-Mesa, Abderrahmane Merzouki
Ethnopharmacological relevanceTransmission of traditional knowledge over time and across culturally and historically related territories is an important topic in ethnopharmacology. Here, we contribute to this knowledge by analysing data on medicinal uses in two neighbouring areas of the Western Mediterranean in relation to a historical text that has been scarcely mentioned in historical studies despite its interest.Aim of the studyThis paper discusses the sharing of popular knowledge on the medicinal uses of plants between eastern Morocco and eastern Andalusia (Spain), focusing on one of the most useful plant families in the Mediterranean area: Lamiaceae. Moreover, we used the classical work of Ibn al-Baytar (13th century CE) The Compendium of Simple Medicaments and Foods as a basis to contrast the possible link of this information, analysing the influence of this historical text on current popular tradition of medicinal plant use in both territories.Materials and methodsFor data collection, we performed ethnobotanical field research in the eastern part of Morocco, recording current medicinal uses for the Lamiaceae. In addition, we systematically reviewed the ethnobotanical literature from eastern Andalusia, developing a database. We investigated the possible historical link of the shared uses and included in this database the information from Ibn al-Baytar's Compendium. To compare the similarity and diversity of the data, we used Jaccard's similarity index.ResultsOur field work provided ethnobotanical information for 14 Lamiaceae species with 95 medicinal uses, serving to treat 13 different pathological groups. Of the total uses recorded in Morocco, 30.5% were shared by eastern Andalusia and found in Ibn al-Baytar's work. There was a higher similarity when comparing current uses of the geographically close territories of eastern Morocco and eastern Andalucía (64%) than for eastern Morocco and this historical text (43%). On the other hand, coincidences between current uses in eastern Andalusia and the ones related in the Compendium are lower, 28%.ConclusionsThe coincidence of the current ethnobotanical knowledge in the two territories is high for the Lamiaceae. Probably the shared historical background, recent exchanges, information flow, and the influence of the historical herbal texts have influenced this coincidence. In this sense, there is a high plant-use overlap between Ibn al-Baytar's text and both territories: nearly half of the uses currently shared by eastern Morocco and eastern Andalusia were included in the Compendium and are related to this period of Islamic medicine, indicating a high level of preservation in the knowledge of plant usage. The study of 14 species of Lamiaceae suggests that this classical codex, which includes a high number of medicinal plants and uses, constitutes a valuable bibliographical source for comparing ancient and modern applications of plants.

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Anticancer and anti-angiogenic activities of extract from Actinidia eriantha Benth root

Publication date: 5 May 2017
Source:Journal of Ethnopharmacology, Volume 203
Author(s): Jian-guo Wu, Li Ma, Shui-hua Lin, Yan-bin Wu, Jun Yi, Bin-jun Yang, Jin-zhong Wu, Ka-hing Wong
Ethnopharmacological relevanceThe roots of Actinidia eriantha Benth (AER) are commonly used traditional folk medicine for the treatment of gastric carcinoma, nasopharyngeal carcinoma, and breast carcinoma. Besides, the anti-proliferative and immunomodulatory effects of AER polysaccharides on tumor-bearing mice have been reported previously.Aim of the studyThis work was carried out to investigate the anticancer and anti-angiogenic activities of AER.Materials and methodsThe growth inhibitory effects of ethanol extracts from the leaves (EEL), stems (EES) and roots (EER) of A. eriantha on human gastric carcinoma SGC7901 cells, human nasopharyngeal carcinoma CNE2 cells, human breast carcinoma MCF7 cells and human umbilical vein endothelial cells (HUVECs) were evaluated by MTT assay. The ethyl acetate fraction from EER (EA-EER) was further investigated for the anticancer activity against SGC7901 cells and the anti-angiogenic activity in HUVECs in vitro. The apoptosis in SGC7901 cells and HUVECs was confirmed by DAPI nuclear staining and flow cytometry analysis, the effect on cellular DNA fragmentation was detected in SGC7901 cells. And the cell cycle-arresting activity in HUVECs was determined by flow cytometry. Moreover, the inhibitory effect of EA-EER on cell migration in HUVECs was observed by both wound-healing and Transwell migration assays. RT-PCR and Western-blotting were performed to determine the mRNA and protein expression levels, respectively, including Bax, Bcl-2 and caspase-3 in SGC7901 cells, as well as VEGF-A and VEGFR-2 in HUVECs. Furthermore, the in vivo anti-angiogenic activity of EA-EER was evaluated by using chick embryo chorioallantoic membrane (CAM) assay. Ultimately, the chemical components in EA-EER were isolated and purified by repeated column chromatography followed by structure characterization using ¹H and ¹³C nuclear magnetic resonance and mass spectroscopy.ResultsCompared with EEL and EES, EER displayed the strongest growth inhibitory effect on SGC7901 cells, CNE2 cells and HUVECs. Among the EER fractions, EA-EER exhibited the most potent growth inhibitory activity against SGC7901 cells, CNE2 cells and HUVECs. Moreover, EA-EER induced obvious apoptosis in SGC7901 and HUVECs, and significantly inhibited the proliferation of HUVECs via blockade of cell cycle G1 to S progression. Furthermore, EA-EER suppressed the expression of Bcl-2 and improved the expression Bax and caspase-3 in SGC7901 cells. EA-EER not only inhibited migration of HUVECs, but also down-regulated the expression of VEGF-A and VEGFR-2 in HUVECs. In vivo, EA-EER exposure reduced the formation of blood vessels in chick embryos. A bio-guided isolation of EA-EER led to the isolation of three compounds for the first time, namely (6R, 7E, 9S)-6, 9-hydroxy-megastigman-4, 7-dien-3-one-9-O-β-D-glucopyranoside, Oleanolic acid-23-O-β-D-glucopyranoside, 3β, 23, 24-trihydroxyl-12-oleanen-28-oic acid.ConclusionThe present research demonstrated that the significant anticancer and anti-angiogenic effects of AER, providing the supportive evidence for its traditional use in the treatment for cancer. It was suggested that AER could be use as a potential source of cancer therapeutic drug.

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Standardization and anti-inflammatory activity of aqueous extract of Psittacanthus plagiophyllus Eichl. (Loranthaceae)

Publication date: 18 April 2017
Source:Journal of Ethnopharmacology, Volume 202
Author(s): Adrielle Nara Serra Bezerra, Laís Tatiele Massing, Ricardo Bezerra de Oliveira, Rosa Helena Veras Mourão
Ethnopharmacological importanceThe hemiparasitic species Psittacanthus plagiophyllus Eichl. (Loranthaceae), also known as erva de passarinho, is used in folk medicine in the Santarém region in the state of Pará, Brazil, to treat gastritis and a variety of inflammatory disorders. In view of the lack of pharmacological studies on this species in the literature and the fact that it is used constantly by the local population, this study sought to standardize the extract of the leaves of P. plagiophyllus (AEPp) and to assess its anti-inflammatory potential in in vivo tests.Material and methodsQuality control and standardization of AEPp were performed following the 5th edition of the Brazilian Pharmacopeia. To assess the in vivo anti-inflammatory activity of AEPp, the carrageenan-induced and dextran-induced rat paw edema models were initially used. To investigate the effect of AEPp on carrageenan-induced leukocyte recruitment and exudate production, the air pouch inflammation model was used. In addition, the antioxidant activity of AEPp was assessed in vitro by the DPPH radical scavenging method.ResultsThe chromatographic profile of AEPp indicated the presence of flavonoids, coumarins and hydrolyzable and condensed tannins. Measurement of phenolics revealed the following percentages in the extract: 12.62±0.18% total phenolics, 5.39±0.01% total tannins, 12.54±0.24% hydrolyzable tannins, 8.37±0.32% condensed tannins and 1.23±0.02% total flavonoids. In 500 and 1000mg/kg doses (p.o.) AEPp had significant edema-inhibiting activity (p<0.01) in both the models used, suggesting that the extract may act in vascular and cell events in the inflammatory response and exert an inhibitory effect on mediators responsible for edema. In all the doses tested [250, 500 and 1000mg/kg (p.o.)], AEPp inhibited total leukocyte and neutrophil migration and reduced the amount of exudate in the air pouch in a dose-dependent manner. Both effects were statistically significant (p<0.01). The extract also reduced the DPPH radical (maximum reduction 93.13±1.71% at a concentration of 75µg/mL), indicating that it has antioxidant activity. AEPp, therefore, exhibited considerable in vivo anti-inflammatory activity and in vitro antioxidant activity. This may be due to its high phenolics content.ConclusionThese findings provide evidence to support the use of P. plagiophyllus in folk medicine to treat inflammatory disorders.

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Effects of antrosterol from Antrodia camphorata submerged whole broth on lipid homeostasis, antioxidation, alcohol clearance, and anti-inflammation in livers of chronic-alcohol fed mice

Publication date: 18 April 2017
Source:Journal of Ethnopharmacology, Volume 202
Author(s): Yuan-Yen Chang, Yi-Chen Liu, Yueh-Hsiung Kuo, Yi-Ling Lin, Yi-Hsieng Samuel Wu, Jr-Wei Chen, Yi-Chen Chen
Ethnopharmacological relevanceAntrodia camphorata is a functional fungus in Taiwan and owns several pharmacological functions. Antrosterol, a bioactive constitute of sterols in edible Antrodia camphorata submerged whole broth, can protect liver from CCl4 damage via enhancing antioxidant and anti-inflammatory capacities.Aim of the studyThe aim of this study was to investigate the hepatoprotection of antrosterol (named as EK100) against alcohol consumption.Materials and methodsA Lieber-DeCarli regular EtOH diet (EtOH liquid diet, 5% (v/v) alcohol) was applied to induce alcoholic liver damage. Mice were randomly divided into 5 groups: (1) Control: control liquid diet; (2) EtOH: EtOH liquid diet; (3) EK100_1X: EtOH liquid diet and 1mg EK100 (Antrosterol)/Kg body weight (bw); (4) EK100_5X: EtOH liquid diet and 5mg EK100/Kg bw; (5) EK100_10X: EtOH liquid diet and 10mg EK100/Kg bw. At the end of experiment, the livers were collected for histo-pathological analyses, RNA and protein extraction, and enzymatic activities.ResultsAntrosterol reduced serum/liver lipids of alcohol-diet fed mice which highly related to upregulated fatty acid β-oxidation and downregulated lipogenesis, and increased fecal lipid/bile-acid outputs. Antrosterol enhanced hepatic antioxidant capabilities in alcohol-diet fed mice while it also lowered serum alcohol level, as well as increased alcohol dehydrogenase (ADH) and catalase (CAT) activities and decreased CYP2E1 protein expression in livers of alcohol-diet fed mice. Besides, antrosterol lowered hepatic inflammation and fibrosis related gene expressions, as well as serum AST/ALT values and TNF-α/IL-1β contents in alcohol-diet fed mice.ConclusionBased on the results, hepatoprotection of antrosterol is mostly attributed to its regulations of lipid homeostasis, antioxidant capability, alcohol metabolism, and anti-inflammation.

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The use of Chinese herbal medicine as an adjuvant therapy to reduce incidence of chronic hepatitis in colon cancer patients: A Taiwanese population-based cohort study

Publication date: 18 April 2017
Source:Journal of Ethnopharmacology, Volume 202
Author(s): Tsai-Hui Lin, Hung-Rong Yen, Jen-Huai Chiang, Mao-Feng Sun, Hen-Hong Chang, Sheng-Teng Huang
Ethnopharmacological relevanceThere is a decided lack of in-depth studies to evaluate the effectiveness of Chinese Herbal Medicine (CHM) as an adjuvant therapy on the incidence of chronic hepatitis in patients with colon cancer.Aim of the studyThe aim of this study is to assess whether CHM treatment decreased the incidence of chronic hepatitis in colon cancer patients who received conventional Western medical treatment.Materials and methodsA Taiwanese nationwide population-based study of colon cancer patients receiving Western medicine treatment in conjunction with CHM treatment, using data provided by the National Health Insurance (NHI) Research Database, was conducted. A total of 61676 patients were diagnosed with colon cancer in Taiwan within the defined study period, from 1997 to 2010. After randomly equal matching for age, sex, excluding patients younger than 18 years of age, chronic hepatitis before colon cancer diagnosis date, receiving acupuncture and/or moxibustion and taking CHM for less than 30 days, data from 155 patients were analyzed. Hazard ratios of incidence rate of chronic hepatitis were used to determine the influence of CHM and the therapeutic potential of herbal products in treating patients with colon cancer.ResultsCHM used for patients with colon cancer exhibited significantly decreased incidence rates of chronic hepatitis [hazard ratio (HR)=0.53; 95% confidence interval (CI):0.38–0.74], with multivariate adjustment, compared to those without CHM use. The protective effect of CHM treatment with statistical significance across the stratification of age, gender, co-morbidity and treatment modality was noted. The cumulative incidence of chronic hepatitis was also reduced in patients with colon cancer receiving CHM treatment during a five-year period. In this study, we provide the ten most used single herbs and herbal formulas that were prescribed for patients with colon cancer; moreover, we identify the eight single herbs and five formulas used in CHM treatment which significantly decreased incidence of chronic hepatitis among colon cancer patients.ConclusionsThis nationwide retrospective cohort study determined that therapy using CHM as an adjuvant modality may have a significant impact on liver protection in patients with colon cancer.

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A review of the ethnopharmacology, phytochemistry and pharmacology of Notopterygium incisum

Publication date: 18 April 2017
Source:Journal of Ethnopharmacology, Volume 202
Author(s): John Teye Azietaku, Huifen Ma, Xie-an Yu, Jin Li, Mahmood Brobbey Oppong, Jun Cao, Mingrui An, Yan-xu Chang
Ethnopharmacological relevanceNotopterygium incisum Ting ex H.T. Chang, known in Chinese as 'Qianghuo' is a traditional Chinese medicinal herb with the rhizome and roots associated with meridians of the kidney and urinary bladder. It is pungent, bitter and warm in nature. It has been used over the years to disperse cold, prevent painful obstructions from wind, damp and warm pain. It has also been used with other herbs to treat wind-cold exterior syndrome and wind-cold-damp bi-syndromes and has been known to grow well in regions of high altitude such as Gansu, Tibet etc.The aim of the reviewThis systematic review focuses on the ethnopharmacological uses of this herb, including recent advances on the phytochemical and pharmacological study of N. incisum. Recent analytical methods developed for the quantitative and qualitative determination of constituents in this herb have also been reviewed. Additionally, future trends and prospects in the study of this herb have been proposed.Materials and methodVarious literature and electronic databases such as Pubmed, Science Direct, Springer, Wiley etc were searched and data obtained. Other online academic libraries such as Google Scholar and ethnopharmacological literature were searched systematically for more information on the herb.ResultsThis review focuses on the ethnopharmacological uses of N. incisum and also the various chemical constituents present in the herb and their various therapeutic effects such as analgesic, anti-inflammatory, anti-cancer and antioxidants effects. Analytical methods developed for the quantitative and qualitative determination of various compounds in this herb were further reviewed.ConclusionIn this paper, we have reviewed various researches conducted on N. incisum especially in areas of its ethnopharmacological use, phytochemicals, pharmacology and developed analytical methods. This herb has been used over the years in treating headache, rheumatoid arthritis, cold, diaphoretic etc, prompting many types of research into identifying which compounds are responsible for these activities and their mechanism of action. More research is needed in the area of pharmacokinetics and toxicology to give further information on the clinical use and control the quality of the herb.



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Treatment effects and mechanisms of Yujin Powder on rat model of large intestine dampness-heat syndrome

Publication date: 18 April 2017
Source:Journal of Ethnopharmacology, Volume 202
Author(s): Wanling Yao, Chaoxue Yang, Yanqiao Wen, Wangdong Zhang, Xiaosong Zhang, Qi Ma, Peng Ji, Yongli Hua, Yanming Wei
Ethnopharmacological relevanceYujin Powder (YJP), an old prescription, is one of the most classical prescription for treating the large intestine dampness-heat syndrome (LIDHS). However, its potential modern pharmacological mechanisms remain unclear.Aim of the studyThe present study was designed to explore the essence of LIDHS and treatment mechanisms of the YJP on the LIDHS.MethodsThe rat model of LIDHS was established by such complex factors as high-sugar and high-fat diet, improper diet, high temperature and humidity environment (HTHE), drinking and intraperitoneal injection of Escherichia coli., which imitated the inducing conditions of LIDHS. Then the clinical symptoms and signs, blood routine, blood biochemistry, whole blood viscosity (WBV), serum inflammatory cytokines levels and the histopathological changes of main organs were detected and observed, respectively.ResultsThe results showed that the clinical symptoms and signs of the model rats were consistent with the diagnostic criteria of LIDHS, moreover, there were obvious systemic inflammatory response and extensive congestion. And after treatment with YJP in different dosages, the clinical symptoms and signs of the rats with LIDHS were improved; the indexes of blood routine and blood biochemistry and inflammatory cytokines levels tended to be normal; the WBV decreased and histopathological changes of major organs were alleviated or returned to normal. There was an obvious dose-effect relationship, and the high dose of YJP (HD-YJP) had the best treatment effects.ConclusionsThese results suggested that in LIDHS, diarrhea was the major clinical manifestation; the large intestine was the main lesion area; mucosa injury, inflammation and congestion of the large intestine with systemic inflammatory response and congestion were the most typical pathological characteristics. Meanwhile, YJP exhibited the comprehensive effects of anti-diarrhea, anti-inflammation, lowering blood lipid, relieving blood stasis, repairing intestinal mucosa and regulation and protection of multiple organs on LIDHS. These findings provided not only important information for understanding the essence of LIDHS but also the theoretical basis for developing new-drugs for treating dampness-heat type of diarrheal diseases.

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IFC (Journal of Ethnopharmacology)

Publication date: 22 March 2017
Source:Journal of Ethnopharmacology, Volume 200





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Biochemical and chemical characterization of Cynara cardunculus L. extract and its potential use as co-adjuvant therapy of chronic myeloid leukemia

Publication date: 18 April 2017
Source:Journal of Ethnopharmacology, Volume 202
Author(s): Antonio Russo, Mariarita Perri, Erika Cione, Maria Luisa Di Gioia, Monica Nardi, Maria Cristina Caroleo
Ethnopharmacological relevanceAncient mediterranean diet was characterized by consuming the spontaneous forms of Cynara cardunculus L. (CCL), commonly called artichoke. Cultivated and/or spontaneous forms of CC studies have demonstrated that methanol extract of CCL flower and/or cynaropicrin showed remarkable anti-proliferative activity in vitro models of leukocyte cancer cell.Aim of the studyChronic myeloid leukemia (CML) is associated with a reciprocal translocation of the long arms of chromosomes 9 and 22 generating the BCR/ABL fusion gene, translated in the p210^BCR/ABL oncoprotein kinase. This chimeric protein is the target of a kinase inhibitor, imatinib, but the development of mutations in the ABL kinase domain resulting in drug resistance and several approaches to overcoming resistance have been study. In this concern, we investigated the effect of CCL extract on human K562 CML and K562 imatinib resistant (IMAR) cell proliferation and on p210^BCR/ABL expression.Materials and methodsChemical characterization of the CCL extracts was performed by GC/MS analysis and semipreparative RP-HPLC chromatography. Structural characterization of compounds was assessed by ¹H–¹³C NMR and LC/MS analysis. The effects of CCL extracts on the proliferation of K562 CML human cell line and K562 IMAR were screened by MTT assay. The p210^BCR/ABL mRNA and protein expressions were analyzed by qRT-PCR and Western blot techniques respectively.ResultsWe demonstrate that CCL extract affect cell viability of both K562 CML human cell line and K562 IMAR. The biocomponents of CCL were chemical characterized and we identify cynaropicrin and its deacyl derivative having the capability to down-regulate the p210^BCR/ABL oncoprotein.ConclusionsOur study suggests that the use of those molecules could represent a novel and promising strategy to potentiate the ability of imatinib or of its analogues to induce cancer growth arrest in CML and to delay or overcome the resistance of CML to chemotherapy.

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Erratum to: Isotherm, kinetic, and thermodynamic study of ciprofloxacin sorption on sediments

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Boswellia ovalifoliolata (Burseraceae) essential oil as an eco-friendly larvicide? Toxicity against six mosquito vectors of public health importance, non-target mosquito fishes, backswimmers, and water bugs

Abstract

The use of synthetic pesticides to control vector populations is detrimental to human health and the environment and may lead to the development of resistant strains. Plants can be alternative sources of safer compounds effective on mosquito vectors. In this study, the mosquito larvicidal activity of Boswellia ovalifoliolata leaf essential oil (EO) was evaluated against Anopheles stephensi, Anopheles subpictus, Aedes aegypti, Aedes albopictus, Culex quinquefasciatus, and Culex tritaeniorhynchus. GC-MS revealed that the B. ovalifoliolata EO contained at least 20 compounds. The main constituents were β-pinene, α-terpineol, and caryophyllene. In acute toxicity assays, the EO was toxic to larvae of An. stephensi, Ae. aegypti, Cx. quinquefasciatus, An. subpictus, Ae. albopictus, and Cx. tritaeniorhynchus with LC₅₀ values of 61.84, 66.24, 72.47, 82.26, 89.80, and 97.95 μg/ml, respectively. B. ovalifoliolata EO was scarcely toxic to mosquito fishes, backswimmers, and water bugs predating mosquito larvae with LC₅₀ from 4186 to 14,783 μg/ml. Overall, these results contribute to develop effective and affordable instruments to magnify the reliability of Culicidae control programs.

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Low-level arsenic causes chronic inflammation and suppresses expression of phagocytic receptors

Abstract

The impact of chronic low-level groundwater arsenic (As) exposure [in the range above the WHO-recommended limit of 10 g/L but ≤50 μg/L (permissible limit of As for many Asian countries)] was investigated for cross talk of inflammatory changes and expression of phagocytic receptors of exposed rural women (N, 45) from districts of 24 Parganas (south) and in matched control groups (N, 43) [As ≤10 μg/L] from the same district. Systemic inflammation was evident from the upregulated levels of pro-inflammatory mediators like tumor necrosis factor-α (TNF-α); interleukins (ILs) like IL-6, IL-8, and IL-12; and C-reactive protein (CRP) in the sera and upregulated expression of protein kinase B phosphorylated at ser473 (pAKTser473)/nuclear factor-κB (NF-κB)/TNF-α axis in the leukocytes of exposed women with respect to control. We found that low-dose As exposure apart from inflicting inflammation altered the expression of phagocytic receptors—Fcγ receptors (FcγRs) and complement receptors (CRs). The leukocytes of the low-As-exposed women exhibited suppression of CD64, CD35, and CD11b and increased expression of CD16 with respect to control. Groundwater As showed a negative correlation with CD64 expression on monocytes [Pearson's r, −0.8205; 95% confidence interval (CI), −0.8789 to −0.7379] and granulocytes [r, −0.7635; 95% CI, −0.8388 to −0.6595] and a positive correlation with CD16 on granulocytes [r, 0.8363; 95% CI, 0.7599 to 0.8899]. A negative correlation of groundwater As was also observed with expression of CD35 on granulocytes [r, −0.8780; 95% CI, −0.9185 to −0.8192] and monocytes [r, −0.7778; 95% CI, −0.8490 to −0.6790] and CD11b on monocytes [r, −0.6035; 95% CI, −0.7218 to −0.4511]. Therefore, it may be indicated that chronic low-level As exposure (11–50 μg/L) not only evoked chronic inflammatory changes but also suppressed the expression of FcγRs and CRs in the exposed women. This, in turn, may lead to susceptibility towards pathogenic infections or in long run may even contribute towards chronic inflammatory diseases including cancer.

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Molecularly imprinted membranes (MIMs) for selective removal of polychlorinated biphenyls (PCBs) in environmental waters: fabrication and characterization

Abstract

Molecularly imprinted membranes (MIMs) with selective removal properties for polychlorinated biphenyls (PCBs) were prepared through the phase inversion technique. The MIMs were obtained from casting the viscous solutions of molecularly imprinted polymers (MIPs), polysulfone (PSf), and N-methyl-2-pyrrolidone (NMP) as the casting solvent. Different membranes were prepared at different concentration of MIPs and PSf. The resulting MIMs were characterized by atomic force microscope (AFM), scanning electron microscope (SEM), and Fourier transform infrared spectroscopy (FTIR). Moreover, the performance of the membranes was evaluated by determining and interpreting the rejection (%), flux (F), permeability coefficient (P), permselectivity factor ( α ^′_{PCB/DDT or anthracene}), and enrichment factors of PCBs, dichlorodiphenyltrichloroethane (p,p′-DDT), and anthracene from model contaminated water using the dead-end filtration cell. Molecularly imprinted membrane prepared with 18 wt% PSf and 20 wt% MIP 4 exhibited a well-defined porous structure, which was accompanied by enhanced PCB enrichment. Furthermore, molecularly imprinted membrane showed good enrichment factors for PCBs even from spiked natural water samples of Hartbeespoort dam.

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Reducing nitrogen losses through ammonia volatilization and surface runoff to improve apparent nitrogen recovery of double cropping of late rice using controlled release urea

Abstract

Controlled release fertilizer can reduce nitrogen losses to the environment while increasing grain yield and improving apparent nitrogen recovery (ANR) of rice. However, few studies have evaluated the comparative efficacy of different polymer-coated urea products on nitrogen (N) losses, ANR, and N uptake of rice. A 2-year field experiment was conducted to compare the effects of three different types of polymer-coated urea fertilizer on nitrogen losses through NH₃ volatilization and surface runoff to the environment, ANR, grain yield, and N uptake as compared to conventional urea of rice. Six treatments including (1) control with 0 kg N ha⁻¹ (CK), (2) basal application of urea (U_b), (3) split application (U_s) of urea (50% at transplanting, 25% at tillering, and 25% at panicle stages), (4) CRU-1 (polyurethane-coated urea), (5) CRU-2 (degradable polymer-coated urea), and (6) CRU-3 (water-based polymer-coated urea) all applied at 165 kg N ha⁻¹. It was found that CRU-2 resulted in the highest grain yield and panicle numbers among the N fertilization treatments in 2013 and 2014. Applying CRU could help increase N uptake in rice, reduce N losses through NH₃ volatilization and surface runoff, and hence improve ANR. Its single dose can meet the nutrient demand of the rice plant. Controlled release urea could be adopted as an effective mitigation alternative to retard N losses through NH₃ volatilization and surface runoff while improving ANR of double cropping of late rice.

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Single nucleotide polymorphisms in an indian cohort and association of CNTN4, MMP2 and SNTB1 variants with oral cancer

Publication date: Available online 23 March 2017
Source:Cancer Genetics
Author(s): Subuhi Yete, Sultan Pradhan, Dhananjaya Saranath
Oral cancer is a high incidence cancer in India primarily due to the prevalent tobacco/areca nut chewing habits and hence a major health concern. India constitutes 26% of the global oral cancer burden. Besides the well-established risk factors, the genomic constitution of an individual plays a role in oral cancer. The aim of the current study was to analyse genomic variants represented as single nucleotide polymorphisms (SNPs), analyse their prevalence and investigate risk association of allelotypes/genotypes to oral cancers. Eleven SNPs in genes associated with biological functions were analysed in an Indian cohort (n=1000) comprising 500 oral cancer patients and 500 long term tobacco habitués as controls, using Allelic discrimination Real-Time PCR assay with SYBR Green dye. Fisher's exact test and Odds Ratio was used for statistical analysis. Increased risk was observed for rs9849237 CC [P=0.008; OR 1.412 (1.09-1.82)] and rs243865 CT [P=0.004; OR 1.469 (1.13-1.90)] genotypes, whereas rs9849237 CT [P=0.034; OR 0.755 (0.58-0.97)], rs243865 CC [P=0.002; OR 0.669 (0.51-0.86)] and rs10090787 CC [P=0.049; OR 0.774 (0.60-0.99)] genotypes indicated decreased risk to oral cancer. The other SNPs showed equidistribution in both groups. Our data indicated genotypes and alleles in specific SNPs rs9849237, rs243865 and rs10090787 with increased/decreased risk to oral cancer.



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Genomic diagnostics leading to the identification of a TFG-ROS1 fusion in a child with possible atypical meningioma

Publication date: Available online 22 March 2017
Source:Cancer Genetics
Author(s): Maria Rossing, Christina Westmose Yde, Astrid Sehested, Olga Østrup, David Scheie, Volodia Dangouloff-Ros, Birgit Geoerger, Gilles Vassal, Karsten Nysom
Meningiomas are rare in children. They are highly complex, harboring unique clinical and pathological characteristics, and many occur in patients with neurofibromatosis type 2. Hereby, we present a case of a two-year-old boy presented with a diagnostically challenging intraventricular tumor. It was incompletely resected 6 times over 14 months but kept progressing and was ultimately deemed unresectable. Histologically, the tumor was initially classified as schwannoma, but extensive international review concluded it was most likely an atypical meningioma, WHO grade II. Comprehensive genomic profiling revealed a TFG-ROS1 fusion, suggesting that ROS1-signaling pathway alterations were driving the tumor growth. In light of this new information, the possibility of a diagnosis of inflammatory myofibroblastic tumor was considered, however the histopathological results were not conclusive. This specific molecular finding allowed the potential use of precision medicine and the patient was enrolled in the AcSé phase 2 trial with crizotinib (NCT02034981), leading to a prolonged partial tumor response which is persisting since 14 months. This case highlights the value of precision cancer medicine in children.



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Recurrent large genomic rearrangements in BRCA1 and BRCA2 in an irish case series

Publication date: Available online 22 March 2017
Source:Cancer Genetics
Author(s): Terri P McVeigh, Nuala Cody, Cliona Carroll, Marie Duff, Michael Farrell, Lisa Bradley, David Gallagher, Trudi McDevitt, Andrew J Green
Mutations in BRCA1 and BRCA2 confer a highly increased risk of cancers, mainly of the breast and ovary. Most variants are point mutations or small insertions/deletionsdetectable by Sanger sequencing. Large genomic rearrangements, including deletions/duplications of multiple exons, are not routinely detectable by Sanger sequencing, but can be reliably identified by Multiplex Ligation-dependent Probe Amplification (MLPA), and account for 5-17% mutations in different populations. Comprehensive mutation testing using these two methods has been facilitated via our centre since 2005. The aim of this study was to investigate the incidence of and phenotype associated with large genomic rearrangements in BRCA1 and BRCA2 in an Irish cohort. An observational cohort study was undertaken. Patients with large genomic rearrangements in BRCA1/BRCA2 were identified from a prospectively maintained database of MLPA test results. Phenotypic and genotypic data were retrieved by chart review. Large genomic rearrangements in BRCA1 were identified in 49 families; and in BRCA2 in 7 families, representing ~11% of mutations in BRCA1/BRCA2 in Ireland. The most common large genomic rearrangement in BRCA1 was deletion of exons 1-23, (11 families, 7 from Co. Galway). Other common mutations included deletions of exon 3 (8 families) and exons 1-2 (6 families). Deletion of exons 19-20 in BRCA2 represented the familial mutation in five families, all from East Ireland (Wexford/Wicklow/Dublin). It is evident that a significant proportion of highly penetrant pathogenic variants in BRCA1 and BRCA2 will be missed if testing is limited to PCR-based Sanger sequencing alone. Screening for large genomic rearrangements in BRCA1 and BRCA2 in the routine diagnostic workflow is critical to avoid false negative results.



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Pituitary Adenoma and Hyperprolactinemia Accompanied by Idiopathic Granulomatous Mastitis.

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Pituitary Adenoma and Hyperprolactinemia Accompanied by Idiopathic Granulomatous Mastitis.

Case Rep Endocrinol. 2017;2017:3974291

Authors: Destek S, Gul VO, Ahioglu S, Serin KR

Abstract
Idiopathic granulomatous mastitis (IGM) is a rare chronic inflammatory disease of the breast, and its etiology remains not fully elucidated. IGM is observed more often in patients with autoimmune disease. Hyperprolactinemia is observed during pregnancy, lactation, and a history of oral contraceptive use. A 39-year-old patient with no history of oral contraceptive use presented with complaints such as redness, pain, and swelling in her left breast. Ultrasound and magnetic resonance imaging (MRI) revealed a suspicious inflamed mass lesion. Core biopsy was performed to exclude breast cancer and to further diagnose. The breast abscess was drained and steroids were given for treatment. In order to monitor any progression during the three months of treatment, hormone levels were routinely examined. Prolactin level was above the reference range, and pituitary MRI revealed a pituitary prolactinoma. After treatment with prolactin inhibitors, IGM also improved with hyperprolactinemia. This report emphasizes attention to hyperprolactinemia in cases of IGM diagnosis and treatment.

PMID: 28321344 [PubMed]

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Extrathyroidal extension—what does it mean

Publication date: May 2017
Source:Oral Oncology, Volume 68
Author(s): Ashok R. Shaha
Prognostic factors and risk group analysis are very well known in well differentiated thyroid cancer. One of the major prognostic factors is presence of extrathyroidal extension and residual gross tumor. It is not uncommon to find the final pathology report showing minimal extrathyroidal extension. The debate continues as to the implication of this microscopic or minimal extrathyroidal extension. The previous staging system had upstaged such tumors. However, several reports in the literature suggest no prognostic implication of microscopic or minimal extrathyroidal extension.



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Deep Brain Stimulation for the Treatment of Aggressive Behaviour: Considerations on Pathophysiology and Target Choice

Stereotact Funct Neurosurg 2017;95:114-116

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Capnography-Assisted Nasotracheal Intubation Using Cuff Inflation and Gum-Elastic-Bougie

Publication date: Available online 23 March 2017
Source:The Journal of Emergency Medicine
Author(s): Rajeev Sharma




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Ultrasound Findings in Tension Pneumothorax: A Case Report

Publication date: Available online 23 March 2017
Source:The Journal of Emergency Medicine
Author(s): Maxine Inocencio, Jeannine Childs, Mikaela L. Chilstrom, Kristin Berona
BackgroundDelayed recognition of tension pneumothorax can lead to a mortality of 31% to 91%. However, the classic physical examination findings of tracheal deviation and distended neck veins are poorly sensitive in the diagnosis of tension pneumothorax. Point-of-care ultrasound is accurate in identifying the presence of pneumothorax, but sonographic findings of tension pneumothorax are less well described.Case ReportWe report the case of a 21-year-old man with sudden-onset left-sided chest pain. He was clinically stable without hypoxia or hypotension, and the initial chest x-ray study showed a large pneumothorax without mediastinal shift. While the patient was awaiting tube thoracostomy, a point-of-care ultrasound demonstrated findings of mediastinal shift and a dilated inferior vena cava (IVC) concerning for tension physiology, even though the patient remained hemodynamically stable.Why Should an Emergency Physician Be Aware of This?This case demonstrates a unique clinical scenario of ultrasound evidence of tension physiology in a clinically stable patient. Although this patient was well appearing without hypotension, respiratory distress, tracheal deviation, or distended neck veins, point-of-care ultrasound revealed mediastinal shift and a plethoric IVC. Given that the classic clinical signs of tension pneumothorax are not uniformly present, this case shows how point-of-care ultrasound may diagnose tension pneumothorax before clinical decompensation.



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Essential design considerations for the resazurin reduction assay to noninvasively quantify cell expansion within perfused extracellular matrix scaffolds

Publication date: June 2017
Source:Biomaterials, Volume 129
Author(s): Joseph S. Uzarski, Michael D. DiVito, Jason A. Wertheim, William M. Miller
Precise measurement of cellularity within bioartificial tissues and extracellular matrix (ECM) scaffolds is necessary to augment rigorous characterization of cellular behavior, as accurate benchmarking of tissue function to cell number allows for comparison of data across experiments and between laboratories. Resazurin, a soluble dye that is reduced to highly fluorescent resorufin in proportion to the metabolic activity of a cell population, is a valuable, noninvasive tool to measure cell number. We investigated experimental conditions in which resazurin reduction is a reliable indicator of cellularity within three-dimensional (3D) ECM scaffolds. Using three renal cell populations, we demonstrate that correlation of viable cell numbers with the rate of resorufin generation may deviate from linearity at higher cell densities, lower resazurin working volumes, or longer incubation times that all contribute to depleting the pool of resazurin. In conclusion, while the resazurin reduction assay provides a powerful, noninvasive readout of metrics enumerating cellularity and growth within ECM scaffolds, assay conditions may strongly influence its applicability for accurate quantification of cell number. The approach and methodological recommendations presented herein may be used as a guide for application-specific optimization of this assay to obtain rigorous and accurate measurement of cellular content in bioengineered tissues.



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Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases

Publication date: Available online 23 March 2017
Source:Journal of Autoimmunity
Author(s): Beidi Chen, Luxi Sun, Xuan Zhang
The interaction between genetic predisposition and environmental factors are of great significance in the pathogenesis and development of autoimmune diseases (AIDs). The human mucosa is the most frequent site that interacts with the exterior environment, and commensal microbiota at the gut and other human mucosal cavities play a crucial role in the regulation of immune system. Growing evidence has shown that the compositional and functional changes of mucosal microbiota are closely related to AIDs. Gut dysbiosis not only influence the expression level of Toll-like receptors (TLRs) of antigen presenting cells, but also contribute to Th17/Treg imbalance. Epigenetic modifications triggered by environmental factors is an important mechanism that leads to altered gene expression. Researches addressing the role of DNA methylation, histone modification and non-coding RNA in AIDs have been increasing in recent years. Furthermore, studies showed that human microbiota and their metabolites can regulate immune cells and cytokines via epigenomic modifications. For example, short-chain fatty acids (SCFAs) produced by gut microbiota promote the differentiation of naïve T cell into Treg by suppressing histone deacetylases (HDACs). Therefore, we propose that dysbiosis and resulting metabolites may cause aberrant immune responses via epigenetic modifications, and lead to AIDs.With the development of high-throughput sequencing, metagenome analysis has been applied to investigate the dysbiosis in AIDs patients. We have tested the fecal, dental and salivary samples from treatment-naïve rheumatoid arthritis (RA) individuals by metagenomic shotgun sequencing and a metagenome-wide association study. Dysbiosis was detected in the gut and oral microbiomes of RA patients, but it was partially restored after treatment. We also found functional changes of microbiota and molecular mimicry of human antigens in RA individuals.By integrating the analysis of multi-omics of microbiome and epigenome, we could explore the interaction between human immune system and microbiota, and thereby unmasking specific and more sensitive biomarkers as well as potential therapeutic targets. Future studies aiming at the crosstalk between human dysbiosis and epigenetic modifications and their influences on AIDs will facilitate our understanding and better managing of these debilitating AIDs.



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Pigmented onychomatricoma: Four cases

Abstract

Onychomatricoma (OM) presenting as a longitudinal melanonychia is a very uncommon clinical presentation with very few cases in the literature. Our aim in this article is to report four cases of pigmented OM, and describe their clinical and dermoscopic findings and the importance of the differential diagnoses, especially with melanoma.

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High serum vitamin D level correlates with better prognostic indicators in primary melanoma: A pilot study

Abstract

Background/Objectives

Sunlight is a major risk factor for cutaneous melanoma. However, its interaction with melanoma is complex. In particular, vitamin D is a UVB-derived hormone that has been shown to have anti-cancer effects. In this retrospective pilot study we sought to determine an association between the clinicopathological features of melanoma and the patients' corresponding serum vitamin D level.

Methods

In total, 109 primary melanomas diagnosed between 2001 and 2013 were retrospectively identified from our institutional database with a corresponding 25-hydroxyvitamin D3 level estimated within 6 months of diagnosis. Tumour, clinical (age, sex, tumour location) and pathological (thickness, mitosis, ulceration, Clark level, subtype, metastatic status) parameters were correlated with vitamin D. For statistical analysis, an unpaired Student's t-test and anova was used for categorical variables, and Spearman's correlation for continuous variables.

Results

Vitamin D level was inversely associated with Breslow thickness as a dichotomous, categorical and continuous variable. The association remained significant when controlled for patient's age and sex (P = 0.026). Vitamin D was higher in non-ulcerated tumours compared with ulcerated tumours (P = 0.006) and in tumours with mitotic rate <1/mm² compared with ≥1/mm² (P = 0.036). A significant association was found between vitamin D level and tumour histological subtype (P = 0.019). On subgroup analysis, significant associations were found between superficial spreading melanoma (SSM) and nodular melanoma (P = 0.026), and SSM and acral lentiginous melanoma (P = 0.007).

Conclusion

A high vitamin D status may benefit prognosis in patients diagnosed with primary melanoma. A prospective cohort analysis with a large sample and controlled for other vitamin D confounders would validate these findings.

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Skin cancer history, sun-related attitudes, behaviour and sunburn among renal transplant recipients versus general population

Abstract

Background/Objectives

Renal transplant recipients (RTR) have both an excessive skin cancer incidence and a high mortality rate. In Australia RTR receive extensive public education on skin cancer and many undergo further education pre/post-transplant. This study examines whether RTR have sufficiently rigorous sun protection behaviour compared with the general population.

Methods

Altogether 179 RTR from two large Melbourne hospitals involving skin clinic teams in patient care were recruited to undergo cross-sectional telephone interviews. Comparisons were made with residents (25–69 years) surveyed using equivalent measures and methods in adjacent summers (2006–2007, n = 904; 2010–2011, n = 942) for regular population monitoring surveys. Multivariate analyses of weekend behaviour were adjusted for related ambient temperature records.

Results

RTR were more compliant with sun protection behaviour on the weekend prior to interview than the residents surveyed. For example, for 2006–2007 and 2010–2011, the odds ratio and confidence intervals (CI 95%) were respectively: used sunscreen: 2.0 (1.1–3.8) and 2.8 (1.4–5.3); wore a long-sleeved top: 4.5 (2.4–8.5) and 3.6 (1.9–7.0). RTR sunburn prevalence (5%) appeared similar to that of residents (odds ratios comparing 2006–2007 and 2010–2011 0.6 [95% CI, 0.2–1.6] and 0.7 [95% CI, 0.3–1.9]). Despite generally good sun protection behaviour, many RTR (47%) had skin cancers treated.

Conclusion

The intensive education of RTR may have contributed to their better sun protection. Some RTR with excessive exposure to UV radiation introduction of may benefit from implementation of further photoprotection strategies. These findings may be particularly relevant to other RTR groups receiving education about sun protection.

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Nursing staff fluctuation and pathogenic burden in the NICU - effective outbreak management and the underestimated relevance of non-resistant strains.

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Nursing staff fluctuation and pathogenic burden in the NICU - effective outbreak management and the underestimated relevance of non-resistant strains.

Sci Rep. 2017 Mar 21;7:45014

Authors: Hensel KO, van den Bruck R, Klare I, Heldmann M, Ghebremedhin B, Jenke AC

Abstract
In the course of a hospital management takeover, a microbial outbreak took place in a tertiary neonatal intensive care unit (NICU). Here, we characterize the outbreak and its management. About 4 months prior to takeover, there was a sharp increase in positive isolates for MSSA and multidrug-resistant organisms (MDROs). Simultaneously, the nursing staff sick leave rate increased dramatically which directly correlated with the number of infection/colonization per week (r(2) = 0.95, p = 0.02). During the following months we observed several peaks in positive isolates of methicillin-sensitive staphylococcus aureus (MSSA), MDROs and subsequently a vancomycin-resistant enterococcus (VRE) outbreak. Interventional outbreak management measures were only successful after substantial recruitment of additional nursing staff. None of the VRE, but 44% (n = 4) of MDRO and 32% (n = 23) of MSSA colonized infants developed symptomatic infections (p = 0.02). Among the latter, 35% suffered from serious consequences such as osteomyelitis. The most important risk factors for colonization-to-infection progression were low gestational age and birth weight. Nursing staff fluctuation poses a substantial risk for both bacterial colonization and infection in neonates. Comprehensive outbreak management measures are only successful if adequate nursing staff is available. Non resistant strains account for most neonatal infections - possibly due to their limited perception as being harmful.

PMID: 28322345 [PubMed - in process]

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Atomic Layer Deposition of a Silver Nanolayer on Advanced Titanium Orthopedic Implants Inhibits Bacterial Colonization and Supports Vascularized de Novo Bone Ingrowth.

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Atomic Layer Deposition of a Silver Nanolayer on Advanced Titanium Orthopedic Implants Inhibits Bacterial Colonization and Supports Vascularized de Novo Bone Ingrowth.

Adv Healthc Mater. 2017 Mar 21;:

Authors: Devlin-Mullin A, Todd NM, Golrokhi Z, Geng H, Konerding MA, Ternan NG, Hunt JA, Potter RJ, Sutcliffe C, Jones E, Lee PD, Mitchell CA

Abstract
Joint replacement surgery is associated with significant morbidity and mortality following infection with either methicillin-resistant Staphylococcus aureus (MRSA) or Staphylococcus epidermidis. These organisms have strong biofilm-forming capability in deep wounds and on prosthetic surfaces, with 10(3) -10(4) microbes resulting in clinically significant infections. To inhibit biofilm formation, we developed 3D titanium structures using selective laser melting and then coated them with a silver nanolayer using atomic layer deposition. On bare titanium scaffolds, S. epidermidis growth was slow but on silver-coated implants there were significant further reductions in both bacterial recovery (p < 0.0001) and biofilm formation (p < 0.001). MRSA growth was similarly slow on bare titanium scaffolds and not further affected by silver coating. Ultrastructural examination and viability assays using either human bone or endothelial cells, demonstrated strong adherence and growth on titanium-only or silver-coated implants. Histological, X-ray computed microtomographic, and ultrastructural analyses revealed that silver-coated titanium scaffolds implanted into 2.5 mm defects in rat tibia promoted robust vascularization and conspicuous bone ingrowth. We conclude that nanolayer silver of titanium implants significantly reduces pathogenic biofilm formation in vitro, facilitates vascularization and osseointegration in vivo making this a promising technique for clinical orthopedic applications.

PMID: 28321991 [PubMed - as supplied by publisher]

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Antimicrobial Percutaneous Nephrostomy Catheters for the prevention of Renal Infections: In vitro studies.

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Antimicrobial Percutaneous Nephrostomy Catheters for the prevention of Renal Infections: In vitro studies.

Antimicrob Agents Chemother. 2017 Mar 20;:

Authors: Vargas-Cruz N, Reitzel RA, Rosenblatt J, Jamal M, Szvalb AD, Chaftari AM, Hachem R, Raad I

Abstract
Purpose - Percutaneous nephrostomy (PCN) catheters are the primary method for draining ureters obstructed by malignancy and preventing a decline of the renal function. However, PCN-related infections such as pyelonephritis and urosepsis remain a significant concern. Currently no antimicrobial PCNs are available for preventing infectious complications. Vascular catheters impregnated with Minocycline/Rifampin (M/R) and M/R with Chlorhexidine coating (M/R+CHD) have previously demonstrated antimicrobial activity. Therefore, in this study we examined whether these combinations could be applied to PCNs and effectively inhibit biofilm formation of common uropathogens.Methods - An in vitro biofilm colonization model was used to assess the antimicrobial efficacy of M/R and M/R +CHD PCNs against nine common multi-drug resistant Gram-positive, Gram-negative, and yeast uropathogens. Experimental catheters were also assessed for durability of antimicrobial activity for up 3 weeks.Results - PCNs coated with M/R+CHD completely inhibited biofilm formation for up to 3 weeks for all organisms tested. The reduction in colonization compared to uncoated PCNs was significant for all Gram-positive, Gram-negative, and fungal organisms (p < 0.05). M/R + CHD PCNs also gave significant reductions in biofilm colonization relative to M/R PCNs for Enterobacter sp., Eschericia coli, Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus, Vancomycin-resistant Enterococci, Candida glabrata and Candida albicans (p< 0.05).Conclusion - M/R+CHD PCNs proved to be highly efficacious in preventing biofilm colonization when exposed to multi-drug resistant pathogens common to PCN-associated pyelonephritis. M/R+CHD PCNs warrant evaluation in a clinical setting to assess their ability to prevent clinically relevant nephrostomy infections.

PMID: 28320713 [PubMed - as supplied by publisher]

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Outcome of neurological early rehabilitation patients carrying multi-drug resistant bacteria: results from a German multi-center study.

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Outcome of neurological early rehabilitation patients carrying multi-drug resistant bacteria: results from a German multi-center study.

BMC Neurol. 2017 Mar 20;17(1):53

Authors: Rollnik JD, Bertram M, Bucka C, Hartwich M, Jöbges M, Ketter G, Leineweber B, Mertl-Rötzer M, Nowak DA, Platz T, Scheidtmann K, Thomas R, von Rosen F, Wallesch CW, Woldag H, Peschel P, Mehrholz J, Pohl M

Abstract
BACKGROUND: Colonization or infection with multi-drug resistant (MDR) bacteria is considered detrimental to the outcome of neurological and neurosurgical early rehabilitation patients.
METHODS: In a German multi-center study, 754 neurological early rehabilitation patients were enrolled and and reviewed in respect to MDR status, length of stay (LOS) and the following outcome variables: Barthel Index (BI), Early Rehabilitation Index (ERI), Glasgow Outcome Score Extended (GOSE), Coma Remission Scale (CRS), Functional Ambulation Categories (FAC).
RESULTS: The mean age of the study population was 68.0 ± 14.8 years. Upon admission, the following prevalence for MDRs was observed: MRSA (methicillin resistant staphylococcus aureus) 7.0% (53/754), ESBL- (extended spectrum beta-lactamase) producing bacteria strains 12.6% (95/754), VRE (vancomycin resistant enterococci) 2.8% (21/754). Patients colonized or infected with MDR bacteria (MDR+) were significantly more frequently diagnosed with a critical illness polyneuropathy - CIP - than non-colonized (MDR-) patients: 29.0% vs. 14.8%. In addition, they were more frequently mechanically ventilated (MDR+: 55/138, 39.9%; MDR- 137/616, 22.2%). MDR+ patients were referred to rehabilitation earlier, had a longer LOS in early rehabilitation, lower BI on admission and at discharge, lower ERI on admission and lower CRS at discharge than MDR- patients. There was a highly significant correlation of the BI upon admission with the BI at discharge (rs = 0.492, p < 0.001). GOSE at discharge differed significantly between both groups (χ (2)-test, p < 0.01). Perhaps of greatest importance, mortality among MDR+ was higher in comparison to MDR- (18.1% vs. 7.6%).
CONCLUSIONS: The outcome of neurological early rehabilitation patients colonized or infected with MDR bacteria including MRSA or ESBL producing strains is significantly poorer than by non-colonized patients. There is some evidence that the poor outcome could be related to the higher morbidity and lower functional status upon admission.

PMID: 28320357 [PubMed - in process]

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Water hardness determines 226Ra uptake in the tropical freshwater mussel

Publication date: June 2017
Source:Journal of Environmental Radioactivity, Volume 172
Author(s): Che Doering, Andreas Bollhöfer
Chemical data for freshwater mussels (Velesunio spp.) and water from 15 sampling sites in the Alligator Rivers Region and Rum Jungle uranium provinces in tropical Northern Australia were analysed to develop a predictive model of radium-226 (²²⁶Ra) bioaccumulation for variable water calcium (Ca) and magnesium (Mg) concentrations. Application of the model as a ²²⁶Ra screening approach for freshwater mussels in tropical waterbodies potentially impacted by operational or remediated uranium mine sites is discussed in relation to Mudginberri Billabong, located approximately 12 km downstream of Ranger uranium mine in the Alligator Rivers Region.



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Radon concentration distributions in shallow and deep groundwater around the Tachikawa fault zone

Publication date: June 2017
Source:Journal of Environmental Radioactivity, Volume 172
Author(s): Fumiaki Tsunomori, Tomoya Shimodate, Tomoki Ide, Hidemi Tanaka
Groundwater radon concentrations around the Tachikawa fault zone were surveyed. The radon concentrations in shallow groundwater samples around the Tachikawa fault segment are comparable to previous studies. The characteristics of the radon concentrations on both sides of the segment are considered to have changed in response to the decrease in groundwater recharge caused by urbanization on the eastern side of the segment. The radon concentrations in deep groundwater samples collected around the Naguri and the Tachikawa fault segments are the same as those of shallow groundwater samples. However, the radon concentrations in deep groundwater samples collected from the bedrock beside the Naguri and Tachikawa fault segments are markedly higher than the radon concentrations expected from the geology on the Kanto plane. This disparity can be explained by the development of fracture zones spreading on both sides of the two segments. The radon concentration distribution for deep groundwater samples from the Naguri and the Tachikawa fault segments suggests that a fault exists even at the southern part of the Tachikawa fault line.



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Plant uptake of 238U, 235U, 232Th, 226Ra, 210Pb and 40K from a coal ash and slag disposal site and control soil under field conditions: A preliminary study

Publication date: June 2017
Source:Journal of Environmental Radioactivity, Volume 172
Author(s): Božena Skoko, Gordana Marović, Dinko Babić, Marko Šoštarić, Mirela Jukić
The aim of this study was to investigate the uptake of ²³⁸U, ²³⁵U, ²³²Th, ²²⁶Ra, ²¹⁰Pb and ⁴⁰K by plants that grow on a coal ash and slag disposal site known for its higher content of naturally occurring radionuclides. Plant species that were sampled are common for the Mediterranean flora and can be divided as follows: grasses & herbs, shrubs and trees. To compare the activity concentrations and the resultant concentration ratios of the disposal site with those in natural conditions, we used control data specific for the research area, obtained for plants growing on untreated natural soil. Radionuclide activity concentrations were determined by high resolution gamma-ray spectrometry. Media parameters (pH, electrical conductivity and organic matter content) were also analysed. We confirmed significantly higher activity concentrations of ²³⁸U, ²³⁵U, ²²⁶Ra and ²¹⁰Pb in ash and slag compared to control soil. However, a significant increase in the radionuclide activity concentration in the disposal site's vegetation was observed only for ²²⁶Ra. On the contrary, a significantly smaller activity concentration of ⁴⁰K in ash and slag had no impact on its activity concentration in plant samples. The calculated plant uptake of ²³⁸U, ²³⁵U, ²²⁶Ra and ²¹⁰Pb is significantly smaller in comparison with the uptake at the control site, while it is vice versa for ⁴⁰K. No significant difference was observed between the disposal site and the control site's plant uptake of ²³²Th. These results can be the foundation for further radioecological assessment of this disposal site but also, globally, they can contribute to a better understanding of nature and long-term management of such disposal sites.



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White Grape Juice Elicits a Lower Breath Hydrogen Response Compared with Apple Juice in Healthy Human Subjects: A Randomized Controlled Trial

Publication date: Available online 22 March 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Jennifer Erickson, Qi Wang, Joanne Slavin
BackgroundDiets low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPS) are used to manage symptoms in individuals with irritable bowel syndrome. Although effective at reducing symptoms, the diet can be complex and restrictive. In addition, there are still large gaps in the literature and many foods with unclear effects in the gastrointestinal (GI) tract, like fruit juice. Although many fruits are allowable on a low-FODMAP diet, consumption of all fruit juice is generally cautioned due to the large fructose load contained in juice, regardless of the glucose concentration. Very little research exists regarding the importance of limiting fructose load during a low-FODMAP diet; therefore, individuals following a low-FODMAP diet may be unnecessarily restricting their diets.ObjectiveTo determine whether there is a difference in GI tolerance between juice from a high-FODMAP fruit (apple juice) and juice from a low-FODMAP fruit (white grape juice) in healthy human subjects. The goal is to provide insight into the role of juice in a low-FODMAP diet.MethodsA double-blind, randomized, controlled crossover study was conducted with 40 healthy adults. Fasted subjects consumed 12 oz of either apple juice or white grape juice. Breath hydrogen measures were taken at baseline, 1, 2, and 3 hours. Subjective GI tolerance surveys were completed at the same time intervals and at 12 and 24 hours. Breath hydrogen and GI symptoms were assessed with area under the curve analysis. Significance was determined with a two-sided t test with a P value <0.05.ResultsConsumption of apple juice resulted in a greater mean breath hydrogen area under the curve at 23.3 ppm/hour (95% CI 13.0 to 33.6) compared with white grape juice at 5.8 ppm/hour (95% CI –4.6 to 16.1) (P<0.001). No differences in reported GI symptoms were seen between treatments.ConclusionsBoth juices were well tolerated and neither produced any severe symptoms in healthy adults. White grape juice consumption resulted in only a small rise in breath hydrogen, which may suggest excluding foods only because of the high fructose load could be unnecessarily restrictive. The results of this study suggest that the fructose-to-glucose ratio is likely more important than the total fructose load of the food when considering the acceptability of a food on a low-FODMAP diet. More research is needed in individuals with irritable bowel syndrome to determine whether white grape juice and other juices from low-FODMAP fruits could be additional beverage options for individuals following a low-FODMAP diet.



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American Brachytherapy Society consensus statement for soft tissue sarcoma brachytherapy

Publication date: Available online 23 March 2017
Source:Brachytherapy
Author(s): A.O. Naghavi, D.C. Fernandez, N. Mesko, A. Juloori, A. Martinez, J.G. Scott, C. Shah, L.B. Harrison
PurposeRadiation therapy represents an essential treatment option in the management of soft tissue sarcomas (STS). Brachytherapy represents an important subset of radiation therapy techniques used for STS, with evolving indications and applications. Therefore, the purpose of this guideline was to update clinicians regarding the data surrounding brachytherapy (BT) and provide recommendations for the utilization of BT in patients with STS.Methods and MaterialsMembers of the American Brachytherapy Society with expertise in STS, and STS BT in particular, created an updated guideline for the use of BT in STS based on a literature review and clinical experience.ResultsGuidelines are presented with respect to dose and fractionation and technical features to improve outcomes and potentially reduce the risk of toxicity. Brachytherapy as monotherapy can be considered in low-risk cases or in situations where re-irradiation is being considered. Brachytherapy boost can be considered in cases at higher risk of recurrence or where BT alone cannot adequately cover the target volume. To limit wound complications, the start of BT delivery should be delayed until final wound closure, or if after immediate reconstruction, started after postoperative Day 5.ConclusionsThe current guidelines have been created to provide clinicians with a review of the data supporting BT in the management of STS as well as providing indications and technique guidelines to ensure optimal patient selection and clinical outcomes.



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The first clinical implementation of a real-time six degree of freedom target tracking system during radiation therapy based on Kilovoltage Intrafraction Monitoring (KIM)

Publication date: Available online 22 March 2017
Source:Radiotherapy and Oncology
Author(s): Doan Trang Nguyen, Ricky O'Brien, Jung-Ha Kim, Chen-Yu Huang, Lee Wilton, Peter Greer, Kimberley Legge, Jeremy T. Booth, Per Rugaard Poulsen, Jarad Martin, Paul J. Keall
PurposeWe present the first clinical implementation of a real-time six-degree of freedom (6DoF) Kilovoltage Intrafraction Monitoring (KIM) system which tracks the cancer target translational and rotational motions during treatment. The method was applied to measure and correct for target motion during stereotactic body radiotherapy (SBRT) for prostate cancer.MethodsPatient: A patient with prostate adenocarcinoma undergoing SBRT with 36.25Gy, delivered in 5 fractions was enrolled in the study. 6DoF KIM technology: 2D positions of three implanted gold markers in each of the kV images (125kV, 10mA at 11Hz) were acquired continuously during treatment. The 2D→3D target position estimation was based on a probability distribution function. The 3D→6DoF target rotation was calculated using an iterative closest point algorithm. The accuracy and precision of the KIM method was measured by comparing the real-time results with kV-MV triangulation.ResultsOf the five treatment fractions, KIM was utilised successfully in four fractions. The intrafraction prostate motion resulted in three couch shifts in two fractions when the prostate motion exceeded the pre-set action threshold of 2mm for more than 5s. KIM translational accuracy and precision were 0.3±0.6mm, −0.2±0.3mm and 0.2±0.7mm in the Left-Right (LR), Superior-Inferior (SI) and Anterior-Posterior (AP) directions, respectively. The KIM rotational accuracy and precision were 0.8°±2.0°, −0.5°±3.3° and 0.3°±1.6° in the roll, pitch and yaw directions, respectively.ConclusionThis treatment represents, to the best of our knowledge, the first time a cancer patient's tumour position and rotation have been monitored in real-time during treatment. The 6 DoF KIM system has sub-millimetre accuracy and precision in all three translational axes, and less than 1° accuracy and 4° precision in all three rotational axes.



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Recurrence patterns after a decreased dose of 40Gy to the elective treated neck in head and neck cancer

Publication date: Available online 22 March 2017
Source:Radiotherapy and Oncology
Author(s): Daan Nevens, Fréderic Duprez, Jean-François Daisne, Julie Schatteman, Aline Van der Vorst, Wilfried De Neve, Sandra Nuyts
PurposeTo investigate the patterns of regional recurrences with emphasis on recurrences in the electively irradiated lymph node regions after dose de-escalation to 40Gy (EQD2Gy) in head and neck cancer.Methods and materialsTwo hundred thirty-three patients treated with radio(chemo)therapy using 40Gy (EQD2Gy) to the elective lymph node regions were included. All regional recurrences were reconstructed and projected on the initial radiotherapy planning Computed Tomography studies to identify the localization of recurrence. Furthermore, patient and treatment characteristics were correlated with the regional recurrences to identify risk factors.ResultsThe median follow-up in our study was 26months. Overall- and disease-specific survival at 2years were 71.2% (95% CI 65.3–77.1) and 64.2% (95% CI 59.2–69.3), respectively. Local, regional and distant control at 2years was 84.1% (95% CI 79.1–89.2), 89.2% (95% CI 84.3–94.1) and 83.2% (95% CI 76.3–90.1), respectively. Twenty-eight patients experienced a regional recurrence. Fourteen of these patients had a recurrence within the high dose volume (14 of 28). Nine had a recurrence in the electively irradiated lymph node regions (9 of 28) and 5 recurrences occurred outside the target volume.The actuarial rate of recurrence in the electively irradiated lymph node regions was 3.9% (95% CI 1.8–6.0) at 2years. No significant associations could be observed between recurrence in electively irradiated lymph node regions and age, gender, tumor site, stage, or the presence of human papillomavirus in oropharyngeal cancers.ConclusionsThe actuarial rate of recurrence in the electively irradiated lymph node regions was 3.9% (95% CI 1.8–6.0) at 2years. This incidence is comparable to recurrence rates after standard dose of 50Gy, suggesting that lower doses to the elective neck do not result in higher regional recurrences.



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Pharmaceutical Solvates, Hydrates and Amorphous Forms

Publication date: Available online 22 March 2017
Source:Advanced Drug Delivery Reviews
Author(s): Anne Marie Healy, Zelalem Ayenew Worku, Dinesh Kumar, Atif M. Madi
Active pharmaceutical ingredients (APIs) may exist in various solid forms, which can lead to differences in the intermolecular interactions, affecting the internal energy and enthalpy, and the degree of disorder, affecting the entropy. Differences in solid forms often lead to differences in thermodynamic parameters and physicochemical properties for example solubility, dissolution rate, stability and mechanical properties of APIs and excipients. Hence, solid forms of APIs play a vital role in drug discovery and development in the context of optimization of bioavailability, filing intellectual property rights and developing suitable manufacturing methods. In this review, the fundamental characteristics and trends observed for pharmaceutical hydrates, solvates and amorphous forms are presented, with special emphasis, due to their relative abundance, on pharmaceutical hydrates with single and two-component (i.e. cocrystal) host molecules.

Graphical abstract

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TNF-inhibitor associated psoriatic alopecia: diagnostic utility of sebaceous lobule atrophy

ABSTRACT

Background

The increasingly successful and widespread use of TNF inhibitors (TNFi) to treat autoimmune and inflammatory conditions has also been accompanied by adverse reactions, both systemic and cutaneous. Psoriasiform cutaneous rashes are well described. Recently, TNF inhibitor associated psoriatic alopecia (TiAPA) is being more frequently reported.

Objective

The purpose of this study is to describe the features of TiAPA, including marked atrophy of sebaceous lobules as a histologic clue to diagnosis, helping to distinguish it from other types of alopecia.

Methods

Clinical and histopathological features of 3 patients who developed scalp alopecia while on TNFi treatment were examined. Clinical follow-up was conducted after discontinuation of TNFi. A review of the previous literature on the subject was also conducted.

Results and Conclusions

Atrophy of sebaceous lobules is a potentially reversible, characteristic and conspicuous feature of TiAPA that can be distinguished from idiopathic psoriatic alopecia (iPA) by clinical history of drug exposure and sometimes by histologic presence of a mixed inflammatory response including plasma cells and eosinophils.

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Small Molecules Inhibit STAT3 Activation, Autophagy, and Cancer Cell Anchorage-Independent Growth

Publication date: Available online 23 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Donghui Zhou, Maya Z. Springer, David Xu, Degang Liu, Andy Hudmon, Kay F. Macleod, Samy O. Meroueh
Triple-negative breast cancers (TNBCs) lack the signature targets of other breast tumors, such as HER2, estrogen receptor, and progesterone receptor. These aggressive basal-like tumors are driven by a complex array of signaling pathways that are activated by multiple driver mutations. Here we report the discovery of 6 (KIN-281), a small molecule that inhibits multiple kinases including maternal leucine zipper kinase (MELK) and the non-receptor tyrosine kinase bone marrow X-linked (BMX) with single-digit micromolar IC50s. Several derivatives of 6 were synthesized to gain insight into the binding mode of the compound to the ATP binding pocket. Compound 6 was tested for its effect on anchorage-dependent and independent growth of MDA-MB-231 and MDA-MB-468 breast cancer cells. The effect of 6 on BMX prompted us to evaluate its effect on STAT3 phosphorylation and DNA binding. The compound's inhibition of cell growth led to measurements of survivin, Bcl-XL, p21^WAF1/CIP1, and cyclin A2 levels. Finally, LC3B-II levels were quantified following treatment of cells with 6 to determine whether the compound affected autophagy, a process that is known to be activated by STAT3. Compound 6 provides a starting point for the development of small molecules with polypharmacology that can suppress TNBC growth and metastasis.

Graphical abstract

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Ester-to-Amide Rearrangement of Ethanolamine-Derived Prodrugs of Sobetirome with Increased Blood-Brain Barrier Penetration

Publication date: Available online 23 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Skylar J. Ferrara, J. Matthew Meinig, Andrew T. Placzek, Tapasree Banerji, Peter McTigue, Meredith D. Hartley, Hannah S. Sanford-Crane, Tania Banerji, Dennis Bourdette, Thomas S. Scanlan
Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.

Graphical abstract

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Design and Synthesis of Quinazolinones as EGFR inhibitors to Overcome EGFR Resistance Obstacle

Publication date: Available online 23 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Harun M. Patel, Rahul Pawara, Azim Ansari, Malleshappa Noolvi, Sanjay Surana
The epidermal growth factor receptor (EGFR) T790M mutant is found in about 50% of clinically acquired resistance to gefitinib among patients with non-small cell lung cancer (NSCLC). New derivatives of 4(3H)-quinazolinones were synthesized and evaluated for their inhibitory activity against NSCLC. The results of the study demonstrated that compound 79, 7-chloro-3-(5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-yl)-2-phenylquinazolin-4(3H)-one was found to be the most potent compounds of the series with IC50 value of 0.031 μM against mutant T790M/L858R EGFR. Compounds 15, 51, 73, 75, 78, 79 and 96 were less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index. The obtained results showed that compounds 15, 51, 73, 75, 78, 79 and 96 could be the promising template to overcome drug resistance mediated by the EGFR T790 Mutant.

Graphical abstract

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Facile access to pseudo-thio-1,2-dimannoside, a new glycomimetic DC-SIGN antagonist

Publication date: Available online 22 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Alice Tamburrini, Silvia Achilli, Francesca Vasile, Sara Sattin, Corinne Vivès, Cinzia Colombo, Franck Fieschi, Anna Bernardi
The synthesis and conformational analysis of pseudo-thio-1,2-dimannoside are described. This molecule mimics mannobioside (Manα(1,2)Man) and is an analog of pseudo-1,2-dimannoside, with expected increased stability to enzymatic hydrolysis. A short and efficient synthesis was developed based on an epoxide ring-opening reaction by a mannosyl thiolate, generated in situ from the corresponding thioacetate. NMR-NOESY studies supported by MM3∗ calculations showed that the pseudo-thio-1,2-dimannoside shares the conformational behavior of the pseudo-1,2-dimannoside and is a structural mimic of the natural disaccharide. Its affinity for DC-SIGN was measured by SPR and found to be comparable to the corresponding O-linked analogue, offering good opportunities for further developments.

Graphical abstract

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Rapid screening the potential mechanism-based inhibitors of CYP3A4 from Tripterygium wilfordi based on computer approaches combined with in vitro bioassay

Publication date: Available online 22 March 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Lili Wang, Yue Hai, Lijun An, Junxiu Chen, Rongjia Liang, Xin He
CYP3A4 is the main human metabolizing enzyme, and many clinically relevant drug/herb-drug interactions (DDIs/HDIs) involving CYP3A4 are due to mechanism-based inhibition. In this study, pharmacophore model together with molecular docking (MD) are used to rapidly screen the potential CYP3A4 mechanism-based inhibitors from Tripterygium wilfordii, and in vitro experiments are conducted to validate the computational data. The results showed that the rate of computational prediction could be improved based on a combination of pharmacophore model and MD, and a combination of computational approaches might be a useful tool to identify potential mechanism-based inhibitor of CYP3A4 from herbal medicines.

Graphical abstract

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Daily ambient air pollution metrics for five cities: Evaluation of data-fusion-based estimates and uncertainties

Publication date: June 2017
Source:Atmospheric Environment, Volume 158
Author(s): Mariel D. Friberg, Ralph A. Kahn, Heather A. Holmes, Howard H. Chang, Stefanie Ebelt Sarnat, Paige E. Tolbert, Armistead G. Russell, James A. Mulholland
Spatiotemporal characterization of ambient air pollutant concentrations is increasingly relying on the combination of observations and air quality models to provide well-constrained, spatially and temporally complete pollutant concentration fields. Air quality models, in particular, are attractive, as they characterize the emissions, meteorological, and physiochemical process linkages explicitly while providing continuous spatial structure. However, such modeling is computationally intensive and has biases. The limitations of spatially sparse and temporally incomplete observations can be overcome by blending the data with estimates from a physically and chemically coherent model, driven by emissions and meteorological inputs. We recently developed a data fusion method that blends ambient ground observations and chemical-transport-modeled (CTM) data to estimate daily, spatially resolved pollutant concentrations and associated correlations. In this study, we assess the ability of the data fusion method to produce daily metrics (i.e., 1-hr max, 8-hr max, and 24-hr average) of ambient air pollution that capture spatiotemporal air pollution trends for 12 pollutants (CO, NO2, NOx, O3, SO2, PM10, PM2.5, and five PM2.5 components) across five metropolitan areas (Atlanta, Birmingham, Dallas, Pittsburgh, and St. Louis), from 2002 to 2008.Three sets of comparisons are performed: (1) the CTM concentrations are evaluated for each pollutant and metropolitan domain, (2) the data fusion concentrations are compared with the monitor data, (3) a comprehensive cross-validation analysis against observed data evaluates the quality of the data fusion model simulations across multiple metropolitan domains. The resulting daily spatial field estimates of air pollutant concentrations and uncertainties are not only consistent with observations, emissions, and meteorology, but substantially improve CTM-derived results for nearly all pollutants and all cities, with the exception of NO2 for Birmingham. The greatest improvements occur for O3 and PM2.5. Squared spatiotemporal correlation coefficients range between simulations and observations determined using cross-validation across all cities for air pollutants of secondary and mixed origins are R² = 0.88–0.93 (O3), 0.81–0.89 (SO4), 0.67–0.83 (PM2.5), 0.52–0.72 (NO3), 0.43–0.80 (NH4), 0.32–0.51 (OC), and 0.14–0.71 (PM10).Results for more spatially heterogeneous (larger spatial gradients) pollutants of primary origin (NOx, CO, SO2 and EC), tend to be better than those for relatively homogeneous pollutants of secondary origin. Generally, background concentrations and spatial concentration gradients reflect interurban airshed complexity and the effects of regional transport, whereas daily spatial pattern variability shows intra-urban consistency in the fused data. With sufficiently high CTM spatial resolution, traffic-related pollutants exhibit gradual concentration gradients that peak toward the urban centers. Ambient pollutant concentration uncertainty estimates for the fused data are both more accurate and smaller than those for either the observations or the model simulations alone.

Graphical abstract

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Diffuse carotid arteriosclerosis and stroke in a Patient with Schimke immune- osseous dysplasia

Publication date: Available online 23 March 2017
Source:Pediatric Neurology
Author(s): Debopam Samanta, Raghu Ramakrishnaiah




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Treatment of Leukoencephalopathy with Calcifications and Cysts with Bevacizumab

Publication date: Available online 23 March 2017
Source:Pediatric Neurology
Author(s): A.J. Fay, A.A. King, J.S. Shimony, Y.J. Crow, J.E. Brunstrom-Hernandez
BackgroundLeukoencephalopathy with Calcifications and Cysts (LCC) is a rare, autosomal recessive cerebral microangiopathy that causes progressive white matter disease, calcifications and cysts within the brain, typically associated with slowly progressive psychomotor regression, seizures, and movement disorders. While LCC affects only the central nervous system, it demonstrates remarkable neuropathological and radiological overlap with Coats plus, a disorder of small vessels of the brain, eyes, gastrointestinal tract and bone. Coats disease without extraocular involvement, a genetically distinct disorder from Coats plus, is characterized by retinal telangiectasias and exudative retinopathy, accompanied by neovascularization. Inhibition of vascular endothelial growth factor (VEGF) signaling with the monoclonal anti-VEGF antibody bevacizumab can improve retinal edema and exudates in Coats disease. Given these observations, we reasoned that VEGF inhibition might also be effective in treating LCC and Coats plus, neither of which has any known therapy.MethodsWe treated an 18-year-old man with LCC using biweekly infusions of the VEGF inhibitor bevacizumab over one year, and performed clinical examinations and brain imaging at three month intervals.ResultsOver one year of treatment, the patient showed improved bradykinesia and range of motion, and brain magnetic resonance imaging (MRI) demonstrated a marked reduction in cyst volume and white matter lesions.ConclusionsFurther studies in a cohort of patients are warranted to investigate the efficacy of VEGF inhibition as a treatment for LCC.



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ecrudescence of Herpes Virus Infections Following Resection of Schwannomas. An Antiviral Role of Merlin?

Publication date: Available online 23 March 2017
Source:Medical Hypotheses
Author(s): İlhan Elmaci, Meric A. Altinoz
After schwannoma resection, reactivation of herpes infections were reported. Also, IgM antibody titers against Herpes Viri increase among 30% of patients, who develop fascial palsy following schwannoma resection. Merlin interacts with p53 pathway and seems to function as a suppressor of viral propagation. Loss of merlin may increase viral particles in nerve fascicles, yet these may fail to cause infections due to immunostimulation by other aberrant antigens present in schwannoma cells. Removal of schwannomas may decrease the antigenic diversity and trigger viral recrudescence. Understanding the viral etiology – molecular merlin interactions in schwannoma tissues may also help to develop strategies against delayed fascial palsy seen following schwannoma resection.



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Effects of hypnosis during pregnancy: A psychophysiological study on maternal stress

Publication date: Available online 23 March 2017
Source:Medical Hypotheses
Author(s): Fabien Legrand, Corinne Grévin-Laroche, Elisabeth Josse, Guillaume Polidori, Hervé Quinart, Redha Taïar
Because it induces a state of reduced awareness and deep relaxation, hypnosis is thought to be efficient at relieving stress and anxiety. This study examined whether hypnosis may alter the pattern and time evolution of maternal and fetal stress. Here we report a 23-yrs-old primigravida woman at 31-weeks' gestation who underwent daily sessions of hypnosis during one week. An A (baseline)-B intervention) - A' (return to baseline) design was used. Each study phase lasted one week. The State Anxiety Inventory (SAI) was completed daily. Uterine contractions as well as maternal and fetal heart rate were recorded over 24-hour periods in each of the study phase. Uterine contractions and maternal systolic blood pressure showed clear reductions during the hypnosis phase. In addition, a statistically significant declining trend in anxiety scores was observed during the hypnosis phase, and anxiety re-increased in the return-to-baseline phase (p < .05). Coefficient of variation of maternal heart rate was found to be considerably lower during the hypnosis phase. Our results suggest that a short-lived hypnosis intervention (combined with standard care) holds sufficient promise for antenatal stress relief to justify testing its efficacy in larger groups of pregnant women.



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The multi-factorial origins of Chronic Traumatic Encephalopathy (CTE) symptomology in post-career athletes: The athlete post-career adjustment (AP-CA) model

Publication date: Available online 22 March 2017
Source:Medical Hypotheses
Author(s): Michael Gaetz
CTE has two prominent components: the pathophysiology that is detected in the brain postmortem and the symptomology that is present in the interval between retirement and end of life. CTE symptomology has been noted to include memory difficulties, aggression, depression, explosivity, and executive dysfunction at early stages progressing to problems with attention, mood swings, visuospatial difficulties, confusion, progressive dementia, and suicidality [e.g.6-10]. There are a number of assumptions embedded within the current CTE literature: The first is the assumption that CTE symptomology reported by athletes and their families is the product of the pathophysiology change detected post-mortem [e.g. 10]. At present, there is little scientific evidence to suggest that all CTE symptomology is the product of CTE pathophysiology. It has been assumed that CTE pathophysiology causes CTE symptomology [38,61] but this link has never been scientifically validated. The purpose of the present work is to provide a multi-factorial theoretical framework to account for the symptomology reported by some athletes who sustain neurotrauma during their careers that will lead to a more systematic approach to understanding post-career symptomology. There is significant overlap between the case reports of athletes with post-mortem diagnoses of CTE, and symptom profiles of those with a history of substance use, chronic pain, and athlete career transition stress. The athlete post—career adjustment (AP-CA) is intended to explain some of the symptoms that athletes experience at the end of their careers or during retirement. The AP-CA model consists of four elements: neurotrauma, chronic pain, substance use, and career transition stress. Based on the existing literature, it is clear that any one of the four elements of the AP-CA model can account for a significant number of CTE symptoms. In addition, depression can be a chronic lifelong co-morbid condition that may be present prior to an athletic career, or may be developed secondary to any of the model elements as shown in Fig. 1. Notably, neurotrauma is a necessary, but not a sufficient condition, for the development of CTE symptomology.



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Die Rolle der Beckenbestrahlung beim nodal-negativen Adenokarzinom der Prostata bleibt unklar

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Diagnosis and Treatment of Metastases to the Thyroid Gland: a Meta-Analysis

Abstract

The thyroid is a rare site of clinically detectable tumor metastases; even though the gland is a highly vascularized structure, the frequency of metastases in the routine practice is less than 0.2% of all thyroid malignancies. The purpose of our meta-analysis is to evaluate the frequency of metastatic diffusion from other primary tumors to the thyroid gland and to suggest the best possible treatment through an evidence-based study. Relevant studies were identified by searching the following databases: PubMed, Scopus, and Web of Science. We selected all English-written articles published from 1995 to 2015. Studies were considered eligible if they reported the timing of metastatic spread and the site of the primary tumor in respect to the diaphragmatic region. Case reports were not included. Twenty-eight studies accounted for 514 patients. The rate of metachronous metastases was 69%. Fifty-three percent of primaries originated from the infradiaphragmatic region. Fine needle aspiration biopsy (FNAB) was done in 154 patients and 195 patients were treated mostly with surgery. A prevalence of primary tumors from the infradiaphragmatic region and of metachronous metastases was observed. Knowledge of the clinical history and the ancillary techniques can improve the sensitivity and accuracy of FNAB. Thyroidectomy may be considered a more effective treatment than radio-chemotherapy.

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Metformin and improved treatment outcomes in radiation therapy-A review.

Publication date: Available online 22 March 2017
Source:Cancer Treatment Reviews
Author(s): Nur Atiqah Binte Samsuri, Michelle Leech, Laure Marignol
BackgroundMetformin, a primary treatment for diabetes mellitus (DM) patients, is associated with improved outcomes for diabetic cancer patients fuelling further investigation on its mechanisms of action. The radiosensitising properties of metformin are increasingly reported in pre-clinical studies. This review discusses whether metformin should be offered to radiotherapy (RT) cancer patients as a means to improve their treatment outcomes.Materials and MethodsA database search was conducted for articles published with metformin as the main intervention between 2010-2016. Three groups of RT cancer patients were analysed: diabetic patients using metformin, diabetic patients not using metformin and non-diabetic patients not using metformin. Data on survival and recurrence metrics were extracted.ResultsThirteen studies were included. Conflicting evidence exists with regards to the impact of metformin administration on recurrence and survival outcomes following radiotherapy. Three studies reported improved tumour response determined by recurrence rates while five studies did not observe differences or metformin use was not the associated reason. One study revealed inconsistent tumour response results. Metformin was reported as improving survival outcomes in 2 studies and not improving outcomes in 5 studies. 4 studies showed indefinite results.ConclusionAlthough metformin may improve tumour response in the non-randomized, retrospective studies analysed, it may not necessarily confer survival benefits. Future prospective and randomised trials are required to translate the positive impact of metformin documented in pre-clinical and retrospective studies into improve management of RT cancer patients.



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Commentary on Combined Jessner Solution and Trichloroacetic Acid Versus Trichloroacetic Acid Alone in the Treatment of Melasma in Dark-Skinned Patients.

No abstract available

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