Heart failure not responsive to standard immunosuppressive therapy is successfully treated with high dose intravenous immunoglobulin therapy in a patient with Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Publication date: April 2017
Source:International Immunopharmacology, Volume 45
Author(s): Antonio Pecoraro, Ludovica Crescenzi, Laura Carucci, Arturo Genovese, Giuseppe Spadaro
Glucocorticoids and immunosuppressive drugs represent the first-line treatment of eosinophilic granulomatosis with polyangiitis (EGPA, former Churg-Strauss syndrome), even though the combined therapy is not successful in achieving the disease remission in some patients with neurological or cardiac involvement. We describe a case of an EGPA male patient with impaired left ventricular function not responsive to glucocorticoid and immunosuppressive therapy. We observed that high-dose (2g/kg/4weeks) intravenous immunoglobulin (IVIG) therapy significantly improved cardiac function, which was deteriorated after reducing IVIG dose at 0.5g/kg/4weeks, and was restored increasing again IVIG dose to 2g/kg/4weeks. The finding highlights the relevance of IVIG as treatment of choice in EGPA patients with cardiac involvement not responsive to the standard glucocorticoid and immunosuppressive therapy. Moreover, at a follow-up of 24months, the continuance of high dose IVIG therapy was required to maintain a sustained remission of the heart failure.



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Therapeutic efficacy of carboxyamidotriazole on 2,4,6-trinitrobenzene sulfonic acid-induced colitis model is associated with the inhibition of NLRP3 inflammasome and NF-κB activation

Publication date: April 2017
Source:International Immunopharmacology, Volume 45
Author(s): Xiaowan Du, Wei Chen, Yufeng Wang, Chen Chen, Lei Guo, Rui Ju, Juan Li, Dechang Zhang, Lei Zhu, Caiying Ye
Excess proinflammatory cytokines owing to the activation of NF-κB and NLRP3 inflammasome play the key role in inflammatory bowel disease (IBD). Previously, we reported the anti-inflammatory activity of carboxyamidotriazole (CAI) resulting from decreasing cytokines. Therefore, we investigated the therapeutic effects of CAI in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rat colitis and the involvement of CAI action with NLRP3 inflammasome and NF-κB pathway. CAI was orally administered to TNBS-induced colitis rat. The severity of colitis was assessed, and NLRP3 inflammasome, NF-κB pathway and cytokines were determined. Our results showed that CAI significantly reduced weight loss and disease activity index (DAI) scores in colitis rats and alleviated the colonic macroscopic signs and pathological damage. In addition, the intestinal inflammatory markers and permeability index were markedly ameliorated by CAI treatment. The decreased levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-18 were also detected in the colon tissues of CAI-treated colitis rats. Moreover, the activation of NLRP3 inflammasome in inflamed colon was significantly suppressed by showing an obvious reduction in the NLRP3 and activated caspase-1 levels. Furthermore, CAI reduced NF-κB p65 expression and IκBα phosphorylation and degradation in colitis rats. Therefore, CAI attenuates TNBS-induced colitis, which may be attributed to its inhibition of NLRP3 inflammasome and NF-κB activation, and down-regulation of proinflammatory cytokines. These results provide further understanding of the intestinal anti-inflammatory effect of CAI and highlight it as a potential drug for the treatment of IBD.

Graphical abstract

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Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice

Publication date: April 2017
Source:International Immunopharmacology, Volume 45
Author(s): Jingyao Zhang, Simin Zhang, Jianbin Bi, Jingxian Gu, Yan Deng, Chang Liu
BackgroundAcetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure.MethodsMale C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30mg/kg or 60mg/kg), APAP and APAP+ASX (30mg/kg or 60mg/kg) groups. Saline, olive oil and ASX were administered for 14days. The APAP group was given a peritoneal injection of 700mg/kg or 300mg/kg to determine the 5-day survival rate and for observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family.ResultsASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2).ConclusionASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS generation, inhibiting oxidative stress, and reducing apoptosis by inhibiting the JNK signaling pathway mediated by TNF-α and phosphorylation of ERK and P38, which is consistent with preventing and treating liver damage.



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Antidesmone, a unique tetrahydroquinoline alkaloid, prevents acute lung injury via regulating MAPK and NF-κB activities

Publication date: April 2017
Source:International Immunopharmacology, Volume 45
Author(s): XinGang Lu, YingXiu Pu, WeiGuang Kong, XiaoDan Tang, JiAn Zhou, HaiXin Gou, Xiao Song, HaiFeng Zhou, NingZhou Gao, Jie Shen
Acute lung injury, characterized by inflammation, is a main cause of respiratory failure that affects patients worldwide. Antidesmone is one compound mainly isolated from Ajugade cumbens Thunb (Labiatae), an herb agent of Labiatae family. In this research, we investigated the anti-inflammation effect of antidesmone in vitro and in vivo. Antidesmone exerted none apparently cytotoxicity in vitro and toxic in vivo. In vitro results demonstrated that antidesmone suppressed the excess inflammatory cytokines production, including tumor necrosis factor-α, interleukin-6 and interleukin-1β in lipopolysaccharide (LPS)-exposed RAW264.7 cells. In vivo results suggested that antidesmone inhibited inflammatory cytokines in the bronchoalveolar lavage fluid and lung tissue after LPS stimulation. Moreover, antidesmone attenuated the nuclear translocation of p65. Mechanism study revealed that mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways play important roles in antidesmone's action. Taken together, our data uncover a relative toxic anti-inflammatory drug, antidesmone, can inhibit inflammation on stimulated macrophages and thereby prevents acute lung injury by regulating MAPK and NF-κB signaling pathways.



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Randomised controlled trial and economic analysis of an internet-based weight management programme: POWeR+ (Positive Online Weight Reduction).

A low-cost internet-based weight management programme in primary care achieved a greater average weight loss over 1 year than brief advice sheets and was highly likely to be cost-effective.

http://ift.tt/2kPOxls

Start2quit: a randomised clinical controlled trial to evaluate the effectiveness and cost-effectiveness of using personal tailored risk information and taster sessions to increase the uptake of the NHS Stop Smoking Services.

An intensive intervention consisting of personalised risk information and an invitation to a taster session increased the uptake of NHS Stop Smoking Services, increased 6-month quit rates and is likely to be cost-effective in the long term.

http://ift.tt/2kPYm2X

Hunter-gatherers in a Changing World.

http://ift.tt/2kNvqN8

Plerixafor for Patients Failing Stem Cell Mobilization: A Review of the Clinical and Cost-Effectiveness and Guidelines [Internet].

In 2012, the CADTH Common Drug Review (CDR) examined the evidence on plerixafor, consisting of two randomized controlled trials, and issued a "do not list" recommendation based on the exclusion of the subpopulation of interest from the included studies (i.e. predicted poor or proven poor mobilizers). This Rapid Response report aims to identify and review the clinical and cost-effectiveness of plerixafor in patients who are failing stem cell mobilization. Guidelines associated with the use of plerixafor in patients failing stem cell mobilization will also be examined.

http://ift.tt/2kPYhfF

Folic Acid Supplementation: An Evidence Review for the U.S. Preventive Services Task Force [Internet].

To assess the benefits and harms of folic acid supplementation in reproductive-age women for the prevention of neural tube defects (NTDs).

http://ift.tt/2kNxrZC

Benzenesulfonamide bearing imidazothiadiazole and thiazolotriazole scaffolds as potent tumor associated human carbonic anhydrase IX and XII inhibitors

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Rajiv Kumar, Silvia Bua, Sita Ram, Sonia Del Prete, Clemente Capasso, Claudiu T. Supuran, Pawan K. Sharma
Two series of 20 novel heterocyclic compounds, imidazothiadiazoles (3a-3j) and thiazolotriazoles (4a-4j) bearing benzenesulfonamide moiety were synthesized in order to investigate the inhibition potential of both scaffolds against four selected human carbonic anhydrase isoforms (hCA I, II, IX & XII). Against human isoform hCA I, compounds 3j, 4a-4c, and 4j showed better inhibition potential (Ki<100nM) than the standard drug acetazolamide (AZA). Against hCA II, all the compounds showed moderate inhibition with the exception of 3a which showed nearly two fold better profile compared to AZA. Against hCA IX, all the compounds showed moderate inhibitory potential than AZA, whereas against hCA XII, compounds 3a-3c showed better inhibitory potential compared to AZA.

Graphical abstract

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Quercetin-glutamic acid conjugate with a non-hydrolysable linker; a novel scaffold for multidrug resistance reversal agents through inhibition of P-glycoprotein

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Mi Kyoung Kim, Yunyoung Kim, Hyunah Choo, Youhoon Chong
Previously, we have reported remarkable effect of a quercetin-glutamic acid conjugate to reverse multidrug resistance (MDR) of cancer cells to a broad spectrum of anticancer agents through inhibition of P-glycoprotein (Pgp)-mediated drug efflux. Due to the hydrolysable nature, MDR-reversal activity of the quercetin conjugate was attributed to its hydrolysis product, quercetin. However, several lines of evidence demonstrated that the intact quercetin-glutamic acid conjugate has stronger MDR-reversal activity than quercetin. In order to evaluate this hypothesis and to identify a novel scaffold for MDR-reversal agents, we prepared quercetin conjugates with a glutamic acid attached at the 7-O position via a non-hydrolysable linker. Pgp inhibition assay, Pgp ATPase assay, and MDR-reversal activity assay were performed, and the non-hydrolysable quercetin conjugates showed significantly higher activities compared with those of quercetin. Unfortunately, the quercetin conjugates were not as effective as verapamil in Pgp-inhibition and thereby reversing MDR, but it is worth to note that the structurally modified quercetin conjugates with a non-cleavable linker showed significantly improved MDR-reversal activity compared with quercetin. Taken together, the quercetin conjugates with appropriate structural modifications were shown to have a potential to serve as a scaffold for the design of novel MDR-reversal agents.

Graphical abstract

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Development of radioiodinated acridine derivatives for in vivo imaging of prion deposits in the brain

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Masao Kawasaki, Takeshi Fuchigami, Nobuya Kobashi, Takehiro Nakagaki, Kazunori Sano, Ryuichiro Atarashi, Sakura Yoshida, Mamoru Haratake, Noriyuki Nishida, Morio Nakayama
Prion diseases are caused by deposition of abnormal prion protein aggregates (PrP^Sc) in the central nervous system. This study aimed to develop in vivo imaging probes that can detect cerebral PrP^Sc deposits. We synthesized several quinacrine-based acridine (AC) derivatives with 2,9-substitution and radioiodinated them. The AC derivatives were evaluated as prion-imaging probes using recombinant mouse prion protein (rMoPrP) aggregates and brain sections of mouse-adapted bovine spongiform encephalopathy (mBSE)-infected mice. The distribution of these compounds in mice was also evaluated. The 2-methoxy derivative [¹²⁵I]2 exhibited the highest binding affinity for rMoPrP aggregates with an equilibrium dissociation constant (Kd) value of 43.4nM. Fluorescence imaging with 2 showed clear signals at the thioflavin T (ThT)-positive amyloid deposits in the mBSE-infected mouse brain. Although a discrepancy was observed between the in vitro binding of AC derivatives to the aggregates and in vivo distribution of these compounds in the brain and we failed to identify prospective prion-imaging probes in this study, the AC derivatives may be considered a useful scaffold for the development of in vivo imaging probes. Further chemical modification of these AC derivatives may discover clinically applicable prion imaging probes.

Graphical abstract

http://ift.tt/2kmLYdw

New N- and O-arylpiperazinylalkyl pyrimidines and 2-methylquinazolines derivatives as 5-HT7 and 5-HT1A receptor ligands: Synthesis, structure-activity relationships, and molecular modeling studies

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Sebastiano Intagliata, Maria N. Modica, Valeria Pittalà, Loredana Salerno, Maria A. Siracusa, Alfredo Cagnotto, Mario Salmona, Rafał Kurczab, Giuseppe Romeo
Based on our earlier studies of structure activity relationships on 4-substituted piperazine derivatives, in this work we synthesized a novel set of long-chain arylpiperazines with the purpose of elucidating if some structural modifications in the terminal fragment could affect the binding affinity for the 5-HT7 and 5-HT1A receptors. In this new series, the quinazolinone system of the previous derivatives was replaced by a 6-phenylpyrimidine or a 2-methylquinazoline, which were used as versatile building blocks for the preparation of new compounds. A 4-arylpiperazine moiety through a five methylene chain was anchored at the nitrogen or oxygen atom of the heterocyclic scaffolds. The substituents borne by the piperazine nucleus were phenyl, phenylmethyl, 3- or 4-chlorophenyl, and 2-ethoxyphenyl. Binding tests, performed on human cloned 5-HT7 and 5-HT1A receptors, showed that, among the newly synthesized derivatives, 4-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentoxy]-6-phenyl-pyrimidine (13) and 3-[5-[4-(2-ethoxyphenyl)-1-piperazinyl]pentyl]-2-methyl-4(3H)-quinazolinone (20) displayed the best affinity values, Ki=23.5 and 8.42nM for 5-HT7 and 6.96 and 2.99nM for 5-HT1A receptors, respectively. Moreover, the functional properties for both compounds were further evaluated using the cAMP assay. Finally, a molecular modeling study has been performed for 5-HT7 and 5-HT1A receptor homology models to investigate the binding mode of N- and O-alkylated pyrimidinones/pyrimidines 4–13, 2-methylquinazolinones/quinazolines 17–22, and previously reported 2- and 3-substituted quinazolinones 23–30.

Graphical abstract

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Editorial board

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3





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Neuritogenic activity of bi-functional bis-tryptoline triazole

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Jutamas Jiaranaikulwanitch, Sarin Tadtong, Piyarat Govitrapong, Valery V. Fokin, Opa Vajragupta
Alzheimer's disease (AD) is a common neurodegenerative disorder, one of the hallmarks of which is the deposition of aggregated β-amyloid peptides (Aβ40,42) as plaques in the brain. Oligomers of these peptides have been reported to be toxic and to inhibit neurite outgrowth, as evidenced by neurite dystrophy and significant loss of synaptic connectivity of neurons in the AD brain resulting in cognitive decline. These peptides also react with biological metal in the brain to generate free radicals, thereby aggravating neuronal cell injury and death. Herein, multifunctional triazole-based compounds acting on multiple targets, namely β-secretase (BACE1), β-amyloid peptides (Aβ) as well as those possessing metal chelation and antioxidant properties, were developed and evaluated for neuritogenic activity in P19-derived neurons. At the non-cytotoxic concentration (1nM), all multifunctional compounds significantly enhanced neurite outgrowth. New bis-tryptoline triazole (BTT) increased the neurite length and neurite number, by 93.25% and 136.09% over the control, respectively. This finding demonstrates the ability of multifunctional compounds targeting Aβ to enhance neurite outgrowth in addition to their neuroprotective action.

Graphical abstract

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Identification of a melampomagnolide B analog as a potential lead molecule for treatment of acute myelogenous leukemia

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Zaineb A.F. Albayati, Venumadhav Janganati, Zheng Chen, Jessica Ponder, Philip J. Breen, Craig T. Jordan, Peter A. Crooks
A series of carbamate derivatives of the antileukemic sesquiterpene melampomagnolide B (MMB) has been synthesized utilizing a 1,2,4-triazole carbamate conjugate of MMB as an intermediate synthon. Five imidazole- and benzimidazole-carbamate analogs of MMB (8a–8e) were prepared and evaluated for anti-leukemic activity against cultured M9 ENL1 AML cells. All the analogs exhibited improved anti-leukemic activity (EC50=0.90–3.93μM) when compared to parthenolide and the parent sesquiterpene, MMB (EC50=7.0μM and 15.5μM, respectively). The imidazole carbamate analog, 8a (EC50=0.9μM), was 16 times more potent than MMB. The comparative bioavailabilities of 8a and MMB were determined in BALB/c mice following oral dosing of these compounds. It has been demonstrated that the absolute plasma bioavailabilities of MMB and 8a were 6.7±0.8%, and 45.5±2%, respectively. These results indicate that, compared to MMB, the PK parameters for 8a display significantly improved bioavailability and exposure after oral administration. Analog 8a is considered to be a potential clinical candidate for treatment of acute myelogenous leukemia.

Graphical abstract

http://ift.tt/2kLfNm5

Highly predictive and interpretable models for PAMPA permeability

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Hongmao Sun, Kimloan Nguyen, Edward Kerns, Zhengyin Yan, Kyeong Ri Yu, Pranav Shah, Ajit Jadhav, Xin Xu
Cell membrane permeability is an important determinant for oral absorption and bioavailability of a drug molecule. An in silico model predicting drug permeability is described, which is built based on a large permeability dataset of 7488 compound entries or 5435 structurally unique molecules measured by the same lab using parallel artificial membrane permeability assay (PAMPA). On the basis of customized molecular descriptors, the support vector regression (SVR) model trained with 4071 compounds with quantitative data is able to predict the remaining 1364 compounds with the qualitative data with an area under the curve of receiver operating characteristic (AUC-ROC) of 0.90. The support vector classification (SVC) model trained with half of the whole dataset comprised of both the quantitative and the qualitative data produced accurate predictions to the remaining data with the AUC-ROC of 0.88. The results suggest that the developed SVR model is highly predictive and provides medicinal chemists a useful in silico tool to facilitate design and synthesis of novel compounds with optimal drug-like properties, and thus accelerate the lead optimization in drug discovery.

Graphical abstract

http://ift.tt/2kLeiE9

The role of cell cycle progression for the apoptosis of cancer cells induced by palladium(II)-saccharinate complexes of terpyridine

Publication date: Available online 31 January 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Omer Kacar, Buse Cevatemre, Ibrahim Hatipoglu, Nazli Arda, Engin Ulukaya, Veysel T. Yilmaz, Ceyda Acilan
ObjectivesPalladium complexes are potent and less toxic molecules in comparison to other metal based agents. Here, we characterized two palladium(II) saccharinate complexes with terpyridine for their cell cycle specificity.Materials and methodsCells were arrested at G1, G1/S boundary or mitosis using mimosine, double-Thymidine block, aphidicolin, nocodazole or colcemid, and evaluated based on morphology and flow cytometry. Synchronized cells were treated with the Pd(II) complexes, and viability was measured via MTT assay.ResultsWhile treatment of arrested cells with the Pd(II) complexes resulted in no significant change in cell death in HCT-116 and MDA-MB-231 cells, HeLa cells were more sensitive in S/G1. The main form of cell death was found to be apoptosis.ConclusionsPd(II) complexes appear to be cell-cycle non-specific, while cell line dependent differences may be observed. Cells die through apoptosis regardless of the cell cycle stage, which makes these complexes more promising as anti-cancer agents.

Graphical abstract

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Design, synthesis and biological evaluation of (E)-3,4-dihydroxystyryl 4-acylaminophenethyl sulfone, sulfoxide derivatives as dual inhibitors of HIV-1 CCR5 and integrase

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Yixing Sun, Weisi Xu, Ningning Fan, Xuefeng Sun, Xianling Ning, Liying Ma, Junyi Liu, Xiaowei Wang
Aiming at the limited effectiveness of current clinical therapeutic effect of AIDS, novel series of compounds bearing (E)-3,4-dihydroxystyryl sulfone (or sulfoxide) and anilide fragments were designed and synthesized as dual inhibitors of HIV-1 CCR5/IN. The biological results indicated that several target compounds showed inhibitory activity against HIV-1 Bal (R5) infection in TZM-bl cells. Besides targeting the chemokine receptor on the host cell surface, they also displayed binding affinities with HIV-1 integrase using the surface plasmon resonance (SPR) binding assays. Molecular docking studies have inferred the possible binding mode of target compounds against integrase. These data demonstrate that the structure of (E)-3,4-dihydroxystyryl sulfone and sulfoxide derivatives have the potential to derive potent dual inhibitors of HIV-1 Integrase and CCR5.

Graphical abstract

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Determination of binding modes and binding constants for the complexes of 6H-pyrido[4,3-b]carbazole derivatives with DNA

Publication date: 1 February 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 3
Author(s): Akihito Shimazu, Masashi Kawagoshi, Shoichi Takeda, Haruaki Kurasaki, Asako Kato, Nahoko Morii, Norio Sakai, Takeo Konakahara
The binding modes and binding constants for the complexes of forty types of pyridocarbazole derivatives 1–40 with double stranded DNAs (dsDNAs) were reported. The binding modes were determined by a combination of a deflection spectroscopy and orientation of the corresponding molecule in the DNA-based film with chain alignment. All of the compounds exhibited the intercalation-binding mode. Its binding constants Ka for the complexes, determined by quartz crystal microbalance (QCM), varied from 1.7×10⁵ to 4.5×10⁷M⁻¹ according to the substituents on the pyridocarbazole framework and the sequences of dsDNA. The binding constants Ka of pyridocarbazole derivatives possessing the 2-(ω-amino)alkyl group and 5-(ω-amino)alkylcarbamyl group were larger than those of the corresponding ω-ureido derivatives. These ω-amino compounds exhibited strong GC base-pair preference in complexation. The Ka values decreased with the increasing NaCl concentration. It was clarified by a molecular modeling that the framework of the 2-tethered ω-amino derivative was completely overlapped with the stacking GC base-pairs leading to the formation of the stable intercalative-complex, and that the framework of the 5-tethered ureido derivative was half overlapped leading to the formation of the unstable complex. Furthermore, there were good linear relationships between lnKa and the relative stabilities Srel of the complexes. Contrary to our expectation, there was no linear relationship between lnKa and IC50 against Sarcoma-180, NIH3T3, and HeLa S-3 cell lines.

Graphical abstract

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From Planar Cell Polarity to Ciliogenesis and Back: The Curious Tale of the PPE and CPLANE proteins

Publication date: Available online 30 January 2017
Source:Trends in Cell Biology
Author(s): Paul N. Adler, John B. Wallingford
Why some genes are more popular than others remains an open question, but one example of this phenomenon involves the genes controlling planar cell polarity (PCP), the polarization of cells within a plane of a tissue. Indeed, the so-called 'core' PCP genes such as dishevelled, frizzled, and prickle have been extensively studied both in animal models and by human genetics. By contrast, other genes that influence PCP signaling have received far less attention. Among the latter are inturned, fuzzy, and fritz, but recent work should bring these once obscure regulators into the limelight. We provide here a brief history of planar polarity effector (PPE) and CPLANE (ciliogenesis and planar polarity effector) proteins, discuss recent advances in understanding their molecular mechanisms of action, and describe their roles in human disease.



http://ift.tt/2kLr6KL

Phase 1 Study of BLU-667 in Patients With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors

Conditions:   Lung Cancer, Nonsmall Cell;   Thyroid Cancer;   Solid Tumor
Intervention:   Drug: BLU-667
Sponsor:   Blueprint Medicines Corporation
Not yet recruiting - verified January 2017

http://ift.tt/2kmTky3

36 cases Adenoid cystic carcinoma of the breast in china: Comparison with matched grade one Invasive Ductal Carcinoma-Not Otherwise Specified

Publication date: Available online 31 January 2017
Source:Pathology - Research and Practice
Author(s): Shuling Wang, Weidong Li, Fang Wang, Yun Niu, Chunfang Hao, Xu Wang, Lihong He, Zhongsheng Tong
ObjectiveThe aim of this study was to investigate the clinicopathological characteristic of adenoid cystic carcinoma (ACC).Materials and methodsThe clininopathological features, along with relapse free survival(RFS) and overall survival(OS) of 36 patients with ACC were retrospectively investigated and compared with those of 108 grade 1 invasive ductal carcinoma not-otherwise-specified (G1-IDC-NOS) patients.ResultsMost cases of ACC were ER, PR and HER-2 negative which was classified as triple-negative subtype. Five cases were concomitant with other pathological types of cancer. Axillary lymph node dissection(ALND) was performed in 31 patients and 2 of them with lymph nodes metastasis. Two patients died of lung metastases at 46 and 116 months after the surgery respectively. Compared with G1-IDC-NOS, ACC showed lower Ki-67 index, less lymph nodes metastasis, lower P53 expression, and higher proportion in location of upper outer quadrant of breast. There was no difference of OS and RFS between ACC and G1-IDC-NOS.ConclusionsACC of the breast was a rare disease with a good prognosis although most of them were classified as triple-negative subtype. And the value of axillary node dissection and adjuvant therapy needs to be further investigated.



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Perineal Ultrasound in Men Before and After Radical Prostatectomy

Condition:   Urinary Incontinence, Stress
Intervention:   Device: Perineal Sonography
Sponsor:   Kantonsspital Winterthur KSW
Not yet recruiting - verified January 2017

http://ift.tt/2kPPTwr

Metabolomic Evidence for a Field Effect in Histologically Normal and Metaplastic Tissues in Patients with Esophageal Adenocarcinoma

Publication date: March 2017
Source:Neoplasia, Volume 19, Issue 3
Author(s): Michelle A.C. Reed, Rishi Singhal, Christian Ludwig, John B. Carrigan, Douglas G. Ward, Phillipe Taniere, Derek Alderson, Ulrich L. Günther
Patients with Barrett's esophagus (BO) are at increased risk of developing esophageal adenocarcinoma (EAC). Most Barrett's patients, however, do not develop EAC, and there is a need for markers that can identify those most at risk. This study aimed to see if a metabolic signature associated with the development of EAC existed. For this, tissue extracts from patients with EAC, BO, and normal esophagus were analyzed using ¹H nuclear magnetic resonance. Where possible, adjacent histologically normal tissues were sampled in those with EAC and BO. The study included 46 patients with EAC, 7 patients with BO, and 68 controls who underwent endoscopy for dyspeptic symptoms with normal appearances. Within the cancer cohort, 9 patients had nonneoplastic Barrett's adjacent to the cancer suitable for biopsy. It was possible to distinguish between histologically normal, BO, and EAC tissue in EAC patients [area under the receiver operator curve (AUROC) 1.00, 0.86, and 0.91] and between histologically benign BO in the presence and absence of EAC (AUROC 0.79). In both these cases, sample numbers limited the power of the models. Comparison of histologically normal tissue proximal to EAC versus that from controls (AUROC 1.00) suggests a strong field effect which may develop prior to overt EAC and hence be useful for identifying patients at high risk of developing EAC. Excellent sensitivity and specificity were found for this model to distinguish histologically normal squamous esophageal mucosa in EAC patients and healthy controls, with 8 metabolites being very significantly altered. This may have potential diagnostic value if a molecular signature can detect tissue from which neoplasms subsequently arise.



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EPSIN 3, a novel p53 target, regulates the apoptotic pathway and gastric carcinogenesis

Publication date: March 2017
Source:Neoplasia, Volume 19, Issue 3
Author(s): Jinichi Mori, Chizu Tanikawa, Naomi Ohnishi, Yuki Funauchi, Osamu Toyoshima, Koji Ueda, Koichi Matsuda
BACKGROUND & AIM: p53 activation by cellular stresses induces the transcription of hundreds of its target genes. To elucidate the entire picture of its downstream pathway, we screened a cDNA microarray dataset of adriamycin-treated HCT116 p53^−/− or p53^+/+ cells and identified EPSIN 3 as a novel p53 target. METHODS: Potential p53 binding sequences in the EPSIN 3 locus were evaluated by reporter and CHIP assays. To investigate the role of EPSIN 3 in the p53 downstream pathway, we assessed DNA damage-induced apoptosis in EPSIN 3-knockdown HCT116 cells or Epsin 3-deficient mice. In addition, we evaluated EPSIN 3 expression levels in various tissues, including gastric adenocarcinoma, human gastric mucosa with or without Helicobacter pylori infection, and mouse acute gastritis tissues induced by indomethacin. RESULTS: In response to DNA damage, p53 induced the expression of EPSIN 3 through the p53 binding elements in the EPSIN 3 promoter and the first intron. Knockdown of EPSIN 3 resulted in resistance to DNA damage-induced apoptosis both in vitro and in vivo. EPSIN 3 expression was down-regulated in gastric cancer tissues compared with normal tissues. In addition, Helicobacter pylori infection and indomethacin-induced acute gastritis repressed EPSIN 3 expression in gastric mucosa. CONCLUSIONS: EPSIN 3 is a novel p53 target and a key mediator of apoptosis. Chronic or acute mucosal inflammation as well as p53 inactivation induced down-regulation of EPSIN 3 and subsequently caused apoptosis resistance, which is a hallmark of cancer cells.



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Could mucin 16 and colony-stimulating factor 2-receptor beta possible graft versus host disease biomarkers? Medical hypotheses.

Publication date: Available online 31 January 2017
Source:Medical Hypotheses
Author(s): Milena Monteiro de Souza, Fabiana Martins de Paula, Ricardo Hsieh, Maria Cristina Martins Almeida Macedo, Marcelo Andreetta Corral, Thaís Borguezan Nunes, Fernanda De Paula, Silvia Vanessa Lourenço
Graft versus host disease (GVHD) occurs after bone marrow transplantation and is one of the most important causes of death worldwide. Reviews demonstrated GVHD patients with involvement of various tissues and organs, such as salivary glands. The diagnosis of acute GVHD has been the biopsies and the histopathologic evaluation of tissue from an involved organ. These procedures are invasive. Saliva proteins as possible biomarker for GVHD could facilitate the management and diagnosis accuracy. For support the proposed hypotheses, in this pilot study we collected whole saliva samples from patients with undergoing allogeneic hematopoietic cell transplantation (HCT) and from healthy subjects. Samples were collected prospectively between pre-transplant, thirty days, one hundred and, two hundred days after transplant. The proteomic profile was analyzed using SDS-PAGE and LCMS–ESI–IT-TOF mass spectrometry. The relevant personal data, past medical history were also recorded. The most relevant proteins found exclusively in GVHD patients were: CSF2RB, Protocadherin (Pcdh) Fat 2 precursor, protein capicua homolog isoform CIC-S, MUC16 and RGPD8_HUMAN RANBP2. This study aims to conduct an initial evaluation of the possible presence of such biomarkers in saliva from GVHD patients, and suggested a potential application of proteomics analysis as a alternative method to diagnose GVHD.



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Horner Syndrome Secondary to Thyroid Surgery.

Related Articles

Horner Syndrome Secondary to Thyroid Surgery.

Case Rep Endocrinol. 2017;2017:1689039

Authors: Demiral M, Binay C, Simsek E, Ilhan H

Abstract
Horner syndrome (HS), caused by an interruption in the oculosympathetic pathway, is characterised by myosis, ipsilateral blepharoptosis, enophthalmos, facial anhydrosis, and vascular dilation of the lateral part of the face. HS is a rare complication of thyroidectomy. A 15-year-old female patient presented with solitary solid and large nodule in the right thyroid lobe. Ultrasound-guided fine-needle aspiration was performed and the cytological examination results were undefined. The patient underwent a total thyroidectomy. On postoperative day 2, she developed right-sided myosis and upper eyelid ptosis. HS was diagnosed. Interestingly, the patient exhibited an incomplete clinical syndrome with the absence of vasomotor symptoms. We herein report a case of HS in a 15-year-old female patient after total thyroidectomy. The possible causes of HS were ischaemia-induced nerve damage and stretching of the cervical sympathetic chain by the retractor during thyroidectomy. Clinicians should be aware of the possibility of this rare but important surgical complication.

PMID: 28133554 [PubMed]

http://ift.tt/2jytPpa

Effect of the combined addition of Zn and Pb on partitioning in sediments and their accumulation by the emergent macrophyte Schoenoplectus californicus

Abstract

Wetlands usually provide a natural mechanism that diminishes the transport of toxic compounds to other compartments of the ecosystem by immobilization and accumulation in belowground tissues and/or soil. This study was conducted to assess the ability of Schoenoplectus californicus growing in natural marsh sediments, with zinc and lead addition, to tolerate and accumulate these metals, taking account of the metal distribution in the sediment fractions. The Zn and Pb were mainly found in available (exchangeable) and potentially available (bound to organic matter) forms, respectively. The absorption of Zn and Pb by plants increased in sediments with added metals. Both metals were largely retained in roots (translocation factor < 1). Lead rhizome concentrations only increased significantly in treatments with high doses of metal independently of added Zn. The addition of Zn increased its concentration in roots and shoots significantly, while its concentration in rhizomes only increased when both metals were added together. Zinc concentration in shoots did not reach the toxic level for plants. Zinc and Pb concentrations in roots were high, but they were not sufficient to reduce biomass growth.

http://ift.tt/2kNrcF6

Drought analysis in the Eastern Nile basin using the standardized precipitation index

Abstract

Drought is considered by many researchers to be the most complex but least understood of all natural hazards, affecting more people than any other hazard. Drought affects many aspects of community and environment, and any future increases in the water demand will be most critical in periods of severe drought. Geospatial analysis of the historical drought events and their causes can be used to mitigate drought impacts and to develop preparedness plans. This study aimed to identify the changes in drought frequency, magnitude, duration, and intensity in the Eastern Nile basin during the period 1965–2000, using the standardized precipitation index (SPI). An SPI program based on C sharp language was developed to monitor drought in the study area. Twenty-eight meteorological stations distributed on the Eastern Nile basin were chosen to collect monthly precipitation data. For drought analysis, SPI series of 3-, 6-, 9-, 12-, and 24-month timescales have been calculated. Results showed that the study area received several drought events during the long rainy season (June to September) and the short rainy season (March to May) as well. Annual analysis of SPI time series indicated that the study area received several drought events, and the most severity event was during the year 1984.

http://ift.tt/2kPIcGN

Clinicopathologic Study of Calcifying Fibrous Tumor of the Gastrointestinal Tract: A Case Series

Publication date: Available online 30 January 2017
Source:Human Pathology
Author(s): Maryam Kherad Pezhouh, M. Katayoon Rezaei, Maryam Shabihkhani, Arunima Ghosh, Deborah Belchis, Elizabeth A. Montgomery, Lysandra Voltaggio
Calcifying fibrous tumor (CFT) is a rare benign mesenchymal lesion known to arise at multiple body sites that may clinically mimic other more aggressive lesions in the gastrointestinal (GI) tract. In this study we describe the clinicopathologic findings of 28 GI tract CFTs. Tumors predominantly arose in middle aged adults with a slight female predominance. The most commonly involved sites were small bowel and colon, followed by stomach and appendix. Tumors ranged from 0.3 to 9.3cm (median 1.4cm) and submucosa was the most commonly involved layer. All tumors were well circumscribed and unencapsulated. Microscopically, tumors were hypocellular and composed of spindle cells with abundant, haphazardly arranged hyalinized collagen. No necrosis and less than 1 mitosis per 10 HPF were identified in all cases. Calcification was present in most (81%) of the cases. All cases had lymphoplasmacytic inflammatory infiltrates either scattered throughout the lesion with occasional perivascular conglomeration or in the form of lymphoid aggregates. A lymphoplasmacytic cuff was usually present (81%). Immunostains showed variable CD34 immunoreactivity and variable numbers of IgG4 positive plasma cells. The lesional cells were negative for DOG-1, ALK-1, S100, C-kit, Sox10, Melan A, HMB45, desmin, CK7, and CK20, and showed cytoplasmic staining for beta-catenin. Follow up information was available in 5 cases with no recurrences reported to date (mean follow up, 3years). CFT is a rare benign tumor that can occur in part of the GI tract and should be distinguished from other mesenchymal tumors due to its low risk of recurrence.



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Removal of anionic surfactant sodium dodecyl benzene sulfonate (SDBS) from wastewaters by zero-valent iron (ZVI): predominant removal mechanism for effective SDBS removal

Abstract

Mechanisms for removal of anionic surfactant sodium dodecyl benzene sulfonate (SDBS) in wastewaters by zero-valent iron (ZVI) were systematically examined. The contributions of four removal mechanisms, i.e., reductive degradation, oxidative degradation, adsorption, and precipitation, changed significantly with solution pH were quantified and the effective removal of SDBS by ZVI was found to be attributed to the adsorption capability of iron oxides/hydroxides on ZVI surface at nearly neutral pH instead of the degradation at acidic condition. The fastest SDBS removal rate and the maximum TOC (total organic carbon) removal efficiency were obtained at pH 6.0. The maximum TOC removal at pH 6.0 was 77.8%, and the contributions of degradation, precipitation, and adsorption to TOC removal were 4.6, 14.9, and 58.3%, respectively. At pH 3.0, which is an optimal pH for oxidative degradation by the Fenton reaction, the TOC removal was only 9.8% and the contributions of degradation, precipitation, and adsorption to TOC removal were 2.3, 4.6, and 2.9%, respectively. The electrostatic attraction between dodecyl benzene sulfate anion and the iron oxide/hydroxide layer controlled the TOC removal of SDBS. The kinetic model based on the Langmuir-Hinshelwood/Eley-Rideal approach could successfully describe the experimental results for SDBS removal by ZVI with the averaged correlation coefficient of 0.994. ZVI was found to be an efficient material toward the removal of anionic surfactant at nearly neutral pH under the oxic condition.

http://ift.tt/2kNuHeQ

Expression of p63 protein in anaplastic large cell lymphoma: Implications for genetic subtyping

Publication date: Available online 30 January 2017
Source:Human Pathology
Author(s): Xueju Wang, Rebecca L. Boddicker, Surendra Dasari, Jagmohan S. Sidhu, Marshall E. Kadin, William R. Macon, Stephen M. Ansell, Rhett P. Ketterling, Karen L. Rech, Andrew L. Feldman
Anaplastic large cell lymphomas (ALCLs) are CD30-positive T-cell non-Hodgkin lymphomas that bear chromosomal rearrangements of the TP53 homologue, TP63, in a subset of cases that demonstrate aggressive clinical behavior. In the present study, we examined the relationship between p63 protein expression by immunohistochemistry and the results of fluorescence in situ hybridization (FISH) using TP63 probes in 116 ALCLs. We also determined the relative expression of full-length TAp63 and truncated ΔNp63 isoforms (e.g. p40) in ALCL cell lines and a subset of clinical cases. Overall, 35.3% of ALCLs were positive for p63 protein. Primary cutaneous and ALK-negative ALCLs were positive more frequently than ALK-positive ALCLs (P=.0034). As previously reported, cases with TP63 gene rearrangements expressed p63 uniformly. p63 expression in non-rearranged cases was associated with extra copies of TP63 on 3q28 (P<.0001). Extra copies of TP63 correlated with extra copies of the DUSP22 locus on 6p25.3 (P<.0001). Results of immunohistochemistry, Western blotting, and RNA sequencing indicated that p63 expression in non-rearranged cases was entirely attributable to TAp63 isoforms. Taken together, these findings indicate that ALCLs without TP63 rearrangements may express TAp63 isoforms of p63 and that this expression is associated with extra copies of TP63, probably due to widespread genomic copy number abnormalities rather than focal gains. Immunohistochemistry for p63 in ALCL is not specific for TP63 rearrangements, but is useful clinically as a screening test to select cases for further testing by FISH. Immunohistochemistry for ΔNp63 (p40) is not informative in the evaluation of ALCL.



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Bioelectro-Fenton: evaluation of a combined biological—advanced oxidation treatment for pharmaceutical wastewater

Abstract

Electro-Fenton (EF), an advanced oxidation process, can be combined with a biological process for efficient treatment of wastewater containing refractory pollutants such as pharmaceuticals. In this study, a biological process was implemented in a sequencing batch reactor (SBR), which was either preceded or followed by EF treatment. The main goal was to evaluate the potential of two sequences of a combined electrochemical-biological process: EF/SBR and SBR/EF for the treatment of real wastewater spiked with 0.1 mM of caffeine and 5-fluorouracil. The biological removal of COD and pharmaceuticals was improved by extending the acclimation time and increasing concentration of biomass in the SBR. Hardly biodegradable caffeine and COD were completely removed during the EF post-treatment (SBR/EF). During the EF/SBR sequence, complete removal of pharmaceuticals was achieved by EF within 30 min at applied current 800 mA. With a current of 500 and 800 mA, the initially very low BOD₅/COD ratio increased up to 0.38 and 0.58, respectively, after 30 min. The efficiency of the biological post-treatment was influenced by the biodegradability enhancement after EF pre-treatment. The choice of an adequate sequence of such a combined process is significantly related to the wastewater characteristics as well as the treatment objectives.

http://ift.tt/2kPGVPJ

Tumor-infiltrating lymphocytes are significantly associated with better overall survival and disease-free survival in triple negative but not estrogen receptor positive breast cancers

Publication date: Available online 30 January 2017
Source:Human Pathology
Author(s): Uma Krishnamurti, Ceyda Sonmez Wetherilt, Jing Yang, Limin Peng, Xiaoxian Li
Correlation between tumor-infiltrating lymphocytes (TILs) and complete pathological response (pCR) in breast cancers in neoadjuvant settings has been reported. In this study, we analyzed the association between TILs and diagnostic and prognostic parameters in estrogen receptor positive (ER+) and triple-negative breast cancer (TNBC) without neoadjuvant treatments. Three hundred and forty-four (344) patients who underwent mastectomy for breast cancer (187 ER+ and 157 TNBC) without neoadjuvant treatments were evaluated. Percentage of overall and peripheral TILs were correlated with lymphovascular invasion (LVI), Nottingham histologic grade (NHG, 1/2 vs. 3), stage, lymph node status (LN), overall survival (OS), and disease-free survival (DFS). In TNBC, both peripheral and overall TILs were significantly associated with NHG 3 (P<.0001). Peripheral but not overall TILs were significantly associated with better OS (Hazard ratio (HR): 0.95; 95% confidence interval (CI): 0.91–1.00; P=.0354) and DFS (HR: 0.95; 95% CI: 0.91–1.00; P=.0314) in univariate and multivariate analysis. In ER+ breast cancer, only peripheral TILs were associated with NHG 3 (P=.018) but not with OS or DFS (both P>.05). In ER+ breast cancer, there was a negative association between Oncotype DX recurrence score and both overall (P=.0007) and peripheral TILs (P=.0119). In conclusion, peripheral but not overall TILs correlate with better OS and DFS in TNBC, indicating the location of TILs may be important in TNBC. The negative association between TILs and Oncotype DX score in ER+ may indicates the possible prognostic value of TILs in ER+ breast cancer.



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Cross talk among PMCA, calcineurin and NFAT transcription factors in control of calmodulin gene expression in differentiating PC12 cells

Publication date: Available online 31 January 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Tomasz Boczek, Malwina Lisek, Bozena Ferenc, Ludmila Zylinska
Brain aging is characterized by progressive loss of plasma membrane calcium pump (PMCA) and its activator – calmodulin (CaM), but the mechanism of this phenomenon remains unresolved. CaM encoded by three genes Calm1, Calm2, Calm3, works to translate Ca²⁺ signal into changes in frequently opposite cellular activities. This unique function allows CaM to affect gene expression via stimulation of calcineurin (CaN) and its downstream target – nuclear factor of activated T-cells (NFAT) and to terminate Ca²⁺ signal by stimulation of its extrusion. PMCA, which exists in four isoforms PMCA1-4, may in turn shape the pattern of Ca²⁺ transients and control CaN activity by its direct binding. Therefore, the interplay between PMCA, CaM and CaN/NFAT is highly plausible. To verify that, we used differentiated PC12 cells with reduced expression of PMCA2 and PMCA3 to mimic the potential changes in aged brain. Manipulation in PMCAs level decreased CaM protein in PMCA2 or PMCA3-reduced lines what was accompanied by down-regulation of Calm1 and Calm2 in both lines, but Calm3 only in PMCA2-reduced cells. Further studies showed substantially higher NFATc2 nuclear accumulation and increased NFAT transcriptional activity. Blocking of CaN/NFAT signalling resulted in almost full CaM recovery, mainly due to up-regulation of Calm2 and Calm3 genes. Moreover, higher occupancy of Calm2 and Calm3 promoters by NFATc2 and increased expression of these genes in response to NFATc2 silencing were demonstrated in PMCA2 and PMCA3-reduced lines. Our results indicate that decrease in CaM level in response to PMCAs downregulation can be driven by CaN/NFAT pathway.



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Thyroid hormone biosynthesis and release

Publication date: Available online 31 January 2017
Source:Molecular and Cellular Endocrinology
Author(s): Denise P. Carvalho, Corinne Dupuy
Thyroid hormones (TH) 3,5,3′,5'- tetraiodothyronine or thyroxine (T4) and 3,5,3'- triiodothyronine (T3) contain iodine atoms as part of their structure, and their synthesis occur in the unique structures called thyroid follicles. Iodide reaches thyroid cells through the bloodstream that supplies the basolateral plasma membrane of thyrocytes, where it is avidly taken up through the sodium/iodide symporter (NIS). Thyrocytes are also specialized in the secretion of the high molecular weight protein thyroglobulin (TG) in the follicular lumen. The iodination of the tyrosyl residues of TG preceeds TH biosynthesis, which depends on the interaction of iodide, TG, hydrogen peroxide (H2O2) and thyroid peroxidase (TPO) at the apical plasma membrane of thyrocytes. Thyroid hormone biosynthesis is under the tonic control of thyrotropin (TSH), while the iodide recycling ability is very important for normal thyroid function. We discuss herein the biochemical aspects of TH biosynthesis and release, highlighting the novel molecules involved in the process.



http://ift.tt/2jqdwQd

Avoiding the pitfalls when quantifying thyroid hormones and their metabolites using mass spectrometric methods: The role of quality assurance

Publication date: Available online 31 January 2017
Source:Molecular and Cellular Endocrinology
Author(s): Keith Richards, Eddy Rijntjes, Daniel Rathmann, Josef Köhrle
This short review aims to assess the application of basic quality assurance (QA) principles in published thyroid hormone bioanalytical methods using mass spectrometry (MS). The use of tandem MS, in particular linked to liquid chromatography has become an essential bioanalytical tool for the thyroid hormone research community. Although basic research laboratories do not usually work within the constraints of a quality management system and regulated environment, all of the reviewed publications, to a lesser or greater extent, document the application of QA principles to the MS methods described. After a brief description of the history of MS in thyroid hormone analysis, the article reviews the application of QA to published bioanalytical methods from the perspective of selectivity, accuracy, precision, recovery, instrument calibration, matrix effects, sensitivity and sample stability. During the last decade the emphasis has shifted from developing methods for the determination of L-thyroxine (T4) and 3,3′,5-triiodo-L-thyronine (T3), present in blood serum/plasma in the 1–100 nM concentration range, to metabolites such as 3-iodo-L-thyronamine (3-T1AM), 3,5-diiodo-L-thyronine (3,5-T2) and 3,3'-diiodo-L-thyronine (3,3′-T2). These metabolites seem likely to be present in the low pM concentrations; consequently, QA parameters such as selectivity and sensitivity become more critical. The authors conclude that improvements, particularly in the areas of analyte selectivity, matrix effect measurement/documentation and analyte recovery would be beneficial.



http://ift.tt/2kca1K1

Dissecting the role of regulators of thyroid hormone availability in early brain development: Merits and potential of the chicken embryo model

Publication date: Available online 31 January 2017
Source:Molecular and Cellular Endocrinology
Author(s): Pieter Vancamp, Veerle M. Darras
Thyroid hormones (THs) are important mediators of vertebrate central nervous system (CNS) development, thereby regulating the expression of a wide variety of genes by binding to nuclear TH receptors. TH transporters and deiodinases are both needed to ensure appropriate intracellular TH availability, but the precise function of each of these regulators and their coaction during brain development is only partially understood. Rodent knockout models already provided some crucial insights, but their in utero development severely hampers research regarding the role of TH regulators during early embryonic stages. The establishment of novel gain- and loss-of-function techniques has boosted the position of externally developing non-mammalian vertebrates as research models in developmental endocrinology. Here, we elaborate on the chicken as a model organism to elucidate the function of TH regulators during embryonic CNS development. The fast-developing, relatively big and accessible embryo allows easy experimental manipulation, especially at early stages of brain development. Recent data on the characterisation and spatiotemporal expression pattern of different TH regulators in embryonic chicken CNS have provided the necessary background to dissect the function of each of them in more detail. We highlight some recent advances and important strategies to investigate the role of TH transporters and deiodinases in various CNS structures like the brain barriers, the cerebellum, the retina and the hypothalamus. Exploiting the advantages of this non-classical model can greatly contribute to complete our understanding of the regulation of TH bioavailability throughout embryonic CNS development.

Graphical abstract

http://ift.tt/2jqdvf7

Everyday Dangers - The Impact Infectious Disease has on the Health of Paramedics: A Scoping Review.

Everyday Dangers - The Impact Infectious Disease has on the Health of Paramedics: A Scoping Review.

Prehosp Disaster Med. 2017 Jan 30;:1-7

Authors: Thomas B, O'Meara P, Spelten E

Abstract
BACKGROUND: Paramedics respond to emergency scenes in often uncontrolled settings without being aware of potential risks. This makes paramedicine one of the most dangerous occupations. One of these dangers is the risk of contracting infectious diseases. Research in this area is predominantly focused on compliance in the use of protective equipment, attitudes and perceptions of paramedics, infectious disease policy, and exposure rates to blood and body fluids. The purpose of this scoping review was to determine what is known about the impact of infectious disease on the health of paramedics.
METHODS: Using the Arskey and O'Malley methodological framework, a scoping review was undertaken, which allows for a broad search of the available evidence.
RESULTS: The literature search identified eight articles for review that reported on paramedic exposure trends; the lack of reported blood-borne infections contracted, such as hepatitis B, hepatitis C, and human immunodeficiency virus (HIV); instances of severe acute respiratory syndrome (SARS) infections; and the higher prevalence of methicillin-resistant staphylococcus aureus (MRSA) nasal infections amongst paramedics.
CONCLUSIONS: Exposure to infectious diseases is decreasing, yet it remains significant. The decrease is attributed to prevention strategies; however, paramedic knowledge and attitudes as well as the uncontrolled environment paramedics work in can be a barrier. Contraction of infectious diseases is generally low; exceptions to this are MRSA colonization, influenza, and SARS. Paramedics are at greater risk of acquiring these infectious diseases compared to the general public. The effect on the health of paramedics is not well reported. Thomas B , O'Meara P , Spelten E . Everyday dangers - the impact infectious disease has on the health of paramedics: a scoping review. Prehosp Disaster Med. 2017;32(2):1-7.

PMID: 28134071 [PubMed - as supplied by publisher]

http://ift.tt/2jPIIGZ

Traversing barriers – How thyroid hormones pass placental, blood-brain and blood-cerebrospinal fluid barriers

Publication date: Available online 30 January 2017
Source:Molecular and Cellular Endocrinology
Author(s): Kelly Landers, Kerry Richard
Thyroid hormone is essential for normal human fetal growth and brain development. As the fetal thyroid does not secrete thyroid hormones until about 18 weeks gestation, early fetal brain development depends on passage of maternal hormone across the placenta into the fetal circulation. To reach the fetal brain, maternally derived and endogenously produced thyroid hormone has to cross the blood-brain and blood-cerebrospinal fluid barriers. In this review we will discuss the complex biological barriers (involving membrane transporters, enzymes and distributor proteins) that must be overcome to ensure that the developing human brain has adequate exposure to thyroid hormone.

Graphical abstract

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Evaluation of the biofilm forming ability and its associated genes in Staphylococcus species isolates from bovine mastitis in Argentinean dairy farms.

Related Articles

Evaluation of the biofilm forming ability and its associated genes in Staphylococcus species isolates from bovine mastitis in Argentinean dairy farms.

Microb Pathog. 2017 Jan 25;:

Authors: Felipe V, Morgante CA, Somale PS, Varroni F, Zingaretti ML, Bachetti RA, Correa SG, Porporatto C

Abstract
Staphylococcus aureus and coagulase-negative staphylococci (CNS) are important causes of intramammary infection in dairy cattle, and their ability to produce biofilm is considered an important virulence property in the pathogenesis of mastitis. However, the published date on mechanisms and factors involved in infection persistence in the mammary gland remains unclear. The aim of this study was to investigate whether the main Staphylococcus species involved in bovine intramammary infections possess specific characteristics that promote colonization of the udder. We evaluated the biofilm-forming ability and distribution of adhesion- and biofilm-associated genes of Staphylococcus spp. isolated from bovine mastitis infected animals in Argentinean dairy farms. For this purpose, the phenotypic biofilm formation ability of 209 Staphylococcus spp. from bovine mastitis was investigated. All isolates produced biofilm in vitro, being 35,0% and 45,0% of the 127 S. aureus or 51,0% and 29,0% of the 82 CNS strong and moderate biofilm producers respectively. All S. aureus samples were PCR-positive for icaA, icaD, clfA, clfB and fnbpA genes, 76.3% were positive for fnbpB gene and 11.0% were positive for bap gene. In CNS isolates, the positive rates for icaA and icaD were 73.2%, while for clfA, clfB, fnbpA fnbpB and bap genes the percentage were lower. The results demonstrate that in Staphylococcus spp. biofilm formation, the polysaccharide and the adhesion- and biofilm-associated genes are of overall importance on bovine mastitis in Argentina. Therefore, future works should focus on these pathogenic specific factors for the development of more effective therapies of control, being essential to consider the ability of isolates to produce biofilm.

PMID: 28131956 [PubMed - as supplied by publisher]

http://ift.tt/2jPI7oN

Follow-up MR imaging of PI-RADS 3 and PI-RADS 4 prostate lesions

Publication date: Available online 30 January 2017
Source:Clinical Imaging
Author(s): E. Hauth, H. Jaeger, H. Hohmuth, M. Beer




http://ift.tt/2kKSWH6

Ossified dysraphic hamartoma with lipomyelocoele/lipomyelomeningocoele—A rare radiological entity

Publication date: Available online 31 January 2017
Source:Clinical Imaging
Author(s): Sudha Bindu Tirumani, Y Raghavendra Prasad, Vijaya Kumari Mudunoor, Suman Chandra Aejmal, Harika Tirumani, Saurabh Rohatgi
Traditionally the presence of fat in closed spinal dysraphism has been referred to as spinal lipoma. Recent reports suggest that these spinal lesions are better described as spinal hamartomas due to the unencapsulated and infiltrating nature of the fat and presence of other heterotopic soft tissue. The presence of ossified bone in spinal hamartomas referred to as ossified dysraphic hamartoma, is extremely rare with only three case reports in literature, all associated with lipomyeloceles, none with lipomyelomeningoceles. We present three cases of ossified dysraphic hamartoma, two of them associated with lipomyelomeningoceles, reviewing imaging features on CT and MRI.



http://ift.tt/2kmSvFk

Intracavitary ethanol ablation for the management of uterine hemorrhage refractory to uterine artery embolization

Publication date: Available online 30 January 2017
Source:Clinical Imaging
Author(s): Taylor M. Morris, David H. Ballard, Horacio B. D'Agostino
A 57-year-old postmenopausal woman with end-stage liver disease secondary to alcoholic cirrhosis, esophageal varices, severe alcoholic cardiomyopathy, and metrorrhagia causing persistent anemia despite multiple transfusions presented with heavy vaginal bleeding. The patient underwent two uterine artery embolizations with proximal coils instead of directed particles due to difficult anatomy but the bleeding continued despite these interventions. Since she was a poor surgical candidate for hysterectomy, the decision was made to attempt achievement of hemostasis via ethanol injection into the uterine cavity. The patient's bleeding ceased, her hemoglobin and hematocrit stabilized post-procedure, and she was discharged home in stable condition.



http://ift.tt/2kL8nir

Involvement of peripheral P2Y1 receptors and potential interaction with IL-1 receptors in IL-1β-induced thermal hypersensitivity in rats

Publication date: Available online 30 January 2017
Source:Brain Research Bulletin
Author(s): Soon-Gu Kwon, Dae-Hyun Roh, Seo-Yeon Yoon, Sheu-Ran Choi, Hoon-Seong Choi, Ji-Young Moon, Suk-Yun Kang, Alvin J. Beitz, Jang-Hern Lee
Although interleukin-1β (IL-1β) is a prototypical pro-inflammatory cytokine, the specific mechanisms underlying the role of its cognate receptor, the interleukin-1 receptor (IL-1R) in peripheral sensitization remain to be investigated. Since emerging evidence in the literature indicates that IL-1β can modulate membrane-bound receptors, we decided to examine the involvement of P2Y1 receptor (P2Y1R) in IL-1β induced pain and the potential interaction of P2Y1Rs and IL-1Rs in both naïve and carrageenan injected rats. Intraplantar (i.pl) injection of IL-1β dose-dependently produced mechanical and thermal hypersensitivity in naïve rats. Pre-treatment with IL-1ra (i.pl, 30 and 100ng), an endogenous IL-1R antagonist, prevented the IL-1β induced mechanical and thermal hypersensitivity. Pre-treatment with MRS2500 (i.pl, 1 and 3 nmol), a specific P2Y1R antagonist, dose-dependently reduced IL-1β induced thermal hypersensitivity, but did not affect the development of mechanical hypersensitivity. Conversely coadministration of MRS2500 (i.pl, 0.1 nmol, sub-effective dose) together with IL-1ra (10 nmol, sub-effective dose) significantly reduced IL-1β induced thermal, but not mechanical hypersensitivity. We next used immunohistochemistry to demonstrate that P2Y1 and IL-1 type I receptors co-localize predominantly in small diameter neurons in the dorsal root ganglion. We also performed experiments to examine the interaction of P2Y1Rs and IL-1Rs under the inflammatory conditions induced by 2% carrageenan. Intraplantar coadministration of MRS2500 (3 nmol, sub-effective dose) and IL-1ra (30ng, sub-effective dose) significantly reduced inflammatory thermal, but not mechanical, hypersensitivity. These data indicate the involvement of P2Y1Rs in IL-1β mediated pain in both naive and carrageenan injected rats. There is a positive interaction between peripheral P2Y1Rs and IL-1Rs in both IL-1β and carrageenan-induced thermal hypersensitivity.



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Molecular formula composition of β-caryophyllene ozonolysis SOA formed in humid and dry conditions

Publication date: April 2017
Source:Atmospheric Environment, Volume 154
Author(s): Shuvashish Kundu, Rebeka Fisseha, Annie L. Putman, Thom A. Rahn, Lynn R. Mazzoleni
We studied the molecular formula composition of six β-caryophyllene SOA samples using ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry under various reaction conditions. The SOA samples were generated in dry or low relative humidity (RH) chamber conditions with or without cyclohexane. All of the studied SOA mass spectra have three distinct clusters of hundreds of negative ions referred to as Group I (100 < m/z < 400), Group II (400 < m/z < 700) and Group III (700 < m/z < 1 000) compounds. C14-16H22-28O2-11, C28-29H42-48O6-16 and C42-43H68-70O14-16 were observed as highly abundant organic compounds in the compound class of Group I, II and III, respectively. The relative intensities of most analytes were higher in humid conditions compared to those in dry conditions, indicating the importance of water-dependent reactions and the catalytic role of water both in the presence and absence of cyclohexane. In addition, molecular formulas with higher average carbon numbers were observed in humid SOA than in dry SOA in the absence of cyclohexane, suggesting a decrease of cleavage reactions in humid condition. This study characterizes β-caryophyllene ozonolysis SOA based on ultrahigh mass resolution and demonstrates the significance of humidity in terms of the molecular distributions and relative abundances of the analytes. We also discuss the possible mechanism for the formation of Group I-III compounds based on the current understanding of SOA formation in the atmosphere.

Graphical abstract

http://ift.tt/2kmd454

EXTRANUCLEAR-INITIATED ESTROGENIC ACTIONS OF ENDOCRINE DISRUPTING CHEMICALS: IS THERE TOXICOLOGY BEYOND PARACELSUS?

Publication date: Available online 31 January 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Angel Nadal, Esther Fuentes, Cristina Ripoll, Sabrina Villar-Pazos, Manuel Castellano-Muñoz, Sergi Soriano, Juan Martinez-Pinna, Ivan Quesada, Paloma Alonso-Magdalena
Endocrine Disrupting Chemicals (EDCs), including bisphenol-A (BPA) do not act as traditional toxic chemicals inducing massive cell damage or death in an unspecific manner. EDCs can work upon bind to hormone receptors, acting as agonist, antagonist or modulators. Bisphenol-A displays estrogenic activity and, for many years it has been classified as a weak estrogen, based on the classic transcriptional action of estrogen receptors serving as transcription factors. However, during the last two decades our knowledge about estrogen signaling has advanced considerably. It is now accepted that estrogen receptors ERα and ERβ activate signaling pathways outside the nucleus which may or may not involve transcription. In addition, a new membrane estrogen receptor, GPER, has been proposed. Pharmacological and molecular evidence, along with results obtained in genetically modified mice, demonstrated that BPA, and its substitute BPS, are potent estrogens acting at nanomolar concentrations via extranuclear ERα, ERβ, and GPER. The different signaling pathways activated by BPA and BPS explain the well-known estrogenic effects of low doses of EDCs as well as non-monotonic dose-response relationships. These signaling pathways may help to explain the actions of EDCs with estrogenic activity in the etiology of different pathologies, including type-2 diabetes and obesity.



http://ift.tt/2jy61ll

Discounting the distant future—Data on Australian discount rates estimated by a stochastic interest rate model

Publication date: April 2017
Source:Data in Brief, Volume 11
Author(s): Chi Truong, Stefan Trück
Data on certainty equivalent discount factors and discount rates for stochastic interest rates in Australia are provided in this paper. The data has been used for the analysis of investments into climate adaptation projects in ׳It׳s not now or never: Implications of investment timing and risk aversion on climate adaptation to extreme events׳ (Truong and Trück, 2016) [3] and can be used for other cost-benefit analysis studies in Australia. The data is of particular interest for the discounting of projects that create monetary costs and benefits in the distant future.



http://ift.tt/2kmagEY

Land use and land cover data changes in Indian Ocean Islands: Case study of Unguja in Zanzibar Island

Publication date: April 2017
Source:Data in Brief, Volume 11
Author(s): Sizah Mwalusepo, Eliud Muli, Asha Faki, Suresh Raina
Land use and land cover changes will continue to affect resilient human communities and ecosystems as a result of climate change. However, an assessment of land use and land cover changes over time in Indian Ocean Islands is less documented. The land use/cover data changes over 10 years at smaller geographical scale across Unguja Island in Zanzibar were analyzed. Downscaling of the data was obtained from SERVIR through partnership with Kenya-based Regional Centre for Mapping of Resources for Development (RCMRD) database (http://ift.tt/1ER88Yp), and clipped down in ArcMap (Version 10.1) to Unguja Island. SERVIR and RCMRD Land Cover Dataset are mainly 30m multispectral images include Landsat TM and ETM+Multispectral Images. Landscape ecology Statistics tool (LecoS) was used to analysis the land use and land cover changes. The data provide information on the status of the land use and land cover changes along the Unguja Island in Zanzibar. The data is of great significance to the future research on global change.



http://ift.tt/2jyaEvI

Identification of diagnostic markers involved in the pathogenesis of gastric cancer through iTRAQ-based quantitative proteomics

Publication date: April 2017
Source:Data in Brief, Volume 11
Author(s): Zhen Jiang, Hongchun Shen, Bo Tang, Hui Chen, Qin Yu, Xingli Ji, Li Wang
We provide detailed datasets from our analysis of proteins that are differentially expressed in gastric cancer tissues compared with adjacent normal gastric tissues, as identified by iTRAQ-based quantitative proteomics. Also included is a set of representative images of immunohistochemical staining of gastric cancer tissues showing four levels of expression of fatty acid binding protein (FABP1) and fatty acid synthase (FASN). The data presented in this paper support the research article "Quantitative proteomic analysis reveals that proteins required for fatty acid metabolism may serve as diagnostic markers for gastric cancer" (Jiang et al., 2017) [1]. We expect that the data will contribute to the identification of sensitive and specific biomarkers for early detection of gastric cancer.



http://ift.tt/2jyhO2Q

CDK5 inhibitors prevent astroglial apoptosis and reactive astrogliosis by regulating PKA and DRP1 phosphorylations in the rat hippocampus

Publication date: Available online 30 January 2017
Source:Neuroscience Research
Author(s): Hye-Won Hyun, Su-Ji Min, Ji-Eun Kim
Status epilepticus (SE) results in the unique pattern of dynamin-related protein 1 (DRP1)-mediated mitochondrial dynamics, which is associated with astroglial apoptosis and reactive astrogliosis in the regional-specific pattern representing the differential astroglial properties. However, less defined are the epiphenomena/upstream effecters for DRP1 phosphorylation in this process. Since cyclin-dependent kinase 5 (CDK5) is involved in reactive astrogliosis, CDK5 is one of the possible upstream regulators for DRP1 phosphorylation. In the present study, both olomoucine and roscovitine (CDK5 inhibitors) effectively ameliorated SE-induced astroglial apoptosis in the dentate gyrus without changed seizure susceptibility. In addition, they inhibited reactive astrogliosis in the CA1 region independent of neuronal death induced by SE. These effects of CDK5 inhibitors were relevant to abrogation of altered DRP1 phosphorylation ratio and mitochondrial length induced by SE. CDK5 inhibitors also negatively regulated protein kinase A (PKA) activity in astrocytes. Therefore, our findings suggest that CDK5 inhibitors may mitigate astroglial apoptosis and reactive astrogliosis accompanied by modulations of DRP1-mediated mitochondrial dynamics.



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Systemic administration of the dietary constituent resveratrol inhibits the nociceptive jaw-opening reflex in rats via the endogenous opioid system

Publication date: Available online 30 January 2017
Source:Neuroscience Research
Author(s): Shyota Kokuba, Shiori Takehana, Katsuo Oshima, Yoshihito Shimazu, Mamoru Takeda
The aim of the present study was to investigate whether, under in vivo conditions, systemic administration of resveratrol could attenuate the rat nociceptive jaw-opening reflex (JOR) via the endogenous opioid system. The JOR evoked by electrical stimulation of the tongue was recorded as digastric muscle electromyograms (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG increased significantly in proportion to the intensity of electrical stimulation (from 1× to 5 × threshold for the JOR). dEMG amplitude in response to 3× threshold electrical stimulation of the tongue was dose-dependently inhibited by intravenous administration of resveratrol (0.5–2mg/kg). Maximum inhibition of dEMG amplitude was seen within approximately 10min. These inhibitory effects were reversible, with dEMG responses returning to control levels after approximately 20min. Pretreatment of rats with naloxone resulted in significant, dose-dependent attenuation of the inhibitory effects of resveratrol on dEMG amplitude compared with control. These findings suggest that resveratrol inhibits the nociceptive JOR via the endogenous opioid system. Further, the findings of the present study strongly support the idea that resveratrol, which is not known to have any toxic side effects, combined with an opioid could be a potential therapeutic agent for the prevention of acute trigeminal nociception.



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Video Review as a Tool to Improve Orthopedic Residents׳ Performance of Closed Manipulative Reductions

Publication date: Available online 30 January 2017
Source:Journal of Surgical Education
Author(s): Nickul S. Jain, Ran Schwarzkopf, John A. Scolaro
ObjectiveOrthopedic residents commonly perform closed manipulative reductions as a part of their training. Traditionally, this skill is taught early in training but difficult to simulate. Proficiency is achieved through repetition and experience; faculty observation and instruction is unfortunately often limited. Direct resident teaching has been shown to increase competency, comfort, and long-term skill retention. We hypothesize that video review of closed fracture reductions will provide an inexpensive and valuable tool for resident education and improve skill performance.DesignClosed reductions performed by orthopaedic residents were recorded using a secured mobile tablet device in the emergency department (ED). Video review sessions were performed with both peer and faculty feedback/analysis of reduction technique. Anonymous resident and faculty surveys were completed following each session to evaluate the usage and perceived benefit of the program.SettingUniversity-based Level I Trauma Center.ParticipantsOrthopedic surgery residents and faculty.ResultsAll junior orthopedic residents (postgraduate year [PGY] 1-3) reported that direct video observation by faculty was beneficial. Furthermore, 97% of junior resident and 100% of faculty responses reported that they would use this educational technology in the future. Residents and faculty both strongly agreed that video review was more useful than other methods, improved resident preparation for ED fracture care, and felt this technique would improve patient care and outcomes. Compared with senior residents (PGY 4-5), PGY-1s believed that this technique helped them prepare for ED fracture care (p = 0.02).ConclusionsVideo review provides a useful, innovative, and inexpensive method to improve resident competency in closed fracture reduction—a critical skill in orthopedic patient care. These procedures are uncommonly available for direct faculty observation. We have demonstrated that both residents and faculty were satisfied with the ability to review procedures, identify weaknesses, and obtain or provide direct feedback on this skill. Additionally, fracture reduction video review may help residents meet and achieve clinical milestones, an area of future investigation.



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Prospective evaluation of Intensity Modulated Radiation Therapy with Simultaneous Integrated Boost (IMRT-SIB) in head and neck squamous cell carcinoma in patients not suitable for chemo-radiotherapy

Publication date: April 2017
Source:Oral Oncology, Volume 67
Author(s): Madhup Rastogi, Shantanu Sapru, Pooja Gupta, Ajeet Kumar Gandhi, Surendra P. Mishra, Anoop K. Srivastava, Rohini Khurana, Rahat Hadi, Kamal Sahni, Farzana S
BackgroundWith conformal radiotherapy techniques, acute and late toxicities can be reduced because of better dose conformity and reduced doses to normal tissue. With Intensity Modulated Radiation Therapy (IMRT) further dose escalation is possible and one of the methods is IMRT with simultaneous integrated boost (IMRT-SIB).AimTo evaluate feasibility, toxicity patterns and loco-regional control rates of IMRT-SIB technique in head and neck cancer patients who are not suitable candidates for concurrent chemoradiation.Study designProspective study of 30 patients treated with IMRT-SIB technique and evaluation of clinical results.Method and materials30 patients received definitive treatment using IMRT-SIB without concurrent chemotherapy. Patients were monitored during and after treatment for toxicity using the Radiation Therapy Oncology group (RTOG) criteria. Analysis of acute and late toxicity and early efficacy is presented.ResultsThe median treatment duration was 42days (range 41–43days). Overall, maximum acute Grade 3 toxicity of mucositis, skin, pharynx/esophageal toxicity and laryngeal were 56.66%, 30%, 26.67%, and 6.67% respectively at treatment completion. None of the patients had Grade 4 acute toxicity. No haematological toxicity was seen. Overall, grade 2 late toxicities were 7% (subcutaneous toxicity) and 13.3% (Xerostomia). Loco regional control rate at a median follow up of 13months was 86%.ConclusionIMRT-SIB is a safe and acceptable treatment option for patients of head and neck squamous cell carcinoma unsuitable for definitive chemo-radiotherapy.

Graphical abstract

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Accurate Measurements of the Skin Surface Area of the Healthy Auricle and Skin Deficiency in Microtia Patients

Background: The limited cranial skin covering auricular implants is an important yet underrated factor in auricular reconstruction for both reconstruction surgery and tissue engineering strategies. We report exact measurements on skin deficiency in microtia patients and propose an accessible preoperative method for these measurements. Methods: Plaster ear models (n = 11; male:female = 2:1) of lobular-type microtia patients admitted to the University Medical Center Utrecht in The Netherlands were scanned using a micro-computed tomographic scanner or a cone-beam computed tomographic scanner. The resulting images were converted into mesh models from which the surface area could be calculated. Results: The mean total skin area of an adult-size healthy ear was 47.3 cm2, with 49.0 cm2 in men and 44.3 cm2 in women. Microtia ears averaged 14.5 cm2, with 15.6 cm2 in men and 12.6 cm2 in women. The amount of skin deficiency was 25.4 cm2, with 26.7 cm2 in men and 23.1 cm2 in women. Conclusions: This study proposes a novel method to provide quantitative data on the skin surface area of the healthy adult auricle and the amount of skin deficiency in microtia patients. We demonstrate that the microtia ear has less than 50% of skin available compared with healthy ears. Limited skin availability in microtia patients can lead to healing problems after auricular reconstruction and poses a significant challenge in the development of tissue-engineered cartilage implants. The results of this study could be used to evaluate outcomes and investigate new techniques with regard to tissue-engineered auricular constructs.

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Spindle Cell Lipoma with Prominent Verocay Bodies: A Potential Diagnostic Pitfall

Abstract

Spindle cell lipoma is a benign lipomatous neoplasm that tends to occur near the upper back, or posterior neck of adult males. The tumor has characteristic histology with variably cellular spindle cell areas surrounding mature adipose tissue. With the classic clinical history diagnosis is usually straight forward. However, the location and or histology may not always be so classic, in which case immunohistochemical stains may be helpful. We present a case of spindle cell lipoma with prominent Verocay bodies and a review of the literature to draw attention to possible diagnostic pitfalls.

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A Woman With Recurrent Facial Ulcers

No abstract available

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Sclerosing Dermatofibrosarcoma Protuberans Shows Significant Overlap With Sclerotic Fibroma in Both Routine and Immunohistochemical Analysis: A Potential Diagnostic Pitfall

Abstract: Dermatofibrosarcoma protuberans (DFSP) is an uncommon, low-to-intermediate grade sarcoma with several histologic variants, including pigmented (Bednar tumor), sclerosing, myxoid, atrophic, and DFSP with fibrosarcomatous changes. Two patterns of sclerosis in DFSP can be observed, a sclerotic fibroma-like pattern and a morphea/lichen sclerosus-like pattern. Partial biopsies of sclerosing DFSPs with the sclerotic fibroma pattern can be misdiagnosed as sclerotic fibroma or other benign sclerosing tumors (eg, perineurioma, dermatofibroma). DFSPs from our tissue archives were screened for tumors with a sclerosing pattern, and then studied with epithelial membrane antigen (EMA), CD34, and elastic tissue staining to investigate whether such stains can differentiate sclerosing DFSP from sclerotic fibroma. Ten cases of sclerotic fibroma were similarly studied. Two of the 27 DFSPs were predominantly sclerosing and 5 additional DFSPs had a mixed histopathologic pattern including a sclerosing component. Immunohistochemically, all DFSPs with sclerosing (predominant or mixed) pattern were positive for CD34, and 5/7 were at least focally positive for EMA. Elastic tissue staining was reduced or absent in the sclerotic areas. All cases of sclerotic fibroma were either positive or focally positive for CD34, whereas EMA was focally positive in 5/10. Elastic tissue staining ranged from reduced to totally absent in the sclerotic fibromas. In conclusion, the similar histopathologic and immunophenotypic characteristics in sclerotic fibroma and sclerosing DFSP found in this analysis highlight the importance of obtaining clinical information and potentially additional excision for partial biopsies showing a sclerotic fibroma-like pattern.

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Cutaneous Reactions to Targeted Therapy

Abstract: Over the past decade, numerous targeted therapeutic agents have become available for clinical use in the oncologic setting with the hopes of realizing personalized cancer treatment. These agents have achieved great improvements in clinical outcomes for patients suffering from solid and hematologic malignancies. However, adverse cutaneous reactions are among the most common toxicities observed in patients undergoing treatment with a targeted agent and can alter the overall clinical management strategy. For these reasons, the practicing dermatopathologist should be mindful of the breadth and depth of adverse cutaneous reaction patterns associated with this mechanistically diverse array of targeted agents.

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Folliculocentric Herpes: A Clinicopathological Study of 28 Patients

Background: The cutaneous manifestations of herpes infection are primarily in the context of active infection and of the post-herpetic zosteriform eruption. The former manifests cytopathic alterations diagnostic of herpes. The latter includes lichen planus–like and granuloma annulare–like eruptions and lymphocytoma cutis. Methods: We encountered skin biopsies from 28 patients whose acute or chronic herpetic or post-herpetic zosteriform lesions manifested folliculocentricity. The clinical appearance of the lesions was correlated with the histopathologic and immunohistochemical features of paraffin-embedded skin biopsies to determine the specific viral etiology. A history of underlying medical disease was noted if present. Results: There were 16 men and 12 women with a folliculocentric eruption occurring after a known herpetic eruption or manifesting cytopathic changes and/or immunohistochemical findings compatible with herpes virus in lesional skin biopsies. Underlying immune dysregulatory states were present in most cases, namely, malignancy, anticonvulsant or antidepressant therapy, diabetes mellitus, psoriasis, Crohn disease, and other conditions. All biopsies demonstrated dense lymphohistiocytic infiltrates in or around hair follicles with variable necrosis, while active infections also showed cytopathic and/or immunohistochemical evidence of herpetic alterations, most commonly varicella zoster. Other features included interfollicular interface dermatitis, lymphocytic eccrine hidradenitis, neuritis, and folliculocentric vasculitis. Conclusions: Cutaneous herpetic eruptions can evoke a predominantly folliculocentric mononuclear cell reaction and vasculitis; there is an association with underlying endogenous and/or iatrogenic immune dysregulation. Most cases are secondary to reactivation of varicella zoster. The histomorphology suggests a role for cell-mediated immunity. Antigenic homology of an endogenous 72-kd heat shock protein in follicles with that of a herpetic heat shock protein, in concert with an intrafollicular proliferative response of γ-δ T lymphocytes, may explain the follicular localization and composition of the infiltrate.

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Pseudo-Bullous Dermatosis Induced by Topical Anesthetic Agent—Clues to This Localized Toxic Reaction

Abstract: Eutectic mixture of 2.5% lidocaine and 2.5% prilocaine (EMLA AstraZeneca, DE) is a widely used topical anesthetic cream for preprocedural cutaneous analgesia. In addition to potential clinical cutaneous and systemic adverse effects, EMLA may also induce microscopic changes detectable by light and electron microscopy leading to difficulty in accurate diagnosis. We report the case of a biopsy demonstrating EMLA-induced histopathologic changes. The biopsy was taken from the back of a 5-month-old infant and submitted to rule out psoriasis. Hematoxylin and eosin (H&E) staining of the biopsy demonstrated spongiosis and a noninflammatory subepidermal bulla, raising the histopathologic possibility of epidermolysis bullosa. Further investigation confirmed that EMLA was applied under occlusion before biopsy. A second biopsy without topical anesthetic did not demonstrate a bulla and supported the clinical diagnosis of psoriasiform dermatitis. Our case highlights the importance of awareness of EMLA-induced histopathologic changes to avoid potential misdiagnosis. The histopathologic findings of this case in conjunction with other previously reported cases of EMLA-induced bullae were analyzed. Vacuolization of the basal and suprabasilar layer, pallor and swelling of upper layer epidermal keratinocytes, a pauci-inflammatory cleavage beneath or within the basal layer, basophilic granular karyorrhectic debris in the subepidermal cleft, and congestion of papillary dermal vessels characterized the biopsy findings of this localized adverse reaction.

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Differential NFATc1 Expression in Primary Cutaneous CD4+ Small/Medium-Sized Pleomorphic T-Cell Lymphoma and Other Forms of Cutaneous T-Cell Lymphoma and Pseudolymphoma

Background: Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (PCSTCL) has recently emerged as a distinct clinicopathological entity. Because of a considerable degree of overlap with pseudolymphoma, the diagnosis is often challenging. Preliminary studies suggest that nuclear upregulation of calcineurin/nuclear factor of activated T cells (NFAT) may play a role in lymphomagenesis. Design: 137 cases (70 males and 67 female, mean age = 55) of various forms of cutaneous T-cell and B-cell infiltration were evaluated for NFATc1 expression. The study comprised 18 cases of PCSTCL, 45 cases of mycosis fungoides (MF), 5 cases of lymphomatoid papulosis (LyP), 5 cases of anaplastic large-cell lymphoma (ALCL), 8 cases of other forms of peripheral T-cell lymphoma, not otherwise specified, 12 precursor lesions of MF (ie, cutaneous T-cell dyscrasias), 35 cases of pseudolymphomas, 8 primary cutaneous B-cell lymphoma, and 1 chronic lymphocytic leukemia. The number of cells exhibiting a nuclear stain was counted per 10  high-power field and 2-tailed statistical analysis was used for comparison of nuclear NFATc1 expression between primary PCSTCL and all other groups. A P-value

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Papillary Dermal Elastosis

Abstract: Papillary dermal elastosis is a rare clinicopathological entity with only 1 case reported. The authors herein report a new case. A 38-year-old woman presented with a 10-month history of slowly progressive appearance of multiple, 1–2 mm, pruritic nonfollicular papules, located on the back. The study of the biopsy with the ordinary staining revealed numerous dermal papillae showing increased elastosis. The Verhoeff elastic stain demonstrated numerous foci of clumped and curled elastic fibers in the papillary dermis. The elastic component of the reticular dermis was normal. This case report confirms this entity and can contribute to a better understanding of the spectrum of the fibroelastolytic entities.

http://ift.tt/2kbzDqL

Mutational Status of NRAS and BRAF Genes and Protein Expression Analysis in a Series of Primary Oral Mucosal Melanoma

Abstract: Primary oral mucosal melanoma is an extremely rare and aggressive tumor arising from melanocytes located in the mucosal epithelium of the oral cavity. Although malignant melanoma of oral mucosa shares some clinical features with its cutaneous counterpart, it has been associated with a worst prognosis; its etiopathogenesis are still only partially unraveled as there is no influence of UV radiation. It is known that the mitogen-activated protein kinase pathway mediates cellular responses to growth signals and its activation is an important phenomenon in melanoma. The aim of this study was to evaluate NRAS and BRAF genes, both components of mitogen-activated protein kinase molecular pathway, and compare with their protein expression. Point mutations of NRAS (codons 12, 13, and 61) and BRAF (codon 600) were screened by pyrosequencing method, and its results were associated to the protein expression of RAS and BRAF performed by immunohistochemistry. The authors observed mutation in BRAF 600 (3/14), NRAS codons 12 and 13 (2/14), and NRAS codon 61 (2/8). One case showed positive RAS protein expression, but no mutation was observed. Twelve in 14 cases showed positive BRAF protein expression: 3 cases showed BRAF mutation; 2 cases showed NRAS codon 61 mutation; 2 cases showed NRAS codons 12 and 13 mutation but not simultaneously. Although NRAS and BRAF mutation frequency and RAS protein expression are low, BRAF protein expression was intense; probably, NRAS and BRAF mutations are independent events and alternative molecular mechanisms in the primary oral mucosal melanoma tumorigenesis.

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Unusual Presentation of Cutaneous Chromoblastomycosis

No abstract available

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Violaceous Nodules on the Face and Back of a Patient With Inflammatory Arthritis: Challenge

No abstract available

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Palisaded Granuloma on the Nose: An Atypical Presentation of Granuloma Annulare

Abstract: Granuloma annulare (GA) is a common, asymptomatic dermatosis of unknown etiology. Many variants exist, among them widespread papules, papules in photodistribution, papules marked by tiny crusts ("perforating" GA), patches, plaques, and nodules (subcutaneous GA). The histopathological hallmark is a palisaded histiocytic infiltrate surrounding a central area of degenerated collagen with abundant mucin deposits. We report 2 women who presented with persistent nodules on the nose, which, on histopathological examination, showed a palisaded granuloma. We propose that these cases represent an unusual variant of GA occurring on the nose.

http://ift.tt/2kbnLVK

A Woman With Recurrent Facial Ulcers

No abstract available

http://ift.tt/2kbndyV

Unusual Interface Dermatoses Distributed Along Blaschko's Lines in Adult Patients

Summary: Linear dermatoses are unusual entities whose distribution reflects cutaneous mosaicism, even when they occur in adult life. Adult blaschkitis (AB) and lichen striatus (LS) always follow this peculiar distribution. Although usually referred to as distinct entities, the clinical and histopathological presentation of lichen striatus in adults may be similar to those of adult blaschkitis. Moreover, some cases with overlapping features between lichen striatus and linear lichen planus have been published, making precise diagnosis very difficult. Recently, the concept of a wide spectrum of blaschkolinear dermatoses with AB and LS located somewhere within it has been proposed but it has not gained general recognition. We report three cases of dermatoses following the lines of Blaschko in adults (two women and one male, ages 35, 50 and 56, respectively). They involved the upper extremity in two cases and the lower in the third. Clinically, they were interpreted as linear lichen planus or blaschkitis but, histopathologically, they showed features consistent with lichen striatus. Lesions subsided with topic steroids and/or tacrolimus ointment, they are an example of the significant overlapping between these three entities, demonstrating that they may exist on a spectrum both clinically and histopathologically and clinico-pathologic correlation is essential to achieve an accurate final diagnosis. A detailed review of previously published cases has also been made.

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Marker Protein Expression Combined With Expression Heterogeneity is a Powerful Indicator of Malignancy in Acral Lentiginous Melanomas

Patients and Methods: Samples of acral lentiginous melanomas (ALMs) were obtained from the Department of Pathology at Escola Paulista de Medicina—Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil. Demographic, clinical, and follow-up data were obtained from the charts of Hospital São Paulo. From 2 tissue microarrays containing 60 nevi and quadruplicate samples of ≥1.0-mm of 49 ALM, sections were stained to evaluate SCF, KIT, BRAF, CYCLIND1, MYC, and PTEN immunohistochemical protein expression. Results: Nevi and ALM from 2006 to 2010 were reviewed and collected. All specimens were in the vertical growth phase, and histopathological parameters indicated that tumors were at an advanced stage at diagnosis. Average tumor thickness was 6.95 mm, 63% were ulcerated, average mitotic index was 5 mitotic cells per mm2, and 43% were at Clark's level V. Compared with nevi, the χ2 test showed that ALM significantly correlated with SCF protein expression (P = 0.001) and expression heterogeneity (P

http://ift.tt/2kbnLFe

Violaceous Nodules on the Face and Back of a Patient With Inflammatory Arthritis

No abstract available

http://ift.tt/2jOXQEF

Lichenoid Dermatologic Toxicity From Immune Checkpoint Blockade Therapy: A Detailed Examination of the Clinicopathologic Features

Abstract: Immunotherapy targeting the programmed cell death 1 (PD-1) receptor has demonstrated tremendous promise in the treatment of advanced solid tumors. Dermatologic toxicities, however, are an emerging consequence of this therapy and have been clearly associated with immune checkpoint blockade antibodies. Distinctive clinical and histologic subtypes of dermatologic toxicity secondary to immunotherapy are emerging and include rare autoimmune bullous reactions (eg, bullous pemphigoid) and lichenoid eruptions. We report three patients who developed lichenoid dermatitis while receiving anti-PD-1 antibody therapy. The mean time to onset of lichenoid dermatologic toxicity was 42 days (range: 1–75 days) from initiation of anti-PD-1 antibody therapy. Lesions most frequently presented on the extremities and trunk as pustules, papules, and plaques. The face was not commonly involved. Of the five skin biopsies examined, all demonstrated dense band-like lymphocytic infiltrate, hyperkeratosis, hypergranulosis, saw-tooth rete ridge pattern, and dyskeratosis. Acanthosis was a feature in all of the skin biopsies, and in one, epidermal hyperplasia was prominent. In several skin biopsies, histologic features supporting a lichenoid drug eruption were present, including parakeratosis, spongiosis, periadnexal/perivascular inflammation, and eosinophils. Furthermore, the histologic features varied in skin biopsy specimens taken from the same patient at different sites, supporting a drug reaction. All patients' skin lesions improved with use of steroids: two were treated with topical steroids and one with systemic steroids. Recognition of the histopathologic patterns of dermatologic toxicities resulting from immune checkpoint blockade therapy will become increasingly important for ensuring appropriate management of dermatologic toxicities and optimal patient care.

http://ift.tt/2jOTMnZ

Cutaneous Perivascular Epithelioid Cell Tumor of Gynecologic Origin Metastatic to Skin, Lung, Stomach, and Brain

No abstract available

http://ift.tt/2jOQalS

Polypoid Spitz Nevus With a Halo Reaction

Abstract: Approximately, 2% of Spitz nevi are polypoid; between 3.6% and 7.4% present with a halo reaction. In tandem, these low percentages make the presence of a polypoid Spitz nevus with a halo reaction uncommon; we have not found reports of any previous cases. In the current report, we present a polypoid Spitz nevus with a halo reaction on the back of a 10-year-old male and discuss the morphologic findings. The lesion showed preserved nuclear expression of BAP1. There was no immunohistochemical expression of BRAF and ALK, while the melanocytic cells expressed p16. Comparative genomic hybridization was performed, and no significant aberrations were found. Only 2 small losses were evidenced in chromosome 8. The patient has been followed now for 2 years with no recurrence.

http://ift.tt/2jOItMg

Zosteriform Mycosis Fungoides: A New Clinical Presentation With a Dermatomal Distribution

Abstract: Classic mycosis fungoides (MF) presents with patches and plaques on the trunk and proximal extremities. However, numerous clinicopathologic variants have been described, making diagnosis challenging. Here, the authors report a 21-year-old woman with immunophenotypically and molecularly confirmed MF occurring in a dermatomal distribution. Awareness of this and other rare variants of MF is critical to avoid misdiagnosis.

http://ift.tt/2jOXON3

Technique: SMiLE-seq illuminates transcription factor motifs

Nature Reviews Genetics. doi:10.1038/nrg.2017.5

Author: Shimona Starling

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Genetic variation: Giving context to phenotype prediction

Nature Reviews Genetics. doi:10.1038/nrg.2017.3

Author: Ross Cloney

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Chromatin dynamics during the cell cycle at centromeres

Nature Reviews Genetics. doi:10.1038/nrg.2016.157

Authors: Sebastian Müller & Geneviève Almouzni

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Evolving health care through personal genomics

Nature Reviews Genetics. doi:10.1038/nrg.2016.162

Author: Heidi L. Rehm

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Non-coding RNA: Pri-miRNA processing: structure is key

Nature Reviews Genetics. doi:10.1038/nrg.2017.6

Author: Louise Adams

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WSSFN Society News

Stereotact Funct Neurosurg 2016;94:421

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ASSFN Society News

Stereotact Funct Neurosurg 2016;94:422

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ESSFN Mission

Stereotact Funct Neurosurg 2016;94:423

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Contents Vol. 94, 2016

Stereotact Funct Neurosurg 2016;94:I-VI

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